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

Dongdong Sun,Ying Chen,Jingyuan Wang,Cundong Fan,Zekun Wang,Yu Sun,Chenyang Yin,Baoliang Sun,Weiyun Wang,Pu Zhang

doi:10.1186/s12951-021-00848-x

Abstract

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

Highlights

Normal cells usually maintain a redox balance between the generation of reactive oxygen species (ROS) and ROS elimination [1]
Vitamin C (VC) and its derivates can be oxidized by a metalloprotein in tumor acidic microenvironment and yield tumoricidal H2O2, which is often employed as H2O2-generating agent in Nano-Fenton reactors [23,24,25]
Kwon et al constructed H2O2-generating benzoyloxycinnamaldehyde (BCA) and ferrocene catalyst, and the result indicated that PolyCAFe micelles can act as a new nano-fenton reactors with amplified oxidative stress in tumor regions for cancer therapy [18]

Summary

Introduction

Normal cells usually maintain a redox balance between the generation of reactive oxygen species (ROS) and ROS elimination [1]. The quantitative analysis of tumor spheroids volume was conducted to evaluate Ru@SiO2-PA-induced anticancer efficiency against SGC-7901 cells. The results confirmed that PA can produce H2O2 in serum-containing DMEM medium, and catalyze the production of a large number of OH free radicals in the presence of Ru@SiO2, which can effectively destroy cancer cells.

Results

Conclusion