Investigation of the intracellular oxidative stress amplification, safety and anti-tumor effect of a kind of novel redox-responsive micelle

Abstract

Reactive oxygen species (ROS) are one of the major intracellular metabolites. Tumor cells are usually under oxidative stress and susceptible to further ROS insults due to the excessive increase in ROS levels. Moreover, tumor cells also upregulate antioxidant systems such as glutathione (GSH) to counteract the damage caused by ROS. Therefore, the amplification of oxidative stress through increasing ROS levels to induce apoptosis could be a strategy for tumor therapy. Here we report a redox-responsive polymer micellar system, which is composed of Pluronic F127-disulfide bond-D-α-tocopheryl polyethylene glycol succinate (F127-SS-TPGS, FSST). The micelles could be degraded by the cleavage of the disulfide bond in the reductive intracellular environment, and release the ROS inducer, TPGS, which induced cytotoxicity through elevating ROS levels and inhibited mitochondrial function in tumor cells. These micelles hardly affected the function of normal cells and showed good biocompatibility. The paclitaxel-loaded FSST-PTX micelles significantly improved the cytotoxicity of PTX. In vivo experiments revealed that the FSST-PTX micelles prolonged the circulation and enhanced the treatment of PTX. In conclusion, FSST could be a potential vehicle for cancer treatment.