Co-delivery of a tumor microenvironment-responsive disulfiram prodrug and CuO(2) nanoparticles for efficient cancer treatment

Disulfiram (DSF) has been used as a hangover drug for more than seven decades and was found to have potential in cancer treatment, especially mediated by copper. However, the uncoordinated delivery of disulfiram with copper and the instability of disulfiram limit its further applications. Herein, we synthesize a DSF prodrug using a simple strategy that could be activated in a specific tumor microenvironment. Poly amino acids are used as a platform to bind the DSF prodrug through the B–N interaction and encapsulate CuO(2) nanoparticles (NPs), obtaining a functional nanoplatform Cu@P–B. In the acidic tumor microenvironment, the loaded CuO(2) NPs will produce Cu(2+) and cause oxidative stress in cells. At the same time, the increased reactive oxygen species (ROS) will accelerate the release and activation of the DSF prodrug and further chelate the released Cu(2+) to produce the noxious copper diethyldithiocarbamate complex, which causes cell apoptosis effectively. Cytotoxicity tests show that the DSF prodrug could effectively kill cancer cells with only a small amount of Cu(2+) (0.18 μg mL(−1)), inhibiting the migration and invasion of tumor cells. In vitro and in vivo experiments have demonstrated that this functional nanoplatform could kill tumor cells effectively with limited toxic side effects, showing a new perspective in DSF prodrug design and cancer treatment.