Cho Hyunah, Kwon Glen S
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin , Madison, WI , USA.
J Drug Target. 2014 Aug;22(7):669-77. doi: 10.3109/1061186X.2014.931406. Epub 2014 Jun 25.
A current treatment strategy for peritoneal ovarian cancer is a combination of peritoneal surgery and multi-drug-based chemotherapy that often involves intraperitoneal (IP) injection. A thermosensitive poly-(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLGA-b-PEG-b-PLGA) hydrogel platform (thermogels) enabled gel loading of poorly work-soluble paclitaxel (cytotoxic agent), 17-allylamino-17-demethoxygeldanamycin (17-AAG, heat shock protein inhibitor), and rapamycin (mammalian target of rapamycin protein inhibitor). PLGA-b-PEG-b-PLGA thermogels (15%) carrying paclitaxel, 17-AAG, and rapamycin (named Triogel) made a successful transition from a free-flowing solution below ambient temperature to a gel depot at body temperature. Triogel gradually released paclitaxel, 17-AAG, and rapamycin at an equal release rate in response to the physical gel erosion. In an ES-2-luc ovarian cancer xenograft model, a single IP injection of Triogel (60, 60, and 30 mg/kg of paclitaxel, 17-AAG, and rapamycin, respectively) significantly reduced tumor burden and prolonged survival of ES-2-luc-bearing nude mice without notable systemic toxicity relative to those delivered by poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles in solution via IP or intravenous (IV) injection route. These results show a great potential of a biodegradable thermogel platform carrying multi-drugs for IP chemotherapy in peritoneal ovarian cancer.
目前，腹膜性卵巢癌的治疗策略是腹膜手术与基于多种药物的化疗相结合，化疗通常涉及腹腔内（IP）注射。一种热敏性聚（D，L-丙交酯-共-乙交酯）-嵌段-聚（乙二醇）-嵌段-聚（D，L-丙交酯-共-乙交酯）（PLGA-b-PEG-b-PLGA）水凝胶平台（热凝胶）能够将难溶性的紫杉醇（细胞毒性剂）、17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG，热休克蛋白抑制剂）和雷帕霉素（哺乳动物雷帕霉素靶蛋白抑制剂）载入凝胶中。负载紫杉醇、17-AAG和雷帕霉素的PLGA-b-PEG-b-PLGA热凝胶（15%）（命名为三联凝胶）在环境温度以下从自由流动的溶液成功转变为体温下的凝胶储库。三联凝胶通过物理凝胶侵蚀以相等的释放速率逐渐释放紫杉醇、17-AAG和雷帕霉素。在ES-2-luc卵巢癌异种移植模型中，相对于通过腹腔内或静脉内（IV）注射途径以溶液形式递送的聚（乙二醇）-嵌段-聚（d，l-乳酸）（PEG-b-PLA）胶束，单次腹腔内注射三联凝胶（分别为60、60和30mg/kg的紫杉醇、17-AAG和雷帕霉素）显著降低了肿瘤负荷并延长了携带ES-2-luc的裸鼠的生存期，且无明显的全身毒性。这些结果表明，一种携带多种药物的可生物降解热凝胶平台在腹膜性卵巢癌的腹腔内化疗中具有巨大潜力。
