GSH-Responsive and Hypoxia-Activated Multifunctional Nanoparticles for Synergetically Enhanced Tumor Therapy

The integration of reactive oxygen species (ROS)-basedchemodynamic therapy (CDT) and photodynamic therapy (PDT) hasattracted enormous attention for synergistic antitumor therapies.However, the strategy is severely hampered by tumor hypoxia andoverproduced antioxidant glutathione (GSH) in the tumor micro-environment. Inspired by the concept of metal coordination-basednanomedicines, we proposed an effective strategy for synergistic cancertreatment in response to the special tumor microenvironmentalproperties. Herein, we present novel metal-coordinated multifunctionalnanoparticles (NPs) by the Cu2+-triggered assembly of photosensitizerindocyanine green (ICG) and hypoxia-activated anticancer prodrugtirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating withintumor sitesviathe enhanced permeability and retention (EPR) effect,the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSHelimination, and Cu+-mediated center dot OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thusachieving synergistic tumor therapy. Bothin vitroandin vivoevaluations suggested that the multifunctional Cu-ICG/TPZ NPs couldrealize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPsto serve as a metallodrug nanoagent for synergetically enhanced tumor treatment

Automated summary

This study proposes a strategy for synergistic cancer treatment by integrating reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) using metal-coordinated multifunctional nanoparticles (NPs). These NPs, triggered by Cu2+, can induce a cascade of combinational therapeutic reactions in the tumor microenvironment, achieving hyperthermia, GSH elimination, Cu+-mediated center dot OH generation, and hypoxia-triggered chemotherapeutic effects. The results suggest the great potential of these Cu-ICG/TPZ NPs in enhancing tumor treatment.