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 gasradiotherapy (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.

Automated summary

A drug delivery system based on gold-capped mesoporous silica nanoparticles is developed for the concurrent delivery of nitric oxide and hydrogen sulfide into hepatocellular carcinoma cells. The combined gasradiotherapy and X-ray irradiation exhibit highly synergistic anti-cancer activity against both normoxic and hypoxic cancer cells. Further studies show that the combined treatment not only retains the individual anticancer mechanisms of NO, H2S, and X-ray, but also alleviates cancer hypoxia through unique pathways involving NO and H2S. In mice, the treatment significantly inhibits the growth of subcutaneous and orthotopic tumors and shows high biocompatibility. This research promotes the clinical application of combined gasradiotherapy as an effective cancer treatment.