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 Cu2+ ions. However, studies have shown that the endogenous Cu2+ dose in tumor tissues is still insufficient to form relatively high levels of a bis(N,N-diethyldithiocarbamate) copper(II) complex (denoted as Cu(DTC)2) to selectively eradicate cancer cells. Here, DSF-loaded hollow copper sulfide nanoparticles (DSF@PEG-HCuSNPs) were designed to achieve tumor microenvironment (TME)-activated in situ formation of cytotoxic Cu(DTC)2 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 Cu2+ ions, causing the in situ formation of cytotoxic Cu(DTC)2, 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 in vitro and in vivo studies confirmed the effective photonic hyperthermia-induced chemotherapeutic efficacy of DSF by integrating the in situ formation of toxic Cu(DTC)2 complexes and evident temperature elevation upon NIR-II laser irradiation. Thus, this study represents a distinctive paradigm of in situ Cu2+ chelation-initiated "nontoxicity-to-toxicity" transformation for photonic hyperthermia-augmented DSF-based cancer chemotherapy.