Intraarterial gelation of injectable cationic pH/temperature-sensitive radiopaque embolic hydrogels in a rabbit hepatic tumor model and their potential application for liver cancer treatment

Abstract

Poly(amino ester urethane) (PAEU) block copolymers have been reported as potential hydrogel systems for drug delivery because of such advantages as their non-toxicity, ability to form electrostatic linkages and hydrogen bonds with bioactive agents, and ability to exhibit a sol-to-gel phase transition after injection into the body to form a hydrogel to act as a depot for the subsequent controlled release of loaded bioactive molecules. In this study, PAEU bock copolymers were synthesized, and their chemical structures and properties were characterized. In aqueous solution, the copolymers exhibited a sol-to-gel phase transition with increasing pH, or a gel-to-sol phase transition with increasing temperature. The formation of in situ gels has been observed within 20 min of subcutaneous injection of copolymer solutions into SD rats due to the sol-to-gel phase transition which occurs in response to local pH and temperature. The prepared polymers were employed for the fabrication of injectable radiopaque embolic materials, which are mixtures of an aqueous copolymer solution and a commercial long-lasting X-ray contrast agent, Lipiodol. The formulated radiopaque embolic hydrogel precursor solutions were then intraarterialy injected via the hepatic arteries feeding the VX2 hepatic tumors in rabbits using a 2.0 Fr microcatheter to investigate their gelability for potential application in liver cancer treatment. CT images and histological examination of excised tumor tissues confirmed the formation of hydrogels in the hepatic arteries and tumors. Doxorubicin (DOX), an anticancer drug, was released from hydrogels with or without Lipiodol in sustained fashion, and the released DOX fully retained its bioactivity via inhibiting the proliferation of cancer cells in vitro. These results have demonstrated that the synthesized PAEU block copolymers can be used to prepare radiopaque embolic solutions, which then exhibit a sol-to-gel phase transition to form hydrogels acting as anticancer drug depots to induce chemoembolization after being injected into tumor-feeding arteries, and therefore offer potential applications for TACE in liver cancer.