| Description |
Each year in the United States, over 14,000 women die from ovarian cancer. Anthracyclines-a class of chemotherapeutics-have long been the primary treatment for this and many other cancers, yet they often leave patients with cardiotoxicity, hepatotoxicity, and a number of other adverse effects. Polymer-drug conjugates using poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA) are nanosized, water-soluble constructs that accumulate passively in solid tumors by the enhanced permeability and retention effect, as well as actively by targeting methods. As such, they have exhibited reduced toxicity in the body. The traditional approach used in conjugating antibody targeting moieties to the HPMA copolymer-drug backbone has proven ineffective in the case of gemcitabine, a chemotherapeutic and nucleoside analog that has demonstrated considerable effectivedfness in recent years treating ovarian cancer. The aims of this study were twofold: 1) to develop a novel pHPMA-OV-TL16 antibody fragment (Fab') conjugation apprach that is compatible with gemcitabine and 2) to optimize existing procedures for the synthesis of all monomeric precursors. The copolymer-gemcitabine conjugate was successfully developed following the synthesis of OVTL16 Fab', diblock chain-transfer agent (di-CTA), N-(2-(2-pyridyldithio)ethyl)methacrylamide (PDTEMA), and polymerizable gemcitabine derivative. Monomers were combined by reversible addition-fragmentation chain-transfer (RAFT) polymerization, and then the Fab' fragment was successfully bound to the copolymer backbone via a disulfide exhange reaction with PDTEMA. Future work will involve in virto and in vivo evaluation of the conjugate's therapeutic efficacy in nude mice bearing OVCAR3-exnografts. |
