A Sustained H2/Fluorouracil‐Releasing Suppository for High‐efficacy and Low‐Toxicity Hydrogenochemotherapy of Colon Cancer

A new anti-cancer formulation of a rectal suppository is constructed by fatty acid glycerides encapsulating 5-fluorouracil (5-FU) and cerium silicide nanoparticles with a sustained hydrolytic H₂ release behavior, realizing synchronous release of 5-FU and H₂ which attenuates the toxic side effects of 5-FU to normal intestinal cells and enhances anti-cancer efficacy of 5-FU by inhibiting the aspiration of colon tumor cells.

Abstract

To attenuate the intestinal toxicity of chemotherapeutic drugs from rectal suppositories and enhance their chemotherapeutic outcome is greatly significant, but maintains a challenge. In this work, a new strategy of local synergistic hydrogenochemotherapy is proposed to attenuate side effects and enhance therapeutic efficacy based on the anti-cancer selectivity and normal cells-protecting effect of H₂, and construct a novel anti-cancer formulation of rectal suppository (5-FU/CSN@FAG) by fatty acid glycerides (FAG) encapsulating 5-fluorouracil (5-FU, a first-line drug for colorectal cancer treatment) and cerium silicide nanoparticles (CSN) with a sustained hydrolytic H₂ release behavior which is synchronous with 5-FU release. The 3-week treatment with the suppository once a day can not only completely eradicate colon tumors without tumor recurrence after suppository administration withdrawal, but also efficiently protect the intestinal tract from chemotherapeutic damage. Mechanistically, H₂ generated by CSN reduces the toxicity of 5-FU to normal cells in the intestinal tract by scavenging over-expressed reactive oxygen species and correcting energy metabolism, and also assists 5-FU to promote the apoptosis of colon tumor cells by inhibiting their respiration through a CO signaling pathway. High biosafety and therapeutic validity endow the developed suppository with a high potential for clinical translation.