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Transcatheter arterial chemoembolization (TACE) is the most common palliative therapy for unresectable hepatocellular carcinoma (HCC). The conventional TACE technique, which employs the Lipiodol® emulsion, has been widely used for human cancer treatments. However, this delivery system seems to be inconsistent and unstable in maintaining a high concentration of drugs at tumor sites. An alternative approach for TACE is loading drugs into a liquid embolic solution that exists as an injectable solution and can exhibit a sol-to-gel phase transition to form a solidified state once delivered to the tumor site. Here, we develop a novel sulfamethazine-based anionic pH-sensitive block copolymer with potential application as a radiopaque embolic material. The copolymer, named PCL-PEG-SM, and comprised of poly(e-caprolactone), sulfamethazine, and poly(ethylene glycol), was fabricated by free radical polymerization. An aqueous solution of the developed copolymer underwent a sol-to-gel phase transition upon lowering the environmental pH to create a gel region that covered the physiological condition (pH 7.4, 37 °C) and the low pH conditions at tumor sites (pH 6.5–7.0, 37 °C). The release of doxorubicin (DOX) from DOX-loaded copolymer hydrogels could be sustained for more than 4 weeks in vitro , and the released DOX retained its fully bioactivity via inhibition the proliferation of hepatic cancer cells. The radiopaque embolic formulations that were prepared by mixing copolymer solutions at pH 8.0 with Lipiodol®, a long-lasting X-ray contrast agent, could exhibit the gelation inside the tumor after intratumoral injection or intraarterial administration using a VX2 carcinoma hepatic tumor rabbit model. These results suggest that a novel anionic pH-sensitive copolymer has been developed with a potential application as a liquid radiopaque embolic solution for TACE of HCC. State of Significance Transcatheter arterial chemoembolization (TACE) has been widely used as a palliative treatment therapy for unresectable hepatocellular carcinoma (HCC). Conventional TACE technique, which usually employs emulsion of DOX-in-Lipiodol®, followed by an embolic agent, has significant limitation of inconsistency and lack of controlled release ability. To address these limitations of conventional TACE material system, we introduced a novel liquid radiopaque embolic material from our pH-sensitive hydrogel. The material has low viscosity that can be injected via a microcatheter, rather biocompatibility, and drug controlled release ability. Importantly, it can form gel in the tumor as well as tumoral vasculature in response to the lowered pH at the tumor site, which proved the potential for the use to treat HCC by TACE therapy.

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.

Transcatheter arterial chemoembolization (TACE) has been the mainstay palliative therapy for unresectable hepatocellular carcinoma (HCC). The conventional TACE systems, comprising of a drug-in-oil emulsion and embolic materials, have been reported to be inconsistent and unable to provide the controlled release of anticancer drugs. To overcome these limitations, we have developed a liquid embolic material formulated from a novel biodegradable pH-sensitive multiblock copolymer that can be intraarterially injected into hepatic tumor sites via microcatheter, and exhibits a sol-to-gel phase transition in response to the local environment to form hydrogels as depots for controlled release of anticancer drugs and suppression of tumor growth. The anionic block copolymer, comprising of poly(e-caprolactone-co-lactide) (PCLA), poly(ethylene glycol) (PEG) and poly(urethane sulfide sulfamethazine) (PUSSM), named PCLA-PUSSM, was synthesized and characterized. In aqueous solution, the prepared copolymer existed as a liquid at high pH (8.5) and exhibited a sol-to-gel phase transition with decreasing pH. The release of doxorubicin (DOX) from PCLA-PUSSM hydrogels was controlled in a sustained fashion, and the released DOX retained its bioactivity. Radiopaque embolic materials prepared by mixing PCLA-PUSSM copolymer solutions with X-ray contrast agents (e.g., Lipiodol® or Iohexol) and DOX could easily be intraarterially injected to a rabbit hepatic tumor using a microcatheter, and formed hydrogels for chemoembolization. Importantly, after intraarterial injection of the DOX loaded hydrogel into the tumor of a VX2 rabbit tumor model, the formed hydrogel inhibited the tumor growth at 2 weeks post-injection. This hydrogel system provides a potential radiopaque chemoembolization candidate for HCC and other cancer therapies.