PROLIFERATIVE DISEASES AFFECTING THE RESPIRATORY TRACT

FIELD

The invention is in the medical field, more specifically in the field of treatment of proliferative diseases affecting the respiratory tract, such as tumours or cancers affecting the respiratory tract. The invention allows specific and selective administration of antineoplastic agents to neoplastic cells affecting the respiratory tract, and provides uses, methods and products useful in the treatment of proliferative diseases affecting the respiratory tract.

BACKGROUND

Lung cancer is one of the most frequent cancers in the world and remains the most deadly. According to the World Health Organization (WHO), about 12.7 million of new cases of cancers have been diagnosed and among them about 1.6 million of new cases of lung cancer in 2008, which therefore ranks it as the third most frequent cancer. Moreover, lung cancer is the most deadly in the world because about 1.4 million patients died in 2008 from their lung cancer of the about 7.6 million of deaths due to cancer during the same year according to WHO's statistics.

Lung cancer include two main types, i.e., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are named following their cell histology and represent about 15% and about 85% of the primary lung cancers, respectively (Molina et al, Mayo Clin Proc 83:584-594, 2008).

SCLC is the most aggressive form and a fast-growing type of lung cancer. Their cells are small and grow quickly to create large tumours. These tumours often metastasize rapidly to other parts of the body like the brain, the bones and the liver. NSCLC is the most common type of lung cancer but it usually grows and metastasizes more slowly than SCLC.

In addition to the above proliferative diseases, the lungs are also a common site for metastasis from different organs such as for metastasis from prostate, breast, colorectal, kidney, head, and neck carcinomas as well as from sarcomas and melanomas (Erhunmwunsee et al, Ann Thorac Surg 88:2052- 2060, 2009).

The available treatments of proliferative diseases of the respiratory tract depend on the stage of the disease and typically consist of surgery, radiotherapy, and/or chemotherapy (Molina et al, supra).

Chemotherapeutic agents are currently administrated by oral administration or by intravenous injections, whereby for both administration routes the chemotherapeutic agents are distributed all over the body, i.e., systemically, before reaching the tumour or cancer. Hence, the chemotherapeutic agent inevitably causes severe systemic toxicities to the patient. The lack of selectivity of the chemotherapeutic agents for neoplastic cells such as tumour or cancer cells in comparison with normal cells, will affect rapidly dividing tissues such as bone marrow, gastrointestinal mucosa, skin and gonads to very often induce adverse side effects such as nauseas and vomiting, myelosuppression and alopecia (Parfitt, Martindale - 32th edition. Pharmaceutical Press, London, 1999). Severity of the adverse effects can be dose- limiting and can induce an interruption of the treatment, for instance when myelosuppression occurs such as for carboplatin, paclitaxel, docetaxel and vinorelbine. Interruption of the treatment is also the case upon nephrotoxicity such as for cisplatin or neurotoxicity such as for paclitaxel. As the toxicity of the chemotherapeutic agents severely limits the delivered dose, the plasmatic concentrations are often not high enough to be therapeutically efficient at the tumour or cancer site. Moreover, due to the interruption of the treatment to allow normal tissue to recover, tumour or cancer cell repopulation occurs in parallel in various organs (Smyth et al, Informa Healthcare, pp81-lll, 2008). Furthermore, systemic treatment is also associated with multiple adverse events including damaged veins, infection at the catheter introduction site, or air embolisms via the intravenous line (Jain, Methods Mol Biol 437:1-50, 2008).

A therapeutic plateau has been reached today with the different types of treatment and the chemotherapeutics employed for NSCLCs. In fact, the five-year survival rate for NSCLC patients has been about 16% in the United States of America (USA) in the period 1999-2006. This rate is strongly dependent of the stage of the disease with 53%, 24%> and 4%> for a local, regional or advanced stage, respectively (Howlader et al., SEER Cancer Statistic Review, 1975-2008, 2011).

To increase the selectivity of the chemotherapeutic agent for neoplastic cells and to minimise the exposure of normal cells to the chemotherapeutic agent, exploitation of folate receptor (FR)-mediated drug delivery has been recently proposed. Folate or folic acid is required by eukaryotic cells for nucleotide and DNA synthesis. Therefore, folate receptors and many of the folate-related cell cycle genes are highly expressed in rapidly proliferating cells such as tumour or cancer cells probably as a consequence of their increased requirement for folic acid needed for cell proliferation. FR, especially FR alpha or folate receptor 1 (FOLR1), is overexpressed in many cancers such as ovary, lung, kidney, endometrium, breast, brain, colon, and myeloid cells of hematopoetic lineage (Xia and Low, J Med Chem 53:6811-6824, 2010). When a medication is formulated with a chemotherapeutic agent, folic acid metabolism can be exploited to carry the non-selective chemotherapeutic agent specifically into the FR- expressing neoplastic cells by linking folate to the chemotherapeutic agent. As the chemotherapeutic agent is released after recognition of the folate by the FR and/or internalization by the FR-expressing neoplastic cells, FR-mediated targeting allows avoiding unwanted effects to FR-negative tissues or low FR-expressing tissues (Xia and Low, supra).

For instance, WO 2011/014821 relates to methods of detecting and assessing functionally active folate receptors on tumours and treatment associated with those tumours. WO 2011/014821 also concerns methods and compositions for treating folate receptor expressing epithelial tumours including ovarian, endometrial, or non-small cell lung cancer tumours with a folate-vinca alkaloid conjugate (generally known as "EC 145") in combination with doxorubicin.

The need for further and/or improved formulations for the treatment of proliferative diseases affecting the respiratory tract, such as tumours or cancers affecting the respiratory tract, is self-evident. SUMMARY

The present inventors have unexpectedly found that pharmaceutical formulations comprising a folate receptor (FR)-targeting antineoplastic substance or composition can be successfully administered by inhalation, and achieve the desired therapeutic effect. This fact can be advantageously exploited in the medical field, particularly in the treatment of proliferative diseases affecting the respiratory tract.

Accordingly, in an aspect the invention provides a pharmaceutical formulation comprising a FR-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation.

Preferably, in an aspect the invention provides a pharmaceutical formulation comprising a FR-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation, wherein the FR-targeting antineoplastic substance or composition is comprised in a nanoparticle and wherein the nanoparticles are comprised in microparticles

A further aspect provides the pharmaceutical formulation as taught herein for use in the treatment of a proliferative disease affecting at least part of the respiratory tract.

A further aspect provides a pharmaceutical formulation comprising an antineoplastic agent and a FR- targeting excipient, for use in the treatment of a proliferative disease affecting at least part of the respiratory tract.

The pharmaceutical formulations embodying the principles of the present invention allow local or specific administration of the FR-targeting antineoplastic substance or composition to the respiratory tract, thereby circumventing the adverse side effects associated with systemic delivery of an antineoplastic substance or composition. The present inventors also found that the present pharmaceutical formulations configured for administration by inhalation selectively target folate receptor-expressing cells such as neoplastic cells leading to higher concentrations of the antineoplastic agent at the tumour or cancer site. Furthermore, the present pharmaceutical formulations may display a desired rate of dissolution once in contact with physiological fluids, thereby conferring controlled liberation of the antineoplastic agent at the tumour or cancer site. Also, the present pharmaceutical formulations may display bioadhesive properties and/or present a long time of retention in the respiratory tract, thereby retaining the pharmaceutical formulations in the respiratory tract. The present pharmaceutical formulations thus confer to the antineoplastic agent an optimal pharmacokinetic behaviour corresponding to a maximization of the time residence in the respiratory tract, while minimizing systemic absorption and elimination of the antineoplastic agent.

Administration of the present pharmaceutical formulations to the respiratory tract by inhalation advantageously allows local delivery of the formulations, thereby maximizing the contribution of the FR- targeting and increasing the selectivity of the treatment of proliferative disease affecting at least part of the respiratory tract. Furthermore, by local administration of the pharmaceutical formulations to the respiratory tract by inhalation, the administered dose of the antineoplastic agent is not diluted in the systemic circulation before reaching the tumour or cancer site, thereby significantly enhancing the therapeutic ratio. Thus, inhalation of the present pharmaceutical formulations allows improving the efficacy of the treatment and also to reduce or even suppress treatment interruptions due to adverse effects, thereby helping to overcome neoplastic cells repopulation. Administration of the present formulations by inhalation allows direct uptake by neoplastic cells but may also target neoplastic cells through the bloodstream through absorption of the antineoplastic agent in the local circulation irrigating the respiratory tract.

Related aspects hence provide:

- Use of the pharmaceutical formulation as taught herein for the manufacture of a medicament for the treatment of a proliferative disease affecting at least part of the respiratory tract;

- A method of treating a proliferative disease affecting at least part of the respiratory tract in a subject in need of said treatment comprising the administration of a therapeutically or prophylactically effective amount of the pharmaceutical formulation as taught herein to the subject.

- Use of a pharmaceutical formulation comprising an antineoplastic agent and a FR-targeting excipient for the manufacture of a medicament for the treatment of a proliferative disease affecting at least part of the respiratory tract;

- A method of treating a proliferative disease affecting at least part of the respiratory tract in a subject in need of said treatment comprising the administration of a therapeutically or prophylactically effective amount of a pharmaceutical formulation comprising an antineoplastic agent and a FR-targeting excipient to the subject.

These and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. The subject-matter of the appended claims is hereby specifically incorporated in this specification.

The independent and dependent claims set out particular and preferred features of the invention. Features from the dependent claims may be combined with features of the independent or other dependent claims as appropriate.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 represents a diagrammatic representation of folate-mediated delivery of therapeutics agents to FR-positive cancer cells (Lu and Low, Adv Drug Deliv Rev 54:675-693, 2002).

Figure 2 represents a graph illustrating laser diffraction particle size distribution (Z- Average) of TMZ- loaded folate-PEO-HTCC 1 NPs prepared according to example 7 (n = 3), as measured with Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK). Figure 3 represents a graph illustrating laser diffraction particle size distribution (Z- Average) of TMZ- loaded folate-PEO-HMD 1 NPs prepared according to example 10 (n = 3) (Zetasizer nano ZS, Malvern Instruments, Worcestershire, UK).

Figure 4 represents a graph illustrating laser diffraction particle size distribution (Z-average) of TMZ- loaded folate-PEO-HTCC 1 NPs prepared according to Example 31 (n = 3), as measured with Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK).

Figure 5 represents a graph illustrating laser diffraction particle size distribution (Z- Average) of PTX- loaded folate-PEO-HTCC 1 NPs prepared according to Example 34 (n = 3), as measured with Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK).

Figure 6 represents a graph illustrating laser diffraction particle size distribution of PTX- loaded folate- PEO-HMD 1 NPs prepared according to example 37 (n = 3), as measured with Zetasizer nano ZS (Malvern Instruments, Worcestershire, UK).

Figure 7 represents a graph illustrating laser diffraction particle size distribution of TMZ-loaded folate- PEO-HMD 1 NPs prepared according to Example 39 (n = 3) (Zetasizer nano ZS, Malvern Instruments, Worcestershire, UK) .

Figure 8 represents a graph illustrating the in vitro pulmonary deposition (in percentage) and fine particle fraction (FPF, in percentage) of the pharmaceutical formulation according to embodiments of the present invention, i.e. pharmaceutical formulation prepared in Example 43, Example 44, and Example 52. DPI: dry powder inhaler, FPF: fine particle fraction.

Figure 9 represents a graph illustrating the in vitro pulmonary deposition (in percentage) and fine particle fraction (FPF, in percentage) of the pharmaceutical formulation according to embodiments of the present invention, i.e. pharmaceutical formulation prepared in Example 45, and Example 54. DPI: dry powder inhaler, FPF: fine particle fraction.

Figure 10 represents a graph illustrating the percentage of viable cells in function of paclitaxel concentration for cells incubated with a DPI formulation according to an embodiment of the present invention (Targeted- Example 45), with a DPI formulations according to an embodiment of the present invention in presence of folic acid (Targeted-Example 45 + folic acid), with non-targeted formulation (Non-targeted), or with water-soluble formulation of paclitaxel (Paclitaxel).

Figure 11 represents a graph illustrating the percentage of viable cells in function of paclitaxel concentration for cells incubated with a DPI formulation according to an embodiment of the present invention (Targeted- Example 54), with a DPI formulations according to an embodiment of the present invention in presence of folic acid (Targeted-Example 54 + folic acid), with non-targeted formulation (Non-targeted), or with water-soluble formulation of paclitaxel (Paclitaxel).

Figure 12 represents a graph illustrating the mean green fluorescent signal (FL1 mean) per 10000 cells (proportional to the number of nanoparticles interacting with FR-expressing cells) after 30 minutes and 3 hours incubation of FR-expressing cells with fresh medium (Negative control), fresh medium containing DiO-loaded folate-PEO-HTCC 1 NPs (Formulation Example 61), fresh medium containing DiO-loaded folate-PEO-HTCC 1 NPs and folic acid (Formulation Example 61 + folic acid), and fresh medium containing DiO-loaded PEO-HTCC NPs (Non targeted).

Figure 13 represents a graph illustrating the mean green fluorescent signal (FL1 mean) per 10000 cells (proportional to the number of nanoparticles interacting with FR-expressing cells) after 30 minutes and 3 hours incubation of FR-expressing cells with fresh medium (Negative control), fresh medium containing DiO-loaded folate-PEO-HMD 1 NPs (Formulation Example 62), fresh medium containing DiO-loaded folate-PEO-HMD 1 NPs and folic acid (Formulation Example 62 + folic acid), and fresh medium containing DiO-loaded PEO-HMD NPs (Non targeted).

DESCRIPTION OF EMBODIMENTS

As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

The terms "comprising", "comprises" and "comprised of as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass "consisting of and "consisting essentially of.

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

The term "about" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of and from the specified value, in particular variations of +/-10% or less, preferably +1-5% or less, more preferably +1-1% or less, and still more preferably +/-0.1 % or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" refers is itself also specifically, and preferably, disclosed.

Whereas the term "one or more", such as one or more members of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

All documents cited in the present specification are hereby incorporated by reference in their entirety. Unless otherwise specified, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions may be included to better appreciate the teaching of the present invention.

As noted, the present inventors have found that pharmaceutical formulations comprising a FR-targeting antineoplastic substance or composition can be successfully administered by inhalation, thereby selectively and specifically targeting neoplastic cells affecting the respiratory tract, and hence, making the pharmaceutical formulations useful in the treatment of proliferative diseases affecting the respiratory tract such as tumours or cancers affecting the respiratory tract.

Accordingly, in a first aspect, the invention provides a pharmaceutical formulation comprising a FR- targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation. As mentioned above, the pharmaceutical formulations embodying the principles of the present invention allow local or specific administration of the FR-targeting antineoplastic substance or composition to the respiratory tract, thereby circumventing the adverse side effects associated with systemic delivery of an antineoplastic substance or composition. The present inventors also found that the present pharmaceutical formulations configured for administration by inhalation selectively target folate receptor-expressing cells such as neoplastic cells leading to higher concentrations of the antineoplastic agent at the tumour or cancer site.

The present pharmaceutical formulations may be useful in increasing the sensitivity of tumour cells to other therapy types, for instance to radiation, and also in potentiating or enhancing damage to tumours by the antineoplastic agents, due to the fact that inhalation of the pharmaceutical formulations can allow obtaining higher concentrations of the antineoplastic agent around and inside the tumour site.

The term "specificity" of the pharmaceutical formulations, as used herein, refers to the ability of the pharmaceutical formulations to be administered to certain cells, tissues, or organs, and not to certain other cells, tissues, or organs. The pharmaceutical formulations as taught herein are configured for inhalation and hence allow specific administration to cells of the respiratory tract. The specificity of the pharmaceutical formulations as taught herein is in contrast with such prior art formulations which only allow systemic and hence non-specific delivery of pharmaceutical formulations.

The term "selectivity" of the pharmaceutical formulations, as used herein, refers to the ability of the pharmaceutical formulations to bind to, target, or impinge on certain cells and not bind to, target, or impinge on certain other cells. The pharmaceutical formulations as taught herein selectively bind to cells expressing folate receptors and not to other cells. Formulations disclosed herein are configured for use in medicine, whether or not comprising one or more pharmaceutically acceptable excipients in addition to the other herein recited elements. Accordingly, the terms "pharmaceutical formulation" and "formulation" may be used interchangeably herein.

In certain embodiments, the pharmaceutical formulation may comprise a FR-targeting antineoplastic substance or composition. In certain embodiments, the pharmaceutical formulation may comprise a FR- targeting antineoplastic substance or composition, preferably wherein the pharmaceutical formulation is configured for administration by inhalation.

The recitation "FR-targeting", as used herein, refers to the targeting of a folate receptor.

The recitation "FR-targeting antineoplastic substance" refers to a substance or compound comprising an FR-targeting moiety and an antineoplastic agent, wherein the FR-targeting moiety and the antineoplastic agent are covalently associated or bound, i.e. they constitute a substance or compound (e.g. molecule). The FR-targeting moiety and the antineoplastic agent may be covalently associated or bound to each other via (by means of) a direct covalent bond or via (by means of) a linker.

The recitation "FR-targeting antineoplastic composition" refers to a composition comprising an FR- targeting moiety and an antineoplastic agent, wherein the FR-targeting moiety or a substance comprising it (e.g., an excipient) and the antineoplastic agent are non-covalently associated. For instance, the FR- targeting moiety or a substance comprising it (e.g., an excipient) and the antineoplastic agent may be comprised in a nanoparticle.

The recitation "configured for administration by inhalation" as used herein refers to the property of the pharmaceutical formulations as taught herein that allows local or exclusive delivery of the pharmaceutical formulations to the respiratory tract.

Preferred statements (features) and embodiments of this invention are set herein below. Each statements and embodiments of the invention so defined may be combined with any other statement and/or embodiments unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered aspects and statements 1 to 25, with any other statement and/or embodiments.

1. A pharmaceutical formulation comprising a folate receptor (FR)-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation.

2. A pharmaceutical formulation comprising a folate receptor (FR)-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation, wherein the FR-targeting antineoplastic substance or composition is comprised in a nanoparticle and wherein the nanoparticles are comprised in microparticles.

3. A pharmaceutical formulation comprising a folate receptor (FR)-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation, wherein the FR-targeting antineoplastic substance or composition comprises at least one antineoplastic agent and at least one FR-targeting excipient, wherein the FR-targeting excipient is a folate-polysaccharide conjugate comprising at least one folate moiety covalently linked to a polysaccharide or functionally-modified polysaccharide; wherein the polysaccharide or functionally- modified polysaccharide is covalently bound to the folate moiety via a linker, wherein the linker comprises a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof.

The pharmaceutical formulation according to any one of statements 1 to 3, which is formulated as a dry powder.

The pharmaceutical formulation according to any one of statements 1 to 4, wherein the FR-targeting antineoplastic substance or composition is comprised in a nanoparticle.

The pharmaceutical formulation according to any one of statements 1 to 5, wherein the FR-targeting antineoplastic substance or composition comprises at least one antineoplastic agent and at least one FR-targeting excipient.

The pharmaceutical formulation according to any one of statements 3 to 6, wherein the antineoplastic agent and the FR-targeting excipient are comprised in a nanoparticle, preferably wherein the antineoplastic agent and the FR-targeting excipient are non-covalently associated in the nanoparticle. The pharmaceutical formulation according to any one of statements 1 to 7, wherein the FR-targeting is effected by at least one folate moiety.

The pharmaceutical formulation according to any one of statements 3 to 8, wherein the FR-targeting excipient is a folate-polysaccharide conjugate comprising at least one folate moiety covalently linked to a polysaccharide or functionally-modified polysaccharide.

The pharmaceutical formulation according to any one of statements 3 to 9, wherein the polysaccharide or functionally-modified polysaccharide is selected from chitosan or functionally- modified chitosan; N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan (HTC) and its salts; N- trimethyl chitosan (TMC) and its salts; N 0-carboxymethyl chitosan (N O-CMC) and its salts; N- carboxymethyl chitosan (N-CMC) and its salts; NN-carboxymethyl chitosan (NN-CMC) and its salts; 0-carboxymethyl chitosan (O-CMC) and its salts; hydrophobically-modified chitosan (HMC) and its salts; dextran or functionally-modified dextran; hydrophobically-modified dextran (HMD) and its salts; starch or functionally-modified starch; hydroxypropyl starch; amylose or functionally- modified amylose; amylopectin or functionally-modified amylopectin; cellulose or functionally- modified cellulose; methylcellulose and its salts; carboxymethylcellulose and its salts; hydroxyethylcellulose and its salts; ethylcellulose and its salts; hydroxyethylmethylcellulose and its salts; hydroxypropylcellulose and its salts; hypromellose and its salts; hypromellose acetate succinate; hypromellose phthalate; croscarmellose and its salts; chitin; cyclodextrin; dextrate; dextrin; maltodextrin; pullulan; or guar gum. The pharmaceutical formulation according to any one of statements 3 to 10, wherein the polysaccharide or functionally-modified polysaccharide is covalently bound to the folate moiety via a single bond or via a linker, wherein the linker comprises a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof, preferably wherein the linker comprises or consists essentially of a polyether selected from polyethylene oxide (PEO), polypropylene oxide (PPO), or a block co-polymer of PEO and PPO, more preferably wherein the linker comprises or consists essentially of a PEO.

The pharmaceutical formulation according to any one of statements 3 to 11, wherein the FR-targeting excipient is a folate-polysaccharide conjugate comprising at least one unit selected from the group consisting of units of Formula Xlb, XIc, Xld, and Xle, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, or any subgroup thereof, wherein

(Xld) (Xle)

Y ¹ is -X^X'-X ³ , or a group selected from -OR ¹⁰ , -N(R ¹⁰⁰ )R ¹⁰¹ , or -N ⁺ (R ¹⁰⁰ )(R ¹⁰¹ )R ¹⁰²

Y ² is -X^X'-X ³ , or a group selected from -OR ²⁰ , -N(R ²⁰⁰ )R ²⁰¹ , or -N ⁺ (R ²⁰⁰ )(R ²⁰¹ )R ²⁰²

Y ³ is -X^X'-X ³ , or a group selected from -OR ³⁰ , -N(R ³⁰⁰ )R ³⁰¹ , or -N ⁺ (R ³⁰⁰ )(R ³⁰¹ )R ³⁰²

R ¹ is -OR ¹¹ or -X^X ¹ -X ³ ,

R ² is -OR ²¹ or -X^X ¹ -X ³ ,

R ³ is -OR ³¹ or -X^X ¹ -X ³ ,

R ⁴ is -OR ⁴¹ or -X^X ¹ -X ³ ,

R ³⁴ is -OR ³¹ or -X^X'-X ³ ,

R ⁴³ is -OR ⁴¹ or -X^-X ³ , R ⁴⁴ is -OR ⁴¹ or -X^-X ³ ,

R ⁵³ is -OR ⁵¹ or -X^X'-X ³ ,

R ⁵⁴ is -OR ⁵¹ or -X^X'-X ³ ,

wherein at least one of Y ¹ , R ¹ , or R ² is -X^X'-X ³ ;

wherein at least one of Y ² , R ³ , or R ⁴ is -X^X'-X ³ ;

wherein at least one of Y ³ , R ⁴³ , or R ⁵³ is -Χ ² -Χ'-Χ ³ ;

wherein at least one of R ³⁴ , R ⁴⁴ , or R ⁵⁴ is -Χ ² -Χ'-Χ ³ ;

wherein

R ¹⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, -Ci. ₆ alkylene-CO-OR ¹² , carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C^alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ³⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci. ₆ alkylene-CO-OR ¹² , carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ⁵¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ¹⁰⁰ is selected from hydrogen, or a group consisting of C^alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^{l u} )(R ^U2 )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰¹ is selected from hydrogen, or a group consisting of C^alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^{l u} )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ ,

C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrogen or Ci^alkyl; R ¹⁰² is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R 200 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 201 is selected from hydrogen, or alky lene-N(R 211 )R 212 a group consisting of Ci_ ₂₅ alkyl, C _h , Ci_

₆ alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 202 is selected from hydrogen, or a group consisting 211 212 of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 300 is selected from hydrogen, or l, C _h alky lene-N(R 211 )R 212 a group consisting of Ci_ ₂₅ alky , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ ,

C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrogen or Ci^alkyl; R 301 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C2_ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrog

R 302 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrog

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof,

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

(XII)

X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-

R 225 O-N(H)R 225 225

, and -C , wherein R is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR, wherein R is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -(C=0), -OR', -COR', and halosubstituted -COR',

wherein R' is H or Ci.galkyl; L is selected from

, or a group consisting of , -Ci_ 6alkylene-N(R ²²⁷ )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . ₆ cycloalkylene, C6_ioarylene,

6alkylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0- C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ . 6alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-(CO)-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene- (CO)-0-C ₃ - ₆ cycloalkylene, Ci_ ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C ₂ . ₆ alkenylene-0-(CO)-C ₂ . 6alkenylene, C ₂ _ ₆ alkynylene-0-(CO)-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-(CO)-C ₃ _ scycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and -(CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or Ci_

222 222

₆ alkyl; wherein the Y is attached to Q and -NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-;

221 229 222

wherein Y is selected from a sing le bond, -0-, -N(R )-, or -S-; Y ^{^} is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -

(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R ²²⁶ is hydrogen or R 22V is hydrogen o R 228 is hydrogen or R 229 is hydrogen or C i_ ₆ alkyl; R 2"30 ^u is hydro gen or ach R 231 is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; R ²³² is

231 232

hydrogen or R and R together with the atoms to with they are attached form a pyrrolidine

221 1 222

ring; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond;

X ⁴ is -O- or -N(R ⁴⁰³ )-, wherein R ⁴⁰³ is selected from hydrogen or Ci^alkyl. The pharmaceutical formulation according to any one of statements 4 to 10, wherein the antineoplastic agent is selected from temozolomide, cisplatin, paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, irinotecan, cyclophosphamide, doxorubicin, vincristine, or a combination thereof.

The pharmaceutical formulation according to any one of statements 3 to 13, wherein the nanoparticles are comprised in microparticles.

An inhaler comprising the pharmaceutical formulation according to any one of statements 1 to 14, preferably a powder inhaler comprising the pharmaceutical formulation according to any one of statements 1 to 14, more preferably a dry powder inhaler comprising the pharmaceutical formulation according to any one of statements 1 to 14.

A pharmaceutical formulation according to any one of statements 1 to 14, for use in the treatment of a proliferative disease affecting at least part of the respiratory tract.

A pharmaceutical formulation comprising an antineoplastic agent and a FR-targeting excipient, for use in the treatment of a proliferative disease affecting at least part of the respiratory tract.

The pharmaceutical formulation for use according to statement 17, wherein the pharmaceutical formulation is administered by inhalation, preferably by dry powder inhalation

The pharmaceutical formulation for use according to any one of statements 14 to 16, wherein the proliferative disease affecting at least part of the respiratory tract is a tumour affecting at least part of the respiratory tract or cancer affecting at least part of the respiratory tract.

The pharmaceutical formulation for use according to any one of statements 16 to 19, wherein the proliferative disease affecting at least part of the respiratory tract is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

The pharmaceutical formulation for use according to any one of statements 16 to 19, wherein the proliferative disease affecting at least part of the respiratory tract is a metastatic tumour affecting at least part of the respiratory tract or metastatic cancer affecting at least part of the respiratory tract. A method for preparing the pharmaceutical formulation according to any one of statements 1 to 14, the method comprising the steps of:

(a) preparing in a first solvent a first composition comprising: (i) at least one FR-targeting antineoplastic substance or composition, and (ii) optionally one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents, wherein the at least one FR-targeting antineoplastic substance or composition is in solution in the first solvent, and the optional one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents are solubilised or dispersed in the first solvent;

(b) preparing in a second solvent a second composition comprising: (i') a FR-targeting excipient, and (ϋ') optionally one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents, wherein the FR-targeting excipient is in solution or in dispersion in the second solvent, and the optional one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents are solubilised or dispersed in the second solvent, and wherein the at least one FR-targeting antineoplastic substance or composition is more soluble in the first solvent than in the second solvent;

(c) mixing of the first composition of step (a) and the second composition of step (b) to produce nanoparticles (in the solvent mixture), wherein the nanoparticles comprise the at least one FR- targeting antineoplastic substance or composition.

The method according to statement 22, wherein the method comprises the steps of:

(a) preparing in a first solvent a first composition comprising: (i) at least one antineoplastic agent, (ii) at least one FR-targeting excipient, and (iii) optionally one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents, wherein the at least one antineoplastic agent and the at least one FR-targeting excipient are in solution in the first solvent, and the optional one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents are solubilised or dispersed in the first solvent;

(b) preparing in a second solvent a second composition comprising: (i') a FR-targeting excipient, and (ϋ') optionally one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents, wherein the FR-targeting excipient is in solution or in dispersion in the second solvent, and the optional one or more polymeric excipients and/or one or more lipid excipients and/or one or more tensioactive agents are solubilised or dispersed in the second solvent, and wherein the at least one antineoplastic agent is more soluble in the first solvent than in the second solvent,

(c) mixing of the first composition of step (a) and the second composition of step (b) to produce nanoparticles, wherein the at least one antineoplastic agent is at least partly coated or dispersed in the at least one FR-targeting excipient.

The method according to statement 22 or 23, for preparing microparticles configured for dry powder inhalation, comprising the steps of:

(a")preparing in a solvent a composition comprising: (i") nanoparticles produced in step (c), (ii") optionally at least one carrier, and (iii") one or more surfactants, wherein the nanoparticles are dispersed in the solvent, the optional carrier is in suspension or solution or dispersed in the solvent, and the one or more surfactants are in solution in the solvent, and

(b") drying, preferably spray drying, the composition of step (a") to produce microparticles containing the nanoparticles.

The method according to statement 24, wherein the method further comprises dissolving or dispersing the microparticles in an aqueous medium to reconstitute the nanoparticles, wherein the particle size distribution of at least 10% of the reconstituted nanoparticles corresponds to the particle size distribution of the nanoparticles (before they were) comprised in the microparticles.

In certain embodiments, the FR-targeting antineoplastic substance or composition comprises at least one antineoplastic agent and at least one FR-targeting excipient.

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients), uses, or methods, as taught herein, the FR-targeting may be effected by at least one folate moiety. Such folate moiety advantageously allows that the present pharmaceutical formulations selectively bind to, target, or impinge on cells expressing folate receptors and not bind to, target, or impinge on other cells.

In certain embodiments, the FR-targeting antineoplastic substance or composition may comprise a folate moiety. In certain embodiments, the FR-targeting antineoplastic substance or composition may comprise at least one folate moiety. In certain embodiments, the FR-targeting antineoplastic substance or composition may comprise at least one folate moiety connected via a single bond or linker as taught herein (i.e., via X ¹ ) to a polysaccharide or functionally-modified polysaccharide as taught herein.

The term "folate moiety" or "folate", as used herein, refers to moieties composed of folic acid, or a derivative thereof (e.g. reduced folic acid), or composed of a subgroup of folic acid (e.g. pteroate moiety), or a derivative thereof (e.g. reduced pteroic acid).

The folate moiety as taught herein may specifically bind a folate receptor. The folate moiety as taught herein may bind a folate receptor with an affinity (dissociation constant or ¾) of about 1.10 ^~8 M or less, such as about 5.10 ^"9 M or less, or about 1.10 ^"9 M or less.

The terms "folate" or "folic acid", as used herein, refer to forms of the water-soluble vitamin B9. Folate or folic acid is also known with CAS Number 59-30-3, or as vitamin M, vitamin B9, vitamin B _c (or folacin), pteroyl-L-glutamic acid (i.e., pte-glu), and pteroyl-L-glutamate.

The term "reduced folic acid", as used herein refers to derivatives of folic acid wherein one or more of the functional groups of folic acid are reduced. Non- limiting examples of reduced folic acid are dihydrofolate (i.e., DHF), tetrahydrofolate (i.e., THF), 5-formyl-tetrahydrofolate (i.e., leucovorin), or 5-methyl- tetrahydrofolate (i.e., 5MTHF).

In certain embodiments, the FR-targeting antineoplastic substance or composition may comprise a pteroate moiety.

The term "pteroate moiety" as used herein refers to moieties composed of pteroic acid or pteroic acid derivatives, such as reduced pteroic acid. Non-limiting examples of reduced pteroic acid are dihydro pteroate (i.e., DHP) or tetrahydro pteroate (i.e., THP).

In certain embodiments of the products (such as pharmaceutical formulations FR-targeting antineoplastic substance or composition or FR-targeting excipients) or uses, as taught herein, the folate moiety may have the structural Formula XV, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

(XV)

X ²²¹ is selected from N, NR , or O; X ²²² is selected from N, NR , or O; X ²²ⁱ is selected from N, NR , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -COR, wherein R'

222 225

is H or Ci.galkyl; R is selected from the group consisting of -N(H)R , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -CO-R', -CO- OR', and -NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_ i ₂ alkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from

Ci

₆ alkylenecarbonyl, Ci_ ₆ alkylene-N(R )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . ₆ cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene- 0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-(CO)-0-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-(CO)-0-C ₂ - ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0- C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-0-(CO)-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-(CO)-C ₂ - ₆ alkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )- (CO)-, and -(CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and -NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²⁵ and the right side of each

221 229 222 group is attached to -(CO)-; wherein Y is selected from a single bond, -0-, -N(R )-, or -S-; Y is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _ _l oarylene, or -(C=0)-; t is an integer selected from 1 , 2, 3, or 4; s is an integer selected from 1 to 20; R ²²⁶ is hydrogen or R 227 is hydrogen or R 228 is hydrogen or R 229 is hydrogen or

Ci_ ₆ alkyl; R 2"30 ^u is hydro gen or each R 231 is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine,

232 231 232

phenylalanine, tyrosine, and tryptophan; R is hydrogen or R and R together with the atoms to with they are attached form a pyrrolidine ring; Q ²²⁴ is hydrogen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); Q ²²⁵ is hydrogen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein 1 224 and 225

(i.e., connecting the folate moiety to X ); wherein at least one of Q ^{^} is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); the dotted bond represents a single bond or a double bond.

In certain preferred embodiments, the folate moiety may have the structural Formula XVa, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

defined herein above.

In certain preferred embodiments, the folate moiety may have the structural Formula XV or XVa, as taught herein, wherein X ²²¹ is selected from N, or NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R is selected from the group consisting of - N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ .i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -

CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _ ₁₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted - COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_ i ₂ alkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -N(R ²²⁹ )-, - N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; R 226 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or Ci_ salkyl; Q ²²⁴ is hydro gen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); Q ²²⁵ is hydrogen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting

1 224 225

the folate moiety to X ); wherein at least one of and is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); the dotted bond represents a single bond or a double bond.

In certain preferred embodiments, the folate moiety may have the structural Formula XVb, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

XVb)

above. In certain preferred embodiments, the folate moiety may have the structural Formula XV, XVa, or XVb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of - N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -

CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _ ₁₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted - COR', wherein R' is H or Ci.galkyl; R is selected from hydrogen, or a group consisting of nitroso, C i ₂ alkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is

229 222 229 selected from a sing le bond, -0-, -NR - or -S-; is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or Q 224 is hydrogen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); Q ²²⁵ is hydrogen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); wherein at least one of Q ²²⁴ and Q ²²⁵ is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); the dotted bond represents a single bond or a double bond.

In certain preferred embodiments, the folate moiety may have the structural Formula XV, XVa, or XVb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²⁴ , Q ²²⁵ , and t have the same meaning as that defined herein above.

In certain preferred embodiments, the folate moiety may have the structural Formula XV, XVa, or XVb, as taught herein, wherein X 221 is selected from N or NH; X 222 is selected from N or NH; X 223 is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²⁴ , Q ²²⁵ , and t have the same meaning as that defined herein above.

In certain preferred embodiments, the folate moiety may have the structural Formula XV, XVa, or XVb, as taught herein, wherein R 222 is selected from the group consisting of -NHR 225 , hydrogen, Ci_i ₂ alkyl, - OR ²²⁵ , preferably -NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci.galkyl, C ₂ _ i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -COR, -COOR', or -NHR', wherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²⁴ , Q ²²⁵ , and t have the same meaning as that defined herein above.

In certain preferred embodiments, the folate moiety may have the structural Formula XVc, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

Q ²² *

(XVc)

221 222 224 225

Y , Y^, Q^, Q^ ^J , and m have the same meaning as that defined herein above.

In certain preferred embodiments, the folate moiety may have the structural Formula XV, XVa, XVb, or

221 229 222

XVc, as taught herein, wherein Y is selected from a sing le bond, -0-, -NR - or -S-; Y^ is selected

229 229

from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1 , 2, or 3; R is hydrogen or Ci_ salkyl; Q ²²⁴ is hydro gen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e., connecting the folate moiety to X ¹ ); Q ²²⁵ is hydrogen or is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e. , connecting

1 224 225

the folate moiety to X ); wherein at least one of and is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e. , connecting the folate moiety to X ¹ ).

In certain preferred embodiments, the folate moiety may have the structural Formula XV, XVa, XVb, or

224 225

XVc, as taught herein, wherein Q is hydrogen and Q is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e. , connecting the folate moiety to X ¹ ).

In certain preferred embodiments, the folate moiety may have the structural Formula XVd, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

(XVd)

Q ²²⁵ is a single bond connecting the folate moiety to a polysaccharide or functionally-modified polysaccharide as taught herein or to a linker as taught herein (i.e. , connecting the folate moiety to X ¹ ). In certain embodiments, a salt of the folate moiety may be a hydrochloride, sodium, potassium, calcium, or magnesium salt.

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients), uses, or methods, as taught herein, the FR-targeting antineoplastic substance or composition may comprise at least one antineoplastic agent and at least one FR-targeting excipient. In certain embodiments, the FR-targeting antineoplastic substance or composition may comprise an antineoplastic agent and a FR-targeting excipient.

The terms "FR-targeting excipient" or "FR-targeting compound" may be used interchangeably herein.

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients), uses, or methods, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one folate moiety covalently linked to a polysaccharide or functionally-modified polysaccharide.

The term "folate-polysaccharide conjugate" as used herein refers to a compound comprising at least a folate moiety and a polysaccharide or functionally-modified polysaccharide, wherein the folate moiety and the polysaccharide or functionally-modified polysaccharide are covalently bound or linked to each other (via at least one single bond or via at least one linker). The term "folate-polysaccharide conjugate" encompasses folate-polysaccharide conjugates and folate-functionally-modified polysaccharide conjugates.

In certain embodiments, FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one folate moiety covalently linked to a polysaccharide or functionally-modified polysaccharide selected from the group consisting of chitosan or functionally-modified chitosan; N-[(2-hydroxy-3- trimethylammonium)propyl] chitosan (HTC) and its salts; N-trimethyl chitosan (TMC) and its salts; N,0- carboxymethyl chitosan (N O-CMC) and its salts; N-carboxymethyl chitosan (N-CMC) and its salts; NN- carboxymethyl chitosan (NN-CMC) and its salts; O-carboxymethyl chitosan (O-CMC) and its salts; hydrophobically-modified chitosan (HMC) and its salts; dextran or functionally-modified dextran; hydrophobically-modified dextran (HMD) and its salts; starch or functionally-modified starch; hydroxypropyl starch; amylose or functionally-modified amylose; amylopectin or functionally-modified amylopectin; cellulose or functionally-modified cellulose; methylcellulose and its salts; carboxymethylcellulose and its salts; hydroxyethylcellulose and its salts; ethylcellulose and its salts; hydroxyethylmethylcellulose and its salts; hydroxypropylcellulose and its salts; hypromellose and its salts; hypromellose acetate succinate; hypromellose phthalate; croscarmellose and its salts; chitin; cyclodextrin; dextrate; dextrin; maltodextrin; pullulan; and guar gum.

In an embodiment, the FR-targeting excipient may be a folate-polysaccharide conjugate selected from the group consisting of folate-chitosan conjugate or folate-functionally-modified chitosan conjugate; folate- HTC conjugate; folate-TMC conjugate; folate-N O-CMC conjugate; folate-N- N-CMC conjugate; folate- NN-CMC conjugate; folate-O-CMC conjugate; folate-HMC conjugate; folate-dextran conjugate or folate-functionally-modified dextran conjugate; folate-HMD conjugate; folate-starch conjugate or folate- functionally-modified starch conjugate; folate-hydroxypropyl starch conjugate; folate-amylose conjugate or folate-functionally-modified amylose conjugate; folate-amylopectin conjugate or folate-functionally- modified amylopectin conjugate; folate-cellulose conjugate or folate-functionally-modified cellulose conjugate; folate-methylcellulose conjugate; folate-carboxymethylcellulose conjugate; folate- hydroxyethylcellulose conjugate; ethylcellulose conjugate; folate-hydroxyethylmethylcellulose conjugate; folate-hydroxypropylcellulose conjugate; folate-hypromellose conjugate; folate-hypromellose acetate succinate conjugate; folate-hypromellose phthalate conjugate; folate-croscarmellose conjugate; folate- chitin conjugate; folate-cyclodextrin conjugate; folate-dextrate conjugate; folate-dextrin conjugate; folate- maltodextrin conjugate; folate-pullulan conjugate; and folate-guar gum conjugate.

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients), uses, or methods, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit selected from the group consisting of units of Formula Xlb, Xlc, Xld, and Xle, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, or any subgroup thereof, wherein

(Xlb) (Xlc)

(Xld) (Xle)

Y ¹ is -X^X'-X ³ , or a group selected from -OR ¹⁰ , -N(R ¹⁰⁰ )R ¹⁰¹ , or -N ⁺ (R ¹⁰⁰ )(R ¹⁰¹ )R ¹⁰²

γ2 is -X^X'-X ³ , or a group selected from -OR ²⁰ , -N(R ²⁰⁰ )R ²⁰¹ , or -N ⁺ (R ²⁰⁰ )(R ²⁰¹ )R ²⁰²

Υ ³ is -X^X'-X ³ , or a group selected from -OR ³⁰ , -N(R ³⁰⁰ )R ³⁰¹ , or -N ⁺ (R ³⁰⁰ )(R ³⁰¹ )R ³⁰²

R ¹ is -OR ¹¹ or -X^X ¹ -X ³ ,

R ² is -OR ²¹ or -X^X ¹ -X ³ ,

R ³ is -OR ³¹ or -X^X ¹ -X ³ ,

R ⁴ is -OR ⁴¹ or -X^X ¹ -X ³ ,

R ³⁴ is -OR ³¹ or -X ² - -X ¹ -X ³ ,

R ⁴³ is -OR ⁴¹ or -X ² - -X ¹ -X ³ ,

_R 44

is -OR ⁴¹ or -X ² - -X ¹ -x ³ ,

R ⁵³ is -OR ⁵¹ or -X ² - -X ¹ -x ³ ,

R ⁵⁴ is -OR ⁵¹ or -X ² - -X ¹ -x ³ ,

wherein at least one of Y ¹ , R ¹ , or R ² is -X^X'-X ³ ;

wherein at least one of Y ² , R ³ , or R ⁴ is -X ² -X ¹ -X ³ ;

wherein at least one of Y ³ , R ⁴³ , or R ⁵³ is -X ² -X ¹ -X ³ ;

wherein at least one of R ³⁴ , R ⁴⁴ , or R ⁵⁴ is -X ² -X ¹ -X ³ ;

wherein

R ¹⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, -Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci. ₆ alkylene-CO-OR ¹² , carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or

R ³⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3.

₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ⁵¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ¹⁰⁰ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ ,

C2- ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰¹ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^{l u} )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰² is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R 200 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R 211 )R 212 , Ci_

₆ alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 201 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R 211 )R 212 , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or wherein R ²¹¹ is selected from hydrogen or R ²¹² is selected from hydrogen o R ²¹³ is selected from hydrogen or and R ²¹⁴ is selected from hydrogen or

R 202 is selected from hydrogen, or ene-N(R 211 )R 212 a group consisting of Ci_ ₂₅ alkyl, C _h alky l , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C2- ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 300 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_

₆ alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydroge R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or R ³¹⁴ is selected from hydrog

R 301 is selected from hydrogen, or a group consisting 211 212 of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrog

R 302 is selected from hydrogen, or 211 212 a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ ,

C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrog

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof,

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

(XII)

X ^zzl is selected from N, NR. , or O; X ^zzz is selected from N, NR , or O; X ^ZZi is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-

225 225 225

R , and -CO-N(H)R , wherein R is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR, wherein R is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR', and halosubstituted -COR',

₂₂ 0

wherein R' is H or Ci.galkyl; is selected from

, or a group consisting of , Ci_ ₆ alkylene-N(R ²²⁷ )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . ₆ cycloalkylene, C6_ioarylene,

6alkylene, -0-, Ci. ₆ alkylene-0-Ci. ₆ alkylene, C ₂ - ₆ alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0- C ₂ - ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-(CO)-0-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-(CO)-0-C ₂ _ ₆ alkynylene, C ₃ . ₆ cycloalkylene- (CO)-0-C ₃ - ₆ cycloalkylene, Ci. ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-0-(CO)-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-(CO)-C ₂ - ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-(CO)-C ₃ . scycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and -(CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or Ci_

222 222

₆ alkyl; wherein the Y is attached to Q and -NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-;

221 229 222

wherein Y is selected from a sing le bond, -0-, -N(R )-, or -S-; Y^ is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or - (C=0)-; t is an integer selected from 1 , 2, 3, or 4; s is an integer selected from 1 to 20; R ²²⁶ is hydrogen or is hydrogen or Ci_ ₆ alkyl; is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; R ²³² is

231 232

hydrogen or R and R together with the atoms to with they are attached form a pyrrolidine

221 1 222

ring; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond;

X ⁴ is -O- or -N(R ⁴⁰³ )-, wherein R ⁴⁰³ is selected from hydrogen or

Advantageously, the present inventors have found that the FR-targeting excipients as taught herein allow the formation of nanoparticles with good stability and physical integrity after administration in vivo and at the same time display a desired rate of dissolution once in contact with physiological media. Also, the FR-targeting excipients as taught herein display bioadhesive properties and/or present a long time of retention in the respiratory tract, thereby retaining the present pharmaceutical formulations in the respiratory tract.

Additionally, the present inventors have surprisingly found that the FR-targeting excipients as taught herein are able to interact with the antineoplastic agents (including hydrophilic antineoplastic agents) and these interactions advantageously lead to a better entrapment and/or encapsulation of the antineoplastic agents in the pharmaceutical formulations. Hence, using such FR-targeting excipients allows high drug encapsulation efficiency and drug loading.

The term "unit", as used herein, refers to a monosaccharide unit or functionally-modified monosaccharide unit.

In certain embodiments, the FR-targeting excipients may comprise at least one unit, such as one or more units, of Formula Xlb, XIc, XI d, or Xle, as taught herein, such as at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least twenty, at least thirty, at least forty, at least fifty, at least sixty, at least seventy, at least eighty, at least ninety, at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1500, at least 2000, or at least 2500 units of Formula Xlb, XIc, Xld, or Xle, as taught herein. For example, the polysaccharide or functionally-modified polysaccharide may comprise from about 50 to about 2000, from about 100 to about 1000, or from about 200 to about 500 units of Formula Xlb, XIc, Xld, or Xle, as taught herein.

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients) or uses, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, and/or Xlm, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, or any subgroup thereof, wherein

( lg) (Xlm)

Y ¹ is -X'-X'-X ³ , or a group selected from -OR ¹⁰ , -N(R ¹⁰⁰ )R ¹⁰¹ , or -N ⁺ (R ¹⁰⁰ )(R ¹⁰¹ )R ¹⁰² , wherein

X is -O- or -N(R , ¹ 1 ^U 03)-, wherein R , ¹ 1 ^U 03 is selected from hydrogen or

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C _2- i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO- R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from , or a group consisting of Ci_

₆ alkylene, , C _h alky lene-N(R ) , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C3. 6cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ - 6alkenylene-0-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ 6cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ - 6alkynylene-(CO)-0-C ₂ - ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene,

0-(CO)-Ci. ₆ alkylene, C ₂ -6alkenylene-0-(CO)-C ₂ -6alkenylene, C ₂ - ₆ alkynylene-0-(CO)-C ₂ - salkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and - (CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and - NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-; wherein Y ²²¹ is selected from a single bond, -0-, - N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is is hydrogen or each R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine,

232 231 232

tyrosine, and tryptophan; R is hydrogen or R and R together with the atoms to with they

221 1 222 are attached form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q^ ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond;

R ¹⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, -Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ . 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ¹⁰⁰ is selected from hydrogen, or a group consisting of C^alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰¹ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_

₆ alkylene-N ⁺ (R ^{l u} )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C2- ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰² is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ 6alkylene-N ⁺ (R ^{l u} )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹ is -OR ¹¹ or -X^X'-X ³ , wherein

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, Ci. ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

R ² is -OR ²¹ or -X^X'-X ³ , wherein

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3.

₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

wherein at least one of Y ¹ , R ¹ , or R ² is -X^X'-X ³ . In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients) or uses, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlc, Xlh, Xlj, Xlk, Xln, Xlp, and/or Xlq, or a stereoisomer, tautomer, salt, hydrate or solvate thereof or any subgroup thereof, wherein

(Xlp) (Xlq)

Y ² is -X'-X'-X ³ , or a group selected from -OR ²⁰ , -N(R ²⁰⁰ )R ²⁰¹ , or -N ⁺ (R ²⁰⁰ )(R ²⁰¹ )R ²⁰² , wherein

X 2 is -O- or -N(R 103 )-, wherein R 103 is selected from hydrogen or

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO- R , -CO-O-R ² , and -CO-N(H)R , wherein R is selected from the group consisting of hydrogen, halo, Ci.i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from

or a group consisting of Ci

₆ alkylene, , -C _h alky lene-N(R )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . ₆ cycloalkylene, C6_ioarylene, -0-, Ci. ₆ alkylene-0-Ci. ₆ alkylene, C ₂ - ₆ alkenylene-0-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ - ₆ alkynylene-(CO)-0-C ₂ - ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene,

0-(CO)-Ci_ ₆ alkylene, C ₂ -6alkenylene-0-(CO)-C ₂ -6alkenylene, C ₂ - ₆ alkynylene-0-(CO)-C ₂ - salkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and - (CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and - NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-; wherein Y ²²¹ is selected from a single bond, -0-, - N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; is hydrog

is hydrogen or

R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine,

232 231 232

tyrosine, and tryptophan; R is hydrogen or R and R together with the atoms to with they

221 1 222 are attached form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q^ ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond;

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. ₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ lkenyl, C ₂ _ ₆ lkynyl, C ₃ . ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

200 211 212

R is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C2- ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

201 211 212

R is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

202 211 212

R is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

3

R ³ is -OR ³¹ or -X^X'-X ³ , wherein

R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

-OR ⁴¹ or -X^X'-X ³ , wherein

R is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

wherein at least one of Y ² , R ³ , or R ⁴ is -X^X'-X ³ .

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients) or uses, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xld as taught herein, or any subgroup thereof, wherein

Y ³ is -X'-X'-X ³ , or a group selected from -OR ³⁰ , -N(R ³⁰⁰ )R ³⁰¹ , or -N ⁺ (R ³⁰⁰ )(R ³⁰¹ )R ³⁰² , wherein

X is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO- R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from

, or a group consisting of Ci_

₆ alkylene, , -C _h alky lene-N(R ²²⁷ )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . 6cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ _ 6alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ 6cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ _ 6alkynylene-(CO)-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene,

0-(CO)-Ci. ₆ alkylene, C ₂ . ₆ alkenylene-0-(CO)-C ₂ . ₆ alkenylene, C ₂ . ₆ alkynylene-0-(CO)-C ₂ . salkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and - (CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and - NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-; wherein Y ²²¹ is selected from a single bond, -0-, -

N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C6-ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; is hydrog

is hydrogen or

R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine,

232 231 232

tyrosine, and tryptophan; R is hydrogen or R and R together with the atoms to with they

221 1 222 are attached form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q^ ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond;

R ³⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R 300 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrog

R 301 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_

₆ alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrogen or Ci^alkyl; R 302 is selected from hydrogen, or 211 212 a group consisting of C _h alky 1, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ³¹⁴ , C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ³¹¹ is selected from hydrogen or R ³¹² is selected from hydrog R ³¹³ is selected from hydrogen or C _h alky 1, and R ³¹⁴ is selected from hydrog

R ⁴³ is -OR ⁴¹ or -X^X'-X ³ , wherein

R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci. ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

R ⁵³ is -OR ⁵¹ or -X^X'-X ³ , wherein

R ⁵¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

wherein at least one of Y ³ , R ⁴³ , or R ⁵³ is -X ² -X ¹ -X ³ .

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients) or uses, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xle as taught herein, or any subgroup thereof, wherein

X ⁴ is -O- or -N(R ⁴⁰³ )-, wherein R ⁴⁰³ is selected from hydrogen or

R ³⁴ is -OR ³¹ or -X ² -X ¹ -X ³ , wherein

R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or Ci^alkyl;

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO- R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from

or a group consisting of Ci_

₆ alkylene, , -C _h alky lene-N(R )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . 6cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ _ 6alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ 6cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ _ 6alkynylene-(CO)-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene,

0-(CO)-Ci. ₆ alkylene, C ₂ . ₆ alkenylene-0-(CO)-C ₂ . ₆ alkenylene, C ₂ . ₆ alkynylene-0-(CO)-C ₂ . salkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and - (CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and - NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-; wherein Y ²²¹ is selected from a single bond, -0-, - N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C6-ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is is hydrogen or each R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; R 232 is hydrogen or R 231 and R 232 together with the atoms to with they

221 1 222 are attached form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q ^{^1} and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond;

R ⁴⁴ is -OR ⁴¹ or -X^X'-X ³ , wherein

R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3.

₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

R ⁵⁴ is -OR ⁵¹ or -X ² -X ¹ -X ³ , wherein

R ⁵¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

wherein at least one of R ³⁴ , R ⁴⁴ , or R ⁵⁴ is -X ² -X ¹ -X ³ .

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, XIc, Xld, Xle, Xlg, Xlh, XIj, Xlk, Xlm, XIn, XIp, and/or Xlq, as taught herein, or any subgroup thereof, wherein Y ¹ , Y ² , Y ³ , X ⁴ , R ¹ , R ² , R ³ , R ⁴ , R ¹¹ , R ²⁰ , R ²¹ , R ³¹ , R ³⁴ , R ⁴¹ , R ⁴³ , R ⁵³ , R ⁵⁴ , X ¹ , and X ³ have the same meaning as defined herein.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising one or more units of Formula Xlb, XIc, Xld, Xle, Xlg, Xlh, XIj, Xlk, Xlm, XIn, XIp, or Xlq, as taught herein, or any subgroup thereof, wherein Y ¹ , Y ² , Y ³ , X ⁴ , R ¹ , R ² , R ³ , R ⁴ , R ¹¹ , R ²⁰ , R ²¹ , R ³¹ , R ³⁴ , R ⁴¹ , R ⁴³ , R ⁵³ , R ⁵⁴ , X ¹ , and X ³ have the same meaning as defined herein.

In certain embodiments, the FR-targeting excipients may comprise at least one unit, such as one or more units, of Formula Xlb, XIc, Xld, Xle, Xlg, Xlh, XIj, Xlk, Xlm, XIn, XIp, or Xlq, as taught herein, such as at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least twenty, at least thirty, at least forty, at least fifty, at least sixty, at least seventy, at least eighty, at least ninety, at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1500, at least 2000, or at least 2500 units of Formula Xlb, XIc, Xld, Xle, Xlg, Xlh, Xlj, Xlk, Xlm, Xln, Xlp, or Xlq, as taught herein. For example, the polysaccharide or functionally-modified polysaccharide may comprise from about 50 to about 2000, from about 100 to about 1000, or from about 200 to about 500 units of Formula Xlb, XIc, Xld, Xle, Xlg, Xlh, Xlj, Xlk, Xlm, Xln, Xlp, or Xlq, as taught herein.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlg, Xlh, Xlj, and/or Xlk, as taught herein, or any subgroup thereof, wherein R ¹¹ , R ²⁰ , R ²¹ , R ³¹ , R ⁴¹ , X ¹ , and X ³ have the same meaning as that defined herein.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit selected from the group consisting of units of Formula Xlg, Xlh, Xlj, and Xlk, as taught herein, or any subgroup thereof. In certain embodiments, the FR-targeting excipient may be a folate- polysaccharide conjugate comprising one or more units of Formula Xlg, Xlh, Xlj, or Xlk, as taught herein, or any subgroup thereof.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlm, Xln, Xlp, and/or Xlq, as taught herein, or any subgroup thereof, wherein R ¹¹ , R ²⁰ , R ²¹ , R ³¹ , R ⁴¹ , X ¹ , and X ³ have the same meaning as that defined herein.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit selected from the group consisting of units of Formula Xlm, Xln, Xlp, and Xlq, as taught herein, or any subgroup thereof. In certain embodiments, the FR-targeting excipient may be a folate- polysaccharide conjugate comprising one or more units of Formula Xlm, Xln, Xlp, or Xlq, as taught herein, or any subgroup thereof.

In certain embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients) or uses, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit selected from the group consisting of units of Formula Xlb, XIc, Xld, Xle, Xlg, Xlh, Xlj, Xlk, Xlm, Xln, Xlp, and Xlq, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X'-X'-X ³ , or a group selected from -OR ¹⁰ , -N(R ¹⁰⁰ )R ¹⁰¹ , or -N ⁺ (R ¹⁰⁰ )(R ¹⁰¹ )R ¹⁰² ,

Y ² is -X'-X'-X ³ , or a group selected from -OR ²⁰ , -N(R ²⁰⁰ )R ²⁰¹ , or -N ⁺ (R ²⁰⁰ )(R ²⁰¹ )R ²⁰² ,

Y ³ is -X'-X'-X ³ , or a group selected from -OR ³⁰ , -N(R ³⁰⁰ )R ²⁰¹ , or -N ⁺ (R ³⁰⁰ )(R ³⁰¹ )R ³⁰² ,

R ¹ is -OR ¹¹ or -X^X'-X ³ ,

R ² is -OR ²¹ or -X^X'-X ³ ,

R ³ is -OR ³¹ or -X^X'-X ³ ,

R ⁴ is -OR ⁴¹ or -X^-X ³ ,

R ³⁴ is -OR ³¹ or -X^X'-X ³ ,

R ⁴³ is -OR ⁴¹ or -X^-X ³ ,

R ⁴⁴ is -OR ⁴¹ or -X'-X'-X ³ , R ⁵³ is -OR ⁵¹ or -X^X'-X ³ ,

R ⁵⁴ is -OR ⁵¹ or -X^X'-X ³ ,

wherein at least one of Y ¹ , R ¹ , or R ² is -X^X'-X ³ ;

wherein at least one of Y ² , R ³ , or R ⁴ is -Χ ² -Χ'-Χ ³ ;

wherein at least one of Y ³ , R ⁴³ , or R ⁵³ is -X^X'-X ³ ;

wherein at least one of R ³⁴ , R ⁴⁴ , or R ⁵⁴ is -Χ ² -Χ'-Χ ³ ;

wherein

R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ³⁰ , R ³¹ , R ⁴¹ , R ⁵¹ are each independently selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C^alkyl, Ci. ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, - Ci. ₆ alkylene-CO-OR ¹² ,

C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and Ce-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or Ci_ ₆ alkyl; preferably R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ³⁰ , R ³¹ , R ⁴¹ , R ⁵¹ are each independently selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, Ci_ ₄ alkyleneCO-OR ¹² , carboxylCi.

₄ alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ³⁰ , R ³¹ , R ⁴¹ , R ⁵¹ are each independently selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, C ₅ _

₂₅ alkenylcarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C^alkyl, or C^alkoxy; preferably R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ³⁰ , R ³¹ , R ⁴¹ , R ⁵¹ are each independently selected from hydrogen, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and Ci ₃ - ₂₅ alkenylcarbonyl; preferably R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ³⁰ , R ³¹ , R ⁴¹ , R ⁵¹ are each independently selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n- heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n-tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n- pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n- nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

_R ioo _{} R} ioi _{} R} io2 _{} R} 2oo ^ _R 2oi ^ _R 202 ^ _R 3oo ^ _R 3oi ^ _R 302 _{are each independently se} i _ecte d from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_ ₆ alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ 2 ₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, wherein R ¹¹¹ is selected from hydrogen or C _h alky 1, R ¹¹² is selecte d from hydrogen or is selected from hydrogen or preferably R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ²⁰⁰ , R ²⁰¹ , R ²⁰² , R ³⁰⁰ , R ³⁰¹ , R ³⁰² are each independently selected from hydrogen, or a group consisting of Ci_ ₆ alkyl, Ci_ ₄ alkylene-N(R ^m )R ¹¹² , Ci_ ₄ alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, Ci. ₄ alkylene-CO-OR ¹¹⁴ , C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrogen or R ¹¹³ is selected from hydrogen and R ¹¹⁴ is selected from

f u nlOO nlOl π 102 _π 200 _{π π} 300 _π 301 _π 302 ι hydrogen or Ci_ ₄ alkyl; preferably R , R , R , R , R R , R , R are each independently selec ted from hydrogen, or a group consisting of i_ ₃ alkylene-N(R ^m )R ¹¹² , Ci_ 3alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₅ - ₂₃ alkenylcarbonyl, Ci_ ₃ alkylene-CO-OR ¹¹⁴ , C ₂ . alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹¹¹ is selected from hydrogen or C^alkyl, R ¹¹² is selected from hydrogen or C^alkyl, R ¹¹³ is selected from hydrogen or C^alkyl, and R ¹¹⁴ is selected from hydrogen or C^alkyl; preferably R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ²⁰⁰ , R ²⁰¹ , are each independently selected from hydrogen, or a group consisting of Ci_ 3alkyl, Ci_ ₃ alkylene-N(R ^m )R ¹¹² , Ci_ ₃ alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C _B - 2ialkenylcarbonyl, and Ci. ₃ alkylene-CO-OR ¹¹⁴ , each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen,

wherein R ¹¹¹ is selected from hydrogen or R ¹¹³ is selected from hydrogen or and R ¹¹⁴ is selected from hydrogen or preferably R ¹⁰⁰ , _R ioi _{} R} io2 _{} R} 2oo _{} R} 2oi ^ _R 202 ^ _R 3oo ^ _R 3oi ^ _R 302 _{are each independently se} i _ecte d from hydrogen, or a group consisting of methyl, ethyl, n-propyl, i-propyl, methylene-N(R ^m )R ¹¹² , ethylene-N(R ^m )R ¹¹² , n- propylene-N(R ^{l u} )R ¹¹² , methylene-N ⁺ (R ^{l u} )(R ¹¹² )R ¹¹³ , ethylene-N ⁺ (R ^{l u} )(R ¹¹² )R ¹¹³ , n-propylene- N ⁺ (R ^{1 U} )(R ¹¹² )R ¹¹³ , methylene-CO-OR ¹¹⁴ , ethylene-CO-OR ¹¹⁴ , n-propylene-CO-OR ¹¹⁴ , Ci_ ₂₅ alkylcarbonyl, and, Ci ₃ _ ₂ ialkenylcarbonyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, methyl, or ethyl, wherein R ¹¹¹ is selected from hydrogen, methyl, or ethyl, R ¹¹² is selected from hydrogen, methyl, or ethyl, R ¹¹³ is selected from hydrogen, methyl, or ethyl, and R ¹¹⁴ is selected from hydrogen, methyl, or ethyl; preferably R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ²⁰⁰ , R ²⁰¹ , R ²⁰² , R ³⁰⁰ , R ³⁰¹ , R ³⁰² are each independently selected from hydrogen, or a group consisting of methyl, ethyl, n-propyl, i-propyl, methylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , ethylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , n-propylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , methylene-CO-OR ¹¹⁴ , ethylene-CO- OR ¹¹⁴ , n-propylene-CO-OR ¹¹⁴ , C^alkylcarbonyl, and, Ci ₃ _ ₂ ialkenylcarbonyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or methyl, wherein R ¹¹¹ is selected from hydrogen or methyl, R ¹¹² is selected from hydrogen or methyl,

R ¹¹³ is selected from hydrogen or methyl, and R ¹¹⁴ is selected from hydrogen or methyl; preferably

_R 100 ^ _R 101 _{s R} 102 ^ _R 200 ^ _R 201 ^ _R 202 ^ _R 300 ^ _R 301 ^ _R 302 ^ _{each independently sdected} fr _{Qm hydrogerij or} a group consisting of methyl, ethyl, n-propyl, i-propyl, 2-hydroxy-propyleneN ⁺ (CH ₃ ) ₃ , methylene-CO- OH, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, i- butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a caprylic amide moiety), n-nonylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a capric amide moiety), n- undecylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a lauric amide moiety), n-tridecylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a myristic amide moiety), n-pentadecylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a palmitic amide moiety), n-heptadecylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a stearic amide moiety), n-nonadecylcarbonyl (e.g. which may form together with the nitrogen to which it is bound an arachidic amide moiety), n-henicosylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a behenic amide moiety), n- tricosylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a lignoceric amide moiety), n-pentacosylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a cerotic amide moiety), n-tridecenylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a myristoleic amide), n-pentadecenylcarbonyl (e.g. which may form together with the nitrogen to which it is bound a palmitoleic amide moiety or sapienic amide moiety), n- heptadecenylcarbonyl (e.g. which may form together with the nitrogen to which it is bound an oleic amide moiety, elaidic amide moiety, vaccenic amide moiety, linoleic amide moiety, linoelaidic amide moiety, or a-linolenic amide moiety), n-nonadecenylcarbonyl (e.g. which may form together with the nitrogen to which it is bound an arachidonic amide moiety or eicosapentaenoic amide moiety), or n- henicosenylcarbonyl {e.g. which may form together with the nitrogen to which it is bound an erucic amide moiety or docosahexaenoic amide moiety);

X 2 is -O- or -N(R 103 )-, wherein R 103 is selected from hydrogen or

X ¹ is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof, preferably X ¹ is a single bond or a linker comprising a poly(Ci_ ₆ alkyleneoxide), C _h alky leneoxide, amine, poly(iminoCi_ ₆ alkylene), amino acid, peptide, polypeptide, monosaccharide, or polysaccharide, preferably X ¹ is a single bond or a linker of Formula X,

-Α'-ΐΛΑ ² - (X)

wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-, -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO- N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO- N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO- L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-

N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO- L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a poly(Ci_ ₆ alkyleneoxide); preferably L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula - (CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q - , wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, and -

L ²⁰ -O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci_ 6alkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or Ci_ 6¾lkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-,

-L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently Ci_ 3alkylene being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently ethylene;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -

COR', wherein R' is H or Ci.galkyl; R 222 is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ - ₁₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci _-g alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted - COR, wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is

selected from , or a group consisting of Ci

₆ alkylene, , -Ci_ ₆ alkylene-N(R )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . ₆ cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-0- C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_6alkylene, C ₂ -6alkenylene-(CO)-0-C ₂ _6alkenylene, C ₂ _6alkynylene-(CO)-0-C ₂ - ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-0-(CO)-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-(CO)-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0- (CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and -(CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or

222 222

wherein the Y is attached to Q and -NH- is attached to -(CO)-, or wherein the left side of each

222 221 group is attached to Q and the right side of each group is attached to -(CO)-; wherein Y is

229 222 229 selected from a sing le bond, -0-, -N(R )-, or -S-; Ύ ^ΔΔΔ is selected from a single bond, -0-, -NR -, - N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R 226 is hydrogen or R 22V is hydrogen or R 228 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or Ci_ ₆ alkyl; each R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; R 232 is hydrogen or R 231 and R 232 together with the atoms to with they are attached

221 1 222

form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a

1 221 222 1 single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xlla, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

Xlla)

defined herein above; preferably X is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X ²²¹ is selected from N, or NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of - N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and

-CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _ ₁₂ alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci _-g alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or

221 229 222

Ci.galkyl; wherein Y is selected from a single bond, -0-, -N(R )-, or -S-; Y is selected from a single bond, -0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -

(C=0)-; t is an integer selected from 1, 2, 3, or 4; R 226 is hydrogen or R 229 is hydrogen or Ci_

6alkyl; is

1 221 222

hydrogen or is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

Xllb)

herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of - N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and

-CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _ ₁₂ alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ ₈ alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR, -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or

221 229 222

Ci.galkyl; wherein Y is selected from a single bond, -0-, -NR - or -S-; Y is selected from a single bond, -0-, -NR 229 -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or

221 1 222

Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond connected to

1 221 222 1

X ; wherein at least one of Q ^{^1} and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NH; X ²²² is selected from N or NH; X ²²³ is selected from N or NH; the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²² is selected from the group consisting of - NHR ²²⁵ , hydrogen, Ci_i ₂ alkyl, -OR ²²⁵ , preferably -NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -COR', -COOR', or -NHR', wherein R' is H or and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula Xllc, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein

(Xllc)

Y , Y , Q , Q , and m have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, Xllb, or Xllc, as taught herein, wherein Y ²²¹ is

229 222 229 selected from a sing le bond, -0-, -NR - or -S-; Ύ ^ΔΔΔ is selected from a single bond, -0-, -NR -, or -

S-; m is an integer selected from 1, 2, or 3; R is hydrogen or Q22 ¹ 1 is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to X ¹ ; wherein at least one

221 222 1 3

of Q ^{^1} and is a single bond connected to X ; preferably X is a folate moiety having the structural

Formula XII, Xlla, Xllb, or Xllc, as taught herein, wherein Q 221 is hydrogen and Q 222 is a single bond connected to X ¹ ; preferably X ³ is a folate moiety having the structural Formula Xlld, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, wherein paid)

Q ²²² is a single bond connected to X ¹ ;

X ⁴ is -O- or -N(R ⁴⁰³ )-, wherein R ⁴⁰³ is selected from hydrogen or

In certain preferred embodiments of the products (such as pharmaceutical formulations or FR-targeting excipients) or uses, as taught herein, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlc, Xld, Xle, Xlg, Xlh, Xlj, Xlk, Xlm, Xln, Xlp, or Xlq, as taught herein, or any subgroup thereof, wherein

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ 2 ₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl,

hydroxyCi_ ₆ alkyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, carboxylCi. 4alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of carboxylCi. 3alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ 3alkyl, or Ci_ 2 ₅ alkylcarbonyl, and Ci ₃ . ₂₅ alkenylcarbonyl; preferably R ¹¹ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n- butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n- nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n- heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n- henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl,

hydroxyCi_ ₆ alkyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, carboxylCi. ₄ alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of carboxylCi. ₃ alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or Ci_

₂₅ alkylcarbonyl, and Ci ₃ _ ₂₅ alkenylcarbonyl; preferably R ²¹ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n- butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n- nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n- heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n- henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl,

hydroxyCi_ ₆ alkyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, carboxylCi. ₄ alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of carboxylCi. ₃ alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_

₃ alkyl, or C^alkoxy; preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and Ci ₃ _ ₂₅ alkenylcarbonyl; preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, i- butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n- undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n- heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n- henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl,

hydroxyCi-ealkyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and Ce-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, carboxylCi.

₄ alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, carboxylCi.

₃ alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and Co^salkenylcarbonyl; preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, i- butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n- undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n- heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n- henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl,

hydroxyCi-ealkyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, carboxylCi. ₄ alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C _h alky!, Ci_ ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, C^alkyleneCOOH, carboxylCi. ₃ alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ 3alkyl, or C^alkoxy; preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and Ci ₃ . ₂₅ alkenylcarbonyl; preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, i- butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n- undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n- heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n- henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

X ¹ is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof, preferably X ¹ is a single bond or a linker comprising a poly(Ci_ ₆ alkyleneoxide), amine, poly(iminoCi_ ₆ alkylene), amino acid, peptide, polypeptide, monosaccharide, or polysaccharide, preferably X ¹ is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein A ¹ is selected from a group consisting of -CO-, -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ ,

L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, - CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene; L ¹ is a poly(Ci_ ₆ alkyleneoxide); preferably L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -

CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 1 10; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90; A ² is a single bond or is selected from a group consisting of - N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, and -L ²⁰ -O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci_ ₆ alkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, or - L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is

1 3 19 20

attached to L and the right side thereof is attached to X , wherein L and L are each independently

Ci_ ₃ alkylene being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or Ci_ ₃ alkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently ethylene;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -

COR', wherein R' is H or Ci.galkyl; R 222 is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _i ₂ alkenyl, C ₂ _ 1 ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -

COR, wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is

selected from , , or a group consisting of Ci_

₆ alkylene, , -Ci_ ₆ alkylene-N(R ²²⁷ )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C3. 6cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-0-

C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ 6alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-(CO)-0-C ₂ _ 6alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C ₂ _ 6alkenylene-0-(CO)-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0-(CO)-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0- (CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and -(CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or

222 222

wherein the Y is attached to Q and -NH- is attached to -(CO)-, or wherein the left side of each

222 221 group is attached to Q and the right side of each group is attached to -(CO)-; wherein Y is

229 222 229 selected from a sing le bond, -0-, -N(R )-, or -S-; Ύ ^ΔΔΔ is selected from a single bond, -0-, -NR -, - N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R 226 is hydrogen or R 22V is hydrogen or R 228 is hydrogen or R 229 is hydrogen or R 230

is hydrogen or Ci-ealkyl; each R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; 232 231 232

R is hydrogen or R and R together with the atoms to with they are attached

221 1 222

form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a

1 221 222 1 single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xlla, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ ,

222 221 222 3

Y ~ Q" ¹ , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X ²²¹ is selected from N, or

NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from 224 225 rom 224 221

N, NR or O; X is selected f NR or O; R is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl;

222 elected from the group consisting of 225

R is s -N(H)R , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ lkenyl, C ₂ - i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -CO-R', -CO-OR', and - NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR', and halosubstituted - COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-;

Y ²²² is selected from a single bond, -0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1 , 2, 3, or 4; R ²²⁶ is hydrogen or is hydrogen or is a single bond

1 222 1 221 connected to X ; Q is hydrogen or is a single bond connected to X ; wherein at least one of Q ^{^1} and Q ²²² is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O;

R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of - N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ .i ₂ alkenyl, C ₂ .i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and

225 , wherein 225

-CO-N(H)R R is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ - i ₂ alkenyl, C ₂ .i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or

221 229 222

Ci.galkyl; wherein Y is selected from a single bond, -0-, -NR - or -S-; Y is selected from a single bond, -0-, -NR 229 -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or

221 1 222

Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond connected to

1 221 222 1

X ; wherein at least one of Q ^{^1} and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NH; X ²²² is selected from N or NH; X ²²³ is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²² is selected from the group consisting of - NHR ²²⁵ , hydrogen, -OR ²²⁵ , preferably -NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -COR, -COOR', or -NHR, wherein R' is H or and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula

XIIc, as taught herein, wherein Y 221 , Y 2"22 , Q 221 , Q 222 , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc,

221 229 222

as taught herein, wherein Y is selected from a sing le bond, -0-, -NR - or -S-; Y ^{^} is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; R is hydrogen or Ci_

221 1 222

₆ alkyl; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 3 connected to X ; wherein at least one of Q ^{^1} and Q ^{^} is a single bond connected to X ; preferably X is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein

221 222 1 3

Q is hydrogen and Q is a single bond connected to X ; preferably X is a folate moiety having the structural Formula XII d, as taught herein, wherein Q ²²² is a single bond connected to X ¹ .

In certain preferred embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, or Xlm, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X'-X'-X ³ , or a group selected from -OR ¹⁰ , -N(R ¹⁰⁰ )R ¹⁰¹ , or -N ⁺ (R ¹⁰⁰ )(R ¹⁰¹ )R ¹⁰² , preferably Y ¹ is - X ² -X ¹ -X ³ ; wherein

X 2 is -O- or -N(R 103 )-, wherein R 103 is selected from hydrogen or preferably X 2 is -

N(R 103 )-, wherein R 103 is selected from hydrogen or preferably X 2 is -NH-;

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof, preferably X ¹ is a single bond or a linker comprising a poly(Ci_ ₆ alkyleneoxide), amine, poly(iminoCi_ ₆ alkylene), amino acid, peptide, polypeptide, monosaccharide, or polysaccharide, preferably X ¹ is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-, -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO- N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to

L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-

N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -

CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently C^alkylene optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and - CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a poly(Ci_ ₆ alkyleneoxide); preferably L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(O- CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, and - L ²⁰ -O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci-ealkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or Ci-ealkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )- , -0-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently Ci_ 4alkylene being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and

L ²⁰ are each independently ethylene;

X ³ is a folate moiety; preferably X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO- R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from , or a group consisting of Ci

₆ al kylene, , -C _h alky lene-N(R ²²⁷ )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C3. ₆ cycloalkylene, C6_ioarylene, -0-, Ci. ₆ alkylene-0-Ci. ₆ alkylene, C ₂ - ₆ alkenylene-0-C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ - ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ -

₆ alkynylene-(CO)-0-C ₂ - ₆ alkynylene, C3_ ₆ cycloalkylene-(CO)-0-C3_ ₆ cycloalkylene,

0-(CO)-Ci. ₆ alkylene, C ₂ -6alkenylene-0-(CO)-C ₂ -6alkenylene, C ₂ - ₆ alkynylene-0-(CO)-C ₂ - salkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and - (CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and -

NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-; wherein Y ²²¹ is selected from a single bond, -0-, -

N(R ²² , or -S-; Y ¹¹¹ is selected from a single bond, -0-, -NR -, -N(R )-C(=NH)-N(R )-, or

-S-; L ²²² is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R 226 is hydroge R 22V is hydrog

R 228 is hydrogen or R 229 is hydrogen or is hydrogen or

R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; R 232 is hydrogen or R 231 and R 232 together with the atoms to with they

221 1 222 are attached form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q ^{^1} and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xlla, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X ²²¹ is selected from N, or NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, 225 C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond,

-0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-

230 222

N(R )-, or -S-; L is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2,

3, or 4; R 226 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or Ci_

221 1 222

₆ alkyl; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ ,

222 221 222 3

Ύ ^ΔΔ Q ^{^} , and m have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N,

NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O- R 225 , and -CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo,

Ci_i ₂ alkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R is H or Ci.galkyl; wherein Y 221 is selected from a single bond, -0-, -NR 229 - or

222 229

-S-; Y is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; is

1 221 222 hydrogen or is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein

X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or

NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3

Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NH; X ²²² is selected from N or NH; X ²²³ is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²² is selected from the group consisting of -NHR ²²⁵ , hydrogen, Ci_i ₂ alkyl, -OR ²²⁵ , preferably -NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -COR', -

COOOORR'',, oorr --NNHHRR'',, wwherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² _:

221 222 221 222 3

Y , Y ^z , Q , and t have the same meaning as that defined herein above; preferably X is a ffoolla: te moiety having the structural Formula XIIc, as taught herein, wherein Y , Y , Q

Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein Y ²²¹ is

229 222

selected from a sing le bond, -0-, -NR - or -S-; Ύ ^ΔΔΔ is selected from a single bond, -0-, - is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to

1 221 222 1 3

X ; wherein at least one of Q" ¹ and is a single bond connected to X ; preferably X is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein

221 222 1 3

Q is hydrogen and Q is a single bond connected to X ; preferably X is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to x ¹ ;

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, C^alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹² , carboxylCi. ₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ . ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or preferably R ¹⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C ₃ . ₂₅ alkenylcarbonyl, Ci_ ₄ alkyleneCO-OR ¹² ,

carboxylC ₆ _ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₄ alkyl, or wherein R ¹² is selected from hydrogen or preferably R ¹⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₄ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, C^alkyleneCOOH, carboxylCi. ₃ alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ¹⁰ is selected from hydrogen, or a group consisting of Ci_ ₃ alkyl, Ci_ ₂₅ alkylcarbonyl, and Ci ₃ _ ₂₅ alkenylcarbonyl; preferably R ¹⁰ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i- propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n- hexylcarbonyl, n-heptylcarbonyl {e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl {e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n- pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

R ¹⁰⁰ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² , Ci_

₆ alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-COOR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰¹ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² ,Ci_ 6alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-COOR ¹¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrog R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrog

R ¹⁰² is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₆ alkylene-N(R ^m )R ¹¹² ,Ci_ 6alkylene-N ⁺ (R ^m )(R ¹¹² )R ¹¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ _ ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ¹¹⁴ ,

C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci^alkyl, carboxyl, or wherein R ¹¹¹ is selected from hydrogen or R ¹¹² is selected from hydrogen o R ¹¹³ is selected from hydrogen or C _h alky 1, and R ¹¹⁴ is selected from hydrogen or

R ¹ is -OR ¹¹ or -X^X'-X ³ , wherein

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or preferably R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3. 2 ₅ alkenylcarbonyl,

carboxylC ₆ _ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₄ alkyl, or wherein R ¹² is selected from hydrogen or preferably R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ 4alkyl, Ci_ ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, C^alkyleneCOOH, carboxylCi. 3alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ¹¹ is selected from hydrogen, or a group consisting of Ci_ 3alkyl, Ci_ ₂₅ alkylcarbonyl, and Ci ₃ _ ₂₅ alkenylcarbonyl; preferably R ¹¹ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i- propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n- hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n- pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

R ² is -OR ²¹ or -X^x'-X ³ , wherein

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or preferably R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3. 2 ₅ alkenylcarbonyl,

carboxylC ₆ _ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₄ alkyl, or wherein R ¹² is selected from hydrogen or preferably R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ 4alkyl, Ci_ ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, C^alkyleneCOOH, carboxylCi. 3alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ²¹ is selected from hydrogen, or a group consisting of Ci_ 3alkyl, Ci_ ₂₅ alkylcarbonyl, and Ci ₃ _ ₂₅ alkenylcarbonyl; preferably R ²¹ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i- propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n- hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n- pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl {e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl {e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl {e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl {e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl {e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl {e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl {e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

wherein at least one of, such as one, two, or three of, Y ¹ , R ¹ , or R ² is -X ² -X ¹ -X ³ .

In certain preferred embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, or Xlm, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X^X'-X ³ , wherein

X 2 is -O- or -N(R 103 )-, wherein R 103 is selected from hydrogen or

X ^I is a single bond or a linker comprising a poly(Ci_ ₆ alkylen amine, poly(iminoCi_ ₆ alkylene), amino acid, peptide, polypeptide, monosaccharide, or polysaccharide, preferably X ¹ is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-, -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO- N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO- N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, - CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently C^alkylene optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -

CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a poly(Ci_ ₆ alkyleneoxide); preferably L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(O- CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, and -

L ²⁰ -O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci_ ₆ alkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or Ci_ ₆ alkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-

, -0-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently Ci_ 4alkylene being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L and L are each independently methylene or ethylene; R and R are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently ethylene;

X is a folate moiety having the structural Formula XII, as taught herein, wherein X is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R 222 is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-

N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _ 1 ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ ₈ alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR, wherein R' is

H or Ci.galkyl; L is selected from , or a group consisting of , -Ci_ ₆ alkylene-N(R ²²⁷ )- , C ₂ _ 6alkenylene, C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene, C6-ioarylene, -0-, Ci_ C ₂ _ ₆ alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene- (CO)-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-(CO)-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ 6cycloalkylene, Ci_ ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-0-(CO)-C ₂ _ ₆ alkenylene, C ₂ . 6alkynylene-0-(CO)-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-(CO)-C ₃ _ ₆ cycloalkylene, -N(R ²²⁸ )-, -

N(R 228 )-(CO)-, and -(CO)-N(R 228 )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or wherein the Y ²²² is attached to Q ²²² and -NH- is attached to -(CO)-, or wherein the left side of each group is

222 221 attached to Q and the right side of each group is attached to -(CO)-; wherein Y is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, - N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R ²²⁶ is hydrogen or

R 22V is hydrogen or R 228 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or each R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine,

232 231 232 methionine, phenylalanine, tyrosine, and tryptophan; R is hydrogen or R and IT" together with the atoms to with they are attached form a pyrrolidine ring; Q ²²¹ is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to X ¹ ; wherein at least one

221 222 1

of Q ^{^1} and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xlla, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X 221 is selected from N, or NR 221 , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR 224 or O; X 225 is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci_ salkyl; R 222 is selected from the group consisting of -N(H)R 225 , hydrogen, halogen,

C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, - OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci _-g alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci-galkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_ i ₂ alkyl, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci_ ₈ alkyl; wherein

221 229 222

Y is selected from a sing le bond, -0-, -N(R )-, or -S-; Y ^{^} is selected from a single bond, - 0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ -ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; R 226 is hydrogen or R 229 is hydrogen or Ci_ ₆ alkyl; R 230 is hydrogen or Q 221 is hydrogen or is a single bond connected to X 1 ; Q 222

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q ^{^1} and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected

224 221

from NR or O; R is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, - OR', -COR', and halosubstituted -COR', wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR 225 ,

-CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or d _-8 alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond, -0-, -NR ²²⁹ - or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or Q 221 is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to X ¹ ; wherein at least one of

221 222 1

Q and Q is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ;

X ²²³ is selected from N or NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X 221 is selected from N or NH; X 222 is selected from N or NH; X 223 is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3

Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²²

225 225

is selected from the group consisting of -NHR , hydrogen, Ci.galkyl, -OR , preferably - NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ _ i ₂ alkynyl, -OR', -COR', -COOR, or -NHR', wherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ ,

X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XIIc, as taught herein, wherein Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc,

221 229 222 as taught herein, wherein Y is selected from a single bond, -0-, -NR - or -S-; Y is

229 229 selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; R is hydrogen or Q 221 is hydrogen or is a single bond connected to X 1 ; Q 222 is hydrogen or

1 221 222

is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb,

221 222 1 or XIIc, as taught herein, wherein Q is hydrogen and Q is a single bond connected to X ; preferably X ³ is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to X ¹ ;

R ¹ is -OR ¹¹ , wherein

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

R ² is -OR ²¹ , wherein

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C2- ₂ salkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C2_ ₆ alkenyl, C2_ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, or Xlm, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X ² -X ¹ -X ³ , wherein

X ^I is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-

L IV 18 IV 1 -, and -CO-L -CO-N(R )-, wherein the right side of each group is attached to L and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO- N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or Ci_ 3alkyl; preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO- L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene; L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula - (CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ - CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, or - L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci_ ₄ alkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or Ci_ ₄ alkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )- , -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is

1 3 19 20 attached to L and the right side thereof is attached to X , wherein L and L are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is

1 3 19 20 attached to L and the right side thereof is attached to X , wherein L and L are each independently ethylene;

is a folate moiety having the structural Formula Xlla, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X ²²¹ is selected from N, or NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR 225 , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-

230 222

N(R )-, or -S-; L is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; R 226 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or Ci_

221 1 222

₆ alkyl; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ ,

222 221 222 3 Y , Q , and m have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of

-N(H)R ²²⁵ , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-

R 225 , and -CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR, wherein R is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y 221 is selected from a single bond, -0-, -NR 229 - or -S-;

222 229

Y is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1 , 2, or 3; is

1 221 222 hydrogen or is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or

NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3 Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NH; X ²²² is selected from N or NH; X ²²³ is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²² is selected from the group consisting of -NHR ²²⁵ , hydrogen, Ci.galkyl, -OR ²²⁵ , preferably -NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -COR', - COOR', or -NHR', wherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3

Y , Y ^z , Q , and t have the same meaning as that defined herein above; preferably X is ing the structural Formula XIIc, as taught herein, wherein Y 221 , Y 222 , Q 221 a folate moiety hav , Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein Y ²²¹ is

229 222

selected from a sing le bond, -0-, -NR - or -S-; Ύ ^ΔΔΔ is selected from a single bond, -0-, - is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to

1 221 222 1 3

X ; wherein at least one of Q" ¹ and is a single bond connected to X ; preferably X is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein

221 222 1 3

Q is hydrogen and Q is a single bond connected to X ; preferably X is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to x ¹ ;

R ¹ is -OR ¹¹ , wherein

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₆ alkyl, Ci_ ₂₅ alkylcarbonyl, C3_ ₂₅ alkenylcarbonyl, carboxylCi. 4alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ - 4alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or

R ² is -OR ²¹ , wherein

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₆ alkyl, carboxylCi. 4alkylenecarbonyl, carboxylCe-ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ - 4alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, or Xlm, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X^-X ³ , wherein

X ² is -NH-;

X ¹ is a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )- L IV -, CO-L 18 -CO-N(R IV )-, wherein the right side of each group is attached to L 1 and - and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of - CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, - CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is n- propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(O-

CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O- , wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and Ci_ ₃ alkyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ - N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ - N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently ethylene;

is a folate moiety having the structural Formula Xllb, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR 225 , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond,

229 222 229

-0-, -NR - or -S-; Y is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or Q 221 is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to X ¹ ; wherein at least one of

221 222 1

Q and Q is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X 221 is selected from N or NR 221 ; X 222 is selected from N or NR 221 ; X ²²³ is selected from N or NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X 221 is selected from N or NH; X 222 is selected from N or NH; X 223 is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3

Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²²

225 225

is selected from the group consisting of -NHR , hydrogen, Ci.galkyl, -OR , preferably - NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ _

₁₂ alkynyl, -OR', -COR', -COOR, or -NHR', wherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XIIc, as taught herein, wherein Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc,

221 229 222 as taught herein, wherein Y is selected from a single bond, -0-, -NR - or -S-; Y is

229 229 selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; R is hydrogen or Q 221 is hydrogen or is a single bond connected to X 1 ; Q 222 is hydrogen or

1 221 222

is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb,

221 222 1 or XIIc, as taught herein, wherein Q is hydrogen and Q is a single bond connected to X ; preferably X ³ is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to X ¹ ;

R ¹ is -OR ¹¹ , wherein

R ¹¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of

Ci_ ₄ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₅ . ₂₅ alkenylcarbonyl, carboxylCi. 3alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy;

R ² is -OR ²¹ , wherein

R ²¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₄ alkyl, C _h alky lcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, carboxylCi.

₃ alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C^alkyl, or C^alkoxy.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, or Xlm, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X ² -X ¹ -X ³ , wherein

X ² is -NH-;

X ¹ is a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-

L IV -, and -CO-L 18 -CO-N(R IV )-, wherein the right side of each group is attached to L 1 and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or C^alkyl; preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to

90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O- , wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or C^alkyl; preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently ethylene;

X 3 is a folate moiety having the structural Formula XIIc, as taught herein, wherein Y 221 , Y 222 , Q 221 , Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein Y ²²¹ is 229 222

selected from a sing le bond, -0-, -NR - or -S-; is selected from a single bond, -0-, -

NR 229 -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or

hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to

1 221 222 1 3

X ; wherein at least one of Q" ¹ and is a single bond connected to X ; preferably X is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein

221 222 1 3

Q is hydrogen and Q is a single bond connected to X ; preferably X is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to x ¹ ;

R ¹ is -OR ¹¹ , wherein

R ¹¹ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkylcarbonyl, and CB_

₂₅ alkenylcarbonyl;

R ² is -OR ²¹ , wherein

R ²¹ is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkylcarbonyl, and CB_ 2 ₅ alkenylcarbonyl.

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlb, Xlg, or Xlm, as taught herein, or any subgroup thereof, wherein

Y ¹ is -X ² -X ¹ -X ³ , wherein

X ² is -NH-;

X ¹ is a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ - , and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently ethylene;

X ³ is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to X ¹ ;

R ¹ is -OR ¹¹ , wherein

R ¹¹ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, t- butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl {e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n- undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n-tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n- pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

R ² is -OR ²¹ , wherein

R ²¹ is selected from hydrogen, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n-tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n- nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n-tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety).

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlc, Xlh, Xlj, Xlk, Xln, Xlp, or Xlq, as taught herein, or any subgroup thereof, wherein

Y ² is -X'-X'-X ³ , or a group selected from -OR ²⁰ , -N(R ²⁰⁰ )R ²⁰¹ , or -N ⁺ (R ²⁰⁰ )(R ²⁰¹ )R ²⁰² , preferably Y ² is - X ² -X ¹ -X ³ , or -OR ²⁰ , wherein

is -0-;

X ^I is a single bond or a linker comprising a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof, preferably X ¹ is a single bond or a linker comprising a poly(Ci_ ₆ alkyleneoxide), amine, poly(iminoCi_ ₆ alkylene), amino acid, peptide, polypeptide, monosaccharide, or polysaccharide, preferably X ¹ is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein A ¹ is selected from a group consisting of -CO-, -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-

N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO- N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, - CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently C^alkylene optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and

R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and - CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is a poly(Ci_ ₆ alkyleneoxide); preferably L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(O- CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, and - L ²⁰ -O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci-ealkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or

Ci-ealkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )- , -0-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently Ci_ 4alkylene being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L L ²⁰ are each independently ethylene;

X is a folate moiety; preferably X is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO- R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; L ²²⁰ is selected from

, or a group consisting of Ci

₆ alkylene, , -C _h alky lene-N(R )- , C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene, C ₃ . 6cycloalkylene, C6_ioarylene, -0-, Ci_ ₆ alkylene-0-Ci_ ₆ alkylene, C ₂ _ 6alkenylene-0-C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-C ₃ _ 6cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene-(CO)-0-C ₂ _ ₆ alkenylene, C ₂ . 6alkynylene-(CO)-0-C ₂ _ ₆ alkynylene, C ₃ _ ₆ cycloalkylene-(CO)-0-C ₃ _ ₆ cycloalkylene,

0-(CO)-Ci. ₆ alkylene, C ₂ . ₆ alkenylene-0-(CO)-C ₂ . ₆ alkenylene, C ₂ . ₆ alkynylene-0-(CO)-C ₂ . salkynylene, C ₃ - ₆ cycloalkylene-0-(CO)-C ₃ - ₆ cycloalkylene, -N(R ²²⁸ )-, -N(R ²²⁸ )-(CO)-, and - (CO)-N(R ²²⁸ )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or and - NH- is attached to -(CO)-, or wherein the left side of each group is attached to Q ²²² and the right side of each group is attached to -(CO)-; wherein Y ²²¹ is selected from a single bond, -0-, - N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R 226 is hydroge R 22V is hydrog

R 228 is hydrogen or R 229 is hydrogen or is hydrogen or

R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; 232 is hydrogen or 231 232

R R and R together with the atoms to with they

221 1 222 are attached form a pyrrolidine ring; Q is hydrogen or is a single bond connected to X ; Q

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q ^{^1} and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xlla, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X ²²¹ is selected from N, or NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from 224 or 221

NR O; R is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of 225 225

-N(H)R , hydrogen, halogen, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-

230 222

N(R )-, or -S-; L is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2, is hydrogen or Ci_

221 1 222

₆ alkyl; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ ,

222 221 222 3

Ύ ^ΔΔ Q ^{^} , and m have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of -N(H)R ²²⁵ , hydrogen, halogen, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-

225 225 225

R , and -CO-N(H)R , wherein R is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or C

8 a' lkyl; R is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0),

OR', -COR, and halosubstituted -COR, wherein R' is H or Ci.galkyl; R is selected from hydrogen, or a group consisting of nitroso, -(C=0), -OR', -COR, and halosubstituted

221 229

-COR', wherein R is H or Ci.galkyl; wherein Y is selected from a single bond, -0-, -NR - or

222 229

-S-; Y is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1 , 2, or 3; is

1 221 222 hydrogen or is a single bond connected to X ; wherein at least one of C " and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or

NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3 Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NH; X ²²² is selected from N or NH; X ²²³ is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² , Y Y ²²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²² is selected from the group consisting of -NHR ²²⁵ , hydrogen, Ci_i ₂ alkyl, -OR ²²⁵ , preferably -NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci.galkyl, C ₂ _i ₂ lkenyl, C ₂ _i ₂ lkynyl, -OR', -COR', - COOR', or -NHR', wherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3

Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is

221 222 221 a folate moiety having the structural Formula XIIc, as taught herein, wherein Y , Y , Q ,

Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein Y ²²¹ is

229 222

selected from a sing le bond, -0-, -NR" ^* -, or -S-; Υ ^ΔΔΔ is selected from a single bond, -0-, - is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to

1 221 222 1 3

X ; wherein at least one of Q" ¹ and is a single bond connected to X ; preferably X is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc, as taught herein, wherein

221 222 1 3

Q is hydrogen and Q is a single bond connected to X ; preferably X is a folate moiety having the structural Formula Xlld, as taught herein, wherein Q ²²² is a single bond connected to X ¹ ;

is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, carboxylCi. ₆ alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6_io ryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3. ₂₅ alkenylcarbonyl,

carboxylC ₆ _ioarylenecarbonyl, C2_ ₄ alkenyl, and C2_ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₄ alkyl, or wherein R ¹² is selected from hydrogen or preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_

₄ alkyl, Ci. ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, C^alkyleneCOOH, carboxylCi. ₃ alkylenecarbonyl, C2_ ₃ alkenyl, and C2_ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly- glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and CB_

₂₅ alkenylcarbonyl; preferably R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n- pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n- tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

0 Ci 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, _ ₆ alkylene-N(R )R , Ci_

₆ alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-COOR ²¹⁴ , C2- ₆ alkenyl, C2_ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 201 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C2- ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R 202 211 212 is selected from hydrogen, or a group consisting of Ci_ ₂₅ alkyl, C _h alky lene-N(R )R , Ci_ 6alkylene-N ⁺ (R ^2U )(R ²¹² )R ²¹³ , Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂₅ alkenylcarbonyl, Ci_ ₆ alkylene-CO-OR ²¹⁴ , C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3_ ₆ cycloalkyl, and C6-ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, carboxyl, or erein R ²¹¹ is selected from hydroge R ²¹² is selected from hydrog R ²¹³ is selected from hydrogen or R ²¹⁴ is selected from hydrog

R ³ is -OR ³¹ or -X^X'-X ³ , wherein

R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3. 2 ₅ alkenylcarbonyl,

carboxylC ₆ _ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₄ alkyl, or wherein R ¹² is selected from hydrogen or preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ 4alkyl, Ci_ ₂₅ alkylcarbonyl, C ₅ . ₂₅ alkenylcarbonyl, C^alkyleneCOOH, carboxylCi. 3alkylenecarbonyl, C ₂ _ ₃ alkenyl, and C ₂ _ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly- glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and C13. 2 ₅ alkenylcarbonyl; preferably R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n- pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n- tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

R ⁴ is -OR ⁴¹ or -X^X'-X ³ , wherein

R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ - ₂ salkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ -i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkylcarbonyl, C3. 2 ₅ alkenylcarbonyl,

carboxylC ₆ _ioarylenecarbonyl, C ₂ _ ₄ alkenyl, and C ₂ _ ₄ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₄ alkyl, or wherein R ¹² is selected from hydrogen or preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₄ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₅ _ ₂₅ alkenylcarbonyl, carboxylCi. 3alkylenecarbonyl, C2_ ₃ alkenyl, and C2_ ₃ alkynyl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, Ci_ ₃ alkyl, or C^alkoxy; preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly- glycosyl moiety, or a group consisting of C _h alky 1, Ci_ ₂₅ alkylcarbonyl, and CB_ 2 ₅ alkenylcarbonyl; preferably R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of methyl, ethyl, methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, z ^' -propylcarbonyl, n-butylcarbonyl, z ^' -butylcarbonyl, i-butylcarbonyl, n- pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl (e.g. which may form together with the oxygen to which it is bound a caprylic ester moiety), n-nonylcarbonyl (e.g. which may form together with the oxygen to which it is bound a capric ester moiety), n-undecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lauric ester moiety), n- tridecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristic ester moiety), n-pentadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitic ester moiety), n-heptadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound a stearic ester moiety), n-nonadecylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidic ester moiety), n-henicosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a behenic ester moiety), n- tricosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a lignoceric ester moiety), n-pentacosylcarbonyl (e.g. which may form together with the oxygen to which it is bound a cerotic ester moiety), n-tridecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a myristoleic ester moiety), n-pentadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound a palmitoleic ester moiety or sapienic ester moiety), n-heptadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an oleic ester moiety, elaidic ester moiety, vaccenic ester moiety, linoleic ester moiety, linoelaidic ester moiety, or a-linolenic ester moiety), n-nonadecenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an arachidonic ester moiety or eicosapentaenoic ester moiety), or n-henicosenylcarbonyl (e.g. which may form together with the oxygen to which it is bound an erucic ester moiety or docosahexaenoic ester moiety);

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

2 3 4 2 1 3

wherein at least one of, such as one, two, or three of, Y , R , or R is -X -X -X .

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlc, Xlh, Xlj, Xlk, Xln, Xlp, or Xlq, as taught herein, or any subgroup thereof, wherein

Y ² is -X ² -X ¹ -X ³ , or -OR ²⁰ , wherein

2 103 103

X is -O- or -N(R )-, wherein R is selected from hydrogen or Ci^alkyl; X ¹ is a single bond or a linker comprising a poly(Ci_ ₆ alkyleneoxide), amine, poly(iminoCi_ ₆ alkylene), amino acid, peptide, polypeptide, monosaccharide, or polysaccharide, preferably X ¹ is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein A ¹ is selected from a group consisting of -CO-, -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-

N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or Chalky 1; preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO- N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, - CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently C^alkylene optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and

R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and - CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene; L ¹ is a poly(Ci_ ₆ alkyleneoxide); preferably L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(O-

CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90; A ² is a ssiinnggllee bboonndd oorr iiss sseelleecctteedd ffrroomm a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, and L ²⁰ -O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci-ealkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or

Ci-ealkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )- , -0-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently Ci_ 4alkylene being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently ethylene;

X ³ is a folate moiety having the structural Formula XII, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O;

X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R 222 is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO- N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C ₂ _

₁₂ alkenyl, C ₂ _i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ ₈ alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR, wherein R' is , or a group consisting of , -Ci_ ₆ alkylene-N(R ²²⁷ )- , C2- ₆ alkenylene, C2_ ₆ alkynylene, C3_ ₆ cycloalkylene, C6_ioarylene, -0-, Ci_ C2- ₆ alkenylene-0-C2_ ₆ alkenylene, C2- ₆ alkynylene-0-C2_ ₆ alkynylene, C3_ ₆ cycloalkylene-0-C3_ ₆ cycloalkylene, Ci_ ₆ alkylene-(CO)-0-Ci_ ₆ alkylene, C2_ ₆ alkenylene-

(CO)-0-C2_ ₆ alkenylene, C2- ₆ alkynylene-(CO)-0-C2_ ₆ alkynylene, C3_ ₆ cycloalkylene-(CO)-0-C3_ ₆ cycloalkylene, Ci_ ₆ alkylene-0-(CO)-Ci_ ₆ alkylene, C2- ₆ alkenylene-0-(CO)-C2_ ₆ alkenylene, C2- ₆ alkynylene-0-(CO)-C2- ₆ alkynylene, C ₃ _ ₆ cycloalkylene-0-(CO)-C ₃ _ ₆ cycloalkylene, -N(R ²²⁸ )-, -

N(R 228 )-(CO)-, and -(CO)-N(R 228 )-, each group being optionally substituted with one or more substituents each independently selected from hydroxyl or wherein the Y ²²² is attached to Q ²²² and -NH- is attached to -(CO)-, or wherein the left side of each group is

222 221 attached to Q and the right side of each group is attached to -(CO)-; wherein Y is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -NR ²²⁹ -, - N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ _i ₀ arylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; s is an integer selected from 1 to 20; R ²²⁶ is hydrogen or

R 22V is hydrog R 228 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or R ²³¹ is independently selected from the group consisting of hydrogen or the amino acid side chain of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, alanine, valine, isoleucine, leucine,

232 231 232 methionine, phenylalanine, tyrosine, and tryptophan; R is hydrogen or R and IT" together with the atoms to with they are attached form a pyrrolidine ring; Q ²²¹ is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to X ¹ ; wherein at least one

221 222 1

of Q ^{^1} and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xlla, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X 221 is selected from N, or NR 221 , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR 224 or O; X 225 is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci_

8 ^; alkyl; R is selected from the group consisting of -N(H)R ³ , hydrogen, halogen, Ci.galkyl,

C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, - OR', -CO-R', -CO-OR, and -NHR, wherein R' is H or Ci _-g alkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_ i ₂ alkyl, -(C=0), -OR', -COR', and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; wherein

221 229 222

Y is selected from a sing le bond, -0-, -N(R )-, or -S-; is selected from a single bond, - 0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-N(R ²³⁰ )-, or -S-; L ²²² is a single bond, C ₆ -i ₀ arylene, or -(C=0)-; t is an integer selected from 1, 2, 3, or 4; R 226 is hydrogen or R 229 is hydrogen or Ci_

₆ alkyl; R 230 is hydrogen or Q 221 is hydrogen or is a single bond connected to X 1 ; Q 222

1 221 222 is hydrogen or is a single bond connected to X ; wherein at least one of Q ^{^1} and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or

O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci.galkyl, 225

C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci.galkyl, nitroso, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci.galkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond,

229 222 229

-0-, -NR -, or -S-; Y is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or Q 221 is hydrogen or is a single bond connected to X ¹ ; Q ²²² is hydrogen or is a single bond connected to X ¹ ; wherein at least one of

221 222 1

Q and Q is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X 221 is selected from N or NR 221 ; X 222 is selected from N or NR 221 ; X ²²³ is selected from N or NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X 221 is selected from N or NH; X 222 is selected from N or NH; X 223 is selected from N or NH; X ²²⁴ is selected from N or NH; X ²²⁵ is NH, and R ²²² , R ²²⁶ , L ²²⁰ , L ²²² ,

221 222 221 222 3

Y , Y , Q , and t have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein R ²²² is selected from the group consisting of -NHR 225 , hydrogen, Ci_i ₂ alkyl, -OR 225 , preferably - NHR ¹²⁵ , or -OR ²²⁵ , wherein R ²²⁵ is selected from hydrogen, halo, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ _ 1 ₂ alkynyl, -OR', -COR', -COOR, or -NHR', wherein R' is H or Ci_ ₈ alkyl, and X ²²¹ , X ²²² , X ²²³ , X ²²⁴ , X ²²⁵ , R ²²⁶ , L ²²⁰ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XIIc, as taught herein, wherein Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² , and m have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb, or XIIc,

221 229 222 as taught herein, wherein Y is selected from a single bond, -0-, -NR -, or -S-; Y is selected from a single bond, -0-, -NR 229 -, or -S-; m is an integer selected from 1, 2, or 3; R 229 is hydrogen or Q 221 is hydrogen or is a single bond connected to X 1 ; Q 222 is hydrogen or

1 221 222

is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, Xllb,

221 222 1 or XIIc, as taught herein, wherein Q is hydrogen and Q is a single bond connected to X ; preferably X ³ is a folate moiety having the structural Formula XII d, as taught herein, wherein

Q ²²² is a single bond connected to X ¹ ;

R ²⁰ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, wherein R ¹² is selected from hydrogen or

R ³ is -OR ³¹ or -X ² -X ¹ -X ³ , wherein

R ³¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, carboxylCi.

₆ alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

R ⁴ is -OR ⁴¹ or -X ² -X ¹ -X ³ , wherein

R ⁴¹ is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of Ci_ ₂₅ alkyl, Ci_ ₂₅ alkylcarbonyl, C ₂ . ₂₅ alkenylcarbonyl, carboxylCi. 6alkylenecarbonyl, carboxylC ₆ _i ₂ arylenecarbonyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3. 6cycloalkyl, and C6_ioaryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C _h alky 1, or wherein R ¹² is selected from hydrogen or

X ² , X ¹ , and X ³ have the same meaning as that defined herein;

wherein at least one of Y ² , R ³ , or R ⁴ is -X^X'-X ³ .

In certain embodiments, the FR-targeting excipient may be a folate-polysaccharide conjugate comprising at least one unit of Formula Xlc, Xlh, Xlj, Xlk, Xln, Xlp, or Xlq, as taught herein, or any subgroup thereof, wherein

Y ² is -X^X'-X ³ , or -OR ²⁰ , wherein

X ² is -0-;

X ¹ is a single bond or a linker of Formula X, as taught herein, wherein the left side of the linker of Formula X is attached to X ² and the right side thereof is attached to X ³ ; wherein

A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-

L -, and -CO-L -CO-N(R )-, wherein the right side of each group is attached to L and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl, R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO- N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ , L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or Ci_ 3alkyl; preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO-L ¹⁶ -CO-N(R ¹⁶ )-L ¹⁷ -, and -CO-L ¹⁸ -CO-N(R ¹⁷ )-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is methylene, ethylene, ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently methylene or ethylene; R ¹⁶ and R ¹⁷ are each independently selected from hydrogen or preferably A ¹ is selected from a group consisting of -CO-L ¹⁴ -0-, -CO-L ¹⁵ -CO-0-, -CO- L ¹⁶ -CO-NH-L ¹⁷ -, and -CO-L ¹⁸ -CO-NH-, wherein the right side of each group is attached to L ¹ and the left side thereof is attached to X ² , wherein L ¹⁴ is ^-propylene; L ¹⁵ , L ¹⁶ , L ¹⁷ , and L ¹⁸ are each independently ethylene;

L ¹ is selected from a polyethylene oxide (PEO), a polypropylene oxide (PPO), or a block copolymer of PEO and PPO; preferably L ¹ is a polyethylene oxide having the Formula - (CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 20 to 120; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ - CH ₂ ) _q -, wherein q is an integer selected from 40 to 110; preferably L ¹ is a polyethylene oxide having the Formula -(CH ₂ -CH ₂ -0) _q - or -(0-CH ₂ -CH ₂ ) _q -, wherein q is an integer selected from 60 to 90;

A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -0-, -L ¹⁹ -N(R ¹⁹ )-, or - L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ andL ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl, Ci_ ₄ alkyl, and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or Ci_ ₄ alkyl; preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )- , -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is attached to L ¹ and the right side thereof is attached to X ³ , wherein L ¹⁹ and L ²⁰ are each independently being optionally substituted with one or more substituents selected from a group consisting of hydroxyl and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(R ¹⁸ )-, -L ¹⁹ -N(R ¹⁹ )-, or -L ²⁰ O-, wherein the left side of each group is

1 3 19 20 attached to L and the right side thereof is attached to X , wherein L and L are each independently methylene or ethylene; R ¹⁸ and R ¹⁹ are each independently selected from hydrogen or preferably A ² is a single bond or is selected from a group consisting of -N(H)-, -L ¹⁹ -N(H)-, or -L ²⁰ O-, wherein the left side of each group is

1 3 19 20 attached to L and the right side thereof is attached to X , wherein L and L are each independently ethylene;

is a folate moiety having the structural Formula Xlla, as taught herein, wherein X 221 , X 222 ' X 223 , X ²²⁴ , X ²²⁵ , R ²²² , R ²²⁶ , L ²²² , Y ²²¹ , Y ²²² , Q ²²¹ , Q ²²² and t have the same meaning as that defined herein above; preferably X ³ is a folate moiety having the structural Formula XII or Xlla, as taught herein, wherein X ²²¹ is selected from N, or NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR 224 or O; R 221 is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²² is selected from the group consisting of -N(H)R 225 , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ _i ₂ alkenyl, C ₂ _i ₂ alkynyl, -OR 225 , -CO-R ¹²⁵ , -CO-O-R ²²⁵ , and -CO-N(H)R ²²⁵ , wherein R ²²⁵ is selected from the group consisting of hydrogen, halo, Ci.galkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R is H or Ci.galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), -OR', -COR', and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -(C=0), -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; wherein Y ²²¹ is selected from a single bond, -0-, -N(R ²²⁹ )-, or -S-; Y ²²² is selected from a single bond, -0-, -N(R ²²⁹ )-, -N(R ²²⁹ )-C(=NH)-

230 222

N(R )-, or -S-; L is a single bond, C6_ioarylene, or -(C=0)-; t is an integer selected from 1, 2,

3, or 4; R 226 is hydrogen or R 229 is hydrogen or R 230 is hydrogen or Ci_ 221 1 222

₆ alkyl; Q is hydrogen or is a single bond connected to X ; Q is hydrogen or is a single bond

1 221 222 1 connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula Xllb, as taught herein, wherein X ²²¹ , X ²²² ' X ²²³ , X ²²⁴ , X ²²⁵ , R ²²² , Y ²²¹ ,

222 221 222 3 Υ ^ΔΔ Q , and m have the same meaning as that defined herein above; preferably X is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N, NR ²²¹ , or O; X ²²² is selected from N, NR ²²¹ , or O; X ²²³ is selected from N, NR ²²³ , or O; X ²²⁴ is selected from N, NR ²²⁴ or O; X ²²⁵ is selected from NR ²²⁴ or O; R ²²¹ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -OR', -COR, and halosubstituted -COR', wherein R' is H or Ci.galkyl; R ²²² is selected from the group consisting of

-N(H)R ²²⁵ , hydrogen, halogen, Ci_i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -OR ²²⁵ , -CO-R ¹²⁵ , -CO-O-

R 225 , and -CO-N(H)R 225 , wherein R 225 is selected from the group consisting of hydrogen, halo, Ci_i ₂ alkyl, C _{2 2} alkenyl, C _{2 2} alkynyl, -OR', -CO-R', -CO-OR', and -NHR', wherein R' is H or Ci_ galkyl; R ²²³ is selected from hydrogen, or a group consisting of Ci_i ₂ alkyl, nitroso, -(C=0), - OR', -COR, and halosubstituted -COR, wherein R' is H or Ci_ ₈ alkyl; R ²²⁴ is selected from hydrogen, or a group consisting of nitroso, Ci_i ₂ alkyl, -(C=0), -OR', -COR, and halosubstituted

-COR', wherein R is H or Ci.galkyl; wherein Y 221 is selected from a single bond, -0-, -NR 229 - or

222 229

-S-; Y is selected from a single bond, -0-, -NR -, or -S-; m is an integer selected from 1, 2, or 3; is

1 221 222 hydrogen or is a single bond connected to X ; wherein at least one of Q" ¹ and is a single bond connected to X ¹ ; the dotted bond represents a single bond or a double bond; preferably X ³ is a folate moiety having the structural Formula XII, Xlla, or Xllb, as taught herein, wherein X ²²¹ is selected from N or NR ²²¹ ; X ²²² is selected from N or NR ²²¹ ; X ²²³ is selected from N or

NR ²²³ ; X ²²⁴ is selected from N or NR ²²⁴ ; X ²²⁵ is NR ²²⁴ , and R ²²¹ , R ²²² , R ²²³ , R ²²⁴ , R ²²⁶ , L ²²⁰ , L ²²² ,