Copper Gluconate/Disulfiram

Disulfiram (DSF) is a safe drug with negligible toxicity and Cu-dependent anti-tumor efficacy. However, the accumulation and combination of DSF and Cu in non-tumor tissues leads to systemic toxicity owing to the formation of highly poisonous diethyldithiocarbamate (CuET). In addition, CuET-mediated tumor-killing reactive oxygen species may be weakened by intra-tumoral glutathione (GSH). Herein, a synergistic treatment was developed that utilized the oral delivery of DSF and an injectable polyphenol-copper (PA-Cu) hydrogel loaded with the glutamine uptake inhibitor 2-amino-4-bis(phenoxymethyl)aminobutane (V9302). The injectable hydrogels were synthesized by the Schiff base reaction of hydroxypropyl chitosan (HPCS) with a PA-Cu reversible cross-linking agent. Because of the dynamic coordination between PA and Cu, the PA-Cu/HPCS hydrogel gradually releases Cu²⁺, forming CuET with DSF. The released V9302 inhibits glutamine uptake, thereby suppressing GSH synthesis and enhancing the therapeutic efficacy of the in situ formed CuET. The synergistic effect of PA-Cu/HPCS/V9302 and DSF in eliminating intracellular GSH and killing tumor cells was validated by in vitro cell experiments. Animal experiments further confirmed that PA-Cu/HPCS/V9302 and DSF have an inhibitory effect on tumor growth while maintaining the biosafety of main organs.

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, Cu²⁺ and GOx to tumor cells. Once internalized by tumor cells, GOx depletes glucose blocking the energy supply leading to ST. Then DSF chelates with Cu²⁺ 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, Cu²⁺ consumes glutathione (GSH) to enhance oxidative stress, and the converted Cu⁺ catalyzes internal and external sources of H₂O₂ into •OH, heightening chemodynamic therapy (CDT). The experimental results demonstrate remarkable multimodal synergistic anticancer effects that overcome MDR.