The construction of hierarchical assemblies with in situ generation of chemotherapy drugs to enhance the efficacy of chemodynamic therapy for multi-modal anti-tumor treatments.

The effectiveness of chemodynamic therapy (CDT) in cancer treatment is limited by insufficient endogenous H2O2 levels in tumor tissue and an increasing ratio of high valence metal ions. To overcome these challenges, a novel nanotherapeutic approach, named GOx-CuCaP-DSF, has been proposed. This approach involves the design of nanotherapeutics that aim to self-supply H2O2 within cancer cells and provide a supplement of low valence metal ions to enhance the performance of CDT. GOx-CuCaP-DSF nanotherapeutics are engineered by incorporating glucose oxidase (GOx) into Ca2+-doped calcium phosphate (CaP) nanoparticles and loading disulfiram (DSF) through surface adsorption. Under the tumor microenvironment, GOx catalyzes the conversion of tumor-overexpressed glucose (Glu) to liberate H2O2. The degradation of CaP further lowers the pH, facilitating the release of Cu2+ ions and DSF. The rapid reaction between Cu2+ and DSF leads to the generation of Cu+, increasing the Cu+/Cu2+ ratio and promoting the Cu+-based Fenton reaction, which enhances the efficiency of CDT. Simultaneously, DSF undergoes conversion to diethyldithiocarbamate acid (ET), forming a copper(II) complex (Cu(II)ET) by strong chelation with Cu ions. This Cu(II)ET complex, a potent chemotherapeutic drug, exhibits a synergistic therapeutic effect in combination with CDT. Moreover, the elevated Cu+ species resulting from DSF reaction promotes the aggregation of toxic mitochondrial proteins, leading to cell cuproptosis. Overall, the strategy of integrating the chemodynamic therapy efficiency of the Fenton reaction with the activation of efficacious cuproptosis using a chemotherapeutic drug presents a promising avenue for enhancing the effectiveness of multi-modal anti-tumor treatments.