Redox-responsive F127-folate/F127-disulfide bond-d-α-tocopheryl polyethylene glycol 1000 succinate/P123 mixed micelles loaded with paclitaxel for the reversal of multidrug resistance in tumors

Jing Lin,* Chaoyue Zhao,* Cuijuan Liu, Shiyao Fu, Luying Han, Xinping Lu, Chunrong Yang College of Pharmacy, Jiamusi University, Jiamusi, Heilongjiang, China *These authors contributed equally to this work Introduction: The development of nanodrug carriers utilizing tumor microenvironment has become a hotspot in reversing multidrug resistance (MDR). Materials and methods: This study synthesized a redox-sensitive copolymer, Pluronic F127-disulfide bond-D-α-tocopheryl polyethylene glycol 1000 succinate (FSST), through the connection of the reduction-sensitive disulfide bond between F127 and D-α-tocopheryl polyethylene glycol 1000 succinate. This polymer could induce the elevation of reactive oxygen species (ROS) levels, ultimately resulting in cytotoxicity. Moreover, the redox-responsive mixed micelles, F127-folate (FA)/FSST/P123 (FFSSTP), based on FSST, Pluronic F127-FA, and Pluronic P123, were prepared to load paclitaxel (PTX). Results: The in vitro release study demonstrated that FFSSTP/PTX accelerated the PTX release through the breakage of disulfide bond in reductive environment. In cellular experiment, FFSSTP/PTX induced significant apoptosis in PTX-resistant MCF-7/PTX cells through inhibiting adenosine triphosphate (ATP)-binding cassette proteins from pumping out PTX by interfering with the mitochondrial function and ATP synthesis. Furthermore, FFSSTP/PTX induced apoptosis through elevating the intracellular levels of ROS. Conclusion: FFSSTP could become a potential carrier for the treatment of MDR tumors. Keywords: redox responsive, mixed micelles, multidrug resistance, paclitaxel, tumor microenvironment