Tumor vasodilation by N-Heterocyclic carbene-based nitric oxide delivery triggered by high-intensity focused ultrasound and enhanced drug homing to tumor sites for anti-cancer therapy.

Nitric oxide (NO) is widely known as an effective vasodilator at low concentrations. Drug delivery systems combined with NO can dilate blood vessels surrounding tumor tissues, and the drug accumulation in tumors is accelerated by the enhanced permeability and retention effect, leading to an improvement in the anti-tumor effect. N-heterocyclic carbene-based NO donors (e.g., 1,3-bis-(2,4,6-trimethylphenyl)imidazolylidene nitric oxide (IMesNO) have been developed for stable NO storing in air and water, and NO release by thermolysis. Herein, we demonstrated on-demand NO release by high-intensity focused ultrasound (HIFU) as a stimulus, which generated high heat and exerted an ablation effect when treated in vivo. We demonstrated IMesNO to be a HIFU-responsive NO donor and its potential application in vivo using IMesNO-loaded micelles. Moreover, IMesNO-loaded micelles mixed with drug-loaded micelles (IMesNO/DOX@MCs) showed acceleration of drug accumulation in tumor sites and enhanced tumor growth inhibition. Thus, our findings suggest a potential clinical bioapplication of NO-releasing drug-loaded micelles owing to the therapeutic function of NO and HIFU treatment for anti-cancer therapy.