Mitochondria-targeted and multistage synergistic ROS-elevated drug delivery system based on surface decorated MnO2 with CeO2 for enhanced chemodynamic/chemotherapy

Mitochondria-targeted drug delivery nano-platform for the generation of endogenous reactive oxygen species (ROS) are envisioned as a promising strategy for inducing cytotoxicity and inhibiting tumor growth. However, how to induce excessive ROS in cancer cell remains a challenge. Herein, mitochondria-targeted combination therapy platform of chemodynamic (CDT)/chemotherapy was constructed for enhanced generation of ROS based on the multistage synergistic effect of MnO2/CeO2-meditated Fenton-like reaction and glutathione (GSH) depletion, as well as camptothecin (CPT). After accumulation in mitochondria via surface targeting molecule TPP, the MnO2 depleted over-expressed GSH to generate Mn2+, which can convert endogenous H2O2 to highly toxic hydroxyl radicals (center dot OH) based on Fenton-like reaction, and outside surface CeO2 can elevate the center dot OH level by Fenton-like reaction. Besides, the gradual depletion of over-expressed GSH decreased the scavenging effect on the highly reactive center dot OH, improving the CDT efficacy. Additionally, the released CPT accompanied by the decomposition of MnO2 would further stimuli ROS generation in mitochondria, resulting in the amplified ROS effect. In vivo experiments suggested that the combination therapy platform performed obvious inhibition to tumor based on the enhanced CDT/chemotherapy, which provide a novel approach for the ROS-based cancer combination therapy.