Acid-responsive drug-loaded copper phosphate nanoparticles for tumor cell therapy through synergistic apoptosis and ferroptosis strategy

Synergistic apoptosis and ferroptosis strategy is quite promising for tumor treatment. Herein, a kind of polyacrylic acid-stabilized, carboxymethyl chitosan-coated, doxorubicin (DOX)-loaded copper phosphate nanoparticles (NPs) were prepared by a simple method for synergistic apoptosis and ferroptosis against tumor cells. The finally formed PAA-Cu-3(PO4)(2)-DOX-CMCS (PCPDC) NPs displayed suitable hydrodynamic size (208.7 nm) and surface charge. When uptaken by tumor cells, they were degraded under acidic circumstances, releasing DOX and Cu2+ ions. The released Cu2+ ions reacted with glutathione (GSH) to produce Cu+ ions and deplete GSH. Through Cu+ ions-mediated Fenton-like reaction, H2O2 can be converted to hydroxyl radical to produce lipid hydroperoxides. Furthermore, the depleted GSH down-regulated the expression of glutathione peroxidase 4 (GPX4) protein, promoting the accumulation of lipid hydroperoxides to enhance ferroptosis. The released DOX can effectively induce apoptosis in tumor cells. These developed Cu-3(PO4)(2)-based nanomaterials can kill tumor cells effectively through the synergistic apoptosis and ferroptosis strategy.