Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO(2) NPs) was presented, which simultaneously delivered exogenous H(2)O(2) and Zn(2+) capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO(2) NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H(2)O(2) and Zn(2+). Intriguingly, Zn(2+) could increase the production of mitochondrial O(2)·(-) and H(2)O(2) by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H(2)O(2) to promote cancer cell killing. Furthermore, ZnO(2) NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO(2)-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.