Polypeptide-Based\nCopper Ionophore for In Situ Glutathione-Triggered\nChemodynamic and Chemotherapy

Intracellular copper ion homeostasis has become an attractive\ntarget\nfor cancer therapy. Herein, we report a 2,2′-dipicolylamine\n(DPA) functionalized polyglutamate derivative (PDHB) which is capable\nof rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong\ncoordination ability of pendant DPA with Cu<sup>2+</sup>. High drug\nloading content of doxorubicin (DOX) (>30 wt %) is realized due\nto\nthe strong affinity of Cu<sup>2+</sup> to DOX, while that is about\n10 wt % for PDHB without Cu<sup>2+</sup>. The obtained PDHB@Cu-DOX\ncan respond to specific endogenous stimuli (pH and glutathione (GSH)),\nreleasing Cu<sup>2+</sup> and DOX. The released DOX directly damages\nthe DNA of tumor cells to cause apoptosis, while Cu<sup>2+</sup> depletes\nintracellular GSH and is reduced to Cu<sup>+</sup> simultaneously,\nwhich reacts with local H<sub>2</sub>O<sub>2</sub> to produce highly\ntoxic ·OH via a Fenton-like reaction, thus realizing synergistic\nchemodynamics and chemotherapy. This report provides an interesting\npolymeric ionophore strategy to deliver enough copper ions into cancer\ncells, which can also easily extend to other metal ions by replacing\nthe ionophore components, thus having a wide application in nanomedicine.