Yin Mingxing, Bao Yuling, Gao Xueqin, Wu Yupei, Sun Yu, Zhao Xinyuan, Xu Hongzhe, Zhang Zhiping, Tan Songwei
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
J Mater Chem B. 2017 Apr 28;5(16):2964-2978. doi: 10.1039/c6tb03282f. Epub 2017 Apr 5.
A redox/pH dual-sensitive graft copolymer, poly(β-amino ester)-g-d-α-tocopherol polyethylene glycol succinate (PBAE-g-TPGS), was synthesized through a Michael-type step polymerization using disulfide linkage-containing TPGS macromonomers. Pluronic F127 (F127) and folate-F127 conjugation were introduced to prepare paclitaxel (PTX)-loaded hybrid micelles to improve their biocompatibility and serum stability and also to achieve targeted delivery. The hybrid micelles exhibited in vitro redox/pH-sensitive PTX release, enhanced cellular uptake through receptor-mediated endocytosis, and strengthened anticancer activities in both the drug-sensitive human breast cancer MCF-7 and drug-resistant MCF-7/ADR cells. P-Glycoprotein inhibition by TPGS and folate-mediated targeted delivery helped overcome multidrug resistance (MDR) and increase the therapeutic efficiency of the drug, leading to good anticancer effects in the MCF-7/ADR xenograft model. Overall, the folate-modified redox/pH-sensitive hybrid micelles provided a three-step approach to enhance anticancer activities via targeted delivery, controlled release, and depressed drug efflux; thus, these micelles may be a powerful weapon against MDR cancers in the future.
通过使用含二硫键的TPGS大分子单体进行迈克尔型逐步聚合反应，合成了一种氧化还原/ pH双敏感接枝共聚物，聚（β-氨基酯）-g-d-α-生育酚聚乙二醇琥珀酸酯（PBAE-g-TPGS）。引入普朗尼克F127（F127）和叶酸-F127共轭物以制备负载紫杉醇（PTX）的混合胶束，以提高其生物相容性和血清稳定性，并实现靶向递送。该混合胶束在体外表现出氧化还原/ pH敏感的PTX释放，通过受体介导的内吞作用增强细胞摄取，并在药物敏感的人乳腺癌MCF-7和耐药的MCF-7 / ADR细胞中增强抗癌活性。TPGS对P-糖蛋白的抑制作用和叶酸介导的靶向递送有助于克服多药耐药性（MDR）并提高药物的治疗效率，从而在MCF-7 / ADR异种移植模型中产生良好的抗癌效果。总体而言，叶酸修饰的氧化还原/ pH敏感混合胶束提供了一种通过靶向递送、控释和抑制药物外排来增强抗癌活性的三步方法；因此，这些胶束未来可能成为对抗MDR癌症的有力武器。
