Polymeric Phosphorylcholine−Camptothecin Conjugates Prepared by Controlled Free Radical Polymerization and Click Chemistry

• Published in: Bioconjugate chemistry 2009-12, Vol.20 (12), p.2331-2341
• Main Authors: Chen, Xiangji, McRae, Samantha, Parelkar, Sangram, Emrick, Todd
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Camptothecin - chemistry; Camptothecin - pharmacology; Cell culture; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Chromatography; Cross-Linking Reagents - chemical synthesis; Cross-Linking Reagents - chemistry; Cross-Linking Reagents - pharmacology; Drug Screening Assays, Antitumor; Drugs; Free radicals; Free Radicals - chemical synthesis; Free Radicals - chemistry; Free Radicals - pharmacology; Humans; Methacrylates - chemical synthesis; Methacrylates - chemistry; Methacrylates - pharmacology; Molecular Structure; Particle Size; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - chemical synthesis; Phosphorylcholine - chemistry; Phosphorylcholine - pharmacology; Polymerization; Polymers; Polymethacrylic Acids; Solubility; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc900339x

Novel polymer−drug conjugates, consisting of zwitterionic poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) as the polymer component, and camptothecin (CPT) as the drug, were prepared by two methods. In one case, CPT was transformed by acylation into a functional initiator for copper catalyzed atom transfer radical polymerization (ATRP), and polyMPC was grown from this therapeutic initiator. In the other case, a one-pot ATRP-“click” conjugation strategy was employed to synthesize novel polyMPC structures containing multiple copies of the drug pendant to the zwitterionic polymer chain. The latter method allows polyMPC-graft-CPT conjugates to be prepared with a high weight percent drug loading (up to 14% CPT) with excellent solubility in pure water (>250 mg/mL). The linkage chemistry chosen between the polyMPC backbone and the pendant drugs proved critically important for assuring drug release within a time frame reasonable to consider these structures as a platform for injectable cancer therapeutics. Liberation of the drug from the polymer backbone was monitored by high-performance liquid chromatography, using size-exclusion and reverse-phase columns, and the toxicity of the polymer−drug conjugates was examined in cell culture against breast (MCF7), ovarian (OVCAR-3), and colorectal (COLO 205) cancer cell lines.