Institute of Science & Engineering, Division of Nanotechnology and Nanomedicine, Hacettepe University, Beytepe 06800, Ankara, Turkey.
Bioorg Med Chem. 2012 Aug 15;20(16):5053-61. doi: 10.1016/j.bmc.2012.05.058. Epub 2012 Jun 5.
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-(α,α'-dimethyl-α"-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 (1)H ((13)C) 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 μg mL(-1), IC(50) = 11.183 μg mL(-1)) and toward Fibroblast cells at high concentrations (IC(50) > 100 μg mL(-1)). The observed highly selective antitumor activity render PMA-RAFT polymers as promising candidates for the utilization in cancer chemotherapy.
一种新型的羧基三硫代碳酸酯功能化聚合物具有高度选择性的抗肿瘤活性，是通过马来酸酐（MA）与过氧化二苯甲酰作为引发剂和 S-1-十二烷基-S-（α，α'-二甲基-α“-乙酸）三硫代碳酸酯作为 RAFT 试剂的可逆加成-断裂链转移（RAFT）聚合合成的，旨在设计和合成具有最小副作用的有效抗癌剂。通过 1 H（13 C）NMR、MALDI-TOF-MS 和 GPC 分析研究了合成聚合物的结构、分子量和组成。结果表明，MA 的 RAFT 聚合伴随着部分控制的酸酐单元脱羧和共轭双键片段在大分子链中的形成。通过使用化学、生化、统计、光谱（SEM 和荧光倒置显微镜）和实时分析（RTCA）方法的组合，研究了原始 RAFT 试剂和 PMA-RAFT 聚合物与癌细胞（HeLa 人宫颈癌）和正常（L929 成纤维细胞）细胞的相互作用机制。在相对较低的浓度（约 7.5-75μg mL（-1），IC（50）= 11.183μg mL（-1））下，PMA-RAFT 对 HeLa 细胞表现出更高和选择性的细胞毒性、凋亡和坏死作用，而在高浓度（IC（50）>100μg mL（-1））下对成纤维细胞表现出更高的选择性。观察到的高度选择性抗肿瘤活性使 PMA-RAFT 聚合物成为癌症化疗中应用的有前途的候选物。
