Copper Gluconate/Disulfiram

Intracellular redox homeostasis and the type of exogenous Fenton reagent play crucial roles in determining the efficacy of chemodynamic therapy (CDT). Herein, we succeeded for the first time in preparing ultrasmall copper sulfide (CuS) nanodots (1-2 nm)-embedded hollow mesoporous organosilica nanoparticle (HMON), which served as an ideal nanocarrier to load both 3-amino-1,2,4-triazole (3-AT) and disulfiram (DSF) after folate-polyethylene glycol-silane (FA-PEG-Silane) modification. The as-prepared nanoplatform (3-AT/DSF@CuS/HMON-FA, denoted as ADCuSi-FA) was found to regulate intracellular redox homeostasis once internalized by 4T1 cells, showing rapid glutathione (GSH)-responsive 3-AT, DSF and Cu⁺ ions release. Specifically, 3-AT restrained the endogenous hydrogen peroxide (H₂O₂) consumption by suppressing catalase (CAT) activity, thereby augmenting hydroxyl radical (OH) generation via Cu⁺-based Fenton-like reaction. DSF, upon complexation with Cu²⁺, exhibited enhanced chemotherapeutic efficacy, while the by-product Cu⁺ ions further boosted the efficacy of CDT. Additionally, CuS nanodots enabled near-infrared-II (NIR-II) photothermal therapy (PTT) and facilitated photoacoustic (PA) imaging, with the ensuing hyperthermia expediting the CDT process. As expected, the tumor growth was dramatically inhibited with PTT/chemotherapy co-synergized CDT. This work offers an innovative paradigm for cooperative cancer treatment as well as new insights into the fabrication of biodegradable inorganic/organic hybrid materials.

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.