A hollow Co3−xCuxS4 with glutathione depleting and photothermal properties for synergistic dual-enhanced chemodynamic/photothermal cancer therapy

Abstract

Chemodynamic therapy has become an emerging cancer treatment strategy, in which tumor cells are killed through toxic reactive oxygen species (ROS), especially hydroxyl radicals (˙OH) produced by the Fenton reaction. Nevertheless, low ROS generation efficiency and ROS depletion by cellular antioxidant systems are still the main obstacles in chemodynamic therapy. In the present work, we propose a dually enhanced chemodynamic therapy obtained by inhibiting ˙OH consumption and promoting ˙OH production based on the administration of bimetallic sulfide Co_3−xCu_xS₄ nanoparticles functionalized by polyethylene glycol. These bimetallic nanoparticles display glutathione depleting and photothermal properties. The nanoparticles are gradually degraded in a tumor microenvironment, resulting in Co²⁺ and Cu²⁺ release. The released Co²⁺ triggers a Fenton-like reaction that turns endogenous hydrogen peroxide into highly toxic ˙OH. In the cellular environment, Cu²⁺ ions are reduced to Cu⁺ by endogenous GSH, which decreases the intracellular antioxidant capacity and additionally up-regulates ˙OH production via the Cu⁺-induced Fenton-like reaction. Moreover, under near-infrared light irradiation, the bimetallic nanoparticles display a photothermal conversion efficacy of 46.7%, which not only improves chemodynamic therapy via boosting a Fenton-like reaction but results in photothermal therapy through hyperthermia. Both in vitro cancer cell killing and in vivo tumor ablation experiments show that the bimetallic nanoparticles display outstanding therapeutic efficacy and negligible systemic toxicity, indicating their anticancer potential.