The integration of
reactive oxygen species (ROS)-based chemodynamic
therapy (CDT) and
photodynamic therapy (
PDT) has attracted enormous attention for synergistic antitumor
therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced
antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of
metal coordination-based nanomedicines, we proposed an effective strategy for synergistic
cancer treatment in response to the special
tumor microenvironmental properties. Herein, we present novel
metal-coordinated multifunctional nanoparticles (NPs) by the Cu2+-triggered assembly of
photosensitizer indocyanine green (ICG) and
hypoxia-activated anticancer
prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within
tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including
hyperthermia, GSH elimination, and Cu+-mediated •OH generation and the subsequent
hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic
tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced
tumor treatment.