A pH-activatable Copper-Axitinib coordinated multifunctional nanoparticles for synergistic chemo-chemodynamic therapy against aggressive cancers

Chemodynamic therapy (CDT) is an emerging oncological treatment that can kill tumor cells by generating lethal hydroxyl radical (•OH) via Fenton or Fenton-like reaction inside tumors. However, the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME) limited the therapeutic efficacy of CDTs. Herein, CDT agents (Cu2+) and chemotherapeutic agent (Axitinib, AXB) were employed to fabricate a novel pH-activatable metal ion-drug coordinated nanoparticles (Cu-AXB NPs) for enhancing the treatment of tumors. The obtained nanoparticles exhibited ultrahigh drug loading capacity of 87.55% and had an average size of 180 nm. Moreover, the characteristics of excellent plasma stability and pH-responsive drug release contribute to the long circulation in the blood and targeted therapy at the weakly acidic tumor site. The released AXB could play a chemotherapeutic role in killing tumor cells and Cu2+ ion could be reduced to Cu+ by GSH, further generating toxic •OH with hydrogen peroxide (H2O2) for CDT through Fenton-like reaction. Cu-AXB NPs could also efficiently break copper metabolic balances and increase the intracellular Cu content, thus amplifying CDT. In vitro research results of cytotoxicity and apoptosis confirmed the optimal tumor cell killing efficacy of the Cu-AXB NPs, which was attributed to the synergistic effect of CDT with chemotherapy. What is more, Cu-AXB NPs exhibited good tumor targeting and potent tumor inhibition effect (77.53% inhibition), while exhibiting good biocompatibility in tumor bearing mice. In conclusion, this work provided a promising strategy for safe and efficient cancer therapy through the combination of CDT with chemotherapy.