Polyprodrug with glutathione depletion and cascade drug activation for multi-drug resistance reversal.

High intracellular glutathione (GSH) levels play an important role in multidrug resistance (MDR) in cancer cells. It remains challenging to develop a drug delivery system that is simultaneously capable of GSH depletion and drug activation for multidrug resistance reversal. Herein, we designed a polyprodrug (denoted as PSSD) based on poly(disulfide) conjugated with doxorubicin (DOX) on the polymer side chains that exhibits GSH depletion and cascade DOX activation for drug resistance reversal. The poly(disulfide) backbone with a high disulfide density depletes intracellular antioxidant GSH via the disulfide-thiol exchange reaction to disrupt intracellular redox homeostasis in cells. Simultaneously, DOX can be activated through a cascade reaction, and degradation of the poly(disulfide) backbone further facilitates its drug release. Therefore, poly(disulfide) can be used as a GSH scavenger to reverse MDR as well as a prodrug backbone to target high intracellular GSH levels in cancer cells, providing a general strategy for drug resistance reversal.