Three birds with one stone: A ferric pyrophosphate based nanoagent for synergetic NIR-triggered photo/chemodynamic therapy with glutathione depletion

Strategies utilizing reactive oxygen species (ROS) to cause cell death are widely practiced for cancer therapy, including photodynamic therapy (PDT) and chemodynamic therapy (CDT). However, the efficiency of PDT alone is greatly hindered by tumor hypoxia, laser penetration depth and the relatively low oxidation performance of O-1(2) and its subsequent products H2O2. Meanwhile, CDT is limited by the deficiency of endogenous H2O2 in cancer cells. If the ROS, produced in PDT process, served as the substrate in CDT, the total ROS production would be greatly enhanced. However, the increased ROS could be scavenged by the overexpressed glutathione (GSH) in cancer cells, impairing the effect of PDT and CDT. Thus, in this study, a self-reinforcing ferric pyrophosphate based nanoagent (FeP-ZnPc) for synergetic NIR-triggered photo/chemodynamic therapy with glutathione depletion ability was constructed. The constructed FeP-ZnPc exhibited triple use: PDT, CDT and GSH depletion function. Upon internalized into cancer cells, the FeP-ZnPc could release Fe3+ which underwent a redox reaction with GSH, resulting in GSH depletion and the production of Fe2+. Upon laser, Zinc phthalocyanine (ZnPc) in the FeP-ZnPc could generate ROS for PDT directly. Moreover, the elevated ROS particularly H2O2 could serve as the substrate of CDT, accelerating the Fenton reaction process, producing the strongest oxidants, hydroxyl radical (center dot OH) and leading to ROS burst to expedite cell death. This combination strategy of enhancing ROS production and inhibiting ROS elimination could eventually break down the redox homeostasis and enhance the ROS-mediated cancer therapy.