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 (60 mg/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 4 weeks. Exposure of MCLs to PTX-
hydrogel showed time-dependent
drug penetration and accumulation. In mice, the
hydrogel mass was well retained over 6 weeks, and the PTX concentration in the
tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound
tumor growth after 14 days of suppression. These data indicate that PTX-
hydrogel should be intratumorally injected every 14 days, 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.