Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China.
Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China.
Colloids Surf B Biointerfaces. 2020 Nov;195:111256. doi: 10.1016/j.colsurfb.2020.111256. Epub 2020 Jul 12.
Multidrug resistance (MDR) is a primary cause of failure in oncotherapy and interest is growing in the design of multi-stimuli responsive nano-carriers to synergistically deliver chemotherapeutic agents and P-gp inhibitors to reverse MDR. The hybrid micelles based on a Platinum (IV)-coordinate polymeric prodrugs and TPGS were developed to improve chemotherapy and reduce side effects. The pH/redox dual-sensitive polymers were synthesized by condensation polymerization using ortho ester monomer and diamminedichlorodisuccinatoplatinum (DSP). The hybrid micelles possessed uniform size (38 nm) and displayed good stability in various physiological conditions. In contrast, in vitro drug release profiles indicated that these micelles could be completely depolymerized under acidic and reducing environment, thereby more than 80 % cisplatin were released within 12 h at pH 5.0 plus 10 mM DTT. More importantly, a large amount of TPGS released simultaneously could effectively inhibit the function of drug efflux pumps, which significantly enhanced the cytotoxicity of cisplatin against A549/DDP cells. The growth inhibition rate of micelles on A549/DDP multicellular spheroids was 79.5 %, while that of free cisplatin was only 6.8 %. Therefore, these hybrid micelles are promising in overcoming tumor MDR and worth doing further research in vivo and extend to other therapeutic agents.
多药耐药（MDR）是肿瘤治疗失败的主要原因，人们对设计多重刺激响应性纳米载体以协同递化疗药物和 P-糖蛋白抑制剂来逆转 MDR 的兴趣日益浓厚。基于铂（IV）配位聚合物前药和 TPGS 的杂化胶束被开发出来以提高化疗效果并降低副作用。通过使用邻酯单体和二氨二氯二琥珀酸合铂（DSP）进行缩合聚合来合成 pH/还原双重敏感聚合物。杂化胶束具有均匀的尺寸（38nm），并在各种生理条件下显示出良好的稳定性。相比之下，体外药物释放曲线表明，这些胶束在酸性和还原环境下可以完全解聚，从而在 pH 5.0 加 10mM DTT 下 12 小时内释放超过 80%的顺铂。更重要的是，同时释放大量的 TPGS 可以有效抑制药物外排泵的功能，从而显著增强顺铂对 A549/DDP 细胞的细胞毒性。胶束对 A549/DDP 细胞球的生长抑制率为 79.5%，而游离顺铂仅为 6.8%。因此，这些杂化胶束在克服肿瘤 MDR 方面具有广阔的应用前景，值得进一步进行体内研究并扩展到其他治疗药物。
