Self-supplying Cu2+ and oxidative stress synergistically enhanced disulfiram-mediated melanoma chemotherapy

Abstract

Abstract Background Disulfiram (DSF) combined Cu2+ ions can target and kill cancer cells by disrupting cellular degradation of extruded proteins, and has therefore received particular attention for its tumor chemotherapeutic potential. However, the Cu2+/DSF ratio and oxidative environment can affect the efficacy of DSF-mediated chemotherapy. Herein, self-supplying Cu2+ and oxidative stress synergistically enhanced DSF-mediated chemotherapy is proposed for melanoma based on PVP-coated CuO2 nanodots (CPNDs). Results Once ingested, DSF is broken down to diethyldithiocarbamate (DTC), which is delivered into the tumor via circulation. Under the acidic tumor microenvironment, CPNDs produce sufficient Cu2+ and H2O2. DTC readily chelates Cu2+ ions to generate CuET, which shows antitumor efficacy. CuET-mediated chemotherapy can be enhanced by H2O2. Sufficient Cu2+ generation can guarantee maximum efficacy of DSF-mediated chemotherapy. Furthermore, Cu2+ can react with H2O2 to generate toxic hydroxyl radicals (•OH) via a Fenton-like reaction, promoting the efficacy of CuET. As a result, accompanied with oral uptaking of DSF and intratumoral injection of CPNDs strategy, the treatment achieves remarkable antitumor activity, which has been systematically verified both in vivo and in vitro assays. Conclusion This study hypothesizes that employing CPNDs instead of Cu2+ ions could generate H2O2 for Cu2+ and oxidative stress synergistically enhanced DSF-mediated melanoma chemotherapy, providing a simple but efficient strategy for achieving chemotherapeutic effeicacy.