Published: April 08, 2011 r2011 American Chemical Society 1738 dx.doi.org/10.1021/bm200135e | Biomacromolecules 2011, 12, 1738–1751 ARTICLE pubs.acs.org/Biomac Thiolyne and Thiolene “Click” Chemistry as a Tool for a Variety of Platinum Drug Delivery Carriers, from Statistical Copolymers to Crosslinked Micelles Vien T. Huynh, † Gaojian Chen, ‡ Paul de Souza, § and Martina H. Stenzel* ,† † Centre of Advanced Macromolecular Design (CAMD), The University of New South Wales, Sydney NSW 2052, Australia ‡ Centre for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou 215006, China § St. George Hospital Clinical School, The University of New South Wales, Sydney NSW 2052, Australia b S Supporting Information ’ INTRODUCTION Despite its effectiveness in the treatment of solid tumors including ovarian, bladder, testicular, head and neck, small-cell, and non-small-cell lung cancers, cis-platin [cis-dichlorodiamine- platinum(II); CDDP] suffers from several major side effects, including nephrotoxicity and neurotoxicity. 1 In addition, the drug is nonselective and, hence, replicating normal and trans- formed cells are equally affected. Further, poor water solu- bility leads to suboptimal distribution in the circulation. Finally, the electrophilic nature of cisplatin in its aquated form (cis- diaminediaquaplatinum(II) dication), which is partly present when dissolved in the circulation, results in high affinity to amino acids and proteins. As a consequence, intrinsic and acquired drug resistance is observed. 2,3 We propose to employ nanoparticles for the delivery of platinum to protect the drug from nonspecific binding, to increase circulation time, and to use the enhanced permeation and retention effect (EPR) of cancer cells, which is their preferred uptake of nanoparticles and deficient clearance ability. Platinum drugs can be physically encapsulated in a polymer matrix, but even more attractive for the delivery of platinum drugs is the binding of the drug to the polymer matrix via metal complex formation. All platinum drugs have in com- mon two permanently bound ligands, frequently based on amines, and two labile leaving ligands usually based on chlorides or carboxylate functional groups. 46 Earlier research efforts in creating carrier-bound platinum complexes were aimed at the development of conjugates in which the two amine ligands were donated by the carrier polymer either as main chain components or as side chain moieties. However, if the drug is tightly bound to the polymer, release is only possible via degradation of the polymer. In our case, a macromolecular platinum drug has been created. 7 A different drug binding strategy involves the coordina- tion by carboxylato ligands, thus, permitting drug release via hydrolytically cleaved carboxyl leaving groups. 8 A range of polymers with inherent ligating groups such as poly(aspartic acid), 9,10 poly(glutamic acid), 11 and poly(methacrylic acid) 12 were employed to generate platinumpolymer complexes. The common feature of these polymers is that two ligands coordinate to platinum in nonspecific geometry, thus, allowing crosslinking of polymer chains to take place. More recent development in platinum drug design has shifted from monodentate carboxylato ligands to well-defined bidentate carboxylato ligands with usually 1,1- or 1,2-geometry resulting in the formation of chelate rings after coordination with platinum. 13 Received: January 27, 2011 Revised: April 4, 2011 ABSTRACT: Statistical and block copolymers based on poly- (2-hydroxyethyl methacrylate) (PHEMA) and poly[oligo- (ethylene glycol) methylether methacrylate] (POEGMEMA) were modified with 4-pentenoic anhydride or 4-oxo-4-(prop-2- ynyloxy)butanoic anhydride to generate polymers with pen- dant vinyl or acetylene, respectively. Subsequent thiolene or thiolyne reaction with thioglycolic acid or 2-mercaptosuccinic acid leads to polymers with carboxylate functionalities, which were conjugated with cisplatin (cis-diamminedichloroplatinum- (II) (CDDP)) to generate a drug carrier for Pt-drugs. Only the polymers modified with 2-mercaptosuccinic acid resulted in the formation of soluble well-defined polymers with gel formation being prevented. Due to the hydrophobicity of the drug, the block copolymers took on amphiphilic character leading to micelle formation. The micelles were in addition crosslinked to further stabilize their structure. Pt-containing statistical copolymer, micelles, and crosslinked micelles were then tested regarding their cellular uptake by the A549 lung cancer cell line to show a superior uptake of crosslinked micelles. However, due to the better Pt release of the statistical copolymer, the highest cytotoxicity was observed with this type of polymer architecture.