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

Abstract

Poly(organophosphazene), a novel thermosensitive hydrogel, 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 of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6% w/w into a 10% w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90% of the dose, respectively, in a sustained manner over 4weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6weeks, and the PTX concentration in the tumor tissue was maximal at 14days, which rapidly decreased and coincided with rebound tumor growth after 14days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone.