This invention relates to polymeric coatings for nanoparticles, the use of polymer coated nanoparticles, and a process of preparing polymer coatings for nanoparticles.

Background

Polymeric coatings for nanoparticles are known in the art and have allowed nanoparticles to be used in numerous applications such as in the application of cosmetics, medical diagnostics and use in electronics. The polymeric coats are used to help improve solubility and functionalization of the nanoparticles. However, most nanoparticle coatings do not provide for stability and solubility in aqueous environments.

US 2014/0050671 teaches for poly (β-amino ester) polymers as coatings for nanoparticles. The nanoparticles exhibit superparamagnetism and find use as MRI contrasting agents, biocompatible and biodegradable. The core of the Iron oxide nanoparticles is tethered to the polymeric (β-amino ester) through covalently coupled anchoring groups, while therapeutic agents are further coupled to the polymer.

The synthesis and use of polymers comprising a terminal phosphonate group is described in US 2009/0123507, for example N-acylaminomethylene phosphonates according to the

following formula: The polymers are used coating of titanium, zirconium silicon, aluminium, and tin metal oxide nanoparticles which find application as antimicrobials in cosmetic and skin care preparations such as skin washing and cleansing products, skin emulsions and skin oils, shampoos, hair sprays deodorants, antiperspirants, and sunscreens.

WO 201 1/131681 (US 2013/0197628) teaches for (amphiphilic) copolymer modified inorganic nanoparticles produced by a process where the nanoparticles are ablated by laser radiation. The amphiphilic copolymers comprise a backbone where hydrophobic or fluorophilic pendant groups are alternated with a hydrophilic group. The laser modification of the nanoparticles allows for the formation non-covalent (absorptive) bonds between the nanoparticles and the pendant groups of the polymer coat due to formation of Lewis acceptor and Lewis donor interactions. The co-polymer modified nanoparticles provided dispersions in the form of gels which were especially useful in fields such as the textile industry, architectural industry, food technology industries and also in the coating of medical articles. copolymers of structure , and the use of these polymers in the coating of magnetic nanoparticles (Fe, Co, Ni and oxides thereof) through covalent binding of the polymer to the nanoparticle. The biocompatible nanoparticles are reportedly useful in medical imaging techniques.

US 201 1/0183140 describes methods for coating and functionalization of metal nano-rods with polymers. The gold nano-rods morph into spherical particles over time, which can be minimised by coating the rod with cetyltrimethylammonium bromide (CTAB). However, CTAB is cytotoxic and the cytotoxicity can be reduced by further coating the CTAB with a cross linked coating material.

US 2010/0027192 describes methods to improve and modify the properties of ceramic and metal oxide nanoparticles to form polymer coated nano-composite materials including BaTi0 ₃ , SrTi0 ₃ , PbTi0 ₃ . The nanoparticles are coated with polymers comprising a terminal phosphonic acid moiety and had enhanced long term stability in solvents such as ethanol, chloroform, acetone, and N-methyl pyrrolidinone, while being useful in the electronic and microelectronic industry in the formation of high dielectric constant films and capacitor systems. However, despite this, nanoparticles coated with the polymer coatings of the prior art are often insoluble or poorly stable in aqueous environments. For example, poor water solubility may result in the formation of emulsions and require the use of additional surfactants and reagents to keep the nanoparticles in solution. Additionally, the coatings are often cytotoxic to cells making them unsuitable for use in biological applications.

Therefore, there is a need to provide coating for nanoparticles that are non-cytotoxic, soluble and stable in aqueous environments. For example, coated nanoparticles that are non- cytotoxic, soluble and stable in aqueous environments may find use in techniques such as MRI imaging agents; cancer treatment, for example hyperthermia; MPI tracer; bio- separation of products of biological origin, cell tracking and as drug delivery scaffolds.

The present inventors have surprisingly and advantageously established polymer coatings for nanoparticles, which render the coated nanoparticles highly soluble in water, stable, and which can be used in living systems.

The present invention also provides methods of synthesising the polymers. The method reduces the number of synthetic steps previously known to prepare the coating providing a more cost effective procedure and also uses more readily available reagents.

It is therefore an object of the present invention to provide coatings for nanoparticles that provide water solubility and water stability or to at least provide the public with a useful alternative.

Any discussion or reference to the prior art throughout the specification, should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

Summary of the invention

The present invention provides a nanoparticle coating compositions comprising:

A. the group (-(R ₈ )-C0 ₂ -Ri R ₂ ) at a terminal end of a backbone; and

B. a hydrophilic homopolymer comprising

wherein,

R ₁₀ -R ₇ -R ₅ -Ri2- is a pendant group;

Ri is absent or is an optionally substituted straight or branched chain C _1-20 aliphatic;

R ₂ is absent or selected from hydrogen and a biomolecule; and provided that both Ri and R ₂ cannot both be absent;

R ₅ may be selected from Ci _-4 alkylene, and a heteroatom group; R ₇ is selected from an optionally substituted, straight or branched chain C _1-6 alkylene, and an optionally substituted, straight or branched chain C _1-6 alkynyl and (C _1-6 alk)aryl;

R ₈ absent or is an optionally substituted straight or branched chain C _1-20 aliphatic;

Rio is a functional group capable of forming an intermolecular interaction;

Ri ₂ is selected from an optionally substituted Ci _-6 aliphatic, carbonyl, thione or a combination thereof;

a is selected from 1 to 700.

The coating compositions of the present invention are water stable and provide for water soluble coated nanoparticles with magnetic properties. Nanoparticles coated with the coatings if the invention may find use in application such as in medical diagnostics and medical treatment of conditions.

Detailed Description

Definitions The words "comprise", "comprising" and the like as used herein, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to", unless the context clearly requires otherwise

As used throughout the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted" In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen or carbon radicals in a given structure with the radical of a specified substituent provided that the normal valency of each atom is not exceeded. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.

The chemical terminologies as used herein have their standard meanings known in the art, in accordance with the lUPAC Goldbook, unless explicitly stated otherwise.

As used herein :

The term "aliphatic" or "aliphatic group" as used herein, means any branched, straight-chain or cyclic, substituted or unsubstituted hydrocarbon radical that is completely saturated or contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl.

The term "alkyl" as used herein means any saturated hydrocarbon radical having up to 80 carbon atoms and includes any C C ₈ o, C ₅ -C ₆₅ , C ₁₀ -C ₅₀ , C ₁₀ -C ₂₅ , C ₁₀ -C ₁₅ , or C C ₆ alkyl group, and is intended to include straight-, branched- and unbranched-chain alkyl groups. Examples of alkyl groups include but are not limited to: methyl group, ethyl group, n-propyl group, / ^' so-propyl group, n-butyl group, / ^' so-butyl group, sec-butyl group, f-butyl group, n- pentyl group, 1 ,1 -dimethylpropyl group, 1 ,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1 -ethylpropyl group, 2-ethylpropyl group, n-hexyl group and 1 -methyl-2-ethylpropyl group. Any alkyl group may optionally be substituted with one or more substituents selected from the group consisting of amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate, and thioketone.

The term "alkylene" is intended to mean any saturated straight, branched, radical having up to 80 carbon atoms of formula C _n H _2n and includes any C ₂ -C ₈₀ , C ₅ -C ₇ o, Ci ₀ -C ₅₀ , Ci ₀ -C ₂₅ , Ci ₀ - Ci5, or Ci-C ₆ alkylene group. Examples of alkylene groups include but are not limited to: methylene [-CH ₂ -] group, ethylene [-CH ₂ -CH ₂ .] group, n-propylene [(-CH ₂ -) ₃ ] group, n- butylene group [(-CH ₂ -) ₄ ], n-pentylene group [(-CH ₂ -) ₅ ]. Any alkenyl group may optionally be substituted with one or more substituents selected from the group consisting of amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate, and thioketone. The term "alkenyl" means any hydrocarbon radical having at least one carbon-carbon double bond (C=C), and having up to 80 carbon atoms, and includes any C ₂ -C ₈₀ , C ₅ -C ₇₀ , C ₁₀ -C ₅₀ , Cio-C ₂₅ , C ₁₀ -C ₁₅ , or C ₂ -C ₆ alkenyl group, and is intended to include both straight- and branched-chain alkenyl groups. Examples of alkenyl groups include but are not limited to: ethenyl group, n-propenyl group, / ^' so-propenyl group, n-butenyl group, / ^' so-butenyl group, sec-butenyl group, f-butenyl group, n-pentenyl group, 1 ,1 -dimethylpropenyl group, 1 ,2- dimethylpropenyl group, 2,2-dimethylpropenyl group, 1 -ethylpropenyl group, 2-ethylpropenyl group, n-hexenyl group and 1 -methyl-2-ethylpropenyl group. Any alkenyl group may optionally be substituted with one or more substituents selected from the group consisting of amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate, thioketone.

The term "alkynyl" means unsaturated hydrocarbon radicals having at least one carbon- carbon triple bond (C≡C) and has up to 30 carbon atoms, and includes any C ₂ -C ₈₀ , C ₅ -C ₇ o, C ₁₀ -C ₅₀ , C ₁₀ -C ₂₅ , C ₁₀ -C ₁₅ , or C ₂ -C ₆ alkynyl group, and is intended to include but not limited to both straight- and branched-chain alkynyl groups. Examples of alkynyl groups include but are not limited to: ethynyl group, n-propynyl group. Any alkynyl group may optionally be substituted with one or more substituents selected from the group consisting of alkoxy, amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate and thioketone.

The term "amine" or "amino" may be used interchangeably and means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NH((Ci-i ₀ )alkyl), N((Ci- ₁₀ )alkyl) ₂ , -NH(aryl), NH(heteroaryl), -N(aryl) ₂ , -N(heteroaryl) ₂ , - NH(cycloalkyl), -NH(heterocycloalkyl), and the like and the further substituents on the nitrogen can themselves be substituted or unsubstituted. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof.

The term "aryl" or "Ar" means an aromatic radical obeying the rule 4n + 2, having 4 to 18 carbon atoms and includes heteroaromatic radicals. Examples include but are not limited to monocyclic groups, as well as fused groups such as bicyclic groups and tricyclic groups. Examples include without limitation, phenyl groups, indenyl groups, naphthyl groups, and biphenyl groups. The term "aryl" may be used interchangeably with the terms "aryl ring" or "aromatic". The term "aryl" also refers to heteroaryl ring systems as defined herein. The term "biomolecule" is intended to mean a molecule or compound that exerts an influence effect or response on a biological system. Biomolecules include antibodies, antigens, nucleic acids, peptides, sugars, folic acid, signalling molecules, targeting molecules, drug molecules, active pharmaceuticals, prodrugs, and fluorescent agents.

The term "bioseparation" is intended to mean the separation and purification of products of biological origin.

The term "carbonyl" is intended to mean a carbon atom (C) attached to an oxy (=0) to form a C=0 group. Carbonyl groups may optionally be protected by carbonyl protecting groups, wherein "protecting groups" is defined below. Suitable protecting groups include, but are not limited to dioxolanes, dioxanes, and acetals. For example, dimethylacetals, 1 ,3-dioxolanes, 1 ,3-dioxanes. The term "heteroatom" means any atom that is not a carbon atom, including but not limited to one or more of oxygen, sulfur, nitrogen, phosphorus, boron or silicon including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternised form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N as in 3,4-dihydro- 2H-pyrrolyl, NH in pyrrolidinyl or NR ⁺ in N-substituted pyrrolidinyl.

The term "homopolymer" means the repeating unit that forms the polymer.

The term "hydroxy" or "hydroxyl" may be used interchangeably and mean the presence of a hydroxyl functional group (-OH). The H of the hydroxy may be replaced with an R group to form an alkoxy group. Unless indicated otherwise, the compounds of the invention containing hydroxy moieties may include protected derivatives thereof, wherein what is to be encompassed by "protected group" and protected derivative are discussed below. Suitable protecting groups for hydroxy moieties include, but are not limited to, tetrahydropyranyl (THP), methoxymethyl (MOM), ferf-butyl (f-Bu), pivalyl (Pv), acetonides, acetals and tert- Butyldiphenylsilyl (TBDPS), fert-butyldimethylsilyl (TBDMS).

The term "MRI contrasting agent" is intended to mean compounds, pharmaceuticals or preparations that improve the visibility of internal body structures in magnetic resonance imaging (MRI).

The term "nanoparticle" as used herein means particles of less than 100 nm. The nanoparticles may comprise a metal core. Nanoparticles may be paramagnetic, superparamagnetic, ferromagnetic, antiferromagnetic, ferrimagnetic, electromagnetic, or diamagnetic. Such nanoparticles may include but are not limited to iron, nickel, cobalt, gadolinium, dysprosium, copper, aluminium, carbon graphite, gold, silver, bismuth, chromium, manganese, and molybdenum and includes combinations selected from any of the aforementioned.

The term "patient" includes human and non-human animals. Non-human animals include, but are not limited to birds and mammals, in particular, mice, rabbits, cats, dogs, pigs, sheep, goats, cows, horses, and possums. It is preferred that the patient is a human patient.

The term "protecting group", as used herein, means an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics:

a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and

b) is selectively removable in good yield by reagents that do not attack the regenerated functional group. Exemplary protecting groups are detailed in Greene, T.W., Nuts, P. G in "Protective Groups in Organic Synthesis", Fourth Edition, John Wiley & Sons, New York: 2006, and other editions of this book, the entire contents of which are hereby incorporated by reference.

The term "radical initiator" means substances that can produce radical species, usually under mild conditions, and promotes radical reactions. Common radical initiators are known and used in the art and include, but are not limited to, azo compounds, peroxides and photoinitiators.

The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, or on storage, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that does not substantially decompose on exposure to certain conditions, or where the chemical structure or compositions is not altered by exposure to those conditions, for example exposure to moisture. The symbols "*ΛΛΛ ", " ^* " # " indicate points of attachment to the remainder of the molecule unless otherwise specified. When "ΝΛΛΛ ", " ^* " # " are used at either end of a moiety, the moiety can be attached through either end. "Treatment" and like terms refer to methods and compositions to prevent, cure, manage or ameliorate a medical disease, disorder, or condition, and/or reduce at least a symptom of such disease or disorder. In particular, this includes methods and compositions to prevent delay or inhibit onset of a medical disease, disorder, or condition; to cure, correct, reduce, slow, or ameliorate the physical or developmental effects of a medical disease, disorder, or condition; and/or to prevent, end, reduce, or ameliorate the pain or suffering caused by the medical disease, disorder, or condition. Unless otherwise indicated, structures depicted herein are also intended to include all isomeric, enantiomeric, diastereomeric, and geometric, or conformational forms of the structure; for example, the (R) and (S) configurations for each asymmetric centre, and (Z) and (E) double bond isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

The inventors of the present invention have found that the specific hydrophilic polymers as disclosed herein provides for stable nanoparticle coatings that confer water solubility and water stability to the nanoparticles.

The scope of the present invention can be described herein:

In a first aspect, the present invention provides a nanoparticle coating composition comprising :

A. the group (-(R ₈ )-C0 ₂ -Ri R ₂ ) at a terminal end of a backbone; and

B. a hydrophilic homopolymer comprising

wherein,

R ₁₀ -R ₇ -R ₅ -Ri2- is a pendant group;

Ri is absent or is an optionally substituted straight or branched chain C _1-20 aliphatic;

R ₂ is absent or selected from hydrogen and a biomolecule; and provided that both Ri and R ₂ cannot both be absent; R ₅ may be selected from an optionally substituted C _{1 -4} alkylene, and a heteroatom group;

R ₇ is selected from an optionally substituted, straight or branched chain C _1-6 alkylene, and an optionally substituted, straight or branched chain C _1-6 alkynyl and (C _1-6 alk)aryl;

R ₈ absent or is an optionally substituted straight or branched chain Ci- ₂₀ aliphatic;

Rio is a functional group capable of forming an intermolecular interaction or of forming a covalent interaction;

Ri ₂ is selected from an optionally substituted Ci _-6 aliphatic, carbonyl, thione or a combination thereof;

a is selected from 1 to 700.

In an embodiment, Ri may be absent, or is selected from an optionally substituted Ci- ₂₀ aliphatic. Preferably, R is an optionally substituted straight or branched chain C _1-20 aliphatic. Alternatively, R is optionally tethered to a biomolecule or an active pharmaceutical agent, targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents. Preferably, R is a optionally substituted straight or branched chain C _1-20 alkylene. More preferably, R is a straight claim C _1-20 alkylene. Even more preferably R is a C _1-6 alkylene. R may also be optionally substituted with groups selected from optionally substituted amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl (C=0), thioketone.

When Ri is absent, the [-(R ₈ )-C0 ₂ -] moiety may be tethered to R ₂ , wherein R ₂ is hydrogen or a biomolecule. Preferably R ₂ is hydrogen. Alternatively preferably, R ₂ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof.

In an embodiment, R ₈ absent or is an optionally substituted straight or branched chain Ci _-20 aliphatic. Preferably R ₈ is an optionally substituted straight or branched chain Cno aliphatic. The optionally substituted straight or branched chain Ci _-10 aliphatic may be selected from an optionally substituted straight or branched chain CM ₀ alkylene, an optionally substituted straight or branched chain a C _1-10 alkenyl, and an optionally substituted straight or branched chain a C _{1 -10} alkynyl. More preferably, R ₈ is an optionally substituted straight or branched chain C _{1 -10} alkylene. Yet even more preferably, R ₈ is a branched C _{1 -10} alkylene. Alternatively, R ₈ is a straight chain C _{1 -10} alkylene. Yet even more preferably, R ₈ is a C _1-4 alkylene. Even more preferably R ₈ is selected from:

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl. In an embodiment, the biomolecules that may be optionally and independently attached to the Ri may be selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof. Targeting molecules include, but are not limited to antibodies, antigens, nucleic acids, peptides, sugars, folic acid, signalling molecules, and combinations and derivatives thereof. Drug molecules and/or active pharmaceuticals and may be selected from anticancer drugs, antibiotic drugs, antiinflammatory drugs, steroid drugs, immunosuppressant drugs.

In an embodiment, R ₅ may be selected from C _1-4 alkylene, and a heteroatom group. Preferably, R ₅ is a heteroatom group is selected from -NR ₉ - ethers (-0-), thioethers (-S-), wherein, R ₉ is selected from hydrogen or a C _1-4 alkyl. Even more preferably R ₅ is selected from -NR ₉ -.

R ₉ is selected from hydrogen and methyl. More preferably R ₉ is hydrogen.

Ri ₂ is selected from an optionally substituted Ci _-6 aliphatic, carbonyl, thione or a combination thereof. Preferably, Ri ₂ is selected from an optionally substituted Ci _-6 alkylene and a carbonyl. Even more preferably, Ri ₂ is a carbonyl. Ri ₂ and R ₅ when taken together may form moieties such as aliphatic chains substituted with ester moieties (-COO-), amides (-CONR ₉ -), and thioesters (-COS-).

In an embodiment, R ₇ is selected from an optionally substituted, straight or branched chain Ci-6 alkylene, an optionally substituted, straight or branched chain (Ci _-6 alk)aryl. Preferably, R ₇ is a an optionally substituted alkylene. Alternatively, R ₇ is a (C _1-2 alk)aryl. Even more preferably, R ₇ is selected from a C _1-6 alkylene and a (C _1-6 alk)aryl. Even more preferably, R ₇ is selected from

wherein ^*** is the point of attachment of R ₇ to R ₁₀ , and · is the point of attachment of R ₇ to R _5. and wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl

In an embodiment, R ₁₀ is a binding functional group that is capable of forming an intermolecular interaction or can form a covalent interaction with the nanoparticle. R ₁₀ may be covalently tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. R ₁₀ may form intermolecular interactions including but not limited to ionic interactions, dipole interactions, ion-dipole interactions, hydrogen bonding, and van der Waals interactions or combinations thereof. The intermolecular interaction may be formed between R ₁₀ and the nanoparticle. Alternatively, the intermolecular interaction may be formed between R ₁₀ and the surrounding environment, for example, water, a solvent, a cell matrix, a pharmaceutical excipient or carrier.

Alternatively, R ₁₀ may form an interaction between the nanoparticle and the environment. Binding functional groups capable of forming intermolecular interactions include polar functional groups and may also include cationic, anionic, neutral and zwitterionic groups. Such groups include but are not limited to amines, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (- SO ₃ H), sulfinic acids (-S0 ₂ H), sulfamic acids (-S0 ₃ NH ₂ ). Without wishing to be bound by theory, the binding functional group that is capable of forming an intermolecular interaction forms an interaction with the surface of the nanoparticle. It is this interaction which allows the adherence of the coating to the nanoparticle. Additionally, due to the branching structure of the nanoparticle coating, the binding functional group that is capable of forming an intermolecular interaction is also present on the external side of the coated nanoparticle as can be seen from Figure 1 . As noted above, the functional groups that are capable of forming an intermolecular interaction form the intermolecular interaction with the surrounding environment to provide improved water solubility over those nanoparticle coatings of the prior art. The surrounding environment can be for example, water, a solvent, a cell matrix, a pharmaceutical excipient or carrier.

In yet another embodiment, R ₁₀ may be optionally protected with any suitable protecting group. For example, the protecting group may be used during synthesis. Protecting groups may be used such as ethyl groups to protect phosphonate acids to form (-(P=0)OEt ₂ ) as shown herein; protecting groups suitable for hydroxy moieties include, but are not limited to, tetrahydropyranyl (THP), methoxymethyl (MOM), ferf-butyl (f-Bu), pivaloyl (Pv), acetonides, acetals and ferf-Butyldiphenylsilyl (TBDPS), fert-butyldimethylsilyl (TBDMS). Similarly, suitable nitrogen protecting groups include but are not limited to acetyl (Ac), benzyl (Bn), tert-butoxycarbonyl (BOC), 9-Fluorenylmethyl (FMOC), Tosyl (Ts). Such protecting groups would also be well known and understood by those of skill in the art and are defined in Greene, T.W., Nuts, P. G in "Protective Groups in Organic Synthesis", Fourth Edition, John Wiley & Sons, New York: 2006, the entire contents of which are hereby incorporated by reference.

Preferably, R ₁₀ is at the terminal end of the pendant group. Preferably, R ₁₀ is selected from amines, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), sulfamic acids (- SO ₃ NH ₂ ). More preferably, R ₁₀ is selected from carboxylic acids (-C0 ₂ H), hydroxyl (-OH), and phosphonic acids (-PO(OH) ₂ ).

In an embodiment, the hydrophilic polymer coating may further optionally comprise a wherein

R ₃ is selected from R ₄ , R ₆ and R ₄ R ₆ ;

R ₄ may be absent, or is selected from an optionally substituted Ci- ₂₀ aliphatic;

R ₆ may be absent, or is selected from a biomolecule; and provided that R ₄ and cannot both be absent;

R ₃ is selected from R ₄ , R ₆ and R ₄ R ₆ R4 or R ₆ may be absent, provided that at least one of R ₄ or R ₆ is present. Preferably, R ₄ is selected from an optionally substituted Ci- ₂₀ aliphatic. Preferably, R ₄ is selected from a Ci- ₂₀ alkyl, a C1-20 alkylene, and C1-20 alkenyl. Even more preferably, R ₄ is selected from C1-20 alkyl, a C1-20 alkylene. Yet even more preferably, R ₄ is selected from C ₂ -i ₅ alkyl, a C2-15 alkylene. Yet even more preferably, R ₄ is selected from C5-15 alkyl, a C5-15 alkylene. R ₆ may be absent, or is selected from a biomolecule. Alternatively, R ₆ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof, and; and provided that when R ₄ is alkyl, R ₆ is absent. Preferably, the homopolymer has a molecular weight of from about 1 kDa to about 25 kDa when calculated using MALDI-TOF mass spectrometry. More preferably, the homopolymer has a molecular weight of from about 5 kDa to about 20 kDa, the homopolymer has a molecular weight of from about 5 kDa to about 15 kDa. Preferably, the homopolymer comprises a formula

wherein, a, R ₉ , R ₇ , and R ₁₀ are as hereinbefore described.

Even more preferably, the homopolymer comprises formula

wherein, a, R ₇ , and R ₁₀ are as hereinbefore described.

Even more preferably, homopolymer comprises formula

wherein a, and R ₁₀ , are as hereinbefore described, and f is 1 to 4.

Even more preferably, the homopolymer comprises a formula selected from:

wherein a and R ₁₀ , are as hereinbefore described.

Most preferably, the homopolymer comprises a formula selected from

wherein a is as hereinbefore described. Most preferably, the homopolymer comprises a formula selected from

wherein a is selected from 10 to 15, 50 to 70 and 600 to 700.

In an embodiment, the nanoparticle coating comprises a formula selected from

^R 23 and ^R 23

wherein,

R23-R21 -R19-R20- is a pendant group;

d is selected from 1 to 700. Preferably d is selected from 5 to 600. Even more preferably d is selected from 10 to 300. Even more preferably d is selected from 10 to 15, 50 to 70 and 600 to 700;

Ri4 is selected from hydrogen or R ₂₅ ;

R19 may be selected from C1-4 alkylene, and a heteroatom group. Preferably, the heteroatom group is NR ₁₈ ;

R ₂₀ is selected from an optionally substituted C _1-6 aliphatic, carbonyl, thione or a combination thereof;

R21 is selected from an optionally substituted, straight or branched chain C _1-6 alkylene, optionally substituted, straight or branched chain (C _1-6 alk)aryl. Preferably, R ₂ i is a straight chain alkylene. Alternatively R ₂ i is a (C _1-2 alk)aryl. Even more preferably R21 is selected from a straight chain C _1-4 alkylene and a (C _1-6 alk)aryl. Even more preferably R _2i is selected from

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl; and wherein ^*** is the point of attachment of R ₂ i to the R ₂ 3 and · is the point of attachment of R ₂ i to Ri ₉ ;

drogen or a Ci _-4 alkyl. Preferably R ₁₈ is hydrogen or methyl. More preferably R ₁₈ is hydrogen.

binding functional group that is capable of forming an intermolecular interaction or can form a covalent interaction with the nanoparticle. R ₂₃ may be covalently tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. Preferably the intermolecular interaction is selected from ionic interactions, dipole interactions, ion-dipole interactions, hydrogen bonding, and van der Waals interactions or combinations thereof. Alternatively groups capable of forming intermolecular interactions include polar functional groups, cationic functional groups, anionic functional groups, neutral functional groups and zwitterionic groups. Preferably, the binding functional group that is capable of forming an intermolecular interaction is selected from amine, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), and sulfamic acids (-S0 ₃ NH ₂ ). Even more preferably, the functional group capable of forming the binding functional group that is capable of forming an intermolecular interaction is selected from carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ).

R ₂₅ is selected from R ₂₄ , R ₂₆ and R ₂₄ R ₂₆ ; either R ₂₄ or R ₂₆ may be absent, provided that only one of R ₂₄ or R ₂₆ is absent.

R ₂₄ is selected from an optionally substituted Ci _-2 o aliphatic, an optionally substituted amine, and optionally substituted amide, a carboxylate, a carbamate a phosphonyl ester, a phsophinyl ester, a sulfonyl ester, a sulfinyl ester, and sulfamyl ester or a combination thereof. Preferably, R ₂₄ is selected from a C _1-20 alkyl, a C _1-20 alkylene, and C _1-20 alkenyl. Even more preferably, R ₂₄ is selected from C _1-20 alkyl, a C _{1 -20} alkylene. Yet even more preferably, R ₂₄ is selected from C _2-15 alkyl, a C _2-15 alkylene. Yet even more preferably, R ₂₄ is selected from C _5-15 alkyl, a C _5-15 alkylene.

R ₂₆ may be absent, or is selected from a biomolecule. Alternatively, R ₂₆ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof, and provided that when R ₂₄ is alkyl or alkenyl, R ₂₆ is absent, and provided that when R ₂₆ is a biomolecule, R ₂₄ is selected from an optionally substituted amine, and optionally substituted amide, a carboxylate, a carbamate a phosphonyl ester, a phsophinyl ester, a sulfonyl ester, a sulfinyl ester, and sulfamyl ester;

R ₂₂ is absent or is an optionally substituted straight or branched chain Ci _-20 aliphatic.

Preferably R ₂₂ is an optionally substituted straight or branched chain Cno aliphatic. The optionally substituted straight or branched chain CM ₀ aliphatic may be selected from an optionally substituted straight or branched chain CM ₀ alkylene, an optionally substituted straight or branched chain a CM ₀ alkenyl, and an optionally substituted straight or branched chain a CM ₀ alkynyl. More preferably, R ₂₂ is an optionally substituted straight or branched chain C _1-10 alkylene. Yet even more preferably, R ₂₂ branched C _1-10 alkylene. Alternatively, R ₂₂ is a straight chain C _{1 -10} alkylene. Yet even more preferably, R ₂₂ is a C _1-4 alkylene. Even more preferably,

R ₂₂ is selected from:

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl. R ₂₈ may be absent, or is selected from an optionally substituted Ci- ₂₀ aliphatic. In another embodiment, R ₂₈ is an optionally substituted straight or branched chain C ₁ - ₂₀ aliphatic. In yet another embodiment, R ₂₈ is optionally tethered to a biomolecule, a targeting molecule, drug molecules, active pharmaceuticals, prodrugs, and fluorescent agents. In a further embodiment, R ₂₈ is a optionally substituted straight or branched chain C _1-20 alkylene. In yet another embodiment, R ₂₈ is a straight claim C _1-20 alkylene. Preferably R ₂₈ is a C _1-6 alkylene. R ₂₈ may also be optionally substituted with groups selected from optionally substituted amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate, thioketone.

R ₂₉ is hydrogen or a biomolecule. Preferably R ₂₉ is hydrogen. Alternatively preferably R ₂₉ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof. When R ₂₈ is absent, the carboxylic acid moiety may be tethered to R ₂₉ , wherein R ₂₉ is hydrogen or a biomolecule. Preferably, the nanoparticle coating comprises a formula selected from

and

wherein, d, R , Ris, R19 R21 , R23, R25, and R ₂₇ are as hereinbefore described.

Preferably, the nanoparticle coating comprises a formula selected from

wherein, d, R , Ris, R21 , R23, R25, and R ₂₇ are as hereinbefore described.

Even more preferably, the nanoparticle coating comprises a formula selected from

wherein, d, R , R21 , R23, R25, and R ₂₇ are as hereinbefore described.

Even more preferably, the nanoparticle coating comprises a formula selected from

wherein, d, R ₁₄ , R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₅ , are as hereinbefore described.

Even more preferably, the nanoparticle coating comprises a formula selected from

wherein, d, R ₂ i , R ₂₂ F½, and R ₂₅ , are as hereinbefore described, and f is 1 to 4.

Even more preferably, the nanoparticle coating comprises a formula selected from

wherein d, R ₁₄ , R ₂₂ , R23, and R ₂₅ , are as hereinbefore described. Preferably R ₂₅ is selected from a R ₂₄ or R ₂₆ , wherein R ₂₄ is a C _1-20 alkyl and R ₂₆ is a biomolecule.

Even more preferably, the nanoparticle coating comprises a formula selected from:

wherein d, R ₂₂ , and R ₂₃ , are as hereinbefore described.

Even more preferably, the nanoparticle coating comprises a formula selected from:

wherein, d, R ₂₂ , R23, are as hereinbefore described.

Yet more preferably, the nanoparticle coating comprises a formula selected from:

wherein, d, and R ₂₂ are as hereinbefore described.

Most preferably, the nanoparticle coating comprises a formula selected from

wherein d is as hereinbefore described.

Most preferably, the nanoparticle coating comprises a formula selected from

wherein d is selected from 10 to 15, 50 to 70 and 600 to 700. In an embodiment, the nanoparticle coating comprises a structural arrangement selected from

wherein R ₁₄ , R ₁₉ , R ₂₀ , R21 , R23, R25 and R ₂₇ are as herein before defined and k is selected from 1 to 350 and h is selected from 150 to 250. Preferably the pendant groups are orientated in an internal and external orientation relative to the nanoparticle. That is, the pendant groups with the binding functional moiety are directed towards the nanoparticle surface and facing the surrounding environment, In an embodiment, the nanoparticles to be coated with the hydrophilic polymer are transition metal nanoparticles. The nanoparticle may comprise a core. The nanoparticle may comprise a shell. The nanoparticle may comprise a core and a shell. Preferably, the nanoparticle core is selected from metal, metal oxide, metal carbide, metal nitride, metal sulfide, or a combination thereof. Preferably, the nanoparticle shell is selected from a metal shell and a metal oxide shell.

In yet another embodiment, the nanoparticles are magnetic. Preferably, the nanoparticles are selected from paramagnetic, superparamagnetic, ferromagnetic, antiferromagnetic, ferrimagnetic, electromagnetic, diamagnetic nanoparticles. Such nanoparticles may include, but are not limited to chromium, manganese, iron, cobalt and molybdenum nanoparticles. More preferably, the nanoparticle is an iron nanoparticle. Alternatively the nanoparticle is an iron oxide nanoparticle. Without wishing to be bound by theory, the present invention works by inducing a magnetic field on the coated nanoparticle. The magnetic field is an alternating magnetic field. This alternating in the magnetic field stimulates the nanoparticles and causes them to heat up. The heat generated by the nanoparticle induces cell death.

Preferably, the nanoparticle coating has a polydispersity of from about 0.5 to about 2. Preferably, the polymer polydispersity is from about 0.7 to about 1 .5. More preferably, the polymer polydispersity is from about 0.9 to about 1 .3. Yet even more preferably, the polymer has a polydispersity of from about 1 to about 1 .15.

In a second aspect, the present invention also provides a coated nanoparticle comprising :

A. a nanoparticle; and

B. a hydrophilic polymer comprising :

i) a carboxylic acid group (-(R ₈ )-C0 ₂ -Ri R ₂ ); and

ii) a hydrophilic homopolymer comprising the formula

wherein,

R ₁₀ -R ₇ - 5- i2- is a pendant group;

Ri is absent or is an optionally substituted straight or branched chain Ci- ₂₀ aliphatic;

R ₂ is absent or selected from hydrogen and a biomolecule; and provided that both

Ri and R ₂ cannot both be absent;

R ₅ may be selected from an optionally substituted C ₁ -4 alkylene, and a heteroatom group;

R ₇ is selected from an optionally substituted, straight or branched chain C ₁ -6 alkylene, and an optionally substituted, straight or branched chain C ₁ -6 alkynyl and (Ci-e alkjaryl;

R ₈ absent or is an optionally substituted straight or branched chain d- ₂₀ aliphatic; R ₁₀ is a functional group capable of forming an intermolecular interaction; R ₁₂ is selected from an optionally C _{1 -6} aliphatic, carbonyl, thione or a combination thereof;

a is selected from 1 to 700.

In an embodiment, R may be absent, or is selected from an optionally substituted C _{1 -20} aliphatic. Preferably, R is an optionally substituted straight or branched chain C _{1 -20} aliphatic. Alternatively, Ri is optionally tethered to a biomolecule, an active pharmaceutical agent, a targeting molecule, drug molecules, prodrugs, fluorescent agents. Preferably, Ri is a optionally substituted straight or branched chain C ₁ - ₂₀ alkylene. More preferably, Ri is a straight claim C ₁ - ₂₀ alkylene. Even more preferably Ri is a Ci _-6 alkylene. Ri may also be optionally substituted with groups selected from optionally substituted amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl (C=0), thioketone.

In another embodiment, when is absent, the [-(R ₈ )-C0 ₂ -] moiety may be tethered to R ₂ , wherein R ₂ is hydrogen or a biomolecule. Preferably R ₂ is hydrogen. Alternatively preferably, R ₂ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents, antibodies, antigens, nucleic acids, peptides, sugars, folic acid, signalling molecules and combinations and derivatives thereof.

In an embodiment, R ₈ absent or is an optionally substituted straight or branched chain C _1-20 aliphatic. Preferably R ₈ is an optionally substituted straight or branched chain C _{I 0} aliphatic. The optionally substituted straight or branched chain Ci _-10 aliphatic may be selected from an optionally substituted straight or branched chain CM ₀ alkylene, an optionally substituted straight or branched chain a CM ₀ alkenyl, and an optionally substituted straight or branched chain a CM ₀ alkynyl. More preferably, R ₈ is an optionally substituted straight or branched chain CM ₀ alkylene. Yet even more preferably, R ₈ is a branched CM ₀ alkylene. Alternatively, R ₈ is a straight chain CM ₀ alkylene. Yet even more preferably, R ₈ is a C ₁ - ₄ alkylene. Even more preferably R ₈ is selected from: V ¾v

wherein χ is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a C _1-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl. In an embodiment, the biomolecules that may be optionally and independently attached to the Ri and the R ₄ may be selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof. Targeting molecules include, but are not limited to antibodies, antigens, nucleic acids, peptides, sugars, folic acid, signalling molecules, and combinations and derivatives thereof. Drug molecules and/or active pharmaceuticals and may be selected from anticancer drugs, antibiotic drugs, anti-inflammatory drugs, steroid drugs, immunosuppressant drugs. In an embodiment, R ₅ may be selected from Ci _-4 alkylene, and a heteroatom group. Preferably, the heteroatom group is selected from -NR ₉ - ethers (-0-), thioethers (-S-), wherein, R ₅ is selected from hydrogen or a Ci _-4 alkyl.

R ₉ is selected from hydrogen and methyl. More preferably R ₉ is hydrogen .

R ₁₂ is selected from an optionally substituted C _1-6 aliphatic, carbonyl, thione or a combination thereof. Preferably, R ₁₂ is selected from an optionally substituted C _1-6 alkylene and a carbonyl. Even more preferably, R ₁₂ is a carbonyl. R ₁₂ and R ₅ when taken together may form moieties such as aliphatic chains substituted with ester moieties (-COO-), amides (-CONR ₉ -), and thioesters (-COS-).

In an embodiment, R ₇ is selected from an optionally substituted, straight or branched chain Ci-6 alkylene, an optionally substituted, straight or branched chain (Ci _-6 alk)aryl. Preferably, R ₇ is a straight chain alkylene. Alternatively R ₇ is a (Ci _-2 alk)aryl. Even more preferably, R ₇ is selected from a Ci _-3 straight chain alkylene and a (Ci _-6 alk)aryl. Even more preferably R ₇ is selected from

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl and wherein ^*** is the point of attachment to the functional group capable of forming an intermolecular interaction, and · is the point of attachment of R ₇ to R ₅ ;

In another embodiment, R ₉ is hydrogen or a C _1-4 alkyl. Preferably R ₉ is hydrogen or methyl. More preferably R ₉ is hydrogen. In an embodiment, the binding functional group is capable of forming an intermolecular or can be covalently tethered to the nanoparticle. The binding functional group may be tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. Intermolecular interactions formed by the binding functional group include but are not limited to ionic interactions, dipole interactions, ion- dipole interactions, hydrogen bonding, and van der Waals interactions or combinations thereof. The intermolecular interaction may be formed between R ₁₀ and the nanoparticle. Alternatively, the intermolecular interaction may be formed between R ₁₀ and the surrounding environment, for example, water, a solvent, a cell matrix, a pharmaceutical excipient or carrier. Alternatively, R ₁₀ may form an interaction between the nanoparticle and the environment. Functional groups capable of forming intermolecular interactions include polar functional groups and may also include cationic, anionic, neutral and zwitterionic groups. Such groups include but are not limited to amines, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (- S0 ₃ H), sulfinic acids (-S0 ₂ H), sulfamic acids (-S0 ₃ NH ₂ ). Without wishing to be bound by theory, the binding functional group that is capable of forming an intermolecular interaction forms an interaction with the surface of the nanoparticle. It is this interaction which allows the adherence of the coating to the nanoparticle. Additionally, due to the branching structure of the nanoparticle coating, the binding functional group that is capable of forming an intermolecular interaction are also present on the external side of the coated nanoparticle as can be seen from Figure 1 . Without wishing to be bound by theory, that is, the functional groups that are capable of forming an intermolecular interaction form the intermolecular interaction with the surrounding environment to provide improved water solubility over those nanoparticle coatings of the prior art. The surrounding environment can be for example, water, a solvent, a cell matrix, a pharmaceutical excipient or carrier.

In yet another embodiment, R ₁₀ may be optionally protected with any suitable protecting group. For example, the protecting group may be used during synthesis. Protecting groups may be used such as ethyl groups could be used to protect phosphonate acids to form (- (P=0)OEt ₂ ) as shown herein; protecting groups suitable for hydroxy moieties include, but are not limited to, tetrahydropyranyl (THP), methoxymethyl (MOM), ferf-butyl (f-Bu), pivaloyl (Pv), acetonides, acetals and ferf-Butyldiphenylsilyl (TBDPS), ferf-butyldimethylsilyl (TBDMS). Similarly, suitable nitrogen protecting groups include but are not limited to acetyl (Ac), benzyl (Bn), tert-butoxycarbonyl (BOC), 9-Fluorenylmethyl (FMOC), Tosyl (Ts). Such protecting groups would also be well known and understood by those of skill in the art and are defined in Greene, T.W., Nuts, P. G in "Protective Groups in Organic Synthesis", Fourth Edition, John Wiley & Sons, New York: 2006, the entire contents of which are hereby incorporated by reference. Preferably, R ₁₀ is at the terminal end of the pendant group. Preferably, R ₁₀ is selected from amines, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), sulfamic acids (- SO ₃ NH ₂ ). More preferably, R ₁₀ is selected from carboxylic acids (-C0 ₂ H), hydroxyl (-OH), and phosphonic acids (-PO(OH) ₂ ).

In an embodiment, the hydrophilic polymer coating may further optionally comprise a

wherein

R ₃ is selected from R ₄ , R ₆ and R ₄ R ₆ ;

R ₄ may be absent, or is selected from an optionally substituted Ci- ₂₀ aliphatic;

R ₆ may be absent, or is selected from a biomolecule; and provided that R ₄ and R ₆ cannot both be absent;

R ₃ is selected from R ₄ , R ₆ and R ₄ R _6. R or R ₆ may be absent, provided that at least one of R ₄ or R ₆ is present. Preferably, R ₄ is selected from an optionally substituted Ci- ₂₀ aliphatic. Preferably, R ₄ is selected from a C ₁ - ₂₀ alkyl, a C ₁ - ₂₀ alkylene, and C ₁ - ₂₀ alkenyl. Even more preferably, R ₄ is selected from Ci- ₂₀ alkyl, a Ci- ₂₀ alkylene. Yet even more preferably, R ₄ is selected from C ₂ -i ₅ alkyl, a C ₂ -15 alkylene. Yet even more preferably, R ₄ is selected from C5-15 alkyl, a C5-15 alkylene. R ₆ may be absent, or is selected from a biomolecule. Alternatively, R ₆ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof, and; and provided that when R ₄ is alkyl, R ₆ is absent.

Preferably, the homopolymer has a molecular weight of from about 1 kDa to about 25 kDa when calculated using MALDI-TOF mass spectrometry. More preferably, the homopolymer has a molecular weight of from about 5 kDa to about 20 kDa, the homopolymer has a molecular weight of from about 5 kDa to about 15 kDa.

Preferably, the homopolymer comprises a formula

wherein, a, R ₉ , R ₇ , and R ₁₀ are as hereinbefore described.

Even more preferably, the homopolymer comprises a formula

wherein, a, R ₇ , and Ri ₀ are as hereinbefore described.

Even more preferably, homopolymer comprises a formula , wherein a, and Ri ₀ , are as hereinbefore described, and f is 1 to 4.

Even more preferably, the homopolymer comprises a formula selected from:

hereinbefore described.

Most preferably, the homopolymer comprises a formula selected from

wherein a is as hereinbefore described. ost preferably, the homopolymer comprises a formula selected from

wherein a is selected from

10 to 15, 50 to 70 and 600 to 700.

The present invention also provides a coated nanoparticle comprising a formula selected from :

wherein

R ₂₀ -R19-R ₂₁ -H23 is a pendant group

d is selected from 1 to 700. Preferably d is selected from 5 to 600. Even more preferably d is selected from 10 to 300. Even more preferably d is selected from 10 to 15, 50 to 70 and 600 to 700.

Ri ₄ is selected from hydrogen or R ₂₅ ;

R19 may be selected from an optionally substituted Ci _-4 alkylene, and a heteroatom group.

Preferably, R ₁₉ is a heteroatom group is selected from -NR ₉ - ethers (-0-), thioethers (-S-), wherein, R ₉ is selected from hydrogen or a C _{1 -4} alkyl. Even more preferably R ₁₉ is selected from -NR ₉ -.

R ₂₀ is selected from an optionally substituted C _{1 -6} aliphatic, carbonyl, thione or a combination thereof. Preferably,R ₁₂ is selected from an optionally substituted C _{1 -6} alkylene and a carbonyl. Even more preferably, R ₁₂ is a carbonyl;

R ₂₁ is selected from an optionally substituted, straight or branched chain C _{1 -6} alkylene, optionally substituted, straight or branched chain (C _{1 -6} alk)aryl. Preferably, R ₂ i is a optionally substituted alkylene. Alternatively R ₂₁ is a (C _{1 -2} alk)aryl. Even more preferably R ₂ i is selected from an optionally substituted Ci _-4 alkylene and a (Ci _-6 alk)aryl. Even more preferably R ₂ i is selected from

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl and wherein ^*** is the point of attachment of R ₂ i to the R ₂ 3 and · is the point of attachment of R ₂ i to Ri ₉ ;

drogen or a Ci _-4 alkyl. Preferably R ₁₈ is hydrogen or methyl. More preferably R ₁₈ is hydrogen.

binding functional group that is capable of forming an intermolecular interaction or can form a covalent interaction with the nanoparticle. R ₂₃ may be covalently tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. Preferably the intermolecular interaction is selected from ionic interactions, dipole interactions, ion-dipole interactions, hydrogen bonding, and van der Waals interactions or combinations thereof. Alternatively groups capable of forming intermolecular interactions include polar functional groups, cationic functional groups, anionic functional groups, neutral functional groups and zwitterionic groups. Preferably, the binding functional group that is capable of forming an intermolecular interaction is selected from amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), and sulfamic acids (-SO ₃ NH ₂ ). Even more preferably, the functional group capable of forming the binding functional group that is capable of forming an intermolecular interaction is selected from carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (- PO(OH) ₂ ).

s selected from R ₂₄ , R ₂₆ and R ₂₄ R ₂₆ ; either R ₂₄ or R ₂₆ may be absent, provided that only one of R ₂₄ and R ₂₆ is absent.

is selected from an optionally substituted Ci- ₂ o aliphatic, an optionally substituted amine, an optionally substituted amide, a carboxylate, a carbamate a phosphonyl ester, a phsophinyl ester, a sulfonyl ester, a sulfinyl ester, and sulfamyl ester or a combination thereof. Preferably, R ₂₄ is selected from a C _1-20 alkyl, a C _1-20 alkylene, and C _1-20 alkenyl. Even more preferably, R ₂₄ is selected from C _1-20 alkyl, a C _{1 -20} alkylene. Yet even more preferably, R ₂₄ is selected from C _2-15 alkyl, a C _2-15 alkylene. Yet even more preferably, R ₂₄ is selected from C _5-15 alkyl, a C _5-15 alkylene.

may be absent, or is selected from a biomolecule. Alternatively, R ₂₆ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, and combinations and derivatives thereof, and provided that when R ₂₄ is alkyl or alkenyl, R ₂₆ is absent, and provided that when R ₂₆ is a biomolecule, R ₂₄ is selected from an optionally substituted an optionally substituted amine, an optionally substituted amide, a carboxylate, a carbamate a phosphonyl ester, a phsophinyl ester, a sulfonyl ester, a sulfinyl ester, and sulfamyl esters;

is absent or is an optionally substituted straight or branched chain Ci _-20 aliphatic.

Preferably R ₂₂ is an optionally substituted straight or branched chain Cno aliphatic. R ₂₂ may be selected from an optionally substituted straight or branched chain d-10 alkylene, an optionally substituted straight or branched chain a d-10 alkenyl, and an optionally substituted straight or branched chain a d-10 alkynyl. More preferably, R ₂₂ is an optionally substituted straight or branched chain Ci _{-1 0} alkylene. Yet even more preferably R ₂₂ , is a branched C _1-10 alkylene. Alternatively, R ₂₂ is a straight chain C _{1 -10} alkylene. Yet even more preferably, R ₂₂ is a C _{1 -4} alkylene. Even more preferably R ₂₂ is selected from:

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl.

R ₂₈ may be absent, or is selected from an optionally substituted straight or branched chain C ₁ - ₂₀ aliphatic. R ₂₈ may be optionally tethered to a biomolecule, an active pharmaceutical agent, a targeting molecule, drug molecules, prodrugs, fluorescent agents. Preferably, R ₂₈ is a optionally substituted straight or branched chain C _1-20 alkylene. Preferably, R ₂₈ is a straight claim C _1-20 alkylene. Preferably, R ₂₈ is a C _1-6 alkylene. R ₂₈ may also be optionally substituted with groups selected from optionally substituted amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate, thioketone.

R ₂₉ is hydrogen or a biomolecule. Preferably R ₂₉ is hydrogen. Alternatively preferably R ₂₉ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, and combinations and derivatives thereof. When R ₂₈ is absent, the carboxylic acid moiety may be tethered to R ₂₉ , wherein R ₂₉ is hydrogen or a biomolecule.

Preferably, the coated nanoparticle comprises a formula selected from

wherein, d, R ₁₄ , R ₂₀ , 21 , f½, R25, and R ₂₇ are as hereinbefore described.

Preferably, the coated nanoparticle comprises a formula selected from

wherein, d, R ₁₄ , R ₁₈ , R ₂₁ , R ₂₃ , R ₂₅ , and R ₂₇ are as hereinbefore described.

Even more preferably, the coated nanoparticle comprises a formula selected from

wherein, d, R ₁₄ , R ₂₁ , R ₂₃ , R ₂₅ , and R ₂₇ are as hereinbefore described.

Even more preferably, the coated nanoparticle comprises a formula selected from

wherein, d, R ₁₄ , R ₂ i , R ₂₂ , R ₂ 3, and R ₂₅ , are as hereinbefore described. ven more preferably, the coated nanoparticle comprises a formula selected from

and R ₂ 5, are as hereinbefore described, and f is 1 to 4. Even more preferably, the coated nanoparticle comprises a formula selected from:

Preferably, R ₂₅ is selected from R ₂₄ or R ₂₆ , wherein R ₂₄ is a C1 -20 alkyl and R ₂₆ is a biomolecule.

Even more preferably, the coated nanoparticle comprises a formula selected from:

wherein d, R ₂₂ , and R ₂₃ , are as hereinbefore described.

Even more preferably, the coated nanoparticle comprises a formula selected from:

, wherein, d, R ₂₂ , R23, are as hereinbefore described.

Yet more preferably, the coated nanoparticle comprises a formula selected from:

Most preferably, the coated nanoparticle comprises a formula selected from

Most preferably, the nanoparticle coating comprises a formula selected from

, wherein d is selected from 10 to 15, 50 to 70 and 600 to 700. In an embodiment, the nanoparticle coating comprises a structural arrangement selected from

wherein R ₁₄ , R ₁₉ , R ₂₀ , R21 , R23, R25 and R ₂₇ are as herein before defined and k is selected from 1 to 350 and h is selected from 150 to 250. Preferably the pendant groups are orientated in an internal and external orientation. That is directed towards the nanoparticle surface and facing the surrounding environment.

The nanoparticles to be coated are transition metal nanoparticles. The nanoparticle may comprise a core. The nanoparticle may comprise a shell. The nanoparticle may comprise a core and a shell. Preferably, the nanoparticle core is selected from metal, metal oxide, metal carbide, metal nitride, metal sulfide, or a combination thereof. Preferably, the nanoparticle shell is selected from a metal shell and a metal oxide shell. In yet another embodiment, the nanoparticles are magnetic. Preferably, the nanoparticles are selected from paramagnetic, superparamagnetic, ferromagnetic, antiferromagnetic, ferrimagnetic, electromagnetic, diamagnetic nanoparticles. Such nanoparticles may include, but are not limited to chromium, manganese, iron, cobalt and molybdenum. More preferably, the nanoparticle is an iron nanoparticle. Alternatively the nanoparticle is an iron oxide nanoparticle. Without wishing to be bound by theory, the present invention works by inducing a magnetic field on the coated nanoparticle. The magnetic field is an alternating magnetic field. This alternating in the magnetic field stimulates the nanoparticles and causes them to heat up, thereby also heating up the biological cells and inducing cell death. In an embodiment, the coated nanoparticles have a hydrodynamic size of less than about 200 nm. Preferably, the coated nanoparticles have a hydrodynamic size of less than about 150 nm. More preferably the hydrodynamic size of the coated nanoparticles is less than about 100 nm. Even more preferably, the hydrodynamic size of the nanoparticles is between aboutI O nm and about 100 nm. Even more preferably, the hydrodynamic size of the coated nanoparticles is between about 10nm and about 50nm. Yet even more preferably, the hydrodynamic size of the coated nanoparticle is between about 16nm to about 20nm.

In an embodiment, the hydrophilic polymer coating has a polydispersity of from about 0.5 to about 2. Preferably, the polymer polydispersity is from about 0.7 to about 1 .5. More preferably, the polymer polydispersity is from about 0.9 to about 1 .3. Yet even more preferably, the polymer has a polydispersity of from about 1 to 1 .15.

In an embodiment, the coated nanoparticles are soluble in polar solvent solutions. Preferably, polar solvent solutions are solutions which comprise water miscible solvents, and water or a combination thereof. Preferably, the coated nanoparticles are soluble in solutions comprising water. Preferably, the coated nanoparticles are freely soluble in water. The present invention further provides for the use of a hydrophilic polymer for coating nanoparticles comprising:

A. a carboxylic acid group (-(R ₈ )-C0 ₂ -Ri R ₂ );and

B. a hydrophilic homopolymer comprising a

R

wherein,

R ₁₀ -R ₇ - 5- i2- is a pendant group

Ri is absent or is an optionally substituted straight or branched chain Ci- ₂₀ aliphatic; R ₂ is absent or selected from hydrogen and a biomolecule; and provided that both and R ₂ cannot both be absent;

R ₅ may be selected from an optionally substituted C _{1 -4} alkylene, and a heteroatom group

R ₇ is selected from an optionally substituted, straight or branched chain C _{1 -6} alkylene, and an optionally substituted, straight or branched chain C _1-6 alkynyl and (C _1-6 alk)aryl;

R ₈ absent or is an optionally substituted straight or branched chain C _{1 -20} aliphatic.

R ₁₀ is a functional group capable of forming an intermolecular interaction

R ₁₂ is selected from an optionally substituted C _{1 -6} aliphatic, carbonyl, thione or a combination thereof;

a is selected from 1 to 700.

In an embodiment, Ri may be absent, or is selected from an optionally substituted Ci _-2 o aliphatic. Preferably, Ri is an optionally substituted straight or branched chain Ci _-2 o aliphatic. Alternatively, Ri is optionally tethered to a biomolecule, an active pharmaceutical agent a targeting molecule, drug molecules, prodrugs, fluorescent agents. Preferably, Ri is a optionally substituted straight or branched chain Ci _-20 alkylene. More preferably, Ri is a straight claim Ci _-20 alkylene. Even more preferably Ri is a Ci _-6 alkylene. Ri may also be optionally substituted with groups selected from optionally substituted amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl (C=0), thioketone. In another embodiment, when is absent, the [-(R ₈ )-C0 ₂ -] moiety may be tethered to R ₂ , wherein R ₂ is hydrogen or a biomolecule. Preferably R ₂ is hydrogen. Alternatively preferably, R ₂ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof.

In an embodiment, R ₈ absent or is an optionally substituted straight or branched chain C ₁ - ₂ 0 aliphatic. Preferably R ₈ is an optionally substituted straight or branched chain Cno aliphatic. The optionally substituted straight or branched chain Ci _-10 aliphatic may be selected from an optionally substituted straight or branched chain CM ₀ alkylene, an optionally substituted straight or branched chain a CM ₀ alkenyl, and an optionally substituted straight or branched chain a CM ₀ alkynyl. More preferably, R ₈ is an optionally substituted straight or branched chain CM ₀ alkylene. Yet even more preferably, R ₈ is a branched CM ₀ alkylene. Alternatively, R ₈ is a straight chain CM ₀ alkylene. Yet even more preferably, R ₈ is a C ₁ - ₄ alkylene. Even more preferably R ₈ is selected from:

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl. In an embodiment, the biomolecules that may be optionally and independently attached to the Ri and the R ₄ may be selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, imaging agents and combinations and derivatives thereof. Targeting molecules include, but are not limited to antibodies, antigens, nucleic acids, peptides, sugars, folic acid, signalling molecules, and combinations and derivatives thereof. Drug molecules and/or active pharmaceuticals and may be selected from anticancer drugs, antibiotic drugs, anti-inflammatory drugs, steroid drugs, immunosuppressant drugs.

In an embodiment, R ₅ may be selected from C _1-4 alkylene, and a heteroatom group. Preferably, the heteroatom group is NR ₉ . Preferably, the heteroatom group comprises -NR ₉ , ethers (-0-), thioethers (-S-), wherein R ₉ is selected from hydrogen or C _1-4 alkyl. Rg is selected from hydrogen or methyl. More preferably R ₉ is hydrogen.

R ₁₂ is selected from an optionally substituted C _{1 -6} aliphatic, carbonyl, thione or a combination thereof; Preferably,R ₁₂ is selected from an optionally substituted C1 -6 alkylene and a carbonyl. Even more preferably, Ri ₂ is a carbonyl.

Ri ₂ and R ₅ when taken together may form moieties such as aliphatic chains substituted with ester moieties (-COO-), amides (-CONR ₉ -), and thioesters (-COS-).

In an embodiment, R ₇ is selected from an optionally substituted, straight or branched chain C ₁ -6 alkylene, an optionally substituted, straight or branched chain (Ci _-6 alk)aryl. Preferably, R ₇ is a an optionally substituted alkylene. Alternatively R ₇ is a (Ci _-2 alk)aryl. Even more preferably, R ₇ is selected from a Ci _-3 straight chain alkylene and a (Ci _-6 alk)aryl. Even more preferably R ₇ is selected from :

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl and wherein ^*** is the point of attachment to the functional group capable of forming an intermolecular interaction, and · is the point of attachment of R ₇ to R ₅ ;

In an embodiment, binding functional group that is capable of forming an intermolecular R ₁₀ is a binding functional group that is capable of forming an intermolecular interaction or can be covalently tethered to the nanoparticle. R ₁₀ may be covalently tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. Intermolecular interactions include but are not limited to ionic interactions, dipole interactions, ion-dipole interactions, hydrogen bonding, and van der Waals interactions or combinations thereof. The intermolecular interaction may be formed between R ₁₀ and the nanoparticle. Alternatively, the intermolecular interaction may be formed between R ₁₀ and the surrounding environment, for example, water, a solvent, a cell matrix, a pharmaceutical excipient or carrier. Alternatively, R ₁₀ may form an interaction between the nanoparticle and the environment. Functional groups capable of forming intermolecular interactions include polar functional groups and may also include cationic, anionic, neutral and zwitterionic groups. Such groups include but are not limited to amines, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (- PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), sulfamic acids (-S0 ₃ NH ₂ ). Without wishing to be bound by theory, the binding functional group that is capable of forming an intermolecular interaction forms an interaction with the surface of the nanoparticle. It is this interaction which allows the adherence of the coating to the nanoparticle. Additionally, due to the branching structure of the nanoparticle coating, the binding functional group that is capable of forming an intermolecular interaction are also present on the external side of the coated nanoparticle as can be seen from Figure 1 . Without wishing to be bound by theory, that is, the functional groups that are capable of forming an intermolecular interaction form the intermolecular interaction with the surrounding environment to provide improved water solubility over those nanoparticle coatings of the prior art. The surrounding environment can be for example, water, a solvent, a cell matrix, a pharmaceutical excipient or carrier.

In yet another embodiment, R ₁₀ may be optionally protected with any suitable protecting group. For example, the protecting group may be used during synthesis. Protecting groups may be used such as ethyl groups could be used to protect phosphonate acids to form (- (P=0)OEt ₂ ) as shown herein; protecting groups suitable for hydroxy moieties include, but are not limited to, tetrahydropyranyl (THP), methoxymethyl (MOM), ferf-butyl (f-Bu), pivaloyl (Pv), acetonides, acetals and ferf-Butyldiphenylsilyl (TBDPS), ferf-butyldimethylsilyl (TBDMS). Similarly, suitable nitrogen protecting groups include but are not limited to acetyl (Ac), benzyl (Bn), tert-butoxycarbonyl (BOC), 9-Fluorenylmethyl (FMOC), Tosyl (Ts). Such protecting groups would also be well known and understood by those of skill in the art and are defined in Greene, T.W., Nuts, P. G in "Protective Groups in Organic Synthesis", Fourth Edition, John Wiley & Sons, New York: 2006, the entire contents of which are hereby incorporated by reference.

Preferably, R ₁₀ is at the terminal end of the pendant group. Preferably, R ₁₀ is selected from amines, amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), sulfamic acids (- S0 ₃ NH ₂ ). More preferably, R ₁₀ is selected from carboxylic acids (-C0 ₂ H), hydroxyl (-OH), and phosphonic acids (-PO(OH) ₂ ). In an embodiment, the hydrophilic polymer coating may further optionally comprise a wherein

R ₃ is selected from R ₄ , R ₆ and R ₄ R ₆ ;

R ₄ may be absent, or is selected from an optionally substituted C _1-20 aliphatic;

R ₆ may be absent, or is selected from a biomolecule; and provided that R ₄ and R ₆ cannot both be absent;

R ₃ is selected from R ₄ , R ₆ and R ₄ R _6. R ₄ or R ₆ may be absent, provided that at least one of R ₄ or R ₆ is present.

R ₄ is selected from an optionally substituted Ci- ₂₀ aliphatic. Preferably, R ₄ is selected from a C ₁ - ₂₀ alkyl, a Ci- ₂₀ alkylene, and Ci- ₂₀ alkenyl. Even more preferably, R ₄ is selected from C ₁ - ₂₀ alkyl, a Ci- ₂₀ alkylene. Yet even more preferably, R ₄ is selected from C ₂ -15 alkyl, a C ₂ -15 alkylene. Yet even more preferably, R ₄ is selected from C ₅ -i ₅ alkyl, a C ₅ . 15 alkylene.

R ₆ may be absent, or is selected from a biomolecule. Alternatively, R ₆ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents and combinations and derivatives thereof, and; and provided that when R ₄ is alkyl, R ₆ is absent.

Preferably, the homopolymer has a molecular weight of from about 1 kDa to about 25 kDa when calculated using MALDI-TOF mass spectrometry. More preferably, the homopolymer has a molecular weight of from about 5 kDa to about 20 kDa, the homopolymer has a molecular weight of from about 5 kDa to about 15 kDa.

Preferably, the use comprises a homopolymer comprises a formula selected from

wherein, a, R ₉ , R ₇ , and R ₁₀ are as hereinbefore described.

Even more preferably, the use comprises a homopolymer comprising a formula selected from

wherein, a, R ₇ , and R ₁₀ are as hereinbefore described.

Even more preferably, the use comprises a homopolymer comprises a formula selected from

wherein a, and R ₁₀ , are as hereinbefore described, and f is 1 to 4.

Even more preferably, the use comprises a homopolymer comprising a formula selected from

wherein a and R ₁₀ , are as hereinbefore described.

Most preferably, the use comprises a homopolymer comprising a formula selected from

wherein a is as hereinbefore described.

Most preferably, the use comprises a homopolymer comprises a formula selected from , wherein a is selected from

10 to 15, 50 to 70 and 600 to 700.

In an embodiment, the use comprises a nanoparticle polymer coating comprising formula:

wherein

-R ₂₀ -R19-H ₂₁ -H23 is a pendant group;

d is selected from 1 to 700. Preferably d is selected from 5 to 600. Even more preferably d is selected from 10 to 300. Even more preferably d is selected from 10 to 15, 50 to 70 and 600 to 700.

R ₁₄ is selected from hydrogen or R ₂₅ ;

R19 may be selected from an optionally substituted Ci _-4 alkylene, and a heteroatom group R ₂₀ is selected from an optionally substituted Ci _-6 aliphatic, carbonyl, thione or a combination thereof;

R ₂₁ is selected from an optionally substituted, straight or branched chain Ci _-6 alkylene, optionally substituted, straight or branched chain (Ci _-6 alk)aryl. Preferably, R ₂ i is a optionally substituted alkylene. Alternatively R ₂ i is a (Ci _-2 alk)aryl. Even more preferably R ₂ i is selected from a straight chain Ci _-4 alkylene and a (Ci _-6 alk)aryl. Even more preferably R ₂ i is selected from

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl and

wherein ^*** is the point of attachment of R ₂ i to the R ₂₃ and · is the point of attachment of

R ₁₈ is hydrogen or a C _1-4 alkyl. Preferably R ₁₈ is hydrogen or methyl. More preferably R ₁₈ is hydrogen;

R ₁₉ may be selected from an optionally substituted C _1-4 alkylene, and a heteroatom group.

In an embodiment, R ₁₉ may be selected from C _1-4 alkylene, and a heteroatom group. Preferably, R ₁₉ is a heteroatom group is selected from -NR ₉ - ethers (-0-), thioethers (-S-), wherein, R ₉ is selected from hydrogen or a C _1-4 alkyl. Even more preferably R ₁₉ is selected from -NR ₉ -. s a binding functional group that is capable of forming an intermolecular interaction or can form a covalent interaction with the nanoparticle. R ₂₃ may be covalently tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. Preferably the intermolecular interaction is selected from ionic interactions, dipole interactions, ion-dipole interactions, hydrogen bonding, and van der Waals interactions or combinations thereof. Alternatively groups capable of forming intermolecular interactions include polar functional groups, cationic functional groups, anionic functional groups, neutral functional groups and zwitterionic groups. Preferably, the binding functional group that is capable of forming an intermolecular interaction is selected from amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), and sulfamic acids (-S0 ₃ NH ₂ ). Even more preferably, the functional group capable of forming the binding functional group that is capable of forming an intermolecular interaction is selected from carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (- PO(OH) ₂ );

selected from R ₂₄ , R ₂₆ and R ₂₄ R ₂₆ ; either R ₂₄ or R ₂₆ may be absent, provided that only one of R ₂₄ or R ₂₆ is absent;

selected from an optionally substituted C _1-20 aliphatic. Preferably, R ₂₄ is selected from a C _1-20 alkyl, a C _1-20 alkylene, and C _1-20 alkenyl. Even more preferably, R ₂₄ is selected from C _1-20 alkyl, a C _1-20 alkylene. Yet even more preferably, R ₂₄ is selected from C _2- 15 alkyl, a C _2-15 alkylene. Yet even more preferably, R ₂₄ is selected from C ₅ . 1 ₅ alkyl, a C _5-15 alkylene. R ₂₆ may be absent, or is selected from a biomolecule. Alternatively, R ₂₆ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, fluorescent agents, and combinations and derivatives thereof, and provided that when R ₂₄ is alkyl or alkenyl, R ₂₆ is absent;

absent or is an optionally substituted straight or branched chain Ci _-20 aliphatic.

Preferably R ₂₂ is an optionally substituted straight or branched chain Cno aliphatic. R ₂₂ may be selected from an optionally substituted straight or branched chain CMO alkylene, an optionally substituted straight or branched chain a d- ₁ 0 alkenyl, and an optionally substituted straight or branched chain a C _1-10 alkynyl. More preferably, R ₂₂ is an optionally substituted straight or branched chain C _1-10 alkylene. Yet even more preferably R ₂₂ is a branched C _1-10 alkylene. Alternatively, R ₂₂ is a straight chain C _{1 -10} alkylene. Yet even more preferably, R ₂₂ is a C _{1 -4} alkylene. Even more preferably R ₂₂ is selected from:

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a Ci _-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl.

R ₂₈ may be absent, or is selected from an optionally substituted Ci- ₂₀ aliphatic. In another embodiment, R ₂₈ is an optionally substituted straight or branched chain C ₁ - ₂₀ aliphatic. In yet another embodiment, R ₂₈ is optionally tethered to a biomolecule or an active pharmaceutical agent. In a further embodiment, R ₂₈ is an optionally substituted straight or branched chain C _1-20 alkylene. In yet another embodiment, R ₂₈ is a straight claim C _1-20 alkylene. Preferably R ₂₈ is a C _1-6 alkylene. R ₂₈ may also be optionally substituted with groups selected from optionally substituted amines, optionally substituted amides, acyl, ethers, heteroatoms (oxygen, sulfur, nitrogen, or phosphorus), carbonyl, carboxylate, carbamate, thioketone;

R ₂₉ is hydrogen or a biomolecule. Preferably R ₂₉ is hydrogen. Alternatively preferably R ₂₉ is a biomolecule independently selected from targeting molecules, drug molecules, active pharmaceuticals, prodrugs, and combinations and derivatives thereof. When R ₂₈ is absent, the carboxylic acid moiety may be tethered to R ₂₉ , wherein R ₂₉ is hydrogen or a biomolecule. Preferably, the use comprises a hydrophilic polymer coating selected from

wherein, d, R ₁₄ , R ₂ i , R ₂₃ , R ₂₅ , and R ₂₇ are as hereinbefore described Preferably, the use comprises a hydrophilic polymer coating selected from

wherein, d, R ₁₄ , R ₁₈ , R ₂₁ , R ₂₃ , R ₂₅ , and R ₂₇ are as hereinbefore described.

Even more preferably the use comprises a hydrophilic polymer coating selected from

wherein, d, R ₁₄ , R ₂ i , R ₂₃ , R ₂₅ , and R ₂₇ are as hereinbefore described.

Even more preferably, the use comprises a hydrophilic polymer coating selected from

wherein, d, R ₁₄ , R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₅ , are as hereinbefore described.

Even more preferably, the use the use comprises a hydrophilic polymer coating selected from

wherein, d, R , R21 , R22 R23, and R ₂₅ , are as hereinbefore described, and f is 1 to 4. Even more preferably, the use comprises a polymer coating of a formula selected:

wherein d, R , R22, R23, and R ₂₅ , are as hereinbefore described.

Even more preferably, the use comprises a polymer coating of a formula selected from:

wherein d, R ₂₂ , and R ₂₃ , are as hereinbefore described.

Even more preferably, the use comprises a polymer coating of a formula selected from:

wherein, d, R ₂₂ , R ₂ 3, are as hereinbefore described.

Yet more preferably, the use comprises a polymer coating of a formula selected from:

wherein, d, and R ₂₂ are as hereinbefore described.

Most preferably, the use comprises a polymer coating of a formula selected from

wherein d is as hereinbefore described.

Most preferably, the use comprises a polymer coating of a formula selected from , wherein d is selected from 10 to 15, 50 to 70 and 600 to 700. In an embodiment, the use comprises a nanoparticle coating having a structural arrangement selected from

wherein R ₁₄ , R ₁₉ , R ₂₀ , R ₂ i , R23, F½ and R ₂₇ are as herein before defined and k is selected from 1 to 350 and h is selected from 150 to 250. Preferably the pendant groups are orientated in an internal and external orientation. That is, directed towards the nanoparticle surface and facing the surrounding environment.

In an embodiment, the nanoparticles to be coated are transition metal nanoparticles. The nanoparticle may comprise a core. The nanoparticle may comprise a shell. The nanoparticle may comprise a core and a shell. Preferably, the nanoparticle core is selected from metal, metal oxide, metal carbide, metal nitride, metal sulfide, or a combination thereof. Preferably, the nanoparticle shell is selected from a metal shell and a metal oxide shell.

In an embodiment, the nanoparticles are magnetic. Preferably, the nanoparticles are selected from paramagnetic, superparamagnetic, ferromagnetic, antiferromagnetic, ferrimagnetic, electromagnetic, diamagnetic nanoparticles. Such nanoparticles may include but are not limited to iron, nickel, cobalt, gadolinium, dysprosium; paramagnetic nanoparticles copper, aluminium carbon graphite, gold, silver, lead and bismuth. More preferably, the nanoparticle is an iron nanoparticle. Alternatively the nanoparticle is an iron oxide nanoparticle. Without wishing to be bound by theory, the present invention works by inducing a magnetic field on the coated nanoparticle. The magnetic field is an alternating magnetic field. This alternating in the magnetic field stimulates the nanoparticles and causes them to heat up, thereby also heating up the biological cells and inducing cell death.

In an embodiment, the coated nanoparticles have a hydrodynamic size of less than 200 nm. Preferably, the coated nanoparticles have a hydrodynamic size of less than 150 nm. More preferably the hydrodynamic size of the coated nanoparticles is less than 100 nm. Even more preferably, the hydrodynamic size of the nanoparticles is between 10 nm and 100 nm.

Preferably, the hydrophilic polymer coating has a molecular weight of from about 1 kDa to about 25 kDa when calculated using MALDI-TOF mass spectrometry. More preferably, the hydrophilic nanoparticle coating has a molecular weight of from about 5 kDa to about 20 kDa, the hydrophilic nanoparticle coating has a molecular weight of from about 5 kDa to about 15 kDa.

Preferably, the hydrophilic polymer coating has a polydispersity of from about 0.5 to about 2. Preferably, the polymer polydispersity is from about 0.7 to about 1 .5. More preferably, the polymer polydispersity is from about 0.9 to about 1 .3. Yet even more preferably, the polymer has a polydispersity of from about 1 to 1 .15. In an embodiment, the invention also provides for the use of the coated nanoparticles in medical applications. For example the coated nanoparticles may find use in drug delivery methods, diagnostic methods in a patient. The patient may be a human or non-human animal. Non-human animals include domestic and non-domestic animals. Such animals include but are not limited to birds and mammals, in particular, mice, rabbits, cats, dogs, pigs, sheep, goats, cows, horses, and possums. It is preferred that the patient is a human patient. In an embodiment, the coated nanoparticles of the present invention may find use in the delivery of active drug materials. Such materials may include targeting molecules, drug molecules, active pharmaceuticals, prodrugs, imaging agents, pharmaceutically acceptable salts thereof, and combinations and derivatives thereof. Targeting molecules include, but are not limited to antibodies, antigens, nucleic acids, peptides, sugars, folic acid, signalling molecules, combinations, pharmaceutically acceptable salts and derivatives thereof. Drug molecules and/or active pharmaceuticals and may be selected from anticancer drugs, antibiotic drugs, anti-inflammatory drugs, steroid drugs, immunosuppressant drugs. Without wishing to be bound by theory, when a biomolecule is tethered to the nanoparticle coating, it may be released into the body by the body's metabolic pathways for example, through

hydrolysis of the carboxyl group and/or cleavage of

The coated nanoparticle may also find use in the induction of cell death, for example, in the treatment of cancer by killing the cancer cells. Without wishing to be bound by theory, the present invention works by inducing a magnetic field on the coated magnetic nanoparticle. Preferably, the magnetic field is an alternating magnetic field. This alternation in the magnetic field stimulates the nanoparticles and causes them to generate heat and consequently inducing cell death (hyperthermia).

The present invention also provides for the use of coated nanoparticles as a method of treating, curing, ameliorating, reducing the symptoms, delaying the onset of, inhibiting the onset of, ameliorating pain, ending the pain, preventing pain associated with a medical disease, disorder or condition that requires a site specific localised treatment. For example such diseases and conditions may include cancer, targeting the site of a tumour, infections caused by bacteria, fungi, protozoa, microbe, atopic disorders, and inflammation. The present invention also provides for the uses of the coated nanoparticles selected from MRI contrast agent, MPI tracker, bio-separations, cell tracking and as drug delivery scaffold.

The present invention also provides for the use of the coated nanoparticle in the manufacture of a medicament for the treatment, cure, amelioration, reduction of the symptoms, delaying the onset of, inhibiting the onset of, ameliorating pain, ending the pain, preventing pain associated with a medical disease, disorder or condition that requires a site specific localised treatment. The present invention also provides for the use of the coated nanoparticles in the manufacture of a medicament for uses selected from a MRI contrast agent, magnetic particle imaging (MPI) trackers, bio-separation agent, cell tracking agent and as drug delivery scaffold. The coated nanoparticles of the present invention may be formulated for administration by means such as oral administration, parenteral administration, inhalation spray administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or via an implanted reservoir. The coated nanoparticles of the invention may be formulated with pharmaceutically acceptable carriers or diluents. Such carriers of diluents include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. It should also be understood to a person of skill in the art that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The coated nanoparticles of the present invention may also further be formulated as sterile injectable forms which may be aqueous or oleaginous suspension or solutions. These suspensions or solutions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, a bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Such agents will be known to those of skill in the art.

In another aspect, the present invention provides for the synthesis of the hydrophilic polymer nanoparticle coating. The hydrophilic polymer nanoparticle coating is prepared by first preparing a polymerisable monomer according to the following scheme:

TBAHS, 10 % wt Pd/C

NaN ₃ , MeOH,

^ R ₃₂ MeOH, 65°C H ₂ (g), RT _R

^R 34 R30 ^► R ₃₀ *~ H ₂ N R ₃₀

Scheme 1 . The polymerisable monomer has a protected binding functional group (R ₃₀ ) that is capable of forming an intermolecular interaction, or is capable of being covalently tethered to the nanoparticle surface. R ₃₀ may be tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. Such groups include protected amides, carboxylic acids (-C0 ₂ H), hydroxyl (-OH), phosphonic acids (-PO(OH) ₂ ), phosphinic acids (-PO(OH)), sulfonic acids (-S0 ₃ H), sulfinic acids (-S0 ₂ H), and sulfamic acids (-SO ₃ NH ₂ ) and an R ₃₂ group which is selected from an optionally substituted, straight or branched chain C _1-6 alkylene, an optionally substituted, straight or branched chain (C _1-6 alk)aryl. R ₃₄ is a halogen atom which is displaced under reaction with tetrabutylammonium hydrogen sulfate and sodium azide. The azide is then reduced by hydrogenation with palladium on carbon 10 wt % to provide an amine moiety. The amine is coupled with an acid chloride containing a terminal alkene bond. The synthetic route above provides a superior synthetic route to achieving an amide substituted monomer by using more readily available reagents with fewer synthetic steps when compared to the literature method [Polymer Chemistry 2013, 4, 795-803].

In an embodiment, the invention provides a process for the synthesis of a monomer as described above in Scheme 1 . The monomer is polymerised to form the homopolymer repeating unit as hereinbefore described.

The process comprises reacting:

A. compound containing a halide and the protected binding functional group of formula

B. a phase transfer reagent; and

C. sodium azide; in a polar protic organic solvent to form an azide moiety of formula ^N 3 ^R 3o . R ₃₄ is selected from a halide atom. Preferably, the halide atom is selected from I, CI, Br, and

F. Preferably the halide is Br.

R ₃₂ is selected from an optionally substituted, straight or branched chain C _1-6 alkylene, optionally substituted, straight or branched chain (C _1-6 alk)aryl. Preferably, R ₃₂ is a straight chain alkylene. Alternatively R ₃₂ is a (Ci _-2 alk)aryl. Even more preferably R ₃₂ is selected from a straight chain Ci _-4 alkylene and a (Ci _-6 alk)aryl. Even more preferably R ₃₂ is selected from

wherein x is one or more selected from -CH ₂ -, -NR ₉ - (-0-), (-S-), and wherein, R ₉ is selected from hydrogen or a C _1-4 alkyl. Preferably, R ₉ is selected from hydrogen or methyl and wherein ^*** is the point of attachment of R ₃₂ to the R ₃₀ .

The polar protic solvent is selected from a C _1-4 alcohol. Preferably the polar protic solvent is selected from ethanol (EtOH) and methanol (MeOH) and isopropanol (IPA). Even more preferably, the solvent is selected from MeOH.

The temperature of the reaction to form the azide moiety ^N 3 so is performed at elevated temperature. Preferably the temperature is from 50 °C to 100 °C. Preferably the reaction is performed at the reflux temperature of the polar protic solvent. Preferably, the reaction is continued over a period of about 5 hours to 24 hours. Even more preferably the reaction is continued over a period of about 10 to 20 hours. Yet even more preferably, the reaction is performed from about 1 2 to 1 8 hours. Preferably the reaction is filtered through a filter agent. Preferably the filter agent is selected from sand, silica, celite (diatomaceous earth) and alumina. Even more preferably the filter agent is celite (diatomaceous earth).

In an embodiment, the process further comprises: reducing a compound of formula ^N s ^R 3o by hydrogenation to give a compound of formula 2 ^{N R} 3o . Preferably the hydrogenation is performed under hydrogen atmosphere. Even more preferably the hydrogenation utilises a transition metal catalyst. Preferably the transition metal catalyst is selected from palladium. Preferably, the palladium catalyst is palladium on carbon.

Preferably, the hydrogenation reaction is carried out in a polar protic solvent. Preferably the solvent is selected from a Ci _-4 alcohol. Even more preferably

Preferably, the formation of an amine of formula ^M 2 ^{N K} 3o by hydrogenation further comprises filtration of the hydrogenation reaction mixture through a filter agent. Preferably the filter agent is selected from sand, silica, celite (diatomaceous earth) and alumina. Even more preferably the filter agent is celite (diatomaceous earth).

/ R32

In yet another embodiment, the amine of formula 2 ^{N R} so is cou led with an acid halide

of formula 36 to form a compound of formula

R ₃₆ is selected from an optionally C _{1 -6} aliphatic, carbonyl, thione or a combination thereof and R ₃₂ and R ₃₀ as hereinbefore described. Preferably the coupling of the acid halide to the amine is performed under an inert atmosphere. Preferably, the inert atmosphere is a nitrogen or argon atmosphere. Preferably, the addition of the acid halide to the amine is performed at reduced temperature. Preferably, the reduced temperature is from about 5 °C to about -25 °C. Even more preferably, the reaction is performed from about 5 °C to -1 1 °C. Yet even more preferably, the reaction is performed at about 0 °C. Preferably, the reaction is warmed after the addition of the acid halide is complete. Preferably, the reaction is warmed to room temperature. Preferably, the reaction is allowed to warm by removing from a cold bath and allowing to stand at room temperature. Preferably the reaction is allowed to progress for a period of between 2 hours and about 24 hours. Even more preferably, the reaction proceeds over a duration of between 5 hours and 20 hours. Yet even more preferably, the reaction proceeds over a period of 12 hours to 18 hours.

In another embodiment, the nanoparticle coating is prepared by polymerisation of the monomer. Preferably, the polymerisation reaction is performed under an inert atmosphere. Preferably, the inert atmosphere is a nitrogen or argon atmosphere.

Preferably the polymerisation reaction is initiated by the use of a radical initiator. Preferably the radical initiator is selected from azo compounds, peroxides and photoinitiators. Preferably the radical initiator is an azo compound. Preferably, the azo compounds are selected from 1 ,1 '-Azobis(cyanocyclohexane) (VAZO™) and Azobisisobutyronitrile (AIBN). Yet even more preferably, the radical initiator is AIBN.

Preferably, the polymerisation reaction is performed at elevated temperature. Preferably the polymerisation reaction is performed at a temperature of about 50 to about 100°C. Even more preferably, the polymerisation reaction is performed at about 80°C.

Preferably, the polymerisation reaction is continued for a period of between 2 hours and about 24 hours. Even more preferably, the reaction proceeds over a duration of between 5 hours and 20 hours. Yet even more preferably, the reaction proceeds over a period of 12 hours to 18 hours.

Preferably the reaction is quenched by rapid cooling. Preferably the reaction is cooled in an acetone/dry ice bath, or cooled in liquid nitrogen. Yet even more preferably the reaction is quenched by rapid cooling in liquid nitrogen. Where the description reference has been made to integers having known equivalents thereof, those equivalents are herein incorporated as if individually set forth. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. It is appreciated that further modifications may be made to the invention as described herein without departing from the spirit and scope of the invention. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed.

Additionally, general principles of organic chemistry are described in texts known to those of ordinary skill in the art, including, for example, Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001 , the entire contents of which are hereby incorporated by reference.

The nanoparticle coating comprises a backbone with pendant groups spaced at regular intervals as exemplified by the schematic in Figure 1 .

At the end of the pendant groups can be found polar hydrophilic functional moieties capable of forming intermolecular interactions as shown in Figure 1 . Without wishing to be bound by theory, these polar hydrophilic groups capable of forming intermolecular interactions have a number of functions on the polymer and coating of the nanoparticle. The hydrophilic groups form intermolecular interactions with the surrounding environment or the nanoparticle, or with both the nanoparticle and the surrounding environment. The intermolecular interactions make the nanoparticle coating compounds polar which provides the feature of water solubility to the coated nanoparticles. The water solubility allows the coated nanoparticle to be dissolved in water. This is beneficial for medical application and overcomes problems associated with the formulation of pharmaceuticals, such as emulsions, suspension, and multiple phases forming in a liquid. Problems of formulation are well known within the art. Furthermore, water solubility is highly important for biological systems because it allows such components to be easily transported through the biological system. Surprisingly and conveniently, nanoparticles coated with the coating of the present invention also have improved water stability over the prior art and have been found to be stable in water for extended periods of time, for example up to a month. Another function of the hydrophilic groups on the pendant arm of the coating is to form intermolecular interactions with the surrounding environment and the nanoparticle itself.

The interactions that form with the nanoparticle allow the coating to adhere to the nanoparticle. The hydrophilic polymer coating may be covalently attached to the nanoparticle surface, or alternatively, by selecting functional moieties that capable of forming intermolecular interactions with high affinity for the nanoparticle, covalent linking may not be required. The hydrophilic coating may be tethered to the nanoparticle through anchoring groups. Suitable anchoring groups would be known to those of skill in the art. The nanoparticles are coated by sonicating solutions containing nanoparticles in toluene, and polymer in methanol at 1 :1 mass ratio. The successful coating of the nanoparticles with the hydrophilic polymer coating can be confirmed through FTIR studies. Without wishing to be bound by theory, FTIR shows characteristic phosphonate bands of the polymer species present on the coated particles. For example, in the case of iron oxide (FeOx) coated nanoparticles, the stretches at 1078 cm ^"1 and 984 cm ^"1 in the FTIR spectrum of correlate with stretches that would be expected for P-O-Fe stretches that are known in the art. These characteristic FTIR stretches confirm that it is the phosphonate that group binds to the FeOx nanoparticle surface as shown in Figure 2. Furthermore, the polymer coating may optionally comprise a biologically cleavable group at the end of the backbone of the hydrophilic polymer, to which an active pharmaceutical compound can be tethered. This allows for the delivery and release of an active pharmaceutical agent or an imaging agent within the body, at a designated target site, for example at the site of a cancerous tumour, a site of inflammation, a site of infection, or for use in imaging diagnosis.

The nanoparticles used within the scope of this invention are required to be metal nanoparticles. Particularly, it is preferred that the nanoparticles have magnetism for example paramagnetic, superparamagnetic, ferromagnetic, antiferromagnetic, ferrimagnetic, electromagnetic, The nanoparticles may also be selected from metal, metal oxide, metal carbide, metal nitride, metal sulfide, or combinations thereof. It is preferred that the nanoparticles are selected from chromium, manganese, iron, cobalt and molybdenum. Without wishing to be bound by theory exposure coated nanoparticles are exposed to magnetic field. The magnetic field causes the nanoparticles to heat which induces cell death, furthermore, the addition of a pharmaceutical or imaging agent provides a double method of treating a condition.

It is also required that the coated nanoparticles have a hydrodynamic size of less than 200 nm. Without wishing to be bound by theory, when the nanoparticles are above 200 nm, such particles are rapidly cleared by the reticuloendothelial system and will accumulate in the kidneys rather than the targeted site. A person of skill in the art will readily understand how to achieve specific hydrodynamic sizes (ACS Nano, 2013, 7, 6244-6257). The hydrodynamic size of the coated NP may be altered by optimisation of the coating protocol by reacting about a 1 :1 ratio of polymer mass to NP mass, It should be noted that larger amounts of polymer may result in extensive crosslinking between coated nanoparticles resulting in a larger hydrodynamic size because more of the particles are encapsulated/coated by the polymer. Reacting in ratios of significantly less that about 1 :1 may result in lack of stabilisation and subsequent rapid precipitation from the final aqueous suspension.

The present inventors have found that the nanoparticles coated with the formulae herein described are effective in the treatment of HeLa cervical cancer cells as shown in Figure 3. In cytotoxicity studies carried out using HeLa cervical cancer cells, the cells are incubated for 24 hr after seeding the cells with the coated nanoparticles at concentrations up to 1 mg mL ^"1 .

Iron oxide nanoparticles coated with showed zero acute toxicity at the highest concentrations tested, while iron nanoparticles showed only 63% cell viability at 1 mg mL ^"1 (as shown in Figure 3). Without wishing to be bound by theory, this is thought to be due to higher rates of aggregation of the iron particles during the incubation period, which results in higher cell death.

Description of the Figures

1 : Schematic of the homopolymer binding to the nanoparticle surface. Some phosphonate head groups are bound to the surface where others are exposed on the outer surface which renders it water soluble. Figure 2: Shows FTIR studies, exemplifying the characteristic phosphonate bands of the polymer species of Formula Z present on the nanoparticles post-coating. The stretches at 1078 cm ^"1 and 984 cm ^"1 in the FTIR spectrum of the coated FeOx NPs (Tops trace), confirming that the phosphonate group binds preferentially over the carboxylate group to the FeOx surface. Figure 3 shows the cytotoxic activity of Iron nanoparticles coated with polymer of formula Z against HeLa cancer cells.■ = Fe oxide nanoparticles coated with formula Z;□ = iron nanoparticles coated with Formula Z. Figure 4 shows the mass spectrometry data for Formula Z, wherein n= 60 to 70. Monomer unit = 235.22 g/mol. Results (m/z): 1752.85 (n=6), 1986 (n=7-not labelled), 2221 .77 (n=8), 2456.62 (n=9), 2691 (n=10-not labelled), 2925.72 (n=1 1 ), 3161 .26 (n=12), 3395 (n=13-not labelled), 3631 (n=14-not labelled), 3861 .53 (n=15), 4101 (n=16-not labelled).

Figure 5 shows the hydrodynamic diameter distribution of nanoparticles coated with

Formula Z.

Figure 6: TEM image of hydrophobic iron nanoparticles suspended in toluene.

Figure 7: TEM image of hydrophilic iron nanoparticles coated with Formula Z suspended in water.

Figure 8 shows cell viability oi HeLa cell cultures incubated for 24 hours in the presence of

FeNPs at a range of Fe concentrations. Fe nanoparticles were coated with

Poiy S, with polymer chain length of 6, 10 or 66 repeating units. N = 4 for each sample group, A - FePoiyM3 (n=6); ·- FePoiy 3 (n=10);■ - FePo!yM3 (n=66).

Figure 9 shows Powder X-ray diffraction patterns for A) as-synthesised, oiey!amine-coated

Fe NPs; B) Fe NPs coated with Poiy 3 containing 10 repeating units (n = 10); and C) Fe NPs coated with Poiy 3 containing 66 repeating units (n = 66).

Abbreviations

AcOH acetic acid

AIBN 2,2-Azobis(isobutyronitrile)

BP boiling point in °C

CDCI3 deuterochloroform

DCE 1 ,2-dichloroethane

DCM methylene chloride

DSC differential scanning calorimetry

ESI electrospray ionisation mass spectrometry

FTIR Fourier transform infrared spectroscopy

HPLC high performance liquid chromatography

MS mass spectrometry

Mn number average molecular weight

Mw mass average molecular weight

NMR nuclear magnetic resonance

TLC thin layer chromatography

μΙ- microliters

Examples

The examples described herein are for purposes of illustrating embodiments of the invention. Other embodiments, methods, and types of analyses are within the capabilities of persons of ordinary skill in the art and need not be described in detail herein. Other embodiments within the scope of the art are considered to be part of this invention.

Materials:

All solvents and reagents are of technical or analytical grade and are used as received unless otherwise stated. AIBN is recrystallised from ethanol and used as a radical initiator. DMF is used for polymerisation reactions and is distilled and degassed fully prior to use in the polymerisation reactions. Silica gel flash chromatography is performed with Davisil silica gel (LC60A 40-63 micron) stationary phase. ¹ H-NMR and ¹³ C-NMR spectra are performed on a Bruker AC 400 MHz using CDCI ₃ or D ₂ 0 as solvent, unless otherwise stated. MALDI- TOF results are obtained using the matrix mixture of dithranol; polymer; silver trifluoroacetate (8;1 ;1 wt. ratio).

Synthesis of diethyl (2-azidoethyl)phosphonate

Diethyl (2-bromoethyl)phosphonate (2.00 mL, 1 1 .02 mmol) and TBAHS (5.60 g, 16.49 mmol) are dissolved in MeOH (50 mL). NaN ₃ (2.86 g, 43.99 mmol) is then added and the reaction mixture is stirred at 65 °C under a reflux condenser for 17 h. The solvent is evaporated to dryness and the residue is diluted with Et ₂ 0 (30 mL) and filtered through celite. The filtrate is then washed with H ₂ 0 (30 mL). The organic layer is dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the title compound (1 .44 g, 63 %) as a yellow oil. ¹ H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 4.1 1 (m, 4H, 2 χ CH ₂ ), 3.53 (m, 2H, CH ₂ ), 2.08 (m, 2H, CH ₂ ), 1 .33 (t, J = 7.9, 6H, 2 ^χ CH ₃ ); ¹³ C-NMR (75 MHz, CDCI ₃ ) δ (ppm): 61 .9 (d, ² J _CP = 6.5, 2 x CH ₂ ), 45.2 (d, ² J _CP = 2.3, CH ₂ ), 24.4 (d, J _C p = 140.0, CH ₂ ), 16.2 (d, ³ J _CP = 6.0, 2 x CH ₃ ).

Synthesis of diethyl (2-aminoethyl)phosphonate

Diethyl (2-azidoethyl)phosphonate (2.50 g, 12.07 mmol) is dissolved in MeOH (180 mL) under N ₂ . 10 % Pd/C (250 mg, 10 wt %) is added and the atmosphere gas is exchanged with H ₂ . The reaction is stirred under H ₂ for 18 h then diluted with Et ₂ 0 and filtered through celite. The filtrate is evaporated under reduced pressure and the crude product is purified by silica gel chromatography using 10% MeOH/DCM as mobile phase to give the title compound (2.17g, quant.) as yellow oil. ¹ H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 4.95 (br s, 2H, NH ₂ ), 4.06 (m, 4H, 2 x CH ₂ ), 3.18 (m, 2H, CH ₂ ), 2.28 (m, 2H, CH ₂ ), 1 .27 (m, 6H, 2 χ CH ₃ ); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ (ppm): 61 .8 (CH ₂ ), 61 .7 (CH ₂ ), 35.9 (CH ₂ ), 28.7 ( = 138.8, CH ₂ ), 16.4 (CH ₃ ), 16.3 (CH ₃ ). Spectroscopic data are in good agreement with those previously reported.' ²¹

Synthesis of diethyl (2-acrylamidoethyl)phosphonate

O 0 0

⁰ ^ p' ^► i P

⁺ H ₂ N'^ ^' | "OEt ^N' v I^OEt

CI OEt OEt

Diethyl (2-aminoethyl)phosphonate (3.93 g, 21 .70 mmol) is dissolved in CHCI ₃ (35 mL) and Et ₃ N (4.54 mL, 32.55 mmol) is added. The mixture is cooled to 0 °C and stirred vigorously under a nitrogen environment. Acryloyl chloride (2.28 mL, 28.21 mmol) in CHCI ₃ (5 mL) is added dropwise to the reaction over 1 h. The mixture is warmed to R.T. and stirred for a further 18 hr under a nitrogen atmosphere. The solvent is then evaporated and the residue diluted with Et ₂ 0 (30 mL) and filtered through celite. The filtrate is concentrated under reduced pressure and the crude material is purified by silica gel flash chromatography (10% MeOH/DCM) to give the title compound (2.96 g, 58 %) as pale yellow oil. ¹ H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 7.03 (br s, 1 H, NH); 6.20 (dd, J = 1 .5, 17.1 , 1 H, H-1 _b ), 6.06 (dd, J = 10.3, 17.1 , 1 H, H-2), 5.67 (dd, J = 1 .5, 10.4, 1 H, H-1 _a ), 4.04 (m, 4H, 2 χ CH ₂ ), 3.53 (m, 2H, H-5), 1 .96 (m, 2H, H-6), 1 .25 (t, J = 7.0, 6H, 2 ^χ CH ₃ ); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ (ppm): 165.5 (C), 130.7 (CH ₂ ), 126.0 (CH), 61 .7 (CH ₂ , ² J _P = 7), 33.4 (CH ₂ , ² J _P = 5), 25.3 (CH ₂ , J _P = 142), 16.2 (CH ₃ , ³ J _P = 6).

RAFT polymerisation of diethyl (2-acrylamidoethyl)phosphonate

The polymerisation target weight is 12,000 g/mol. Diethyl (2-acrylamidoethyl)phosphonate (1 .50 g, 6.38 mmol), CTA (47 mg, 0.128 mmol), AIBN (7 mg, 0.33 mmol) and distilled DMF (10 mL) are added to a Schlenk tube. The mixture is then degassed thoroughly by bubbling nitrogen through the mixture for at least 1 h. The reaction vessel is then evacuated and refilled with nitrogen (x3 times) and stirred at 80 °C for 18 hr. The reaction is quenched by rapid cooling in liquid nitrogen and a small sample taken for ¹ H-NMR analysis to ensure polymerisation. The polymer is purified by precipitation from cold hexane (-400 mL) (x 2) to give the title compound (1 .08 g) as a sticky yellow substance (Monomer conversion = 72 %). MALDI-TOF: m/z 3161 .26 (n=12). ¹ H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 4.04 (OCH ₂ ); 3.51 (CH ₂ N), 1 .98 (CH ₂ P and CH ₂ -CH), 1 .47 (CH ₂ -CH), 1 .27 (CH ₃ ). ³¹ P-NMR (162 MHz, MeOD) δ (ppm): 29.2.

Deprotection of polyM3

Polymer (1 .05 g, 3.72 mmol of phosphorus moieties) is dissolved in dry CHCI ₃ (35 mL). TMS-Br (2.35 mL, 17.84 mmol) is added dropwise and the reaction and is left to stir at RT for 20 h. The solvent is evaporated under reduced pressure and the residue dissolved in MeOH (50 mL) and stirred for a further 4 h. The solvent is then evaporated to dryness and the residue freeze dried to give the title compound (1 .037 g, 94%) as a brown solid. ¹ H-NMR (400 MHz, D ₂ 0) δ (ppm): 3.43 (CH ₂ N), 2.01 (CH ₂ P and CH ₂ -CH), 1 .53 (CH ₂ -CH). ³¹ P-NMR (162 MHz, D ₂ 0) 5 (ppm): 26.5. General Procedure for coating of the nanoparticles

Coating experiments are carried out by sonicating a solution containing hydrophobic nanoparticles in toluene and the polymer in methanol at 1 :1 mass ratio. After sonication, the nanoparticles are isolated from the toluene:methanol solution via centrifugation, dried and re-suspended in deionised water. Further centrifugation is carried out to remove any unbound polymer, followed by re-suspension of the polymer coated nanoparticles in deionised water (pH 7). For example, in iron oxide (FeOx) coated nanoparticles, the stretches at 1078 cm ^"1 and 984 cm ^"1 in the FTIR spectrum of correlate with stretches that would be expected for P-O-Fe stretches. These characteristic FTIR stretches confirm that it is the phosphonate that group binds to the FeOx nanoparticle surface as shown in Figure 2. Figures 6 and 7 respectively show images of the uncoated nanoparticles in toluene, and the coated nanoparticles in water.

General Procedure for Cytotoxicity studies

HeLa cells are cultured in complete medium supplemented with IL-4 and GM-CSF in 6 well plates at 2x10 ⁶ cells in 5ml per well, The HeLa cells are then transferred to a 24 well plate at 5000 cells/well in complete medium. Fe NPs and FeOx NPs are added at concentrations ranging from 0-200 μg Fe ml ^"1 in triplicate wells. As a control, wells with media only (no cells) are set up for every concentration of NPs. After 24 hours, trypsin is added to fix the cells (liberating them from the bottom of the well plate), followed by further incubation for 1 hour. 10 μΙ aliquots are removed from each well, into a new 96 well plate and trypan blue dye added, and counted using a haemacytometer. Live cells are distinguished by the exclusion of trypan blue dye (Invitrogen).