卵巢癌是病死率最高的妇科肿瘤，以铂类为基础的化疗是各阶段患者综合治疗的最重要部分。但临床常用二价铂类药物（铂(Ⅱ)）如顺铂、卡铂、奥沙利铂等由于药效低、毒副作用大以及耐药性的产生限制了它们的用量及疗效，是导致治疗失败、生存率低的重要原因。研究发现四价铂前药（铂(Ⅳ)）相比传统铂(Ⅱ)有副作用小、肿瘤组织药物浓度高等优点，能更有效抑制肿瘤生长。申请者前期在体内外实验中发现转染shEZH2降低EZH2的表达后能有效逆转卵巢癌铂类耐药。本课题旨在研究合成一种靶向输送、稳定控释、副作用小并能逆转耐药的全新的纳米抗癌药物：将铂(Ⅳ)键合到可生物降解的高分子上,在其亲水端连接靶向分子促黄体生成素释放激素（LHRH），最后与shEZH2共组装成纳米胶束，利用卵巢癌干细胞、耐药细胞株及动物模型在体内外水平研究该药物治疗耐药性卵巢癌的效果及安全性。并从分子生物学水平阐述药物逆转卵巢癌耐药以及抗肿瘤机制。

Ovarian cancer is a common gynecological cancer that seriously threatens women's health and life.Severe side effects, low efficacy of traditional chemotherapy and drug-resistance related problems are the main obstacles to the treatment of ovarian cancer, so targeted delivery, polymer drugs and RNAi technology are becoming new research focuses.Sdudies found that, compared to platinum(Ⅱ), the form of clinical platinum drugs, polymer-platinum(Ⅳ) prodrugs have higher efficacy, lower side effects,etc.,and can more effectively inhibit tumor growth and improve survival.Our previous studies found that EZH2-knockdown through transfection of shEZH2 in drug-resistant ovarian cancer cells can effectively reverse the resistance to platinum drugs.This project intends to design and test a new anti-tumor drug that is prepared by firstly conjugating the Pt(Ⅳ) to a biodegradable polymer molecule, then connecting the Luteinizing Hormone Releasing Hormone (LHRH) as a targeting moiety to the hydrophilic end of the conjugate, and finally co-assembling the congugate with shEZH2 into nanoscale micelles.This new drug is expected to have the advantages of all the polymer drugs,RNAi technology,platinum(Ⅳ) prodrugs and targeted delivery system.Specifically,it can deliver both platinum(Ⅳ) prodrugs and shEZH2 into tumor tissue and cancerous cells and once the micelles are internalized by the cells, The platinum(Ⅳ) prodrugs are rapidly reduced into platinum(Ⅱ),shEZH2 can reverse the resistant to platinum drugs through RNAi mechanism and the biodegradable polymers degrade into water and carbon dioxide.And with tumor-specific accumulation and low toxicity in the circulatory system,its side effects are much lighter and fewer.