顺铂耐药是卵巢癌治疗中亟待解决的难题。近年来，靶向抗肿瘤药物发展迅速，其中，构建高靶向纳米药物成为克服卵巢癌耐药的重要策略。我们在前期已发现促性腺激素释放激素类似物（GnRHa）在耐药卵巢癌细胞上有显著抑癌作用，可能与其阻断自噬流有关。而卵巢癌上高表达GnRH受体，故GnRHa亦可作为极佳的靶向基团与其结合，引导纳米药物特异靶向卵巢癌细胞。本课题拟开展以下工作：（1）以介孔二氧化硅MSNs纳米粒和DOPA脂质体为载体，构建顺铂-MSNs-GnRHa和顺铂-DOPA-GnRHa两种新型纳米给药系统；（2）在动物荷瘤模型上，全面考察这两种靶向纳米药物对耐药卵巢癌的靶向性、抗肿瘤作用；（3）围绕“自噬流”机制，系统探讨GnRHa介导的靶向纳米药物克服卵巢癌顺铂耐药的关键分子机制。本项目有望阐明GnRHa介导的新型纳米靶向给药系统在耐药卵巢癌治疗中的应用价值和分子机制，具有重要的科学和临床意义。

Autophagy is an important mechanism for the resistant to platinum drugs in ovarian cancer treatment. The expression of Gonadotrophin-releasing hormone (GnRH) receptor in ovarian cancer is very high so that GnRH receptor is an ideal candidate for targeting drug delivery for treatment of ovarian cancer. In the previous studies, we for the first time showed that supramolecular nano vesicles loading GnRH analogs significantly eliminated the cisplatin-resistance in human ovarian cancer cells. Moreover, we found that the modulation on autophagy may contribute to this effect of GnRH analogs-conjugated nanometer particles. However, this therapeutic action of GnRH analogs-conjugated nanometer particles needs to be verified in vivo and further investigation. In this proposal, we intend to perform the following studies: (1) generating GnRH analogues-conjugated nanoparticles targeting ovarian cancer using mesoporous silica nanoparticles and lipid nanoparticles as drug carrier for in vivo study; (2) investigating the anti-cancer action of GnRH analogues-conjugated nanoparticles targeting ovarian cancer in vivo model using transmission electron microscope, flow cytometry, transwell chamber and etc; (3) exploring the potential mechanisms underlying the overcoming of platinum resistance in ovarian cancer, such as the regulation on autophagy by the GnRH analogues-conjugated nanoparticles. This project may provide new perspectives for the therapeutic value of GnRH analogues-conjugated nanoparticles in platinum-resistant ovarian cancer.