Thiol–yne and Thiol–ene “Click” Chemistry as a Tool for a Variety of Platinum Drug Delivery Carriers, from Statistical Copolymers to Crosslinked Micelles

• Published in: Biomacromolecules Vol. 12; no. 5; pp. 1738 - 1751
• Main Authors: Huynh, Vien T, Chen, Gaojian, Souza, Paul de, Stenzel, Martina H
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 09.05.2011
• Subjects: Applied sciences; Biological and medical sciences; Chromatography, High Pressure Liquid; Drug Carriers; Exact sciences and technology; General pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Micelles; Organic polymers; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Physicochemistry of polymers; Platinum - administration & dosage; Platinum - chemistry; Polymers - chemistry; Polymers with particular properties; Preparation, kinetics, thermodynamics, mechanism and catalysts; Spectrophotometry, Ultraviolet; Sulfhydryl Compounds - chemistry; Antineoplastic agent; Ligand substitution; Graft copolymer; Propargylic compound; Drug carrier; Mercaptoacid; Crosslinked copolymer; Chain transfer; Acid copolymer; Tumor cell; Release; Control release polymer; Crosslinking; Hydroxyethyl methacrylate copolymer; Organic anhydride; Dithioester; Ethylene oxide copolymer; Experimental study; Sulfur copolymer; In vitro; Biological activity; Cisplatin; Esterification; Random copolymer; Monodispersed polymer; Chemical modification; Free radical polymerization; Preparation; Addition reaction; Diblock copolymer; Kinetics; Methacrylate copolymer; Aqueous solution; Radical copolymerization; Micellar solution
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm200135e

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 pendant 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.