Self-sufficient copper peroxide loaded pKa-tunable nanoparticles for lysosome-mediated chemodynamic therapy

Abstract Chemodynamic therapy (CDT) has recently gained much attention for Fenton chemistry-mediated cancer treatment, but the anti-tumor efficacy of CDT suffers from insufficient amount of endogenous H2O2 and inefficient decomposition of metal oxides to catalytic ions. Although tremendous progress has been made to increase the amount of H2O2 in the tumor region, the antitumor activity of CDT remains limited due to the suboptimal ionization to release enough amounts of catalytic ions for converting endogenous H2O2 to reactive oxygen species (e.g. highly toxic hydroxyl radical ·OH). Here, a series of nanoparticles with tunable acid dissociation constant (pKa) values from 5.2 to 6.2 were prepared to load H2O2 self-supplying copper peroxide, which can be used to trap copper peroxide in acidic lysosome to produce ample catalytic ions that convert self-supplied H2O2 into ·OH by a robust Fenton reaction. The highly reactive ·OH effectively permeate the lysosomal membrane through lipid peroxidation and thus kill tumor cells in a lysosome-mediated manner. Most importantly, the Fenton reaction is processed inside the lysosomal compartment, which avoids the cytoplasmic antioxidants such as glutathione (GSH) to scavenge ·OH. Overall, this work provides a new strategy to enhance CDT efficacy.