A cascade nanoplatform for intelligent response to tumor microenvironment and collaborative cancer therapy

Disulfiram (DSF), a new potential anticancer drug, has been shown to exhibit anticancer activity dependent on the formation of CuET, the chelation product of DSF with Cu2+. However, the poor stability of DSF and insufficient physiological concentration of Cu2+ hinder its practical application. To achieve the co-delivery of DSF and Cu2+ while overcoming the inefficiency of single chemotherapy, in this study, a cascade nanoplatform, DSF/Ce6@ZIF-8@CuO2, was constructed by encapsulating DSF and chlorin e6 (Ce6, a photosensitizer) in zeolite imidazole framework-8 (ZIF-8, a nanocarrier) and then loading CuO2, which self-supplied H2O2/O2, onto DSF/Ce6@ZIF-8. By triggering the response of DSF/Ce6@ZIF-8@CuO2 to the acidic tumor microenvironment, encapsulated DSF, Ce6 and CuO2 were released to achieve multimodal synergistic treatment with enhanced DSF chemotherapy and chemodynamic/photodynamic therapy (CDT/PDT). In vitro and animal studies indicated that the designed DSF/Ce6@ZIF-8@CuO2 has strong tumor-inhibitory effects and provides a promising paradigm for designing smart nanoplatforms. The DCZCu nanoplatform provides a powerful multimodal synergistic anticancer strategy for tumor growth inhibition in terms of enhanced chemotherapy.