Self-supplying Cu²⁺ and H₂O₂ synergistically enhancing disulfiram-mediated melanoma chemotherapy

Disulfiram (DSF) 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 uncontrollable Cu²⁺/DSF ratio reduces 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). Once ingested, DSF is broken down to diethyldithiocarbamate (DTC), which is delivered into a tumor via the 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 the maximum efficacy of DSF-mediated chemotherapy. Furthermore, released Cu²⁺ can be reduced to Cu⁺ by glutathione (GSH) and O^2- in tumor cells, and Cu⁺ can react with H₂O₂ to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, promoting the efficacy of CuET. Therefore, this study hypothesizes that employing CPNDs instead of Cu²⁺ ions could enhance DSF-mediated melanoma chemotherapy, providing a simple but efficient strategy for achieving chemotherapeutic efficacy.