Hydrogel co-delivery of 5-fluorouracil and siRNA attenuates TGF-β1-mediated MMT to prevent postoperative peritoneal metastasis and adhesion in colorectal cancer

Abstract

Cytoreductive surgery is the treatment protocol for colorectal cancer. Nonetheless, a major medical challenge remains to fully eliminate malignant tumor cells, along with a number of complications such as peritoneal adhesion and tumor peritoneal metastasis. The occurrence of peritoneal adhesions compromises not only the ability to do subsequent surgery, but also the efficacy of adjunct chemotherapy. More and more evidence suggest that the process of mesothelial-mesenchymal transition (MMT) influenced by transforming growth factor-β1 (TGF-β1) has a role to play in these disturbances, therefore making TGF-β1 a viable target for therapy. This study has designed a hydrogel-based physical barrier drug delivery system loaded with RNA interference technology, designated as FC@MT. The 5-fluorouracil (5-FU), which is known for its antitumor effects, was firmly linked to the FCGCM hydrogel matrix through the formation of hydrogen bonds. Meanwhile, APTES-modified mesoporous silica nanoparticle (AMSN)/TGF-β1 siRNA complexes were incorporated to facilitate the cellular uptake of siRNA and enable their escape from lysosomes. The localized co-delivery of 5-FU and TGF-β1 siRNA induces residual tumor cells killing by silencing TGF-β1 expression and reverses MMT. The combination of FC@MTs was shown to have a synergistic anti-peritoneal metastasis and anti-adhesion effects, which could be an effective strategy to enhance the clinical therapeutics of CRC.