A Copper-loaded Self-assembled Nanoparticle for Disturbing the Tumor Redox Balance and Triple Anti-tumor Therapy

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed by copper ion (Cu2+), Doxorubicin (Dox), Zinc phthalocyanine (ZnPc) and a trace amount of poly (2-(di-methylamino) ethylmethacrylate)-poly [(R)-3-hydroxybutyrate]-poly (2-(dimethylamino) ethylmethacrylate (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. This triple factors-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radical (∙OH), thereby enhancing chemodynamic and photodynamic therapy. Herein, this study provided a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.