FIELD OF THE INVENTION

The present invention relates generally to amphiphilic diblock and/or triblock copolymers and/or star-shaped block copolymers of biodegradable materials (e.g., PEG-Jb-PCL and PEG-a- PCL) as drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same. More particularly, the present invention provides poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.

BACKGROUND OF THE INVENTION

Block copolymers, which comprise hydrophilic and hydrophobic polymers covalently bound to one another are by definition amphiphilic polymers. Above a certain concentration, called the critical micellar concentration (CMC) or critical aggregation concentration (CAC), block copolymers can self-assemble to form supramolecular aggregates (micelles or nanoparticles) in aqueous medium. The micelles consist of two distinct regions: an interior region of hydrophobic polymer chains (the core region), which has the ability to solubilize hydrophobic molecules; and an outer region of well-solvated hydrophilic polymer chains (the shell region), which imparts colloidal stability. Block copolymers can be designed to exhibit low CAC (few milligrams per liter) and high thermodynamic stability, compared to low molecular weight surfactants. Generally, the size of block copolymer micelles is of the order of 10-40 nanometers. (See, Reiss, G., et. a!., Block Copolymers, In Encyclopedia of Polymer Science and Engineering; Korschwitz, J. I. Ed.; Wiley-lnterscience, New York, NY (1985)). Due to these properties, block copolymer micelles comprising hydrophilic-biocompatible and hydrophobic biodegradable segments have attracted considerable attention related to their use as nanosized carriers of poorly water-soluble drugs. These micelles can facilitate the solubilization of poorly water-soluble drugs, increase their circulation time in vivo and eventually target them passively or actively by means of targeting ligands to specific tissues (e.g., tumoral tissues). (See, Kataoka, K., et al., Adv. Drug Deliv. Rev., 47:113-131 (2001); Torchilin, V. P., J. Controlled Rel., 73:137-172 (2001); and Jones, M. C., and Leroux, J. C., Eur. J. Pharm. Biopharm., 48:101-111 (1999)). Block copolymers having a variety of architectures, e.g., A-B, A-B-A, and star-shaped block copolymers are known in the art. Among A-B type diblock copolymers, monomethoxy poly(ethylene glycol)-block-poly(D,L-lact- ide) (MPEG-b-PDLLA) (Yasugi, K., etal., J. Controlled Rel., 62:89-100 (1999)); monomethoxy poly(ethylene glycol)-block-poly(£-caprolactone) (MPEG- b-PCL) (See, Shin, I. G., et aL, J. Controlled Rel., 51:1-11 (1998)) and monomethoxy poly(ethylene glycol)-bloc k-poly^-benzyl L-aspartate) (MPEG-b-PBLA) (See, Yokoyama, M et ai, J. Controlled Rel., 11:269-278 (1990)) have been studied for micellar drug delivery. MPEG- b-PDLLA has been synthesized by ring opening polymerization of D,L-lactide initiated either with potassium monomethoxy poly(ethylene glyco)late at 25 °C in tetrahydrofuran (THF) (See, Jeong, B., etal., Nature, 388:860-862 (1997)) or with MPEG at 110 to 150 °C in the bulk. (Kim, S. Y., et al., J. Controlled Rel., 56:197-208 (1998)). Similarly, MPEG-b-PCL has also been synthesized by ring opening polymerization of e-caprolactone initiated with potassium MPEG alcoholate in THF at 25 °C (See, Deng, X. M. et al., J. Polym. Sci. Polym. Chem. Ed., 35:703- 708 (1997)) or with MPEG at 140 to 180 °C in the bulk (See, Cerrai, P., et al., Polymer, 30:338- 343 (1989)). MPEG-b-PBLA was synthesized by polymerization of N-carboxyanhydride of aspartic acid initiated with MPEG amine, in a solvent at 25 °C. (See, Yokoyama, M., et ai, Makromol. Chem. Rapid Commun., 8:431-435 (1987)).

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings and figures herein further illustrate, but do not limit, some embodiments of invention as follows:

FIG. 1A shows molecular weights (MW) of exemplary mPEG-OH and mPEG-Jb-PCL. The MW was calibrated using polystyrene standards. FIG. 1B shows an exemplary ¹ H NMR spectrum of mPEG-b-PCL, mPEG-OH, and e-caprolactone.

FIG. 2 shows an exemplary GPC profile of mPEG-b-PCL and mPEG-OH.

FIG. 3 shows exemplary UV-visible spectrum and calibration curves of PTX in MeCN; Panel A) absorption spectrum of PTX in MeCN at different concentrations; and Panel B) calibration curve of PTX.

FIG. 4 describes exemplary schemes for preparing PTX-loaded micelles, wherein: Panel A) provides a pictorial representation of a scheme for PTX-loaded micelle preparation; and Panel B) provides mixing conditions of reagents for PTX-loaded micelles in one embodiment.

FIG. 5 shows an exemplary absorption spectrum of PTX loaded micelle and mPEG-Jb- PCL in MeCN. FIG. 6 shows size analyses of representative PTX loaded micelles, wherien: Panel A) shows a DLS spectrum of PTX loaded micelle; and Panel B) shows a TEM image of PTX loaded micelles. The micelles are about 20 to 30 nm in diameter.

FIG. 7 shows an exemplary ¹ H NMR spectrum of alkyne-PCL and e-caprolactone.

SUMMARY OF THE INVENTION

The present invention relates generally to amphiphilic diblock and/or triblock copolymers and/or star-shaped block copolymers of biodegradable materials (e.g., PEG-Jb-PCL and PEG-a- PCL) as drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same. More particularly, the present invention provides poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.

The polymeric block copolymers of the present invention, upon association (e.g., attachment thereto) of one or more active drug substances (or prodrug substances) are useful delivery platforms and carriers for administering compounds of interest to a subject. In various embodiments, the drug substances are typically intended to provide a therapeutic benefit to the subject.

Thus, in certain preferred embodiments, the present invention relates to polymeric block copolymers based drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same. More particularly, the present invention provides polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) based drug delivery platforms comprising one or more copolymers with controlled molecular weights and/or polydispersities as well as selective methods for associating one or more drug substances to the copolymer.

In preferred embodiments, the drug delivery platforms are polymer compounds that are substantially biocompatible, biodegradable, and hydrophilic, or alternatively, substantially hydrophobic or hydrophilic. In particularly preferred embodiments, the drug delivery platforms comprise copolymer compounds comprising hybrid polymers having a main chain containing nitrogen and phosphorous linked through a plurality of interchangeable C-C single and double bonds and optionally further comprising one or more types of advantageous side-chains. Suitable hybrid polymers compounds are preferentially, though not exclusively, found in the broad class of methoxy poly(ethylene glycol)-block-poly(£-caprolactone) polymers (e.g., PEG-Jb- PCL and PEG-a-PCL) formulated as nanoshperes, microspheres, micelles, films, or hydrogels. The polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) compounds of the present invention are subsequently, or concomitantly with production, derivitized (e.g., loaded) with one or more active drug substances (or prodrug) substances. Suitable therapeutic agents including drugs and drug substances including, but not limited to, one or more anticancer agents (e.g., chemotherapeutic agent(s), hormone therapies, targeted cancer drugs, bisphosphonates, anticancer and/or anti-tumorigenic agents, anti-proliferative agents, antiangiogenic agents, anti metastatic agents, neoadjuvant therapies and agents, and immunological therapies (e.g., “checkpoint inhibitor” agents)).

In still other embodiments, suitable hybrid polymers compounds are preferentially, though not exclusively, found in the broad class of methoxy poly(ethylene glycol)-block-poly(£- caprolactone) (“mPEG-b-PCL” or “mPEG-PCL”) compounds that are subsequently derivitized with one or more drug substances (pharmacologically active or prodrug) such as one or more anticancer agents or drugs. In preferred embodiments, the concentration, loading characteristics, adsorption, absorption, or otherwise the chemical association (e.g., covalent, ionic bonding and the like) of the agent(s) to the drug carrier is analyzed by ¹ H NMR, HPLC, GC, MS, GC-MS, and/or immunological techniques.

Preferred drug loading ratios of therapeutic agent (e.g., chemotherapeutic agent) to polymeric block copolymer drug carrier(s) is from about % to about 20%, and more preferably, from about 5% to about 10% drug/copolymer ratio (w/w).

Aqueous solubility in preferred compositions ranges range from about 1 to about 10%, and when Paclitaxel (“PTX”) is the agent being delivered, the aqueous solubility is from about 1% to about 6%, and more preferably, from about 3% to about 4%.

In another embodiment, one or more targeting moieties (e.g. folic acid, sugars, and antibodies, and the like) can be conjugated to chemical active moieties or functional groups on the drug carrier(s) such as pendant functional groups in diblock, triblock, and star block copolymers. For example, at least one targeting moiety may be conjugated to a pendant functional groups in a vinyl polymer segment, said targeting moiety being at least one member selected from the group consisting of vitamins, sugars, lectins, antibodies and antibody fragments, peptides, receptors, ligands, and combinations thereof. In other embodiments, the compositions provide one or more targeting comprising folic acid, sugars, and antibodies, and the like.

In preferred embodiments, the drug delivery systems when loaded with one or more drugs or therapeutic agents are optionally freeze dried, lyophilized, or otherwise stabilized to enhance storage and logistic considerations and/or safety and efficacy considerations upon administration. In some of these embodiments, one or more cryoprotectants are optionally added to the freeze dried and/or lyophilized products. Suitable cryoprotectants include, but are not limited to, polysaccharides (sugars and sugar alcohols) (e.g., Arabinose, Ribose, Ribulose, Xylose, Xylulose, Lyxose, Allose, Altrose, Fructose, Galactose, Glucose, Gulose, Idose, Mannose, Sorbose, Talose, Tagatose, Sedoheptulose, Mannoheptulose, Sucrose, Maltose, Trehalose, Lactose, Mellibiose, Amylaose, and Mannan and the like). (See e.g., Lee, M.K., “Cryoprotectants for freeze drying of drug nano-suspensions: effect of freezing rate,” J. Pharm. Sci. , 98(12) pp. 4808-4817, 2009). The present invention contemplates, the use of one or more sugar cryoprotectants, and more preferably, the use of sucrose, to stabilize the drug delivery systems during freeze drying and/or lyophilization processing. Percentages of the cryoprotectants in particular drug delivery systems range from about 0.001% to about 10% or more, from about 0.01% to about 10% or more, from about 0.1% to about 10% or more, from about 0.001% to about 5% or more, from about 0.01% to about 5% or more, from about 0.1% to about 5% or more, from about 0.5% to about 5% or more, from about 0.5% to about 10% or more, from about 1% to about 10% or more, from about 2% to about 8% or more, from about 3% to about 7% or more, and from 4% to about 6% or more, and about 5%.

In further embodiments, the drug delivery systems and compositions of the present invention further comprise one or more excipients, for example, pharmaceutically, or physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the composition. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human.

Certain methods of the present invention provide readily scalable production schemes for producing polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) based drug delivery platforms with enhanced efficiency.

Still other embodiments of the present invention provide production schemes for producing polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) based drug delivery platforms at scale while maintaining current Good Laboratory Practice (“cGLP”), and/or current Good Manufacturing Practice (“cGMP”) standards, related to experimental and non-clinical trial materials, compared to clinical trial materials, respectively.

Preferred embodiments of the instant compositions provide drug carrier compositions (e.g., nanospheres) that range in size from about 10 nm to about 100 nm, and preferably, having a mean of about 50 nm. Methods are provided herein for producing drug carrier compositions (e.g., nanospheres) with a mean particle size of about 50 nm, as measured, for example by Dynamic Light Scattering (DLS) techniques. Standard techniques can be used to concentration and/or filter nanospheres.

DESCRIPTION OF THE INVENTION

The present invention relates generally to amphiphilic diblock and/or triblock copolymers and/or star-shaped block copolymers of biodegradable materials (e.g., PEG-Jb-PCL and PEG-a- PCL) as drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same. More particularly, the present invention provides poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.

This invention is disclosed in the following description, and is illustrated in the working examples. The working examples are merely illustrative of selected specific embodiments of the invention, and are not intended to be construed to limit its scope. Given the disclosure, one of ordinary skill in the art can routinely modify the processes as necessary or desired.

DEFINITIONS

The terms “drug,” “drug substance,” “active drug substance,” or “biological agent,” as used herein, refer to organic and/or inorganic molecules including, but not limited to, small molecule drugs, proteins, polysaccharides, nucleoproteins, lipoproteins, synthetic polypeptides, small molecules linked to a protein(s), saccharides, oligosaccharides, carbohydrates, glycoploymers, glycoproteins, steroids, nucleic acids, nucleotides, nucleosides, oligonucleotides (including antisense oligonucleotides), cDNA, nucleic acids, vitamins, including, but not limited to, vitamin C and vitamin E, lipids, or combination and portions thereof, that causes a biological effect when administered in vivo to an animal such as mammal and in particular, a human. As used herein, these terms more particularly in certain embodiments, further refer to any substance used internally or externally in an animal (e.g., a human) as medicaments, medicines, or prophylactics (i.e., vaccines and immunological active compositions) for the treatment, cure, or prevention of a disease, disorder, or medical condition, including, but not limited to, antifungal, agents (e.g., Fluconazole and Voriconazole), antiepileptic drugs (e.g., Rufinamide and Topiramate), immunosuppressants, antioxidants, anesthetics, chemotherapeutic agents, steroids (e.g., retinoids, hormones and the like), antibiotics, antivirals, antiproliferatives, antihistamines and allergy treatments (e.g., Triamcinolone acetonide), anticoagulants, antiphotoaging agents, biological agents (e.g., nucleotides, oliogonucleotides, polynucleotides, and nucleic acid sequences (e.g., DNAs and/or RNAs, and derivatives thereof), amino acids, oligopeptides, polypeptides, and proteins (e.g., therapeutic peptides and proteins, and antibodies and fragments and derivatives thereof, and the like), bisphosphonates, melanotropic peptides, nonsteroidal and steroidal anti-inflammatory compounds, and targeted cancer drugs. In preferred embodiments, the drug delivery systems of the present invention are formulated and/or optimized to carry and deliver (e.g., release over time) one or more chemotherapeutic agents. In other embodiments, suitable chemotherapeutic agents include, but are not limited to, small molecule chemotherapeutic drugs and anticancer and/or anti- tumorigenic agents, antiproliferative agents, antiangiogenic agents, anti-metastatic agents, neoadjuvant therapies and agents, immunological therapies (e.g., “checkpoint inhibitor” agents)).

The term “aliphatic,” as used herein, refers to a hydrocarbon, typically of Ci , to C20, that can contain one or a combination of alkyl, alkenyl, or alkynyl moieties, and which can be straight, branched, or cyclic, or a combination thereof. A lower aliphatic group is typically from Ci to C5·

The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, preferably of Ci to C20, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. (“Protective Groups in Organic Synthesis,” John Wiley and Sons, Second Edition, 1991). The term “lower alkyl,” as used herein, refers to an alkyl group of Ci to C5. The term “alkylamino” or “arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively.

The term “protected,” as used herein, and unless otherwise defined, refers to a group that is added to an oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

The term “amino acid,” as used herein, refers to a natural or synthetic amino acid, and includes, but is not limited to alanyl, valinyl, leucinyl, isoleucinyl prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl. The term “amino acid ester” refers to the aliphatic, aryl or heteroaromatic carboxylic acid ester of a natural or synthetic amino acid.

The term “aryl,” as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, etal., "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991.

As used herein, the term “halo” includes chloro, bromo, iodo, and fluoro.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to an aromatic moiety that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring. Non-limiting examples are furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbozolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N ⁶ -alkylpurines, N ⁶ - acylpurines (wherein acyl is C(O) (alkyl, aryl, alkaryl, or aralkyl)), N ⁶ -benzylpurine, N ⁶ - halopurine, N ⁶ -vinylpurine, N ⁶ -acetylenic purine, N ⁶ -acyl purine, N ⁶ -hydroxyalkyl purine, N ⁶ - thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrimidine, uracil, N ⁵ - alkylpyrimidines, N ⁵ -benzylpyrimidines, N ⁵ -halopyrimidines, N ⁵ -vinylpyrimidine, N ⁵ -acetylenic pyrimidine, N ⁵ -acyl pyrimidine, N ⁵ -hydroxyalkyl purine, and N ⁵ -thioalkyl purine, and isoxazolyl. Functional oxygen and nitrogen groups on the heterocyclic base can be protected as necessary or desired during the reaction sequence. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl, alkyl groups, acyl groups such as acetyl and propionyl, methylsulfonyl, and p-toluylsulfonyl.

The terms “alkylheterocyclic” or “alkylheteroaromatic” refer to a moiety in which the alkyl group is covalently attached to the heteroaromatic, is preferably Ci, to C4 alkylheteroaromatic, and more preferably CH2 -heteroaromatic.

The term “aralkyl,” as used herein, refers to an aryl group with an alkyl substituent.

The term “alkoxy,” as used herein, and unless otherwise specified, refers to a moiety of the structure -O-alkyl.

The term “alkynyl,” as referred to herein, refers to a C2 to C10 straight or branched hydrocarbon with at least one triple bond.

The term “protected-oxy” refers to an oxygen atom that has been protected from undesired reactions with any of the oxygen protecting group known to those skilled in the art, including but not limited to, for example, a trisubstituted silyl group such as trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl group, acyl groups such as acetyl, propionyl, benzoyl, P-NO2 benzoyl, toluyl, methylsulfonyl, or p-toluylsulfonyl.

As used herein, the term “heteroalkyl” refers to an alkyl group that includes a heteroatom such as oxygen, sulfur, or nitrogen (with valence completed by hydrogen or oxygen) in the carbon chain or terminating the carbon chain. Examples of these compounds include a series of lower alkyls interrupted by a heteroatom such as oxygen, sulfur or nitrogen, including -O- [(alkyl)0] _x -CH ₂ )NH ₂ , wherein the alkyl group can vary within the moiety, including -0-[(CH ₂ ) _x 0] _y -CH ₂ ) _x NH ₂ ; -0-[(CH ₂ ) _x 0] _y CH ₂ ) _x NH(CH ₂ ) _x S0 ₃ H, and -0-[(alkyl)-0] _y -(alkyl), wherein the alkyl group can vary within the moiety, including -0-[(CH ₂ ) _x 0] _y -(alkyl), wherein x is 1-8 (which can vary within the moiety) and y is an integer of 1 to 40. Specific examples of these compounds include (methoxyethoxy)ethoxy, ethoxyethoxy and methoxyethoxy. The heteroalkyl groups can also be halogenated such as -OCH2 CF ₃ and the like.

The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” In this document, the term “or” is used to refer to a nonexclusive or, such that “A or B” includes “A but not B,” “B but not A,” and “A and B,” unless otherwise indicated. In the appended claims, the terms “including” and “in which” are used as the plain-English equivalents of the respective terms “comprising” and “wherein.” Also, in the following claims, the terms “including” and “comprising” are open-ended; that is, a composition, article, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms “first,” “second,” and “third,” and so forth are used merely as labels, and are not intended to impose numerical requirements on their objects.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value within the range is incorporated into the specification as if it were individually recited herein.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Unless otherwise defined herein, technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. In this application, the use of “or” means “and/or” unless stated otherwise.

Although the embodiments of the present invention have been described with reference to specific example embodiments, it will be evident that various modifications and changes may be made to these embodiments without departing from the broader scope of the inventive subject matter. Accordingly, the specification and Figures are to be regarded in an illustrative rather than a restrictive sense. The accompanying Figures that form a part hereof, show by way of illustration, and not of limitation, specific embodiments in which the subject matter may be practiced. The embodiments illustrated are described in sufficient detail to enable those skilled in the art to practice the teachings disclosed herein. Other embodiments may be used and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. This Description, therefore, is not to be taken in a limiting sense, and the scope of various embodiments is defined only by the appended claims, along with the full range of equivalents to which such claims are entitled.

Such embodiments of the inventive subject matter may be referred to herein, individually and/or collectively, by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept if more than one is in fact disclosed. Thus, although specific embodiments have been illustrated and described herein, it should be appreciated that any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

That the present invention may be more readily understood, select terms are defined below.

Example 1

PTX-loaded poly( ethylene glycol)-b/oc/c-poly(£-caprolactone) (mPEG-b-PCL) copolymers

Materials

Monomethoxy poly(ethylene glycol) (mPEG-OH, M _n = 2000 g/mol), toluene, and e- caprolactone (e-CL, 97 %) were purchased form Sigma-Aldrich Co. (St. Louis, MO). Tin (II) 2- ethylhexanoate (Sn(Oct)2) was obtained from Alfa Aesar (Haverhill, MA, USA). Tetrahydrofuran (THF, HPLC grade) was obtained from Burdick & Jackson (Muskegon, Ml, USA). Methylene chloride (CH2CI2, 99.5 %), Acetonitrile (MeCN, 99.5 %) and diethyl ether (94.5%) were purchased from Samchun chemicals (Seoul, Korea). The monomer e-CLwas dried over calcium hydride and distilled under reduced pressure prior to use.

Characterizations

¹ H NMR spectra were recorded on a Bruker Avance 500 MHz FT-NMR in deuterated solvents. The chemical shifts are expressed in parts per million (ppm) and referenced to the solvent residual signals following previous report. (See, Fulmer, G. R., etal., “NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist,” Organometallics, 29: 2176-2179 (2010)). Gel permeation chromatography (GPC) profile was obtained on a Waters Alliance e2695 GPC system, equipped with Styragel column set (HR1, HR2, and HR4) and 2414 refractometer. THF was used as the eluent at a flow rate of 1 mL/min. The molecular weights were calibrated using polystyrene standards. (FIG. 1A). The dynamic light scattering (DLS) measurements were performed using a Zetasizer Nano S90 system (Malvern Instruments, Worcestershire, U.K.). (FIG. 6, Panel A). UV-Visible spectra were acquired by using UV 2550 spectrophotometer (Shimadzu, Japan). (FIG. 3).

Synthesis of monomethoxy poly( ethylene glycol)-b/oc/c-poly(£-caprolactone) (mPEG-b- PCL) copolymer mPEG-Jb-PCL was synthesized by ring-opening polymerization of e-CL using mPEG-OH as an initiator and Sn(Oct)2 as a catalyst (Scheme 1) according to G. Saravanakumar et al. (Saravanakumar, G., etal., “Miktoarm Amphiphilic Block Copolymer with Singlet Oxygen-Labile Stereospecific b-Aminoacrylate Junction: Synthesis, Self-Assembly, and Photodynamically Triggered Drug Release,” Biomacromolecules, 19:2202-2213 (2018)).

Scheme 1

Synthetic scheme of mPEG-b-PCL

Briefly, mPEG-OH (2 g), e-CL (2.283 g) and Sn(Oct)2 (0.081 g) and 10 L of toluene were charged into a flame-dried Schlenk flask equipped with a magnetic stirring bar under dry nitrogen. After deoxygenating the solution by nitrogen purging, polymerization was carried out in a heated oil bath at 110 °C for 24 h. After cooling to room temperature, the polymer was precipitated in excess diethyl ether. The precipitated polymer was redissolved in CH2CI2 and re precipitated in diethylether. The purified polymer was filtered and dried under vacuum at 30 °C. ¹ H NMR (500 MHz, CDC ): d 4.24 (-CH ₂ -COO-); 4.08 (-COO-CH2- of PCL), 3.40 (-OCH ₃ of PEG), 3.52-3.80 (-CH2CH2O- of PEG), 2.33 (-CH2-COO- of PCL), 1.68(-COOCH ₂ CH ₂ - of PCL), 1.40 (-CH ₂ - of PCL). (FIG. 1B). Preparation of drug-loaded mPEG-b-PCL micelle

Drug-loaded mPEG-Jb-PCL micelles were prepared by thin film hydration method according to G. Saravanakumar etal., 2018, supra. (FIG. 4, Panel A) 41 mg of mPEG-Jb-PCL and 3.2 mg of drug (Paclitaxel “PTX”) were dissolved in 3 ml_ THF in a 40 ml_ vial. After complete dissolution, THF was evaporated to form a thin film on the surface of vial. (FIG. 4, Panel A and Panel B). The film was then rehydrated with distilled water 30 ml_ with sonication. The non-encapsulated drugs were removed by dialysis and filtration through a syringe filter (0.45 pm). Finally, the drug-loaded micelles were freeze dried and stored at -20 °C. The loading contents and loading efficiency of PTX in the micelle were determined using UV-visible spectrophotometer at 227 nm. Drug loading contents (LC) (%) = mass of PTX in micelles / mas of micelles x 100 %, Drug loading efficiency (LE) (%) = actual loading contents / theoretical drug loading contents x 100. The LC of PTX in the micelle = 7.0 %. The LE of PTX in the micelle = 89 %. Example 2 pH-Responsive Drug Loaded Polymeric Micelles For Drug Delivery

This Example describes the preparation of drug loaded mPEG-a-PCL micelles using an acetal/ketal linker and thin film methodology.

Scheme 2

Synthetic scheme for production of acid-labile mPEG-a-PCL Materials

Monomethoxy poly(ethylene glycol) (mPEG-OH, M _n = 2000 g/mol and 5000 g/mol), toluene, e-caprolactone (e-CL, 97%), propargyl alcohol (99%), sodium azide (Nal h, 99.8%), Copper (I) bromide (CuBr, 98%), N,N,N',N",N"-pentamethyldiethylenetriamine (PMDETA, 99%) and pyridinium p-toluenesulfonate (PPTS, >99.0%) were purchased form Sigma-Aldrich Co.,

St. Louis, MO). Tin (II) 2-ethylhexanoate (Sn(Oct)2) was obtained from Alfa Aesar, Haverhill,

MA, Tetrahydrofuran (THF, HPLC grade) was obtained from Burdick & Jackson, Muskegon, Ml. Methylene chloride (CH2CI2, 99.5%), acetonitrile (MeCN, 99.5%), sodium carbonate (Na ₂ C0 ₃ , 99.0%), anhydrous sodium sulfate (Na ₂ S0 ₄ , 99.0%) and diethyl ether (94.5%) were purchased from Samchun Chemicals Co., Ltd., Seoul, Korea. 2-Chloroethyl vinyl ether (>97.0%) was obtained from Tokyo Chemical Industry CO., LTD. The monomer e-CL was dried over calcium hydride and distilled under reduced pressure prior to use.

Characterizations

¹ H NMR spectra were recorded on a Bruker Avance (Bruker, Inc., Billerica, MA, USA) 500 MHz FT-NMR in deuterated solvents. The chemical shifts are expressed in parts per million (ppm) and referenced to the solvent residual signals following the method of G.R. Fulmer et al., 2010, supra. Gel permeation chromatography (GPC) profile was obtained on a Waters Alliance e2695 GPC system equipped with STYRAGEL ^® column set (HR1, HR2, and HR4) and 2414 refractometer (Waters Corp., Milford, MA, USA). THF was used as the eluent at a flow rate of 1 mL/min. The molecular weights were calibrated using polystyrene standards. The dynamic light scattering (DLS) measurements were performed using a Zetasizer Nano S90 system (Malvern Instruments, Worcestershire, U.K.). UV-Visible spectra were acquired by using UV 2550 spectrophotometer from Shimadzu Corp. (Kyoto, Japan).

Synthesis of alkyne functionalized poly(£-caprolactone) (Alkyne-PCL)

Alkyne-PCL was synthesized by ring-opening polymerization of e-CL using propargyl alcohol as an initiator and Sn(Oct)2 as a catalyst using the methods described by G. Saravanakumar et al., and H. Wang etal. (See, Saravanakumar, G., et al., “Miktoarm Amphiphilic Block Copolymer with Singlet Oxygen-Labile Stereospecific b-Aminoacrylate Junction: Synthesis, Self-Assembly, and Photodynamically Triggered Drug Release,” Biomacromolecules, 19:2202-2213 (2018); and Wang, H., et al., “Biocompatible and acid- cleavable poly(£-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(E-caprolactone) triblock copolymers: synthesis, characterization and pH-triggered doxorubicin delivery,” J. Mater. Chem. B, 1:6596-6607 (2013)). Briefly, propargyl alcohol (23.2 pL, 0.4 mmol), e-CL (2 ml_, 17.5 mmol), Sn(Oct)2 (20 pl_, 0.06 mmol) and 9 ml_ of toluene were charged into a flame-dried Schlenk flask equipped with a magnetic stirring bar under dry nitrogen. After deoxygenating the solution by nitrogen purging, polymerization was carried out in a heated oil bath at 110 °C for 24 h. After cooling to room temperature, the polymer was precipitated in excess diethyl ether. The purified polymer was filtered and dried under vacuum at 30 °C. ¹ H NMR (500 MHz, CDC ): d 4.68 (- CHºC-); 4.07 (-COO-CH2- of PCL), 3.67 (-C-CH2-COO-), 2.32 (-CH2-COO- of PCL), 1.67(- COOCH2CH2- of PCL), 1.41 (-CH2- of PCL). (FIG. 7).

Synthesis of l\l ₃ -acetal-poly( ethylene glycol) (N ₃ -a-PEG)

N3-a-PEG was synthesized by following a previous synthetic method with modification. (See, Wang, H., et al., 2013, supra). First, acetal linker was conjugated to the chain end of mPEG-OH. In brief, dried mPEG-OH (2 g, 0.4 mmol, mPEG-OH of M _n = 5 g/mol), PPTS (20 mg. 0.08 mmol) and 20 mL of anhydrous CH2CI2 were charged into a flame-dried round- bottomed flask. Thereafter, 0.4 mL of 2-chloroethyl vinyl ether (4 mL, 4 mmol) was added dropwise into the flask at 0 °C with constant stirring. After stirring the solution for 1 h, 4 mL of 5 wt% Na ₂ C0 ₃ solution into the flask to quench the reaction. Subsequently, the compound was extracted by using CH2CI2. The organic phase was washed with brine solution and dried over anhydrous Na ₂ S0 ₄ before concentrating on rotary evaporator. The concentrated solution was dissolved in a small amount of CH2CI2 and precipitated in excess of cold hexane, then filtered and dried under vacuum at 30 °C for 24 h to afford chloroethyl vinyl ether functionalized polymer (CI-a-PEG). Subsequently, CI-a-PEG (1.5 g, 0.3 mmol), NaN3 (214 mg, 3 mmol) and anhydrous dimethylformamide (10 mL) were charged into 50 mL round flask. The solution was then heated in an oil bath at 60 °C with constant stirring for 24 h. Then, the dimethylformamide was evaporated and the residue was added with 20 mL of CH2CI2, and the excess Nal\l3 was removed by washing with water and brine solution. The combined organic phase was dried over anhydrous Na ₂ S0 ₄ . The solution was filtered, evaporated and subsequently precipitated in excess of diethyl ether to obtain I h-a-PEG, which was dried under vacuum at 30 °C for 24 h.

Synthesis of pH-responsive mPEG-a-PCL

The pH-responsive mPEG-a-PCL was synthesized by click chemistry between the synthesized alkyne-PCL and I h-a-PEG. In brief, N3-a-PEG (1 g, 0.2 mmol) and alkyne-PCL (780 mg, 0.2 mmol) were dissolved in 25 mL THF. Then, CuBr (28.8 mg, 0.2 mmol) and PMDETA (42 pL, 0.2 mmol) were added into the flask. This solution was then deoxygenated by nitrogen purging or three exhausting-refilling nitrogen cycles. After deoxygenation, the resulting solution was stirred at room temperature for 24 h under N ₂ . Subsequently, 50 ml_ of CH ₂ CI ₂ was added into the solution and the organic phase was pass through a basic AI ₂ O ₃ column for the removal of copper catalyst. After concentration under vacuum, the residue was precipitated in excess of diethyl ether. The product was filtered and dried under vacuum at 30 °C for 24 h to obtain mPEG-a-PCL.

Preparation of drug loaded mPEG-a-PCL micelle

Drug loaded mPEG-a-PCL micelles were prepared by a thin film hydration method described in G. Saravanakumar. (Saravanakumar, G., et al., 2018, supra). 41 mg of mPEG-a- PCL and 3.2 mg of drug (Paclitaxel) were dissolved in 3 ml_ THF in a 40 ml_ vial. After complete dissolution, THF was evaporated to form a thin film on the surface of vial. The film was then rehydrated with distilled water 30 mL with sonication. The non-encapsulated drugs were removed by dialysis and filtered through a syringe filter (0.45 pm). Finally, the drug-loaded micelles were freeze dried and stored at -20 °C. The loading contents and loading efficiency of PTX in the micelle were determined using UV-Visible spectrophotometer at 227 nm, by the following equation. Drug loading contents (LC) (%) = mass of PTX in micelles / mass of the micelles x 100%, Drug loading efficiency (LE) (%) = actual loading contents / theoretical drug loading contents x 100%.

Exemplary Therapeutic and Chemotherapeutic Agents

Preferred embodiments of the present polymeric drug carrier and delivery systems are formulated and optimized to delivery one or more anticancer or antitumor drug agents or substances such as, but not limited to: Abemaciclib, Abiraterone Acetate, Acalabrutinib, Adriamycin, Afatinib Dimaleate, Afinitor (Everolimus), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alimta (Pemetrexed Disodium), Aliqopa, (Copanlisib Hydrochloride), Aloxi (Palonosetron Hydrochloride), Alpelisib, Alunbrig (Brigatinib), Ameluz (Aminolevulinic Acid Hydrochloride), Amifostine, Aminolevulinic acid hydrochloride, Anastrozole, Apalutamide, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Asparaginase Erwinia Chrysanthemi, Asparlas, (Calaspargase Pegol-Mknl), Axicabtagene Ciloleucel, Axitinib, Azacitidine, Azedra (lobenguane I 131), Balversa (Erdafitinib), Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, Bendeka, (Bendamustine Hydrochloride), Bexarotene, Bicalutamide, Bicnu (Carmustine), Binimetinib, Bleomycin Sulfate, Bortezomib, Bosulif (Bosutinib), Bosutinib, Braftovi (Encorafenib), Brigatinib, Bumel, Busulfan, Cabazitaxel, Cabometyx (Cabozantinib-S-Malate), Cabozantinib-S-Malate, Calaspargase Pegol-Mknl, Calquence (Acalabrutinib), Camptosar (Irinotecan Hydrochloride), Capecitabine, Carboplatin, Carfilzomib, Carmustine, Casodex (Bicalutamide), Ceritinib, Cerubidine (Daunorubicin Hydrochloride), Chlorambucil, Cisplatin, Cladribine, Clofarabine, Clolar (Clofarabine), Cobimetinib, Cometriq, (Cabozantinib-S-Malate), Copanlisib Hydrochloride, Copiktra (Duvelisib), Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Crizotinib, Cyclophosphamide, Cytarabine, Dabrafenib Mesylate, Dacarbazine, Dacogen (Decitabine), Dacomitinib, Dactinomycin, Darolutamide, Dasatinib, Daunorubicin Hydrochloride, Daurismo (Glasdegib Maleate), Decitabine, Defibrotide Sodium, Defitelio (Defibrotide Sodium), Degarelix, Denileukin Diftitox, Dexamethasone, Dexrazoxane Hydrochloride, Doxorubicin Hydrochloride, Duvelisib, Eligard (Leuprolide Acetate), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Eloxatin (Oxaliplatin), Eltrombopag Olamine, Elzonris (Tagraxofusp-Erzs), Emend (Aprepitant), Enasidenib Mesylate, Encorafenib, Enzalutamide, Epirubicin Hydrochloride, Erdafitinib, Eribulin Mesylate, Erivedge (Vismodegib), Erleada (Apalutamide), Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia Chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Everolimus, Evista (Raloxifene Hydrochloride), Evomela (Melphalan Hydrochloride), Exemestane, Fareston (Toremifene), Farydak (Panobinostat), Faslodex (Fulvestrant), Fedratinib Hydrochloride, Femara (Letrozole), Filgrastim, Firmagon (Degarelix), Fludarabine Phosphate, Flutamide, Folotyn (Pralatrexate), Fostamatinib Disodium, Fulvestrant, Fusilev (Leucovorin Calcium), Gefitinib, Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Dimaleate), Gilteritinib Fumarate, Glasdegib Maleate, Gleevec (Imatinib Mesylate), Glucarpidase, Goserelin Acetate, Granisetron, Granisetron Hydrochloride, Granix (Filgrastim), Halaven (Eribulin Mesylate), Hemangeol (Propranolol Hydrochloride), Hycamtin (Topotecan Hydrochloride), Hydrea (Hydroxyurea), Hydroxyurea, Ibrance (Palbociclib), Ibrutinib, lclusig (Ponatinib Hydrochloride), Idamycin PFS (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Idhifa (Enasidenib Mesylate), Ifex (Ifosfamide), Ifosfamide, Imatinib Mesylate, Imbruvica (Ibrutinib), Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta (Axitinib), Inrebic (Fedratinib Hydrochloride), lobenguane I 131, Iressa (Gefitinib), Irinotecan Hydrochloride, Istodax (Romidepsin), Ivosidenib, Ixabepilone, Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), Jevtana (Cabazitaxel), Kepivance (Palifermin), Kisqali (Ribociclib), Kymriah (Tisagenlecleucel), Kyprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, Larotrectinib Sulfate, Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate, Levulan Kerastik (Aminolevulinic Acid Hydrochloride), Lomustine, Lonsurf (Trifluridine And Tipiracil Hydrochloride), Lorbrena (Lorlatinib), Lorlatinib, Lutathera (Lutetium Lu 177-Dotatate), Lutetium (Lu 177-Dotatate), Lynparza (Olaparib), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megestrol Acetate, Mekinist (Trametinib), Mektovi (Binimetinib), Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Methotrexate, Methylnaltrexone Bromide, Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, Mozobil (Plerixafor), Mustargen (Mechlorethamine Hydrochloride), Myleran (Busulfan), Navelbine, (Vinorelbine Tartrate), Nelarabine, Neratinib Maleate, Nerlynx (Neratinib Maleate), Neulasta, (Pegfilgrastim), Neupogen (Filgrastim), Nexavar (Sorafenib Tosylate), Nilandron (Nilutamide), Nilotinib, Nilutamide, Ninlaro (Ixazomib Citrate), Niraparib Tosylate Monohydrate, Nplate (Romiplostim), Nubeqa (Darolutamide), Odomzo (Sonidegib), Olaparib, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ondansetron Hydrochloride, Ontak (Denileukin Diftitox), Osimertinib Mesylate, Oxaliplatin, Paclitaxel (“PTX”) (Taxol), Palbociclib, Palifermin, Palonosetron Hydrochloride, Panobinostat, Pazopanib Hydrochloride, Pegaspargase, Pegfilgrastim, Pemetrexed Disodium, Piqray (Alpelisib), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib Hydrochloride, Pralatrexate, Prednisone, Procarbazine Hydrochloride, Proleukin (Aldesleukin), Promacta (Eltrombopag Olamine), Propranolol Hydrochloride, Provenge (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (Mercaptopurine), Radium 223 Dichloride, Raloxifene Hydrochloride, Rasburicase, Regorafenib, Relistor (Methylnaltrexone Bromide), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Ribociclib, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin (Daunorubicin Hydrochloride), Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Ruxolitinib Phosphate, Rydapt (Midostaurin), Sancuso (Granisetron), Selinexor, Sipuleucel-T, Sonidegib, Sorafenib Tosylate, Sprycel (Dasatinib), Stivarga (Regorafenib), Sunitinib Malate, Sustol (Granisetron), Sutent (Sunitinib Malate), Synribo (Omacetaxine Mepesuccinate), Tabloid (Thioguanine), Tafinlar (Dabrafenib Mesylate), Tagraxofusp-Erzs, Tagrisso (Osimertinib Mesylate), Talazoparib Tosylate, Talimogene Laherparepvec, Talzenna (Talazoparib Tosylate), Tamoxifen Citrate, Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib), Tavalisse (Fostamatinib Disodium), Temodar (Temozolomide), Temozolomide, Temsirolimus,

Thalidomide, Thalomid (Thalidomide), Thioguanine, Thiotepa, Tibsovo (Ivosidenib), Tisagenlecleucel, Topotecan Hydrochloride, Toremifene, Torisel (Temsirolimus), Totect (Dexrazoxane Hydrochloride), Trabectedin, Trametinib, Treanda (Bendamustine Hydrochloride), Trexall (Methotrexate), Trifluridine and Tipiracil Hydrochloride, Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Uridine Triacetate, Valrubicin, Valstar (Valrubicin), Vandetanib, Varubi (Rolapitant Hydrochloride), Veip, Velcade (Bortezomib), Vemurafenib, Venclexta (Venetoclax), Venetoclax, Verzenio (Abemaciclib), Vidaza (Azacitidine), Vinblastine Sulfate, Vincristine Sulfate, Vinorelbine Tartrate, Vismodegib, Vistogard (Uridine Triacetate), Vitrakvi (Larotrectinib Sulfate), Vizimpro (Dacomitinib), Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib Hydrochloride), Xalkori (Crizotinib), Xeloda (Capecitabine), Xofigo (Radium 223 Dichloride), Xospata (Gilteritinib Fumarate), Xpovio (Selinexor), Xtandi (Enzalutamide),

Yescarta (Axicabtagene Ciloleucel), Yondelis (Trabectedin), Zaltrap (Ziv-Aflibercept), Zarxio (Filgrastim), Zejula (Niraparib Tosylate Monohydrate), Zelboraf (Vemurafenib), Zinecard (Dexrazoxane Hydrochloride), Ziv-Aflibercept, Zofran (Ondansetron Hydrochloride), Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), and Zytiga (Abiraterone Acetate), and the like.

Various embodiments of the drug delivery compositions of the present invention are formulated and optimized for treating, ameliorating, or retarding the metastasis thereof regarding a particular type of tumor or cancer, or a tumor or cancer of a particular organ, tisues, or structure, including, but not limited to: Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS-Related Cancers (e.g., Kaposi Sarcoma (Soft Tissue Sarcoma), AIDS-Related Lymphomas, Anal Cancer, Appendix Cancer and Gastrointestinal Carcinoid Tumors, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma of the Skin, Bile Duct Cancer (e.g., Cholangiocarcinoma), Bladder Cancer, Bone Cancer (e.g., Ewing Sarcoma and Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumors, Breast Cancer (e.g., Ductal Carcinoma in situ), Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumors, Carcinoma of Unknown Primary, Cardiac Tumors, Central Nervous System Tumors, Medulloblastoma and other CNS Embryonal Tumors, Germ Cell Tumor, Primary CNS Lymphoma, Cervical Cancer, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Neoplasms, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma (e.g., Mycosis Fungoides and Sezary Syndrome), Embryonal Tumors (e.g., Medulloblastoma), Endometrial Cancer (Uterine Cancer), Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Eye Cancer (e.g., Intraocular Melanoma, Retinoblastoma), Fallopian Tube Cancer, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST) (Soft Tissue Sarcoma), Ovarian Germ Cell Tumors, Testicular Cancer, Gestational Trophoblastic Disease, Hairy Cell Leukemia, Laryngeal Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kidney (Renal Cell) Cancer, Langerhans Cell Histiocytosis, Lip and Oral Cavity and mouth Cancer, Liver Cancer, Non-Small Cell and Small Cell Lung Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Merkel Cell Carcinoma, Malignant Mesothelioma, Metastatic Cancer, Occult Primary Metastatic Squamous Neck Cancer, Midline Tract Carcinoma, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasms, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms,

Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Chronic Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer,

Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors, Papillomatosis, Paraganglioma, Parathyroid Cancer,

Penile Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Prostate Cancer, Rectal Cancer, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Ewing Sarcoma, Kaposi Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Uterine Sarcoma, Sezary Syndrome, Small Intestine Cancer, Squamous Cell Carcinoma of the Skin, Occult Primary Squamous Neck Cancer, T-Cell Lymphoma, Cutaneous (e.g., Mycosis Fungoides and Sezary Syndrome), Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Urethral Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Vascular Tumors, and Wilms Tumor, and the like.

Exemplary Formulation, Dosing, and Administration Methods

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of preparing pharmaceutical formulations as well as administration and dosing techniques which are well known in the art. Generally speaking, final administrable formulations of the drug delivery systems and compositions of the present invention may optionally be prepared by means standard in the art. A number of standard texts are known in the art regarding preparation and formulation considerations. (See e.g., Remington’s Pharmaceutical Sciences).

In certain embodiments, the drug delivery systems and compositions of the present disclosure are provided as sterile and, optionally, preservative-free formulations. In other embodiments the drug delivery systems and compositions are sterile, optionally preservative- free, and formulated in a single-use or unit-dose formats. In still further embodiments the sterile formulations contain one or more preservatives, stabilizers, sugars, or sugar alcohols. The methods and drug delivery systems and compositions of the present invention provide treatments for cancer and other proliferative diseases in a subject in order to confer a medicinal or therapeutic benefit in the subject by the administration of an effective dose of the one or more of compositions described herein. Methods of administering the compounds of the invention may be by metered dose or by one or more controlled release devices. The compositions may be in unit dosage forms suitable for single administration of precise dosages.

In some embodiments, the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,

14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In yet some other embodiments, the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%,

19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%,

16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%,

13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%,

10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,

6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In still some other embodiments, the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some other embodiments, the amount of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g,

0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g,

3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

Other embodiments provide, amounts of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, 1-3 g, or 1-10 g. The target dose may be administered in a single dose. Alternatively, the target dose may be administered in about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or more doses.

The administration schedule may be repeated according to any prescribed regimen, including any administration schedule described herein or known in the art. The one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention may be administered in one dose or multiple dosages. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the particular compositions used, the purpose of the use, the target cells or tissues being contacted, and the subject being treated. Single or multiple administrations (e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 50, more doses) over the course of from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 50, or more, minutes, hours, days, weeks, months, or even years.

In some particularly preferred embodiments, one dose of the composition is administered every 1-3, 1-7, 1-10, 1-12, 1-14, 1-28, 1-30, or more, days as prescribed by a physician or as otherwise deemed necessary for therapeutic benefit. Administration can be carried out with the dose level and pattern being selected by the treating physician. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimens is necessary for optimal therapy. Dosing for compositions of the present invention may be found by routine experimentation in light of the instant disclosure and one’s skill in the art.

Additionally, it is to be noted that, similar to the approaches described in the fields of medicinal and pharmaceutical chemistry, a suitable pharmaceutical preparation may also include, optionally, in addition to one or more compounds of the present invention, other agents, including, but not limited to, excipients, diluents, extenders, stabilizers, colors, flavors, formulating agents (e.g., gels and thickeners), antioxidants (e.g., ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, EDTA, phosphoric acid, sodium ascorbate, sodium metabisulfite, tartaric acid, tertiary butyl hydroquinone), preservatives, sterile aqueous solutions, buffers, sugars, and the like, as are generally known and accepted.

In other embodiments, one or more additional small molecule drug and/or biological agents may be preferentially combined in an admixture (or administered concomitantly) with the one or more active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention of the present invention to achieve a beneficial, or even synergistic, outcome in the subject. The compositions of the present invention can be formulated for delivery into the subject’s mouth ( e.g ., by ingestion, buccal and/or sublingual deposit). In other embodiments, the compositions are formulated for injection (e.g., intramuscular, intradermal, intrathecal, intraperitoneal, intra-arterial, and/or subcutaneous, and the like), infusion (e.g., intraosseous and/or intravenous, and the like), irrigation, instillation (e.g., dropwise instillation) and the like. In still further embodiments, are formulated for topical delivery. In certain cases, delivery of the desired formulation is aided by one or more mechanical device(s) such as microneedles and patches, syringes, pumps, catheters, ports, inhalant delivery devices, biolistic delivery devices, and the like. Modifications and variations of the present invention will be obvious to those skilled in the art from the foregoing description of the invention. Such modifications and variations are intended to come within the scope of the appended claims.

INCORPORATION BY REFERENCE All U.S. Patent Publications, U.S. Patent Applications, and U.S. Patents are hereby expressly and specifically incorporated by reference in their entireties, specifically, U.S. Patent Publication US2003/0181613.