One stone, three birds: Construction of Cu/ZIF-8@DSF@GOx/HA nanoplatform for synergistic starvation therapy enhanced chemo-/chemodynamic therapy.

Disulfiram (DSF), as a sixpenny drug for the treatment of alcohol dependence, has demonstrated copper-dependent chemotherapy (CT) effects in recent years. However, as the most common modality in clinical treatment, prolonged use of CT will lead to multidrug resistance (MDR). In this work, a versatile and ingenious nanoparticle Cu/ZIF-8@DSF@GOx/HA (CZDGH) was constructed to deliver DSF, Cu and GOx to tumor cells. Once internalized by tumor cells, GOx depletes glucose blocking the energy supply leading to ST. Then DSF chelates with Cu in situ to generate CuETs, achieving toxicity-intensified CT, the reduced ATP in this process also inhibits the efflux function of P-gp. In the meantime, Cu consumes glutathione (GSH) to enhance oxidative stress, and the converted Cu catalyzes internal and external sources of HO into •OH, heightening chemodynamic therapy (CDT). The experimental results demonstrate remarkable multimodal synergistic anticancer effects that overcome MDR.