Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
J Control Release. 2013 Feb 28;166(1):1-9. doi: 10.1016/j.jconrel.2012.12.005. Epub 2012 Dec 13.
Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET imaging, and overall survival. (18)F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles.
卵巢癌是最致命的妇科恶性肿瘤，其特点是化疗耐药率高。目前卵巢癌的治疗策略侧重于细胞毒药物和分子靶向药物的新型药物组合，或新型药物输送策略，这些策略通常涉及腹腔内（IP）注射。聚乙二醇-嵌段-聚（ε-己内酯）（PEG-b-PCL）胶束负载紫杉醇（细胞毒药物）、环巴胺（ hedgehog 抑制剂）和棉酚（Bcl-2 抑制剂）。在重点关注组合药物增溶的理化研究之后，在 2-D 和 3-D 细胞培养以及卵巢癌异种移植模型中评估了 3 种药物的 PEG-b-PCL 胶束，在 IP 注射后跟踪 ES-2 和 SKOV3 人卵巢癌细胞系的生物发光信号。与紫杉醇相比，3 种药物的 PEG-b-PCL 胶束在 2-D 细胞培养中并没有明显更有效；然而，它们使 ES-2 肿瘤球体解聚，而单一药物或 2 种药物组合仅减缓 ES-2 肿瘤球体的生长或没有明显的效果。在 ES-2 和 SKOV3 异种移植模型中，基于生物发光成像、3'-去氧-3'-（18）氟-胸腺嘧啶核苷（（18）F-FLT）PET 成像和总生存情况，3 种药物的 PEG-b-PCL 胶束的肿瘤负担明显低于紫杉醇。（18）F-FLT-PET 图像清楚地表明，与紫杉醇和载体对照相比，3 种药物的 PEG-b-PCL 胶束可显着减少肿瘤体积。总之，PEG-b-PCL 胶束使紫杉醇、环巴胺和棉酚的腹腔联合药物输送成为可能，导致肿瘤生长抑制和生存时间延长，优于单独使用紫杉醇。这些结果验证了基于细胞毒药物和分子靶向药物组合的卵巢癌治疗的新策略，通过纳米级药物输送系统（例如 PEG-b-PCL 胶束）同时递送。
