Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts

다국어 초록 (Multilingual Abstract)

Poly(organophosphazene), a novel thermosensitivehydrogel, is an injectable drug delivery system (DDS)that transforms from sol to gel at body temperature. Paclitaxel(PTX) is a mitotic inhibitor used in the treatment ofvarious solid tumors. Due to its poor solubility in water andefflux systems in the gastrointestinal tract, PTX is a goodcandidate for local DDS. Here, we evaluated the penetrationkinetics of PTX released from the PTX-poly(organophosphazene)hydrogel mixture in multicellular layers (MCLs)of human cancer cells. We also investigated the tumorpharmacokinetics of PTX (60 mg/kg) when administered asan intratumoral injection using poly(organophosphazene) inmice with human tumor xenografts. When PTX was formulatedat 0.6 % w/w into a 10 % w/w hydrogel, thein vitro and in vivo release were found to be 40 and 90 % ofthe dose, respectively, in a sustained manner over 4 weeks.Exposure of MCLs to PTX-hydrogel showed time-dependentdrug penetration and accumulation. In mice, the hydrogelmass was well retained over 6 weeks, and the PTX concentrationin the tumor tissue was maximal at 14 days, whichrapidly decreased and coincided with rebound tumor growthafter 14 days of suppression. These data indicate that PTXhydrogelshould be intratumorally injected every 14 days, ordrug release duration should be prolonged in order to achievea long-term antitumor effect. Overall, poly(organophosphazene)represents a novel thermosensitive DDS for intratumoraldelivery of PTX, which can accommodate a large doseof the drug in addition to reducing its systemic exposure byrestricting biodistribution to tumor tissue alone.

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