Zhou Dezhong, Gao Yongsheng, A Sigen, Xu Qian, Meng Zhao, Greiser Udo, Wang Wenxin
Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland.
School of Materials Science and Engineering, School of Materials Science and Engineering, Tianjin 300072, China.
ACS Macro Lett. 2016 Nov 15;5(11):1266-1272. doi: 10.1021/acsmacrolett.6b00777. Epub 2016 Nov 1.
Here we report the synthesis of a well-defined amphiphilic conjugate, tetraethylthiuram disulfide (disulfiram, DS)-poly(ethylene glycol) methyl ether acrylate (DS-PEGMEA), and its multifacet self-assembly in aqueous solutions and application in DS drug delivery to melanoma cells. The DS-PEGMEA was synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization utilizing DS, a 90 year old anticancer drug, as a precursor to generate RAFT agent in situ. Results demonstrate that the in situ formed RAFT can effectively control the polymerization of PEGMEA. Depending on the concentration in aqueous solution, the amphiphilic DS-PEGMEA conjugate can self-assemble to form layered, toroidal, hairy, or spherical nanostructures, respectively. Moreover, DS drug can be further encapsulated by DS-PEGMEA to formulate core-shell structured DS/DS-PEGMEA nanoparticles mediating the apoptosis of melanoma cells (A375) while inducing minimal cytotoxicity to normal (hADSC and NIH fibroblast) cells. Both DS and PEGMEA are approved by the American Food and Drug Administration (FDA); therefore, the DS-PEGMEA has great potential for application in clinical drug delivery to melanoma.
在此，我们报道了一种结构明确的两亲性共轭物——二硫化四乙秋兰姆（戒酒硫，DS）-聚乙二醇甲基醚丙烯酸酯（DS-PEGMEA）的合成，及其在水溶液中的多方面自组装以及在向黑色素瘤细胞递送DS药物中的应用。DS-PEGMEA是通过可逆加成-断裂链转移（RAFT）聚合反应合成的，利用有90年历史的抗癌药物DS作为前体原位生成RAFT试剂。结果表明，原位形成的RAFT能够有效控制PEGMEA的聚合。根据在水溶液中的浓度，两亲性DS-PEGMEA共轭物可分别自组装形成层状、环形、毛发状或球形纳米结构。此外，DS药物可被DS-PEGMEA进一步包封，以制备核壳结构的DS/DS-PEGMEA纳米颗粒，介导黑色素瘤细胞（A375）凋亡，同时对正常（人脂肪间充质干细胞和NIH成纤维细胞）细胞诱导最小的细胞毒性。DS和PEGMEA均已获得美国食品药品监督管理局（FDA）批准；因此，DS-PEGMEA在黑色素瘤临床药物递送中具有巨大的应用潜力。
