First preclinical evaluation of a thermogel delivering mitomycin C: sustained local release with preserved surgical safety in a large animal model.

Abstract

BACKGROUND: Peritoneal recurrence remains a major concern in colorectal cancer surgery. We aimed to evaluate the safety and preliminary efficacy of a novel poloxamer-based thermogel delivering Mitomycin C (TGel-MMC) as a simple prophylactic approach to reduce peritoneal carcinomatosis risk. METHODS: The cytotoxicity effect of the MMC within the thermogel was assessed over time on CT26 cells using the alamar blue assay. TGel biocompatibility and cytoreductive effect was evaluated on a murine model. Finally, TGel-MMC safety was tested in a porcine model with laparotomy and anastomoses to assess tissue reaction, adhesions, and anastomotic integrity. RESULTS: Prolonged exposure of CT26 to TGel-MMC enhanced MMC cytotoxicity at low doses in vitro. In mice, TGel alone did not cause significant adhesions or diffuse inflammation up to 63 days. The TGel-MMC group showed effective prophylactic cytoreduction comparable to MMC alone. In pigs, no anastomotic fistulae and no chemical peritonitis were observed up to day 15. Pharmacokinetic profiles showed MMC absorption highly comparable to standard HIPEC, with peak levels at 1 h and gradual decline over 6 h. CONCLUSION: This study shows the sustained release of MMC in thermogel in-vitro. It demonstrates for the first time the feasibility and short-term safety of intraperitoneal TGel-MMC administration in a large animal model with digestive sutures. These results support further investigation on TG-MMC as a prophylactic strategy to reduce peritoneal metastases in high-risk colorectal surgery.