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 3 weeks, 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.

尽管手术切除和一线化疗后上皮性卵巢癌（EOC）的临床缓解，但约60％的患者会重新发展腹膜转移，约50％的患者会因化学耐药性疾病复发。临床研究表明，腹膜内（ip）化疗可通过直接进入腹膜腔有效地治疗细胞减少后的残留EOC，从而使药物水平相对于静脉内（iv）注射。然而，化学抗性疾病仍然是有问题的。为了克服对紫杉烷等微管稳定剂的抗性，埃博霉素B（EpoB）具有优势，特别是与抑制热激蛋白90（Hsp90）和/或雷帕霉素哺乳动物靶标（mTOR）的分子靶向药物联用。在本文中，我们报道了在埃博霉素B的在聚成功加载和增溶（d，升-lactic-共-glycolic酸） -嵌段-聚（乙二醇） -嵌段-聚（d，升-lactic-共-乙醇酸）（PLGA- b -PEG- b-PLGA）热敏凝胶（gE）。此外，我们报道了17-AAG（Hsp90）和雷帕霉素（mTOR）（g-EAR）的成功共同装载。在小鼠腹腔注射后，g-EAR在腹膜中显示出凝胶化，并持续局部释放EpoB，17-AAG和雷帕霉素。在表达萤光素酶的ES-2（ES-2- luc）卵巢癌异种移植模型中，尽管进行了快速药物治疗，单次ip注射gE和g-EAR分别使转移了ES-2- luc细胞的生物发光延迟了2和3周。体内和体外释放g-EAR的情况。总之，PLGA- b -PEG- b-PLGA溶胶-凝胶对EpoB及其与17-AAG和雷帕霉素的组合具有负载和释放能力，从而为ip输送，持续的多药暴露以及在ES-2上的有效抗肿瘤功效提供了平台-luc，卵巢癌ip异种移植模型。