Redox-sensitive nanoscale drug delivery systems for cancer treatment

Pharmaceutical nanotechnology introduces novel strategies in designing smart nanoscale drug delivery systems (NDDSs) capable of responding to specific conditions. These smart responsive NDDSs respond to specific conditions already established in the tumor microenvironment (TME) resulting in greater drug release following accumulation through enhanced permeation and retention (EPR) effect. Among various specific conditions, reactive oxygen species (ROS) and glutathione (GSH) have been extensively used to improve tumor targeting. While cells of the tumor microenvironment including immune cells, cancer-associated fibroblasts, endothelial cells and tumor invasive cells are responsible for the production and elevation of ROS levels, high levels of GSH inside tumor cells establish highly reducing environment, which in turn maintain cell survival. Abnormal ROS generation in the tumor microenvironment helps with designing highly specific ROS-sensitive NDDSs with the potential to release the payload next to the tumor cells. On the other hand, elevated levels of tumor GSH allows for designing NDDSs bearing reductively cleavable linkage to enhance drug release exploiting the dramatic higher intracellular GSH. The aim of the current review is to emphasize the requirements for developing various NDDSs including liposomes, polymeric nanoparticles, micelles, mesoporous silica nanoparticles, nanogels and prodrugs, capable of responding to TME using their Redox-sensitive moieties.