Zinc ion-coordinated high-drug-loading nanoparticles for enhanced anti-tumor therapy

Disulfiram (DSF), a clinically approved anti-alcoholism drug, has recently gained prominence as a repurposed antitumor candidate owing to its metal-chelating capability for potentiated therapeutic outcomes. The complex formed by the coordination between DSF and zinc ions (Zn²⁺) is a key active ingredient that exerts anticancer effects. Directly delivering the complex is an effective strategy for improving the therapeutic effect of DSF. However, its application is hindered due to the poor aqueous solubility and limited delivery efficiency. To overcome these critical barriers, we engineered a metal-coordination-driven self-assembled nanoplatform through Zn²⁺-mediated complexation with diethyldithiocarbamate (DDTC, the bioactive metabolite of DSF), subsequently functionalized with polyvinylpyrrolidone (PVP) and hyaluronic acid (HA) to construct Zn(DDTC)₂ nanoparticles (NPs) for high-efficacy cancer therapy. This approach enabled efficient production of Zn(DDTC)₂ NPs with high reproducibility and scalability. The optimized Zn(DDTC)₂ NPs exhibited high drug encapsulation efficiency (close 100%), remarkable drug-loading capacity (96.05%), excellent colloidal stability, and uniform dispersibility in physiological media. In vitro studies have shown that nanoparticles effectively internalized into tumor cells via endocytosis or HA-CD44-mediated endocytosis. Subsequently, zinc ions and DDTC exert a synergistic therapeutic effect by disrupting mitochondrial function, promoting reactive oxygen species production, inducing cell apoptosis, and inhibiting cell migration. This metal ion–coordinated nanoplatform not only enhances the therapeutic potential of DSF but also provides a promising strategy for low-toxicity, high-efficacy cancer therapy by leveraging metal-drug synergism.