exosome介导microRNA let-7靶向治疗卵巢癌的实验研究

Ovarian cancer is the leading cause of gynecologic malignancies. Most patients are diagnosed at advanced stages with a 5-year survival rate of only 30%. Establishing targeting strategies and improving drug efficiency and safety have been widely-studied issues in the field of ovarian cancer therapy. Downregulation of the tumor suppressor microRNA let-7 is usually seen in ovarian caners. Let-7 can also suppress ovarian cancer onset and development. It is a prospective way to treat ovarian cancer with let-7 replacement method. Folate receptor-α (FRα) is overexpressed on epithelial ovarian cancers (EOC) but limited in normal tissues. FRα can serve as a biomarker and target for ovarian cancer treatment. This study aims to employ exosomes, which express FRα-specific single chain variable fragment (scFv) as a targeting moiety towards ovarian cancer tissues, as a delivery device for let-7. The chemically synthesized microRNA let-7 will be loaded into the exosomes and targeted to ovarian cancer cells, by which let-7 can perform its function of growth inhibition and tumor suppression. The combinatory teatment with exosomal let-7 and traditional chemodrugs will be evaluated for the effects on cancer cell adhesion, implantation and metastasis both in vitro and in vivo. The in vivo biological safety of this system will also be administrated. This study helps on developing new cancer therapeutics based on targeted exosome-mediated let-7 delivery device, as well as providing a novel strategy for ovarian cancer treatment.

卵巢癌治疗的现状是病人生存期短，预后较差，还需提高药物的靶向性和安全性。研究发现，抑癌基因microRNA let-7在卵巢癌中的表达常见下调，并能显著抑制卵巢癌的恶性发展，以之进行替代疗法，具有治疗卵巢癌的广阔应用前景。同时，卵巢癌组织特异表达叶酸受体α（FRα），可作为靶向治疗的重要靶点。本研究拟借助外吐小体exosome作为let-7的载体，通过FRα的特异性抗体确立对卵巢癌的靶向性，将let-7定向导入卵巢癌，使之发挥抑制癌细胞生长的功能，并进一步结合传统的铂类药物，考察该联合治疗方案在体内外环境下对卵巢癌细胞粘附、种植和转移的影响，并评估药物的安全性。本研究有利于发展exosome介导的microRNA let-7新型抗肿瘤药物，为治疗卵巢癌提供新思路。

卵巢癌治疗的现状是病人生存期短，预后较差，需要提高药物的靶向性和安全性。研究发现，抑癌基因microRNA let-7 在卵巢癌中的表达常见下调，并能显著抑制卵巢癌的恶性发展，以之进行替代疗法，具有治疗卵巢癌的广阔应用前景。同时，卵巢癌组织特异表达叶酸受体α（FRα），可作为靶向治疗的重要靶点。本研究拟借助外吐小体exosome作为let-7 的载体，通过FRα的特异性抗体确立对卵巢癌的靶向性，将let-7 定向导入卵巢癌，使之发挥抑制癌细胞生长的功能，并进一步结合传统的铂类药物，考察该联合治疗方案在体内外环境下对卵巢癌细胞粘附、种植和转移的影响，并评估药物的安全性。..在本项目的资助下，我们的研究结果表明：人工设计合成的let-7模拟物功能良好，在卵巢癌细胞系中能够显著下调靶基因的表达，说明以let-7作为卵巢癌疾病治疗的靶标是可行的；其次，经过多种实验手段验证，我们已了解叶酸受体FRα在不同的卵巢癌细胞系中的表达水平，有利于后续体外研究工作中以之作为靶向治疗FRα阳性的卵巢癌的靶点；另外，我们已熟练掌握外吐小体exosome的纯化方法，以及较高效地将microRNA let-7装载到exosome中的手段，初步实现以exosome作为新型载药体系的目标。以上实验结果为后续工作奠定了关键的技术平台，有利于本项目研究目标的顺利达成。..总的来说，本研究有利于发展exosome 介导的microRNA let-7 新型抗肿瘤药物，为治疗卵巢癌提供新思路。