A drug ligand based bimetallic coordination-driven self-assembly nanodrug for high-efficiency tumor chemodynamic therapy

Low chemodynamic catalytic efficiency at weakly acidic microenvironment, inadequate H2O2 and high glutathione (GSH) levels in tumor cells severely limit the efficacy of chemodynamic therapy (CDT). To address these problems, a bimetallic coordination-driven self-assembly nanoparticle named AZC@HA NP is fabricated using the catalase inhibitor 3-amino-1, 2, 4-triazole (3-AT) as the coordination ligands of both copper (II) and zinc (II) ions. Interestingly, parts of Cu2+ converted into Cu+ after coordination. Cu+ ions in AZC@HA NPs catalyze the Fenton-like reaction at weakly acidic and neutral microenvironment to produce •OH for CDT. 3-AT elevates intracellular H2O2 level thus augments the •OH generation by inactivating the catalase. AZC@HA NPs decrease intracellular GSH level thus reduce the resistance of tumor cells to CDT through both Cu2+-mediated GSH depletion and "Zn2+ interference" mediated GSH synthesis suppression. Surface coating of hyaluronic acid (HA) allow the targeted accumulation of AZC@HA NPs on CD44 overexpressed tumor cells. The AZC@HA NPs show significantly enhanced tumor inhibition in vitro and in vivo. Overall, the as-prepared tumor targeting, H2O2 elevating and dual GSH exhausting coordination-driven self-assembly nanodrugs AZC@HA NPs provide an innovative strategy for high efficient CDT.