Glutathione and Reactive Oxygen Species Dual-Responsive Block Copolymer Prodrugs for Boosting Tumor Site-Specific Drug Release and Enhanced Antitumor Efficacy

A remarkable hall mark of cancer cells is heterogeneous co-existence of overproduced intracellular glutathione (GSH) and high level of reactive oxygen species (ROS) compared with normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g. GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG) and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide and thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in aqueous solution with the diameter ~ 50 nm. As compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with ...