Block copolymer and therapeutic use thereof

Abstract

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Description

[0001]BLOCK COPOLYMER AND THERAPEUTIC USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from United Kingdom patent application number 2318926.9 filed on 12 December 2023, which is incorporated by reference herein. FIELD The disclosure relates to a block copolymer and its use in treating a disease, in particular cancer. BACKGROUND Cancer is one of the world’s leading causes of premature death. Small molecule platinum drugs, including cisplatin, carboplatin and oxaliplatin, are known first line chemotherapeutic agents for treating several solid tumours including prostrate, ovarian, cervical and lung cancer. These platinum drugs are known to undergo premature activation and non- selective binding to many essential biomolecules, which reduces their bioavailability and also causes severe side effects including hair loss, hepatoxicity, nephrotoxicity, neurotoxicity and ototoxicity. These serious systemic toxicities limit the clinical use of small molecule platinum drugs. The undesirable effects of small molecule platinum drugs can be reduced or avoided by selectively delivering the drugs to tumours. This can be done by using nanocarriers as vectors through a passive targeting process which capitalizes on the enhanced permeation retention (EPR) effect of tumours. Tumor tissue exhibits an enhanced permeability which is caused by a leaky vasculature which is unique to tumours, as well as an abnormal retention of nanosized macromolecules due to the impaired intratumoural lymphatic drainage. Consequently, nanoparticles selectively accumulate in tumours, leading to enhanced tumour selectivity of nanoparticle encapsulated drugs and reduced off-target toxicity. Additional benefits of using nanocarriers in this manner include better solubilization of the drugs, protection from undesirable binding events during circulation, reduced renal clearance, and more efficient intracellular uptake by cancer cells via endocytosis. Nanocarriers are usually composed of amphiphilic block copolymers (BCPs), i.e. hybrid materials composed of two (or more) distinct covalently linked polymer chains, which spontaneously self- assemble in an aqueous solution into nanosized aggregates such as core-shell micelles. Therapeutic agents or drugs can be conjugated to carboxylate groups on the BCPs. When the micelles form, the drugs are either physically or covalently entrapped in the micelle core whilst the hydrophilic shell stabilizes the aggregate, affording the drugs dual protection by the hydrophobic core and the hydrophilic corona and forming so-called “nanodrugs”. Ideally the carrier should not leak out its drug prematurely, but release it inside cancer cells, in response to an external stimulus. Upon uptake into cancer cells via endocytosis, hydrolysis of the nanoparticles results in the aquation / activation of the drugs, cleaving them from the polymer backbone and freeing the drugs in their active form. Drug release is also enhanced by the low pH environment in endosomes as carboxylate–ester bonds are more rapidly hydrolyzed at a low pH. However, a significant challenge is the need to perform multistep synthesis procedures, each with intermediate isolation and purification steps, in order to obtain BCPs with the desired COOH functionality. Accordingly, there is a need for a simple, low cost method for preparing BCPs with carboxylate groups for the preparation of polymer-platinum drugs. The preceding discussion is intended only to facilitate an understanding of the present invention. It should be appreciated that the discussion is not an acknowledgment or admission that any of the material referred to was part of the common general knowledge in the art as at the priority date of the application. SUMMARY According to a first aspect, there is provided a block copolymer of Formula (I): B1— block — (R2)n(I) where B1is (R1—alt—R2)mor (R2—alt—R1)m; R1is an electron poor anhydride functional monomer that can be hydrolyzed into a dicarboxylic acid; R2is an electron rich vinyl monomer that is polymerizable to form water soluble and biocompatible polymers; m is an integer from 1 to 1000; and n is an integer from 1 to 1000. R1may be selected from maleic anhydride (MAnh), citraconic anhydride (CAnh) and itaconic anhydride (IAnh). R2may be polymerizable by reversible deactivation radical polymerization (RDRP) to form water soluble and biocompatible polymers. R2may be N-vinylpyrrolidone (NVP), N-vinylformamide (NVF), N-vinylacetamide (NAM), N-vinyl-N-methylacetamide (NVMA), N-vinylcaprolactam (NVC), vinyl acetate (VAc) or vinyl pivalate (VPi). R2 is preferably not styrene. The block copolymer may be any one of the following: poly(N-vinylpyrrolidone-alt-maleic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt- MAnh)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-citraconic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt- CAnh)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-itaconic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt- IAnh)-block-PVP) block copolymer; poly(N-vinyl formamide-alt-maleic anhydride)-block-polyvinylformamide (poly(NVF-alt- MAnh)-block-PVF) block copolymer; poly(N-vinylformamide-alt-citraconic anhydride)-block-polyvinylformamide (poly(NVF-alt- CAnh)-block-PVF) block copolymer; poly(N-vinylformamide-alt-itaconic anhydride)-block-polyvinylformamide (poly(NVF-alt- IAnh)-block-PVF) block copolymer; poly(N-vinylacetamide-alt-maleic anhydride)-block-polyvinylacetamide (poly(NAM-alt- MAnh)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-citraconic anhydride)-block-polyvinylacetamide (poly(NAM-alt- CAnh)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-itaconic anhydride)-block-polyvinylacetamide (poly(NAM-alt- IAnh)-block-PAM) block copolymer; poly(N-vinyl-N-methylacetamide-alt-maleic anhydride)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-MAnh)-block-PNVMA block copolymer; poly(N-vinyl-N-methylacetamide-alt-citraconic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-CAnh)-block-PNVMA) block copolymer; poly(N-vinyl-N-methylacetamide-alt-itaconic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-IAnh)-block-PNVMA) block copolymer; poly(N-vinylcaprolactam-alt-maleic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt- MAnh)-block-PNVC block copolymer; poly(N-vinylcaprolactam-alt-citraconic anhydride)-block-polyvinylcaprolactam (poly(NVC- alt-CAnh)-block-PNVC) block copolymer; poly(N-vinylcaprolactam-alt-itaconic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt- IAnh)-block-PNVC) block copolymer; poly(vinyl acetate-alt-maleic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt-MAnh)- block-PVAc block copolymer; poly(vinyl acetate-alt-citraconic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt-CAnh)- block-PVAc) block copolymer; poly(vinyl acetate-alt-itaconic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt-IAnh)- block-PVAc) block copolymer; poly(vinyl pivalate-alt-maleic anhydride)-block-poly(vinyl pivalate) (poly(VPi-alt-MAnh)- block-PVPi block copolymer; poly(vinyl acetate-alt-citraconic anhydride)-block-poly(vinyl acetate) (poly(VPi-alt-CAnh)- block-PVPi) block copolymer; poly(vinyl pivalate-alt-itaconic anhydride)-block-poly(vinyl pivalate) (poly(VPi-alt-IAnh)- block-PVPi) block copolymer; poly(N-vinylpyrrolidone-alt-maleic acid)-block-polyvinylpyrrolidone (poly(NVP-alt-MA)- block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-citraconic acid)-block-polyvinylpyrrolidone (poly(NVP-alt-CA)- block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-itaconic acid)-block-polyvinylpyrrolidone (poly(NVP-alt-IA)- block-PVP) block copolymer; poly(N-vinyl formamide-alt-maleic acid)-block-polyvinylformamide (poly(NVF-alt-MA)- block-PVF) block copolymer; poly(N-vinylformamide-alt-citraconic acid)-block-polyvinylformamide (poly(NVF-alt-CA)- block-PVF) block copolymer; poly(N-vinylformamide-alt-itaconic acid)-block-polyvinylformamide (poly(NVF-alt-IA)-block- PVF) block copolymer; poly(N-vinylacetamide-alt-maleic acid)-block-polyvinylacetamide (poly(NAM-alt-MA)-block- PAM) block copolymer; poly(N-vinylacetamide-alt-citraconic acid)-block-polyvinylacetamide (poly(NAM-alt-CA)- block-PAM) block copolymer; poly(N-vinylacetamide-alt-itaconic acid)-block-polyvinylacetamide (poly(NAM-alt-IA)-block- PAM) block copolymer; poly(N-vinyl-N-methylacetamide-alt-maleic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-MA)-block-PNVMA block copolymer; poly(N-vinyl-N-methylacetamide-alt-citraconic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-CA)-block-PNVMA) block copolymer; poly(N-vinyl-N-methylacetamide-alt-itaconic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-IA)-block-PNVMA) block copolymer; poly(N-vinylcaprolactam-alt-maleic acid)-block-polyvinylcaprolactam (poly(NVC-alt-MA)- block-PNVC block copolymer; poly(N-vinylcaprolactam-alt-citraconic acid)-block-polyvinylcaprolactam (poly(NVC-alt- CA)-block-PNVC) block copolymer; poly(N-vinylcaprolactam-alt-itaconic acid)-block-polyvinylcaprolactam (poly(NVC-alt-IA)- block-PNVC) block copolymer; poly(vinyl alcohol-alt-maleic acid)-block-poly(vinyl alcohol) (poly(VA-alt-MA)-block-PVA block copolymer; poly(vinyl alcohol-alt-citraconic acid)-block-poly(vinyl alcohol) (poly(VA-alt-CA)-block-PVA) block copolymer; and poly(vinyl alcohol-alt-itaconic acid)-block-poly(vinyl alcohol) (poly(VA-alt-IA)-block-PVA) block copolymer. The block copolymer may be conjugated to a therapeutic molecule, such as a cancer drug. The cancer drug may be a platinum-based cancer drug with cis-ammine or substituted amine, non- leaving ligands. According to a second aspect, there is provided a block copolymer as described above for use in treating a disease, such as cancer. According to a third aspect, there is provided a pharmaceutical composition comprising a block copolymer as described above and a pharmaceutically acceptable carrier. The pharmaceutical composition may be for use in treating cancer. According to a further aspect, there is provided a method of synthesizing a block copolymer as described above, the method comprising the step of copolymerizing a first monomer R1with an excess of a second monomer R2to form a first block segment comprising an R1-alt-R2copolymer or R2-alt-R1copolymer and thereafter, once R1has been depleted, to continue to grow an essentially pure R2segment on the copolymer, thereby obtaining a block copolymer having the formula: B1— block — (R2)n(I), wherein B1, R1, R2, m and n are as defined above. The copolymerization step may be performed using reversible addition fragmentation transfer (RAFT) mediated copolymerization. The RAFT mediated copolymerization may be performed in the presence of a RAFT chain transfer agent, such as a xanthate, dithiocarbamate or trithiocarbonate. The RAFT mediated polymerization may be thermally- or photo-initiated. The block copolymer may be formed in a one pot, one step process. The method may further comprise the step of hydrolyzing R1 anhydride groups in the block copolymer to carboxylate groups. The method may further comprise the step of conjugating a therapeutic molecule to the carboxylate groups of the block copolymer. The therapeutic molecule may be a cancer drug, such as a drug having a cis- diammineplatinum(II) fragment. The conjugating step may be performed by mixing the block copolymer and therapeutic molecule together and allowing the therapeutic molecule to bind to a carboxylate group of the hydrolyzed R1in the block copolymer and / or to an amide group of R2in the block copolymer. The conjugates formed from the block copolymer and therapeutic molecule may be allowed to assemble into nanoparticles, for example core shell micelles. According to a further aspect, there is provided a use of a block copolymer as described above in the manufacture of a medicament for treating cancer. According to a further aspect, there is provided a method of treating or preventing a disease, the method comprising administering to a subject in need thereof an effective amount of a block copolymer described above. The disease may be cancer. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a synthetic strategy for the synthesis of a poly(NVP-alt-MAnh)-block-PVP block copolymer, subsequent fabrication of the polymer-drug conjugate, and self-assembly into a micelle drug delivery vehicle. Figure 2 shows a schematic illustration of block copolymer functionalization with platinum(II) drugs, subsequent self-assembly into micelles, and end release of the drugs. DETAILED DESCRIPTION Block copolymers of the formula: B1 — block — (R2)n (I) where B1 is (R1—alt—R2)m or (R2—alt—R1)m and methods of their synthesis are described herein. The block copolymers have a first block segment B1 formed from alternating first and second comonomers ((R1-alt-R2)m or (R2-alt-R1)m) and a second block segment B2 formed from the second monomer ((R2)n). These di-block copolymers, and pharmaceutical compositions including them, can be used to form pharmaceutical compositions for treating or preventing diseases. R1, the first monomer, is an electron poor anhydride functional monomer that can be hydrolyzed into a dicarboxylic acid. Suitable monomers include maleic anhydride (MAnh), citraconic anhydride (CAnh), itaconic anhydride (IAnh) and the like. R2, the second monomer, is an electron rich vinyl monomer that is polymerizable to form water soluble and biocompatible polymers, in particular by radical polymerization techniques such as reversible addition fragmentation transfer (RAFT) mediated copolymerization. R2is typically a monomer including a vinyl moiety, such as N-vinylpyrrolidone (NVP), N-vinylformamide (NVF), N- vinylacetamide (NAM), N-vinyl-N-methylacetamide (NVMA), N-vinylcaprolactam (NVC), vinyl acetate (VAc), vinyl pivalate (VPi), vinyl alcohol (VA) or the like. Monomers which polymerize into a hydrophobic polymer, which is not able to provide colloidal stability to the nanoparticles in an aqueous suspension, are not suitable for use as R2. These will be readily known to a person of skill in the art. For example, styrene polymerizes into polystyrene (a hydrophobic polymer), and is therefore not a suitable polymer for R2. In formula (I), m is an integer from 1 to about 1000, and more particularly is in the range of from about 1 to about 300, and even more particularly from about 20 to about 100; n is an integer from 1 to about 1000, and more particularly is in the range of from about 20 to about 100. It will be apparent to a person skilled in the art that the first block segment can comprise the comonomers R1 and R2 in either order, i.e. R1-alt-R2 or R2-alt-R1. In this description and the figures, reference to either one of these options is intended to also include reference to the other option. As used herein, the term “monomer” takes its usual definition in the art, and so refers to a molecular compound that may chemically bind to another monomer to form a polymer. The term “copolymer” takes its usual definition in the art, and so refers to a polymer whose polymer chains comprise two or more different types of monomers. An alternating copolymer refers to a copolymer wherein the different types of monomers alternate, e.g. -R1-R2-R1-R2… The term “hydrophilic monomer” or “hydrophilic polymer” refers to a monomer or polymer with an affinity for water molecules. The term “hydrophobic monomer” or “hydrophobic polymer” refers to a monomer or polymer that repels water molecules. The block copolymers can be synthesized in a one-pot, one-step process by, for example, copolymerizing R1with an excess of R2, via RAFT mediated copolymerization. R2copolymerizes alternatingly with R1and a predominantly linear R1-alt-R2or R2-alt-R1copolymer is obtained in the initial stage (before R1is exhausted). Upon complete consumption of R1and with continued propagation, R2is able to homopolymerize and the copolymer continues to grow an essentially pure R2segment that is free of R1. A poly(R1-alt-R2)-block-R2or poly(R2-alt-R1)-block-R2block copolymer is thus obtained (Figure 1). The block copolymers described herein are used to generate nanoparticles ranging from about 1 to about 300 nm in diameter, more preferably from about 1 to about 200 nm in diameter and even more preferably from about 1 to 100 nm in diameter. RAFT chain transfer agents such as xanthates, dithiocarbamates and trithiocarbonates can be used to perform the copolymerization, which may be thermally- or photo-initiated. In an embodiment where R2is vinyl alcohol, the copolymer is first synthesized with either vinyl acetate or vinyl pivalate as R2, before acid or alkaline hydrolysis to access the vinyl alcohol derivative. The mol ratio of R2:R1is typically at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1 or even greater than 10:1. Unlike polymers formed from conventional radical polymerization, which have large molar mass dispersities and poorly defined end-groups, the polymers formed by the method described herein are well-defined polymers with predictable molar masses, low molar mass dispersities and well- defined chain end-groups. Examples of block copolymers formed according to the method described above include: poly(N-vinylpyrrolidone-alt-maleic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt- MAnh)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-citraconic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt- CAnh)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-itaconic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt- IAnh)-block-PVP) block copolymer; poly(N-vinyl formamide-alt-maleic anhydride)-block-polyvinylformamide (poly(NVF-alt- MAnh)-block-PVF) block copolymer; poly(N-vinylformamide-alt-citraconic anhydride)-block-polyvinylformamide (poly(NVF-alt- CAnh)-block-PVF) block copolymer; poly(N-vinylformamide-alt-itaconic anhydride)-block-polyvinylformamide (poly(NVF-alt- IAnh)-block-PVF) block copolymer; poly(N-vinylacetamide-alt-maleic anhydride)-block-polyvinylacetamide (poly(NAM-alt- MAnh)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-citraconic anhydride)-block-polyvinylacetamide (poly(NAM-alt- CAnh)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-itaconic anhydride)-block-polyvinylacetamide (poly(NAM-alt- IAnh)-block-PAM) block copolymer; poly(N-vinyl-N-methylacetamide-alt-maleic anhydride)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-MAnh)-block-PNVMA block copolymer; poly(N-vinyl-N-methylacetamide-alt-citraconic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-CAnh)-block-PNVMA) block copolymer; poly(N-vinyl-N-methylacetamide-alt-itaconic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-IAnh)-block-PNVMA) block copolymer; poly(N-vinylcaprolactam-alt-maleic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt- MAnh)-block-PNVC block copolymer; poly(N-vinylcaprolactam-alt-citraconic anhydride)-block-polyvinylcaprolactam (poly(NVC- alt-CAnh)-block-PNVC) block copolymer; poly(N-vinylcaprolactam-alt-itaconic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt- IAnh)-block-PNVC) block copolymer; poly(vinyl acetate-alt-maleic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt-MAnh)- block-PVAc block copolymer; poly(vinyl acetate-alt-citraconic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt-CAnh)- block-PVAc) block copolymer; poly(vinyl acetate-alt-itaconic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt-IAnh)- block-PVAc) block copolymer; poly(vinyl pivalate-alt-maleic anhydride)-block-poly(vinyl pivalate) (poly(VPi-alt-MAnh)- block-PVPi block copolymer; poly(vinyl acetate-alt-citraconic anhydride)-block-poly(vinyl acetate) (poly(VPi-alt-CAnh)- block-PVPi) block copolymer; and poly(vinyl pivalate-alt-itaconic anhydride)-block-poly(vinyl pivalate) (poly(VPi-alt-IAnh)- block-PVPi) block copolymer. In one embodiment, the anhydride rings of R1 in the poly(R1-alt-R2)-block-R2 block copolymer or poly(R2-alt-R1)-block-R2 block copolymer can be hydrolyzed to form a carboxylic acid, thereby obtaining a block copolymer with carboxylate moieties. The hydrolysis is typically performed under basic conditions. Unlike the block copolymer with the anhydride form of R1, the block copolymer with the carboxylate groups is water soluble. Suitable block copolymer with carboxylate groups include: poly(N-vinylpyrrolidone-alt-maleic acid)-block-polyvinylpyrrolidone (poly(NVP-alt-MA)- block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-citraconic acid)-block-polyvinylpyrrolidone (poly(NVP-alt-CA)- block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-itaconic acid)-block-polyvinylpyrrolidone (poly(NVP-alt-IA)- block-PVP) block copolymer; poly(N-vinyl formamide-alt-maleic acid)-block-polyvinylformamide (poly(NVF-alt-MA)- block-PVF) block copolymer; poly(N-vinylformamide-alt-citraconic acid)-block-polyvinylformamide (poly(NVF-alt-CA)- block-PVF) block copolymer; poly(N-vinylformamide-alt-itaconic acid)-block-polyvinylformamide (poly(NVF-alt-IA)-block- PVF) block copolymer; poly(N-vinylacetamide-alt-maleic acid)-block-polyvinylacetamide (poly(NAM-alt-MA)-block- PAM) block copolymer; poly(N-vinylacetamide-alt-citraconic acid)-block-polyvinylacetamide (poly(NAM-alt-CA)- block-PAM) block copolymer; poly(N-vinylacetamide-alt-itaconic acid)-block-polyvinylacetamide (poly(NAM-alt-IA)-block- PAM) block copolymer; poly(N-vinyl-N-methylacetamide-alt-maleic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-MA)-block-PNVMA block copolymer; poly(N-vinyl-N-methylacetamide-alt-citraconic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-CA)-block-PNVMA) block copolymer; poly(N-vinyl-N-methylacetamide-alt-itaconic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-IA)-block-PNVMA) block copolymer; poly(N-vinylcaprolactam-alt-maleic acid)-block-polyvinylcaprolactam (poly(NVC-alt-MA)- block-PNVC block copolymer; poly(N-vinylcaprolactam-alt-citraconic acid)-block-polyvinylcaprolactam (poly(NVC-alt- CA)-block-PNVC) block copolymer; poly(N-vinylcaprolactam-alt-itaconic acid)-block-polyvinylcaprolactam (poly(NVC-alt-IA)- block-PNVC) block copolymer; poly(vinyl alcohol-alt-maleic acid)-block-poly(vinyl alcohol) (poly(VA-alt-MA)-block-PVA block copolymer; poly(vinyl alcohol-alt-citraconic acid)-block-poly(vinyl alcohol) (poly(VA-alt-CA)-block-PVA) block copolymer; and poly(vinyl alcohol-alt-itaconic acid)-block-poly(vinyl alcohol) (poly(VA-alt-IA)-block-PVA) block copolymer. The block copolymers described herein are versatile, functional block copolymers that can be functionalized for biomedical applications. The carboxylate groups formed from hydrolysis of the anhydride rings of R1, or the amide groups of R2, are capable of forming well-defined, stable chelate rings following coordination with the therapeutic molecules. The block copolymer- therapeutic molecule conjugate will be amphiphilic when the therapeutic ligand is hydrophobic. Such block copolymer-therapeutic molecule conjugates will be capable of spontaneously self- assembling in water to form nanoparticles, with the therapeutic molecule encapsulated inside. In one embodiment, the therapeutic molecule contains platinum (Pt). Therapeutic platinum based drugs have the general form: cis-PtA2X2, where the A group is amine or a substituted amine and X2is an anionic ligand or a chelating dianionic ligand. Examples of such therapeutic molecules are the cancer drugs cisplatin, carboplatin and oxaliplatin. Cisplatin (i.e. cis- diamminedichloroplatinum(II)) is used to treat a wide variety of cancers, including head, neck, ovarian and testicular tumours. Carboplatin is a cisplatin analogue with the chloride ligands replaced by 1,1-cyclobutanedicarboxylate ligand. In oxaliplatin, the ammonia ligands are replaced by R,R-diaminocyclohexane (DACH) ligands and the chloride ligands are replaced with an oxalate chelate. Cisplatin Carboplatin Oxaliplatin Conjugates formed with therapeutically active components of these platinum compounds and the block copolymers as described herein can be in the form of vesicles, nanospheres or micelles. In one embodiment, the conjugates are able to self-assemble into nanoparticles. These nanoparticles are characterized by a spherical structure in which the hydrophobic core is formed by the aggregation of the hydrophobic blocks of the polymer chains and acts as a micro-reservoir encapsulating the therapeutic agent, while the hydrophilic blocks create an outer shell that acts as stabilizing interface between the hydrophobic core and the biological environment (Figure 2). Pharmaceutical compositions comprising these polymer-therapeutic molecule conjugate block copolymers are provided, as is the use of these block copolymers and polymer-therapeutic molecule conjugate block copolymers in the manufacture of a medicament for treating a disease, such as cancer. A method of treating or preventing a disease is also provided. The method includes the step of administering a therapeutically effective amount of a polymer-therapeutic molecule conjugate block copolymer as described above to a subject in need thereof. The disease can be cancer. The cancer can be any cancer, but is typically a solid tumour such as gynaecological cancers (e.g. cervical cancer), oesophageal cancer, breast cancer, ovarian cancer, gastro-intestinal cancers (e.g. gastric cancer), prostate cancer, testicular cancer, pancreatic cancer, lung cancer, liver cancer, colorectal cancer, stomach cancer, bladder cancer, head and neck cancer, brain tumour, mesothelioma, neuroblastoma and gliomas. In particular, the cancer may be prostate cancer, ovarian cancer, cervical cancer or lung cancer. The polymer-therapeutic molecule conjugate block copolymer functions as a nanocarrier which acts as a vector through a passive targeting process which capitalizes on the enhanced permeation retention (EPR) effect. It is envisaged that the polymer-conjugate block copolymer will selectively accumulate in a cancerous tumour due to this EPR effect and enhance tumour selectivity of nanoparticle encapsulated cancer drugs, thereby reducing off-target toxicity. A kit for synthesizing the block copolymers and polymer-therapeutic molecule conjugate block copolymers as described herein is also provided. In the examples that follow, a functional block copolymer, i.e., poly(NVP-alt-MAnh)-block-PVP, was developed using maleic anhydride as R1 and NVP as R2. To demonstrate its utility, the fully water soluble COOH functional BCP, i.e., poly(NVP-alt-MA)-block-PVP, was hydrolyzed and the bidentate 1,2-dicarboxylate functionalities of the MA repeat units was used as labile leaving ligands for reversibly binding (DACH-Pt), via metal complex formation, forming a BCP based polymer-platinum drug conjugate. DACH-Pt is the active component of oxaliplatin, an anticancer drug. The polymer-platinum drug conjugate is amphiphilic in character, due to the hydrophobicity of the platinum’s DACH ligands, and spontaneously self-assembles in aqueous solution into drug loaded nanoparticles. Drug release kinetics were faster at low pH, than at physiological pH, which is desirable and is closer to the intracellular conditions of the cancer cell. Preliminary studies were performed to evaluate the anticancer properties of the polymer-Pt nanocarrier. In vitro MTT assays were used to evaluate the cytotoxicity of the polymer prodrug against HeLa and MDA-MB-231 cervical and breast cancer cell lines, respectively, with IC50values of 3.1 ± 1.2 mM (48 h) and 1.2 ± 0.2 mM (72 h) against HeLa cells and 3.7 ± 0.8 mM (48 h) and 1.4 ± 0.6 mM (72 h) against MDA-MB-231 cells. These values represent an approximate 20- fold increase in activity compared to the free DACH-Pt-Cl2, against both HeLa and MDA-MB-231 cells. The conjugates were also approximately 10-fold more cytotoxic against both cancer cell lines compared to cisplatin. The poly(NVP-alt-MA)-block-PVP BCP itself was found to be non- cytotoxic up to 1000 mg.mL-1. It is anticipated that due to the encapsulation and thus protection of the drug from extracellular metabolism or degradation, due to its enhanced release rate under acidic conditions that mimic the cancer cell environment, and its demonstrated improved in vitro cytotoxicity against cancer cell lines, this nanocarrier may be used in the development of more efficient anticancer Pt-based therapeutics, with an improved pharmacokinetic profile, better cancer cell targeting and improved efficacy with fewer side effects than the free drug. The invention will now be described in more detail by way of the following non-limiting examples. In these examples, maleic anhydride was used for R1and NVP was used for R2. However, it will be apparent to a person of ordinary skill in the art that the same methods could be used to make alternative block copolymers with the same or substantially similar properties using other monomers, such as those monomers mentioned above. Materials and analytical methods 1-Bromoethylbenzene (97%), (1R,2R)-(−)-1,2-diaminocyclohexane (DACH) (98%), N,N- dimethylformamide (anhydrous), dimethylterephthalate, 1,4-dioxane (anhydrous), ethyl-2- bromoisobutyrate (98%) magnesium sulphate (anhydrous), potassium hexachloroplatinate (98%), potassium ethyl xanthogenate (96%), silver nitrate, sodium bicarbonate (≥ 99.7%), phosphate-buffered saline (PBS) tablets, and fetal bovine serum (FBS) were purchased from Merck Life Science and used as received. Sodium carbonate (anhydrous) was obtained from Saarchem. Azoisobutyronitrile (AIBN, Aldrich) was recrystallized from ethanol. Maleic anhydride (MAnh, Merck Life Science) was recrystallized from toluene and sublimed. N-vinylpyrrolidone (NVP, ≥ 99.5 %, stabilized with ~ 0.1% sodium hydroxide, Merck Life Sciences) was purified by vacuum distillation. Distilled deionised water was obtained from a Millipore Milli-Q purification system. Other solvents were purchased from Kimix and were used without further purification. The NMR solvents CDCl3 (99.9%, Merck Life Sciences), DMSO-d6 (99.9%, MagniSolv) and D2O (99.9%, MagniSolv) were used as received. TLC plates (0.2 mm silica gel 60 with fluorescent indicator UV254) and silica gel 60 (0.063 – 0.2 mm / 70 – 230 mesh) were purchased from Machery-Nagel. Snakeskin™ (Thermo Scientific™) and Float-A-Lyzer™ G2 dialysis tubes (Spectrum™) were used as specified. Acetate buffer was made up with sodium acetate anhydrous (≥ 99%, Merck Life Science) and acetic acid glacial (≥ 99.85 %, Merck Life Science) to a pH of 5.5. PBS buffer was prepared by dissolving 1 PBS tablet in 200 mL H2O. Dulbecco’s modified Eagle’s medium (DMEM), 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) (Merck Life Sciences), fetal bovine serum (FBS) sodium dodecyl sulfate (SDS), phosphate buffered saline (PBS), cisplatin. All reagents were purchased from Merck Life Sciences, Trypsin-EDTA (BioWest), unless stated otherwise. For NMR Spectroscopy,1H-NMR spectra were obtained with Varian VXR-Unity (400 and 600 MHz) and Bruker AscendTM(400 and 600 MHz) spectrometers with samples dissolved in deuterated solvents with tetramethylsilane (TMS) as the internal reference. ATR-FT-IR spectroscopy was carried out on a Nexus infrared spectrometer equipped with a Smart Golden gate attenuated total reflectance diamond from Thermo Nicolet with ZnSe lenses and data acquisition on Omnic Software version 7.2. UV-vis spectroscopy was conducted using Thermo Scientific MultiskanSky microplate spectrophotometer at 25 °C. Dynamic Light Scattering analysis was carried out on a Malvern Instrument ZetaSizer Nano ZS90 equipped with a 4 mW He-Ne laser, operating at a wavelength of 633 nm. The scattered light was detected at a scattering angle of 90° at 25 °C or 37 °C. The final particle size and size distribution were obtained from six measurements, each comprising 10 – 15 sub-runs, and calculated via the Malvern ZetaSizer software. ICP-MS analysis was conducted on an ICP-MS: Agilent 7900; digested solid samples were introduced into the instrument via an auto sampler and peristaltic pump. Instrument conditions: RF Power 1600 W, carrier gas – Ar 0.83 L / min, sample depth 10 mm, HMI dilution gas - Ar 0.15 L / min, He flow 5 mL / min, H2 flow 6 mL / min, nebulizer 0.2 mL / min micro mist. ICP-OES analysis was carried out on a Thermo iCAP 6000. Instrument conditions: RF power 1350 W, carrier gas – Ar 0.65 L / min, aux gas - Ar 1.0 L / min, nebulisern2 mL / min micro mist, internal standard used – 1 ppm Yttrium. Transmission Electron Microscopy was conducted on a Tecnai 20 transmission electron microscope (Thermo Fisher) fitted with a LaB6 emitter and operating at 200 kV and a Gatan Tridiem 863 UHS (Gatan). The images were collected using the embedded Gatan CCD camera (2048 ´ 2048 pixels). A drop of the sample solution was deposited onto a copper grid and dried at room temperature. TEM images were further processed using ImageJ. Synthetic procedures Polymerisation commences upon the application of conditions under which radicals are generated, such as the addition of a suitable initiator system, and the subsequent application of heat. An example synthesis of Poly(MAnh-alt-VP)-b-PVP , via RAFT mediated polymerization with the process mediated by a xanthate chain transfer agent, is given below. Firstly, a suitable chain transfer agent, ethyl-2-((ethoxycarbonothioyl)thio)-2-methylpropanoate was prepared. Ethyl-2-((ethoxycarbonothioyl)thio)-2-methylpropanoate (RAFT X) A 1 L RBF containing a Teflon-coated magnetic stirrer bar was charged with potassium ethyl xanthogenate (26.50 g, 0.17 mol) in 500 mL acetone. The solution was homogenized by stirring before the addition of ethyl-2-bromoisobutyrate (27.88 g, 0.15 mol). The mixture was left to stir at room temperature for 24 hours. The solution was filtered through a short silica plug to remove KBr. The filtrate was then extensively washed with hexane:diethyl ether (2:1) followed by further purification via column chromatography hexane:ethyl acetate (9:1) (Rf= 0.62). The solvent was removed via a rotary evaporator and yielded a yellow oil (15.79 g, 0.067 mol) (43 % yield). Compound purity was found to be approximately 99 % by1H-NMR spectroscopy.1H NMR (400 MHz, Chloroform-d) δ: 4.58 (q, J = 7.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.59 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H). Poly(MAnh-alt-VP)-b-PVP synthesis A Schlenk flask containing a Teflon-coated magnetic stirrer bar was charged with RAFT X (0.10 g, 0.42 mmol) and NVP monomer (9.00 mL, 0.084 mol). MAnh (0.62 g, 6.35 mmol), AIBN (0.019 g, 0.11 mmol), and DMT (internal standard) (0.26 g, 1.37 mmol) were dissolved separately in dioxane (8 mL) and added into the Schlenk flask. The reaction contents were mixed, and an initial1H-NMR sample was taken. Upon mixing, the reaction contents were faint yellow. The solution was degassed via Argon purging for 30 minutes before submersion in a pre-heated oil bath at 60 °C. After 24 hours, the reaction was stopped by the removal of the heat source and exposure of the flask contents to air, and the polymer solution was subjected to thermolysis. Before precipitation in diethyl ether, the aliquot was diluted with an appropriate amount of reaction solvent. The polymer was then isolated by filtration and dried in vacuo. Thermolysis Following the completion of the polymerization procedure outlined above. The polymer was redissolved in dioxane, and the reaction vessel containing the remaining polymer solution was subsequently heated at 120 °C for 16 hours. The polymer solution was precipitated in diethyl ether and isolated via vacuum filtration. The obtained polymer powder was subsequently dried in vacuo. Hydrolysis A 100 mL RBF containing a Teflon-coated magnetic stirrer bar was charged with BCP2 (0.10 g, 0.21 mmol MAnh) and 8 mL deionized water. The reaction vessel was then allowed to stir at 50 °C for 30 minutes. Na2CO3 (0.056 g, 0.45 mmol) in 2 mL deionized water was subsequently added to the reaction vessel and allowed to stir at 50 °C overnight. Before isolation via lyophilization, the copolymer was dialyzed against deionized water. DACH-Pt-(NO3)2 synthesis A glass vial was charged with potassium tetrachloroplatinate (1.51 g, 3.63 mmol) and 15 mL H2O. The platinum solution was filtered into a 50 mL round-bottom flask containing a Teflon-coated magnetic stirrer bar. DACH (0.42 g, 3.69 mmol) was dissolved in 20 mL H2O and added dropwise to the reaction flask while stirring. The reaction flask was covered and allowed to continue at room temperature and yielded a yellow solid. The product was subsequently filtered and successively washed with 50 mL H2O, acetone, and diethyl ether. The product (DACH-Pt-Cl2) was then dried. A 50 mL round-bottom flask containing a Teflon-coated stirrer bar was charged with DACH-Pt-Cl2(0.68 g, 17.9 mmol). Silver nitrate (0.61 g, 3.58 mmol) was dissolved in 25 mL H2O and added to the reaction vessel. The flask was covered and allowed to react at room temperature. After 48 hours, a precipitate which had formed was separated from the solution. The DACH-Pt-(NO3)2was analyzed via1H-NMR spectroscopy. DACH-Pt-(NO3)2-polymer conjugation A 100 mL round-bottom flask containing a Teflon stirrer bar was charged with PVPMAnh BCP (0.20 g, 0.33 mmol MAnh) and 50 mL H2O. The reaction flask was placed in a hot water bath at 50 °C for 30 minutes to dissolve the polymer. Na2CO3 (0.09 g, 0.82 mmol) was added to the polymer solution and allowed to reaction for 30 minutes at room temperature followed by the addition of DACH-Pt-(NO3)2(3.53 mL, 0.33 mmol). The solution was allowed to react for 24 hours in the dark while stirring. The solution was then purified by dialysis against H2O. Kinetic stability The prodrug was diluted to 5 mg / mL using PBS (pH 7.4) and PBS-FBS (10 %) buffers. The solutions were then maintained at storage and physiological conditions and analyzed at various time intervals via dynamic light scattering (DLS). Drug-release studies The prodrug was diluted to 5 mg / mL using PBS (pH 7.4) and acetate (pH 5) buffers. The prodrug solutions (4 mL) were placed into dialysis tubes and submerged in 40 mL pre-equilibrated buffer at 37 °C and sealed. Kinetic samples were removed from the outside of the dialysis tube at various times and replaced with an equivalent amount of the respective buffer to maintain sink conditions. The kinetic samples were analyzed via ICP-OES to determine the percentage elemental platinum released; 100 % release was determined by analyzing the prodrug solution before dialysis. Complete media preparation The formulation for complete media consisted of 10% FBS (fetal bovine serum), 1% penicillin- streptomycin in DMEM (Dulbecco's Modified Eagle Medium). Cell lines Two cancer cell lines, HeLa and MDA-MB-231, were purchased from American Tissue Culture Collection (ATCC). The cells were cultured as monolayers in complete media at 37 °C in a humidified incubator of 95% air and 5% CO2. Preparation of cells Cells were grown in 10 cm dishes containing complete media and allowed to proliferate at 37 °C in a humidified incubator of 95 % air and 5 % CO2 to 80 % confluence. Thereafter the media was removed followed by addition of 2 mL trypsin-EDTA which was incubated with the cells at 37 °C for 2 minutes to allow the cells to detach from the plates. Complete media (2 mL) was added, and cells were centrifuged 1080xg for 4 minutes to form a cell pellet. After removal of the supernatant, 3 mL media was added to resuspend the pellet. 10 mL of the cell suspension was mixed with 10 mL trypan blue and the concentration of live cells determined using a Countess cell counter. The cell suspension was subsequently diluted with completed media to obtain the required concentration for plating. Cell viability assay The MAnh units in the copolymer were hydrolyzed via dissolution in sterile PBS and left overnight to ensure complete solubilization. The solution was subsequently sterilized via UV irradiation for 1 hour at room temperature prior to administration. Following their preparation, all tested compounds were sterilized in this manner. The metabolic effects of the antagonists were probed via the MTT colorimetric assay. Briefly, cell cultures were seeded in 96-well plates at 2500 cells per well. The cells were incubated at 37 °C for 24 hours before exposure to the test compounds. The vehicle alone (PBS) was added to untreated (control) cells. The MTT reagent (5 mg / mL) was prepared in sterile PBS at room temperature. After incubation with the drugs, MTT (10 mL) was added to each well and allowed to incubate for 4 hours at 37 °C. The formazan crystals were solubilized via the addition of 10 % SDS (100 mL) solution in 0.01 M HCl. The optical density (OD) of the 96-well plate was measured at 595 nm using a spectrophotometer. The data were analyzed using GraphPad Prism software, where the absorbance values were corrected for the contributions of the MTT, drug, and media.The data was plotted and fitted to a dose−response curve to determine the IC50 value.Statistical analysis The data were analyzed using GraphPad Prism v8, where the background absorbance of the media, test compound, and MTT reagent (without cells) was subtracted from each measurement. The data was plotted and fitted to a dose−response curve to give the cytotoxicity IC50value. ResultsA new versatile functional block copolymer, i.e., poly(NVP-alt-MAnh)-block-PVP, was synthesizedin one step. Hydrolysis of the MAnh rings affords a poly(NVP-alt-MA)-block-PVP BCP, with COOHfunctionalities, which can then be used as a platinum drug nanocarrier. To demonstrate this one-step synthesis, RAFT mediated copolymerization of NVP and MAnh in a mol ratio of 7:1,respectively, in the presence of a xanthate RAFT agent was conducted (Scheme 1). Monomerconversions were profiled, as a function of time using 1H NMR spectroscopy. Scheme 1. One-step block copolymer synthesis of poly(NVP-alt-MA)-block-PVP via RAFT polymerization MAnh was rapidly and quantitatively consumed after ~0.5 h. NVP’s consumption was initially fast but slowed down after complete consumption of MAnh. Thereafter the monomer feed was solely NVP, its continued propagation resulting in the synthesis of the PVP segment.Successful synthesis of the BCP was confirmed using 1H NMR spectroscopic analysis. Signalscharacteristic of NVP repeat units, NVP-alt-MAnh residues as well as Z end-group were clearlyobserved (not shown). The synthesized poly(NVP-alt-MAnh)-block-PVP BCP is insoluble inwater. It was first thermolyzed to remove the RAFT Z-end group (Scheme 2), which readilyundergoes nucleophilic attack to form a thiol, complicating subsequent self-assembly studies.This end-group modification was also confirmed by 1H NMR spectroscopic analysis (not shown). Scheme 2. Synthesis of drug-loaded block copolymer Afterwards, the end-modified BCP was hydrolysed under basic conditions, converting the MAnhrings into MA, rendering the BCP water soluble (Scheme 2). Hydrolysis was qualitativelyassessed via FT-IR spectroscopy. Absorption bands at 1846 cm-1and 1774 cm-1found in poly(NVP-alt-MAnh)-block-PVP, due to the anhydride ring, were absent in ring opened poly(NVP-alt-MA)-block-PVP BCP, which, instead displayed a new absorption band at 1550 cm-1due to the maleate’s carbonyl moieties. In addition, the appearance of an absorption at ~3500 cm-1, attributable to broad hydroxyl stretching, further suggested that the hydrolysis step was successful. The absorption band at 1669 cm-1, assigned to the carbonyl group in the NVP lactam ring, was found to be well preserved in both MAnh and MA functional copolymers, albeit slightly shifted.1H NMR analysis also revealed the presence of the NVP and MA signals in the BCP. The anticancer drug, [(1R,2R)-1,2-diaminocyclohexane]platinum(II) (DACH-Pt) was synthesized as described in Vollano et al. (J. F. Vollano, S. Al-Baker, J. C. Dabrowiak and J. E. Schurig,Journal of Medicinal Chemistry, 1987, 30, 716-719). In order to facilitate chelation between thePt drug and the carboxylate functional BCP, DACH-Pt-Cl2 was first reacted with silver nitrate, and suspended in water, forming an aqueous complex of DACH-Pt2+-(H2O)2-(NO"!)2. The formed supernatant DACH-Pt2+-(H2O)2-(NO3-)2was reacted with the COO- moieties of the poly(NVP-alt- MA)-block-PVP BCP over 24 h, in the dark, at room temperature. The solution was subsequently dialyzed against distilled deionized water to remove any unreacted DACH-Pt. Nanoparticle formation was indicated by the formation of a cloudy, white solution, due to the amphiphilic nature of the polymer-drug conjugate, i.e., poly(NVP-alt-MA / Pt)-block-PVP. The PVP segment functions as the hydrophilic shell stabilizing the nanoparticles, whilst the poly(NVP-alt-MA / Pt) segment forms the hydrophobic core. In the scenario shown in Scheme 2, the Pt2+in the DACH-Pt drug chelates across two COO- moieties from the same repeat unit. Chelation of two COO- ligands on repeat units in different chains, or with the amide nitrogen, also occurs, resulting in crosslinking the nanoparticle. The platinum content of the BCP-Pt conjugate was determined to be 13% w / w via ICP-MS, which translates to a 65% conjugation efficiency, calculated using Equation 1. The sterically demanding nature of the complex likely prevents the realization of fully-modified polymeric backbones. Equation 1 where CE is the calculated conjugation efficiency; Pt (%) is the percentage of elemental Pt determined via ICP-MS; %%%+@, >?-%%%A@BC"DE, and >?-%%%FGDare the molecular weight of maleic acid, DACH-Pt, and NVP, respectively; H'FGDand H'+@IJ%are the number of NVP and MAnh units in the parent copolymer; and >?-%%%DE%is the molecular weight of elemental platinum. The solution state size of the nanoparticles, determined via DLS (not shown), was found to be <150 nm, and their spherical morphology was confirmed via TEM (not shown). The nanoparticle size determined via TEM was smaller than that determined via DLS, presumably due to drying-in effects experienced in TEM sample preparation whilst DLS gives the solution state size. The kinetic stability of the Pt-prodrug was investigated by tracking the hydrodynamic size of the particles, via DLS, in PBS (pH 7.4) at 4 °C and in PBS-FBS (90 % PBS / 10 % FBS) at 37 °C, to mimic potential storage and physiological conditions, respectively. It is important to evaluate nanoparticle stability in a biologically relevant media considering the possibility of destabilization caused by opsonization. The polymeric prodrugs appeared stable in both PBS and in PBS-FBS, as their DLS traces did not change over seven days. The relative stability of the nanoparticles in FBS is likely due to the PVP corona adequately shielding the hydrophobic core from the aqueous environment. The observed slight increase in hydrodynamic size in the presence of FBS (10 %) is likely due to the presence of globular serum proteins intercalating with the PVP corona or the partitioning of proteins into the micelle core, leading to morphological changes. Evaluation of the prodrug release kinetics is critical for the development of an effective drug delivery system (DDS). The rate and extent of drug release affect the efficacy of the drug and its associated toxicity profile. Hence, sustained and controlled release of the active drug can improve the therapeutic efficacy by maintaining a constant concentration of the drug at the target site. DACH-Pt release from the prodrug was investigated in PBS (pH 7.4) and acetate buffer (pH 5.0) at 37 °C by the dialysis method, and the kinetic samples were analyzed via ICP-OES to determine the platinum content. The cumulative % platinum release curve (not shown) showed that the release of platinum species was enhanced under acidic conditions. After 168 hours, approximately 80 % of the platinum was released at pH 5, compared to 40 % platinum release at pH 7, likely due to the increased sensitivity of the Pt–carboxylate linkages to acid hydrolysis. No burst release was observed, indicating that DACH-Pt incorporation was mainly through the carboxylate complex and not via physical entrapment. The biocompatibility of the poly(NVP-alt-MA)-block-PVP BCP was evaluated in concentrations ranging from 7.8–103mg / mL. The polymer solutions were sterilized via UV irradiation before incubation with the cancer cell lines for 72 hours. The BCP did not demonstrate any cytotoxicity against the cancer cell lines up to the highest concentration range tested of 1000 mg / mL, indicating the suitability of the BCP as a drug carrier. The cytotoxicities of cisplatin, DACH-Pt-Cl2, and the polymeric prodrug were assessed against both HeLa and MDA-MB-231 cell lines. Cisplatin, a clinical cancer chemotherapeutic and DACH- Pt-Cl2, the active component of oxaliplatin (also a clinical anticancer drug), were used as positive controls and both evaluated at concentrations of 1.4 – 180 mM. Table 1 below shows the individual IC50values calculated for each experimental repeat as well as the overall average and standard deviation for the three independent determinations. Table 1. IC50values of tested compounds obtained via least squares fit to a dose-response curve. Drugs and experimental compounds tested on Hela and MDA-MB-231 cell lines. IC50 fold change IC5 fold change vs IC (4 0 50 8 h) IC50 (72 h) from 48 – 72 h DACH-Pt sllProdrug 3.10 ± 1.20 1.20 ± 0.20 2.60 21 (48 h), 27 (72 h) e c Cisplatin 25.5 ± 4.50 10.6 ± 3.10 2.40 a Le H DACH-Pt-Cl2 65.6 ± 21.8 32.6 ± 17.8 2.00 D -BM A M- Prodrug 3.70 ± 0.80 1.40 ± 0.60 2.60 19 (48 h), 18 (72 h) Cisplatin 28.1 ± 2.40 8.80 ± 2.90 3.20 DACH-Pt-Cl2 71.6 ± 23.1 25.5 ± 14.8 2.80 *All IC50 values are averages of three determined independently. The IC50 values for cisplatin were found to be 25.5 ± 4.50 mM (48 h) and 10.6 ± 3.10 mM (72 h) against HeLa cells, and 28.1 ± 2.40 mM (48 h) and 8.80 mM ± 2.90 (72 h) against MDA-MB-231 cells. The IC50 values for DACH-Pt-Cl2 were found to be 65.6 ± 21.8 mM (48 h) and 32.6 ± 17.8 mM (72 h) against HeLa cells, and 71.6 ± 23.1 mM (48 h) and 25.5 ± 14.8 mM (72 h) against MDA- MB-231 cells. In comparison, the prodrug had IC50values of 3.10 ± 1.20 mM (48 h) and 1.20 ± 0.20 mM (72 h) against HeLa cells and 3.70 ± 0.80 mM (48 h) and 1.40 ± 0.60 mM (72 h) against MDA-MB-231 cells. This represents a 20-fold enhancement in activity for the polymer-DACH-Pt conjugate vs the free drug, indicating that the polymer encapsulation is having a significant, favorable effect on the overall cytotoxicity of this drug for both cancer cell lines. For all tested compounds, the IC50 values obtained after 72 hours were found to be 2-3 fold greater than their 48-hour counterparts. Thus, the effect of the drugs on the cancer cells appears to become accentuated over time leading to increased cytotoxicity. It also implies that the cells are not able to recover with time. The approximate 20-fold decrease in IC50 following conjugation of DACH-Pt-Cl2 to the polymer is hypothesized to be due to several factors. The polymer may increase the solubility of DACH-Pt which in turn may lead to enhanced uptake and transport across cellular membranes, thus improving the intracellular bioavailability of the drug. Relative to cisplatin, the presence of carboxyl leaving ligands may influence the rate of aquation, which may in turn enhance the formation of mono- and di-adducts of DACH-Pt with DNA. The measured cytotoxic activity by the polymer prodrug nanoparticles indicates that the DACH-Pt drug is indeed released from the nanoparticles, and the known mode of action of this class of drugs is DNA intercalation. The foregoing description has been presented for the purpose of illustration; it is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Persons skilled in the relevant art can appreciate that many modifications and variations are possible in light of the above disclosure. Finally, throughout the specification and accompanying claims, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Claims

CLAIMS:

1. A block copolymer of Formula (I): B1— block — (R2)n(I) where B1is (R1—alt—R2)mor (R2—alt—R1)m; R1is an electron poor anhydride functional monomer that can be hydrolyzed into a dicarboxylic acid; R2is an electron rich vinyl monomer that is polymerizable to form water soluble and biocompatible polymers; m is an integer from 1 to 1000; and n is an integer from 1 to 1000.

2. The block copolymer of claim 1, wherein R2 is polymerizable by reversible deactivation radical polymerization (RDRP) to form water soluble and biocompatible polymers.

3. The block copolymer of either one of claims 1 or 2, wherein R1 is selected from the group consisting of maleic anhydride (MAnh), citraconic anhydride (CAnh) and itaconic anhydride (IAnh).

4. The block copolymer of any one of claims 1 to 3, wherein R2 is selected from the group consisting of N-vinylpyrrolidone (NVP), N-vinylformamide (NVF), N-vinylacetamide (NAM), N-vinyl-N-methylacetamide (NVMA), N-vinylcaprolactam (NVC), vinyl acetate (VAc) and vinyl pivalate (VPi).

5. The block copolymer of any one of claims 1 to 4, which is selected from the group consisting of: poly(N-vinylpyrrolidone-alt-maleic anhydride)-block-polyvinylpyrrolidone (poly(NVP- alt-MAnh)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-citraconic anhydride)-block-polyvinylpyrrolidone (poly(NVP-alt-CAnh)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-itaconic anhydride)-block-polyvinylpyrrolidone (poly(NVP- alt-IAnh)-block-PVP) block copolymer; poly(N-vinyl formamide-alt-maleic anhydride)-block-polyvinylformamide (poly(NVF- alt-MAnh)-block-PVF) block copolymer; poly(N-vinylformamide-alt-citraconic anhydride)-block-polyvinylformamide(poly(NVF-alt-CAnh)-block-PVF) block copolymer; poly(N-vinylformamide-alt-itaconic anhydride)-block-polyvinylformamide (poly(NVF- alt-IAnh)-block-PVF) block copolymer; poly(N-vinylacetamide-alt-maleic anhydride)-block-polyvinylacetamide (poly(NAM- alt-MAnh)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-citraconic anhydride)-block-polyvinylacetamide (poly(NAM-alt-CAnh)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-itaconic anhydride)-block-polyvinylacetamide (poly(NAM- alt-IAnh)-block-PAM) block copolymer; poly(N-vinyl-N-methylacetamide-alt-maleic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-MAnh)-block-PNVMA block copolymer; poly(N-vinyl-N-methylacetamide-alt-citraconic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-CAnh)-block-PNVMA) block copolymer; poly(N-vinyl-N-methylacetamide-alt-itaconic anhydride)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-IAnh)-block-PNVMA) block copolymer; poly(N-vinylcaprolactam-alt-maleic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt-MAnh)-block-PNVC block copolymer; poly(N-vinylcaprolactam-alt-citraconic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt-CAnh)-block-PNVC) block copolymer; poly(N-vinylcaprolactam-alt-itaconic anhydride)-block-polyvinylcaprolactam (poly(NVC-alt-IAnh)-block-PNVC) block copolymer; poly(vinyl acetate-alt-maleic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt- MAnh)-block-PVAc block copolymer; poly(vinyl acetate-alt-citraconic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt- CAnh)-block-PVAc) block copolymer; poly(vinyl acetate-alt-itaconic anhydride)-block-poly(vinyl acetate) (poly(VAc-alt- IAnh)-block-PVAc) block copolymer; poly(vinyl pivalate-alt-maleic anhydride)-block-poly(vinyl pivalate) (poly(VPi-alt- MAnh)-block-PVPi block copolymer; poly(vinyl acetate-alt-citraconic anhydride)-block-poly(vinyl acetate) (poly(VPi-alt- CAnh)-block-PVPi) block copolymer; and poly(vinyl pivalate-alt-itaconic anhydride)-block-poly(vinyl pivalate) (poly(VPi-alt- IAnh)-block-PVPi) block copolymer.

6. The block copolymer as claimed in any one of claims 1 to 4, which is selected from the group consisting of: poly(N-vinylpyrrolidone-alt-maleic acid)-block-polyvinylpyrrolidone (poly(NVP-alt- MA)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-citraconic acid)-block-polyvinylpyrrolidone (poly(NVP-alt- CA)-block-PVP) block copolymer; poly(N-vinylpyrrolidone-alt-itaconic acid)-block-polyvinylpyrrolidone (poly(NVP-alt- IA)-block-PVP) block copolymer; poly(N-vinyl formamide-alt-maleic acid)-block-polyvinylformamide (poly(NVF-alt- MA)-block-PVF) block copolymer; poly(N-vinylformamide-alt-citraconic acid)-block-polyvinylformamide (poly(NVF-alt- CA)-block-PVF) block copolymer; poly(N-vinylformamide-alt-itaconic acid)-block-polyvinylformamide (poly(NVF-alt-IA)- block-PVF) block copolymer; poly(N-vinylacetamide-alt-maleic acid)-block-polyvinylacetamide (poly(NAM-alt-MA)- block-PAM) block copolymer; poly(N-vinylacetamide-alt-citraconic acid)-block-polyvinylacetamide (poly(NAM-alt- CA)-block-PAM) block copolymer; poly(N-vinylacetamide-alt-itaconic acid)-block-polyvinylacetamide (poly(NAM-alt-IA)- block-PAM) block copolymer; poly(N-vinyl-N-methylacetamide-alt-maleic acid)-block-polyvinyl-N-methylacetamide (poly(NVMA-alt-MA)-block-PNVMA block copolymer; poly(N-vinyl-N-methylacetamide-alt-citraconic acid)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-CA)-block-PNVMA) block copolymer; poly(N-vinyl-N-methylacetamide-alt-itaconic acid)-block-polyvinyl-N- methylacetamide (poly(NVMA-alt-IA)-block-PNVMA) block copolymer; poly(N-vinylcaprolactam-alt-maleic acid)-block-polyvinylcaprolactam (poly(NVC-alt- MA)-block-PNVC block copolymer; poly(N-vinylcaprolactam-alt-citraconic acid)-block-polyvinylcaprolactam (poly(NVC- alt-CA)-block-PNVC) block copolymer; poly(N-vinylcaprolactam-alt-itaconic acid)-block-polyvinylcaprolactam (poly(NVC-alt- IA)-block-PNVC) block copolymer; poly(vinyl alcohol-alt-maleic acid)-block-poly(vinyl alcohol) (poly(VA-alt-MA)-block- PVA block copolymer;poly(vinyl alcohol-alt-citraconic acid)-block-poly(vinyl alcohol) (poly(VA-alt-CA)- block-PVA) block copolymer; and poly(vinyl alcohol-alt-itaconic acid)-block-poly(vinyl alcohol) (poly(VA-alt-IA)-block- PVA) block copolymer.

7. The block copolymer as claimed in any one of claims 1 to 6, conjugated to a therapeutic molecule.

8. The block copolymer as claimed in claim 7, wherein the therapeutic molecule is a cancer drug.

9. The block copolymer as claimed in claim 8, wherein the cancer drug is a platinum-based cancer drug with cis-ammine or substituted amine, non-leaving ligands.

10. The block copolymer as claimed in any one of claims 7 to 9 for use in treating a disease.

11. The block copolymer as claimed in claim 10, wherein the disease is cancer.

12. A pharmaceutical composition comprising a block copolymer as claimed in any one of claims 7 to 9 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12 for use in treating cancer.

14. A method of synthesizing a block copolymer of any one of claims 1 to 6, the method comprising the step of copolymerizing a first monomer R1 with an excess of a second monomer R2to form a first block segment B1comprising an R1-alt-R2copolymer or R2-alt- R1 copolymer and thereafter, once R1 has been depleted, to continue to grow a R2 segment on the copolymer, thereby obtaining a block copolymer having the formula: B1— block — (R2)n(I), wherein B1, R1, R2, m and n are as defined in any one of claims 1 to 4.

15. The method of claim 14, wherein the copolymerization step is performed using reversible addition fragmentation transfer (RAFT) mediated copolymerization.

16. The method of claim 15, wherein the RAFT mediated copolymerization is performed in the presence of a RAFT chain transfer agent.

17. The method of claim 16, wherein the RAFT chain transfer agent is selected from xanthates, dithiocarbamates and trithiocarbonates.

18. The method of any one of claims 15 to 17, wherein the RAFT mediated polymerization is thermally- or photo-initiated.

19. The method of any one of claims 14 to 18, wherein the block copolymer is formed in a one pot, one step process.

20. The method of any one of claims 14 to 19, which further comprises the step of hydrolyzing R1 anhydride groups in the block copolymer to carboxylate groups.

21. The method of claim 20, which further comprises the step of conjugating a therapeutic molecule to the carboxylate groups of the block copolymer.

22. The method of claim 21, wherein the therapeutic molecule is a cancer drug.

23. The method of claim 23, wherein the cancer drug has a cis-diammineplatinum(II) fragment.

24. The method of any one of claims 21 to 23, wherein the block copolymer and therapeutic molecule are mixed and the therapeutic molecule is allowed to bind to a carboxylate group of the hydrolyzed R1 in the block copolymer and / or to an amide group of R2 in the block copolymer.

25. The method of any one of claims 21 to 24, wherein the conjugates formed from the block copolymer and therapeutic molecule are allowed to assemble into spherical nanoparticles.

26. Use of a block copolymer as claimed in any one of claims 1 to 9 in the manufacture of a medicament for the treatment of cancer.

27. A method of treating or preventing a disease, the method comprising administering to a subject in need thereof an effective amount of a block copolymer according to any one of claims 7 to 9.

28. The method as claimed in claim 27, wherein the disease is cancer.