Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Jiangnan University, No. 1800, Lihu Road, Wuxi 214122, PR China.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
Biomaterials. 2014 Dec;35(37):9877-9887. doi: 10.1016/j.biomaterials.2014.08.008. Epub 2014 Sep 15.
P-glycoprotein (P-gp) mediated drug efflux has been recognized as a key factor contributing to the multidrug resistance (MDR) in tumor cells. To address this issue, a new pH-sensitive mixed copolymer micelles system composed of hyaluronic acid-g-poly(l-histidine) (HA-PHis) and d-α-tocopheryl polyethylene glycol 2000 (TPGS2k) copolymers was developed to co-deliver doxorubicin (DOX) and TPGS2k into drug-resistant breast cancer MCF-7 cells (MCF-7/ADR). The DOX-loaded HA-PHis/TPGS2k mixed micelles (HPHM/TPGS2k) were characterized to have a unimodal size distribution, high DOX loading content and a pH dependent drug release profile due to the protonation of poly(l-histidine). As compared to HA-PHis micelles (HPHM), the HPHM/TPGS2k showed higher and comparable cytotoxicity against MCF-7/ADR cells and MCF-7 cells, respectively. The enhanced MDR reversal effect was attributed to the higher amount of cellular uptake of HPHM/TPGS2k in MCF-7/ADR cells than HPHM, arising from the inhibition of P-gp mediated drug efflux by TPGS2k. The measurements of P-gp expression level and mitochondrial membrane potential indicate that the blank HPHM/TPGS2k inhibited P-gp activity by reducing mitochondrial membrane potential and depletion of ATP but without inhibition of P-gp expression. In vivo study of micelles in tumor-bearing mice indicate that HPHM/TPGS2k could reach the tumor site more effectively than HPHM. The pH-sensitive mixed micelles system has been demonstrated to be a promising approach for overcoming the MDR.
P-糖蛋白（P-gp）介导的药物外排已被认为是导致肿瘤细胞多药耐药（MDR）的关键因素。为了解决这个问题，开发了一种由透明质酸-g-聚（L-组氨酸）（HA-PHis）和 d-α-生育酚聚乙二醇 2000（TPGS2k）共聚物组成的新型 pH 敏感混合胶束系统，以将阿霉素（DOX）和 TPGS2k 共递送至耐药乳腺癌 MCF-7 细胞（MCF-7/ADR）。负载 DOX 的 HA-PHis/TPGS2k 混合胶束（HPHM/TPGS2k）具有单峰粒径分布、高 DOX 载药量和 pH 依赖性药物释放特性，这是由于聚（L-组氨酸）的质子化。与 HA-PHis 胶束（HPHM）相比，HPHM/TPGS2k 对 MCF-7/ADR 细胞和 MCF-7 细胞分别表现出更高和相当的细胞毒性。增强的 MDR 逆转作用归因于 HPHM/TPGS2k 在 MCF-7/ADR 细胞中的细胞摄取量高于 HPHM，这是由于 TPGS2k 抑制了 P-gp 介导的药物外排。P-gp 表达水平和线粒体膜电位的测量表明，空白 HPHM/TPGS2k 通过降低线粒体膜电位和耗尽 ATP 来抑制 P-gp 活性，但不抑制 P-gp 表达。荷瘤小鼠体内研究表明，HPHM/TPGS2k 比 HPHM 更能有效地到达肿瘤部位。该 pH 敏感混合胶束系统已被证明是克服 MDR 的一种有前途的方法。
