Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu²⁺. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu²⁺ to DOX, while that is about 10 wt % for PDHB without Cu²⁺. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu²⁺ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu²⁺ depletes intracellular GSH and is reduced to Cu⁺ simultaneously, which reacts with local H₂O₂ to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.