Two birds with one stone: Copper metal-organic framework as a carrier of disulfiram prodrug for cancer therapy

Disulfiram (DSF) has a copper (II)-potentiated anticancer activity in various cancers. Synchronous delivery of DSF and cupric ions to tumor tissues is challenging but holds great potential in improving antitumor outcomes and promoting clinical translation. Herein, we reported a disulfiram prodrug (DQ)-loaded and glucose oxidase (GOD) conjugated copper (II)-based nanoscale metal-organic framework (MOF), MPDG, for tumor-specific, enhanced chemo-chemodynamic therapy. Copper MOF, MOF-199, played a dual role of drug nanocarrier of DQ and copper ion reservoir for sufficient generation of copper (II) diethylthiocarbamate (Cu(DTC)2), a complex of DSF and Cu2+. GOD improved the stability of Cu(II) nano-depot and enabled catalytic generation of H2O2 in response to high concentration of glucose in cancer cells. The catalytically generating and endogenous H2O2 boosted the activation of encapsulated H2O2-activatable prodrug DQ to generate highly cytotoxic Cu(CDTC)2 in situ for tumor-specific chemotherapy. Meanwhile, the elevated H2O2 significantly augmented the production of OH for enhanced chemodynamic therapy. The self-activated amplified chemo-chemodynamic therapy nanosystem led to a significantly enhanced inhibition of 4T1 murine breast cancer cells (half inhibitory concentration reduced from 5 μg/mL to 0.8 μg/mL) in the presence of glucose. The in vivo study verified that MPDG showed the highest tumor inhibition rate of 86.2% and negligible toxicity to main organs. Overall, this study provides a novel disulfiram prodrug/Cu2+ co-delivery strategy for enhanced and selective cancer treatment.