A nano-catalyst promoting endogenous NO production to enhance chemotherapy efficacy by vascular normalization

Abstract

Poor perfusion and low accumulation of drugs caused by abnormal tumor blood vessels significantly reduce the chemotherapy efficacy. Nowadays, the synergistic therapy of vascular normalization and chemotherapy has become an ideal choice to increase the tumor inhibition rate. Delivering an appropriate amount of NO around tumor vessels proved to be an effective vascular normalization strategy. In order to meet the demand for continuous and stable production of NO at the tumor site, herein, we developed a strategy to normalize tumor blood vessels by catalyzing NO generation from endogenous NO donors (RSNO). Concretely, the surface of copper-doped mesoporous silica was modified with PAA by electrostatic interactions to form CuMSN-PAA nanoparticles. The system was simple in structure and could catalyze NO production by exposing the CuMSN surface in response to a slightly acidic environment. In vivo, the NO level in the tumor increased 5.8-fold after CuMSN-PAA treatment, and blood perfusion increased by 70%, which in turn induced vascular normalization. Consequently, DOX accumulation of the CuMSN-PAA group increased 2.4-fold compared with the control group. More importantly, after the synergistic treatment of vascular normalization and chemotherapy, the anti-tumor efficacy was increased by 37.2% compared with the DOX-treated group with no overt toxicity observed.