Tumor microenvironment-responsive Zn/Cu nanoparticles for enhanced chemodynamic therapy

Chemodynamic therapy (CDT) has emerged as an effective and safe anticancer therapeutic strategy by catalytic generation of hydroxyl radicals via Fenton chemistry to kill notorious cancer cells. Herein, we decorated the Cu-based nanoparticles with pH-responsive ZnO nanoparticles to give new Zn/Cu nanoparticles (Zn/Cu NPs) which showed good biocompatibility and stability for enhanced therapeutic efficacy of CDT. The newly developed Zn/Cu NPs had a small size of ∼20 ​nm, which could prolong blood circulation time of NPs and facilitate their accumulation in tumor tissues. The mode of therapeutic mechanism was experimentally verified. Upon arriving at the acidic cancer cells, ZnO on Zn/Cu NPs dissolved leading to the release of Cu²⁺ ions which were then reduced by the overexpressed glutathione (GSH), yielding Cu⁺ ions. The presence of Cu⁺ ions favorably catalyzed the conversion of endogenous H₂O₂ into hydroxyl radicals by Fenton-like reactions. Such generated ROS would cause serious oxidative damage to cellular constituents resulting in cell death. Importantly, as the Zn/Cu NPs are pH sensitive, they exhibited much higher cytotoxicity against tumor cells than normal cells. In vivo studies also demonstrated that Zn/Cu NPs could effectively inhibit tumor growth without adverse side effects. Therefore, these Zn/Cu NPs hold great potential for direct and effective tumor therapy for personalized medicine applications.