Bioengineering functional copolymers. XXI. Synthesis of a novel end carboxyl-trithiocarbonate functionalized poly(maleic anhydride) and its interaction with cancer cells

Abstract

A novel carboxyl-trithiocarbonate functionalized polymer with a highly selective antitumor activity was synthesized by a reversible addition-fragmentation chain transfer (RAFT) polymerization of maleic anhydride (MA) with benzoyl peroxide as an initiator and S-1-dodecyl-S-(alpha, alpha'-dimethyl-alpha ''-acetic acid)-trithiocarbonate as a RAFT agent with the aim to design and synthesize an effective anticancer agent with minimum side effects. The structure, molecular weights and composition of synthesized polymers were investigated by H-1 (C-13) NMR, MALDI-TOF-MS and GPC analyzes. It was demonstrated that RAFT polymerization of MA was accompanied by a partially controlled decarboxylation of anhydride units and the formation of conjugated double bond fragments in backbone macromolecular chains. The mechanism of interaction of pristine RAFT agent and PMA-RAFT polymer with cancer (HeLa human cervix carcinoma) and normal (L929 Fibroblast) cells was investigated by using a combination of chemical, biochemical, statistical, spectroscopic (SEM and fluorescence inverted microscope) and real-time analysis (RTCA) methods. PMA-RAFT exhibited higher and selective cytotoxicity, apoptotic and necrotic effects toward HeLa cells at relatively low concentrations (around 7.5-75 mu g mL (1), IC50 = 11.183 mu g mL (1)) and toward Fibroblast cells at high concentrations (IC50 > 100 mu g mL (1)). The observed highly selective antitumor activity render PMA-RAFT polymers as promising candidates for the utilization in cancer chemotherapy. (C) 2012 Elsevier Ltd. All rights reserved.