A mitochondria-targeted supramolecular nanoplatform for peroxynitrite-potentiated oxidative therapy of orthotopic hepatoma

Oxidative therapy, which generates reactive oxygen species (ROS) via intracellular enzymatic reactions to achieve tumor ablation, is considered as an emerging approach to cancer treatment. Herein, nitric oxide (NO)-combined oxidative therapy is reported by integrating glutathione (GSH)-sensitive NO donor and pH-sensitive cinnamaldehyde (CA) prodrug into a mitochondria-targeted drug nanocarrier, which is prepared by the host-guest interaction between α-cyclodextrin (α-CD) and polyethylene glycol (PEG). After internalized by cancer cells, CA can be released in acidic endo/lysosome and finally induce ROS generation in mitochondria for oxidative therapy. At the same time, NO can be targeted delivered to mitochondria by a mitochondria-targeting strategy and then realize selective release of NO in mitochondria. NO can deplete intracellular predominant antioxidant GSH, which will enhance oxidative therapy of CA. Furthermore, peroxynitrite (ONOO−) with strong peroxidation and nitration capability can be produced in mitochondria by the reaction between NO and ROS for reactive nitrogen species (RNS)-mediated oxidative therapy. The generation of ONOO− in mitochondria is very effective in facilitating mitochondrial membrane permeabilization, which can cause mitochondrial dysfunction and finally induce mitochondrial apoptosis. The antitumor ability of mitochondria-targeted ONOO−-potentiated oxidative therapy is fully investigated on subcutaneous and orthotopic hepatoma model on nude mice. This innovative strategy for the selective generation of ONOO− in mitochondria may serve as an afflatus for future applications in cancer treatment.