Pre-clinical evaluation of a themosensitive gel containing epothilone B and mTOR/Hsp90 targeted agents in an ovarian tumor model.

Despite clinical remission of epithelial ovarian cancer (EOC) after surgical resection and first-line chemotherapy, about 60% of patients will re-develop peritoneal metastasis and about 50% will relapse with chemoresistant disease. Clinical studies suggest that intra-peritoneal (i.p.) chemotherapy effectively treats residual EOC after cyto-reduction by gaining direct access into the peritoneal cavity, enabling elevated drug levels versus intravenous (i.v.) injection. However, chemoresistant disease is still problematic. To overcome resistance against microtubule stabilizing agents such as taxanes, epothilone B (EpoB) has merit, especially in combination with molecular targeted agents that inhibit heat shock protein 90 (Hsp90) and/or mammalian target of rapamycin (mTOR). In this paper, we report on the successful loading and solubilization of EpoB in a poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (PLGA-b-PEG-b-PLGA) thermosensitive gel (g-E). Further, we report on successful co-loading of 17-AAG (Hsp90) and rapamycin (mTOR) (g-EAR). After i.p. injection in mice, g-EAR showed gelation in the peritoneum and sustained, local-regional release of EpoB, 17-AAG, and rapamycin. In a luciferase-expressing ES-2 (ES-2-luc) ovarian cancer xenograft model, single i.p. injections of g-E and g-EAR delayed bioluminescence from metastasizing ES-2-luc cells for 2 and 3weeks, respectively, despite fast drug release for g-EAR in vivo versus in vitro. In summary, a PLGA-b-PEG-b-PLGA sol-gel has loading and release capacities for EpoB and its combinations with 17-AAG and rapamycin, enabling a platform for i.p. delivery, sustained multi-drug exposure, and potent antitumor efficacy in an ES-2-luc, ovarian cancer i.p. xenograft model.