A nitric oxide and hydrogen sulfide dual-donating nanosystem for highly synergistic gas-radiotherapy against hepatocellular carcinoma

A drug delivery system (DDS) based on gold-capped mesoporous silica nanoparticles (MSN) is fabricated for loading NOSH-aspirin, a nitric oxide (NO) and hydrogen sulfide (H2S) dual-donating cytotoxic molecule. The liver targeting and tumor microenvironment responsive properties of the nanosystem enable, for the first time, the concurrent delivery of NO and H2S from a DDS into hepatocellular carcinoma (HCC) cells. Combined gas-radiotherapy (GT-RT) from drug-loaded DDS (NOSH@MSN-Au-Gal) and X-ray irradiation shows highly synergistic anti-cancer activity against both normoxic and hypoxic HCC cells. Further studies revealed that the combined GT-RT not only retains the well-known anticancer mechanism of NO, H2S, and X-ray individually, but also alleviates HCC hypoxia via NO- and H2S- involved unique pathways. In mice, the GT-RT greatly slows the growth of both subcutaneous and orthotopic HCC tumors and shows high biocompatibility. The current work is expected to promote the clinical application of combined GT-RT as an effective cancer treatment.