pH-Activatable copper-axitinib coordinated multifunctional nanoparticles for synergistic chemo-chemodynamic therapy against aggressive cancers.

Chemodynamic therapy (CDT) is an emerging oncological treatment that eliminates tumor cells by generating lethal hydroxyl radicals (˙OH) through Fenton or Fenton-like reactions within tumors. However, the effectiveness of CDT is limited by the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME). To address these challenges and enhance tumor treatment, we developed a novel pH-activatable metal ion-drug coordinated nanoparticle (Cu-AXB NPs) system, incorporating a CDT agent (Cu 2+ ) and a chemotherapeutic agent (axitinib, AXB). The obtained Cu-AXB NPs exhibited exceptional characteristics, including ultrahigh drug loading capacity (87.55%) and an average size of 180 nm. These nanoparticles also demonstrated excellent plasma stability and pH-responsive drug release, enabling prolonged circulation in the bloodstream and targeted therapy at weakly acidic tumor sites. Upon release, AXB acted as a chemotherapeutic agent, effectively eliminating tumor cells, while Cu 2+ ions were reduced to Cu + by GSH, further generating toxic ˙OH with hydrogen peroxide (H 2 O 2 ) for CDT through a Fenton-like reaction. Additionally, the Cu-AXB NPs efficiently disrupted the copper metabolic balance and increased the intracellular Cu content, further amplifying the therapeutic impact of CDT. In vitro studies assessing cytotoxicity and apoptosis confirmed the superior tumor cell-killing efficacy of the Cu-AXB NPs. This enhanced efficacy can be attributed to the synergistic effect of CDT and chemotherapy. Moreover, the Cu-AXB NPs exhibited excellent tumor targeting capabilities, resulting in significant tumor inhibition (77.53% inhibition) while maintaining favorable biocompatibility in tumor-bearing mice. In conclusion, this study presents a promising and safe strategy for cancer therapy by combining CDT with chemotherapy, offering a potential breakthrough in the field of oncology.