Considering the chemodynamic therapy and chemotherapy independent of external stimulus witnessing great advantage in the clinical translation, developing a smart nanoplatform that can realize enhanced chemo/chemodynamic synergistic therapy in the tumor microenvironment (TME) is of great significance. Herein, we highlight the enhanced pH-responsive chemo/chemodynamic synergistic cancer therapy based on in situ Cu2+ di-chelation. The alcohol-withdrawal drug disulfiram (DSF) and chemotherapeutic drug mitoxantrone (MTO) were embedded into PEGylated mesoporous CuO (denoted as PEG-CuO@DSF@MTO NPs). The acidic TME triggered the collapse of CuO and the concurrent release of Cu2+, DSF, and MTO. Then, the in situ complexation between Cu2+ and DSF, as well as the coordination between Cu2+ and MTO not only prominently enhanced the chemotherapeutic performance but also triggered the chemodynamic therapy. In vivo mouse model experiments demonstrated that the synergistic therapy can remarkably eliminate tumors. This study provides an interesting strategy to design intelligent nanosystems, which could proceed to clinical translations.
Keywords: disulfiram; enhanced chemo/chemodynamic; in situ Cu2+ di-chelation; mesoporous CuO; mitoxantrone; synergistic therapy.