Delivery of short chain fatty acid butyrate to overcome Fusobacterium nucleatum-induced chemoresistance

J Control Release. 2023 Nov:363:43-56. doi: 10.1016/j.jconrel.2023.09.028. Epub 2023 Sep 23.

Abstract

The gut microbiota is closely associated with the progression of colorectal cancer (CRC) in which Fusobacterium nucleatum (F. nucleatum) was found to induce cancer resistance to chemotherapeutics. To relieve F. nucleatum-induced drug resistance, herein, we found that short-chain fatty acid butyrate can inhibit the growth, enrichment and adhesion of F. nucleatum in colorectal cancer tissues by downregulating the expression of adhesion-associated outer membrane proteins, including RadD, FomA, and FadA, to reduce the colonization and invasion of F. nucleatum and relieve the chemoresistance induced by F. nucleatum. Leveraging the killing effect of butyrate on F. nucleatum, sodium butyrate (NaBu) was encapsulated in liposomes or prepared as NaBu tablets with Eudragit S100 coating and administered by intravenous injection or oral administration, respectively. Interestingly, both intravenous administration of NaBu liposomes and oral delivery of NaBu tablets could effectively inhibit the proliferation of F. nucleatum and significantly improve the therapeutic efficacy of oxaliplatin in mice with subcutaneous colorectal tumors, orthotopic colorectal tumors and even spontaneously formed colorectal tumors. Thus, our work provides a simple but effective formulation of NaBu to relieve F. nucleatum-induced chemoresistance, exhibiting ideal clinical application prospects.

Keywords: Chemoresistance; Fusobacterium nucleatum; Orthotopic CT26 tumor model; Sodium butyrate liposomes; Sodium butyrate tablets; Spontaneous colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butyrates
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / metabolism
  • Drug Resistance, Neoplasm
  • Fusobacterium Infections* / complications
  • Fusobacterium Infections* / metabolism
  • Fusobacterium Infections* / microbiology
  • Fusobacterium nucleatum / metabolism
  • Liposomes / metabolism
  • Mice

Substances

  • Butyrates
  • Liposomes