Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of a-tocopheryl succinate-based polyphosphoester copolymers  

作　　者：Feng-qian CHEN Jin-ming ZHANG Xie-fan FANG Hua YU Yu-ling LIU Hui LI Yi-tao WANG Mei-wan CHEN 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macao, Macao, China [2]Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA [3]Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Belling 100700, China [4]College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China

出　　处：《Acta Pharmacologica Sinica》2017年第6期859-873,共15页中国药理学报（英文版）

摘　　要：P-glycoprotein （P-gp）-mediated multidrug resistance （MDR） is a major obstacle in achieving the therapeutic benefits of paclitaxel （PTX） in the treatment of human ovarian carcinoma. This study is aimed to develop an efficient PTX drug delivery approach to overcome MDR. Redox-responsive micelles consisting of amphiphilic polymers containing disulfide linkages, ie, poly （phosphate ester）-SS-D-a- tocopheryl succinate （POPEA-SS-TOS, PSST） were prepared. PTX-loaded PSST micelles （PTX/PSST-M） designed to display synergistic functions, including reversible inhibition of P-gp, intracellular redox-sensitive release and potent anticancer activities. The average size of PTX/PSST-M was 68.1＋4.9 nm. The encapsulated PTX was released quickly through redox-triggered dissociation of micelles. The inhibition of P-gp activity and enhanced cellular accumulation of the PSST micelles were validated. PTX/PSST-M showed significantly increased cytotoxicity against PTX-resistant human ovarian cancer A2780/PTX cells： when the cells were treated with PTX/PSST-M for 48 h, the equivalent IC5o value of PTX was reduced from 61.51 to 0.49 pmot/L. The enhanced cytotoxic effects of PTX/PSST-M against A2780/PTX cells were attributed to their synergistic effects on reducing the mitochondrial transmembrane potential, ATP depletion, ROS production, and activation of apoptotic pathways. Furthermore, PTX/PSST-M significantly increased cell apoptosis/necrosis and cell cycle arrest at the Gz/M phase in A2780/PTX cells. These results demonstrate that the redox-responsive PSST micelles inhibit P-gp activity and have a good potential to effectively reverse PTX resistance in human ovarian carcinoma cells by activating intrinsic a poptotic pathways.P-glycoprotein （P-gp）-mediated multidrug resistance （MDR） is a major obstacle in achieving the therapeutic benefits of paclitaxel （PTX） in the treatment of human ovarian carcinoma. This study is aimed to develop an efficient PTX drug delivery approach to overcome MDR. Redox-responsive micelles consisting of amphiphilic polymers containing disulfide linkages, ie, poly （phosphate ester）-SS-D-a- tocopheryl succinate （POPEA-SS-TOS, PSST） were prepared. PTX-loaded PSST micelles （PTX/PSST-M） designed to display synergistic functions, including reversible inhibition of P-gp, intracellular redox-sensitive release and potent anticancer activities. The average size of PTX/PSST-M was 68.1＋4.9 nm. The encapsulated PTX was released quickly through redox-triggered dissociation of micelles. The inhibition of P-gp activity and enhanced cellular accumulation of the PSST micelles were validated. PTX/PSST-M showed significantly increased cytotoxicity against PTX-resistant human ovarian cancer A2780/PTX cells： when the cells were treated with PTX/PSST-M for 48 h, the equivalent IC5o value of PTX was reduced from 61.51 to 0.49 pmot/L. The enhanced cytotoxic effects of PTX/PSST-M against A2780/PTX cells were attributed to their synergistic effects on reducing the mitochondrial transmembrane potential, ATP depletion, ROS production, and activation of apoptotic pathways. Furthermore, PTX/PSST-M significantly increased cell apoptosis/necrosis and cell cycle arrest at the Gz/M phase in A2780/PTX cells. These results demonstrate that the redox-responsive PSST micelles inhibit P-gp activity and have a good potential to effectively reverse PTX resistance in human ovarian carcinoma cells by activating intrinsic a poptotic pathways.

关 键 词：ovarian carcinoma paclitaxel multidrug resistance NANOMEDICINES D-（x-tocopheryl succinate redox-responsive micelles P-gp apoptosis cell cycle arrest A2780/PTX cells 

分 类 号：Q344.13[生物学—遗传学] O621.254[理学—有机化学]