Synergistic Thermochemotherapy via Injectable Polyurethane Hydrogel Co-Delivering Cisplatin and 17AAG for Peritoneal Metastasis of Colorectal Cancer.

Abstract

Colorectal cancer peritoneal metastasis (CRC-PM) often has poor prognosis after traditional hyperthermic intraperitoneal chemotherapy (HIPEC) due to constraints of respiratory movements, intestinal peristalsis and peritoneum plasma barrier. Herein, cisplatin and 17AAG were loaded into a thermoresponsive biodegradable polyurethane (PU) hydrogel, forming the CDDP/17AAG@PU system. This system showed favorable in vitro sustained release properties, controllable thermosensitive gelation at 43°C and excellent biocompatibility. Benefiting from the hydrogel's sustained release at safe doses, compared with the free drug group, this system significantly reduced serum biochemical abnormalities, as indicated by lower serum ALT/CREA levels and less apoptosis of normal intestinal cells. Moreover, its thermosensitive treatment enhanced antitumor efficacy by promoting DNA cross-linking and inhibiting oncogenic signaling-related proteins (p-PI3K, p-AKT, MMP2). In vivo experiments showed it more effectively inhibited CRC-PM compared to single-drug treatment and the control group. In conclusion, the safe, degradable CDDP/17AAG@PU system spreads to cover CRC-PM tumors at 37°C and gels rapidly at 43°C (clinical HIPEC temperature). It reduces antitumor drug induced hepatorenal toxicity, exerts good efficacy against CRC-PM and thus hold considerable potential for clinical translation.