Sulfamethazine-based pH-sensitive hydrogels with potential application for transcatheter arterial chemoembolization therapy

Abstract

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(ε-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 4weeks 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.

Keywords: Cancer therapy; Drug delivery; Hepatocellular carcinoma (HCC); Injectable hydrogel; Transcatheter arterial chemoembolization (TACE); pH-sensitive.