Ruthenium-loaded mesoporous silica as tumor microenvironment-response nano-fenton reactors for precise cancer therapy

Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (H₂O₂) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy.

Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO₂-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO₂-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO₂-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO₂-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO₂-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO₂-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO₂-PA showed no side effects in vivo, predicting the safety and potential application in clinic.

Our findings validated the rational design that Ru@SiO₂-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy.