Nanomedicine Enables Drug-Potency Activation with Tumor Sensitivity and Hyperthermia Synergy in the Second Near-Infrared Biowindow.

Disulfiram (DSF), a U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism, is also used as an antitumor drug in combination with Cu ions. However, studies have shown that the endogenous Cu dose in tumor tissues is still insufficient to form relatively high levels of a bis(,diethyldithiocarbamate) copper(II) complex (denoted as Cu(DTC)) to selectively eradicate cancer cells. Here, DSF-loaded hollow copper sulfide nanoparticles (DSF@PEG-HCuSNPs) were designed to achieve tumor microenvironment (TME)-activated formation of cytotoxic Cu(DTC) for NIR-II-induced, photonic hyperthermia-enhanced, and DSF-initiated cancer chemotherapy. The acidic TME triggered the gradual degradation of DSF@PEG-HCuSNPs, promoting the rapid release of DSF and Cu ions, causing the formation of cytotoxic Cu(DTC), to achieve efficient DSF-based chemotherapy. Additionally, DSF@PEG-HCuSNPs exhibited a notably high photothermal conversion efficiency of 23.8% at the second near-infrared (NIR-II) biowindow, thus significantly inducing photonic hyperthermia to eliminate cancer cells. Both and studies confirmed the effective photonic hyperthermia-induced chemotherapeutic efficacy of DSF by integrating the formation of toxic Cu(DTC) complexes and evident temperature elevation upon NIR-II laser irradiation. Thus, this study represents a distinctive paradigm of Cu chelation-initiated "nontoxicity-to-toxicity" transformation for photonic hyperthermia-augmented DSF-based cancer chemotherapy.