利用新型免疫靶向性外泌体运载系统运载miRNA治疗上皮性卵巢癌的相关研究

Epithelial ovarian cancer (EOC) patients often relapse, develop chemo-resistant and mortality rates remain high for last two decades. Therefore, there is an urgent need for more selective, effective and safe interventions. The tumor suppressor function of let-7 is mediated by simultaneously targeting multiple oncogenes. It has been demonstrated that let-7 represses the cell cycle, inhibits metastasis, and differentiates cancer stem cells. Therefore, let-7 replacement therapy holds promise as independent therapeutics and as chemotherapy response modifiers. However, non-immunogenic systematic delivery of nucleic acid to tumor cells remains challenging. This proposal intends to fill the gap. Exosomes are naturally occurring biological extracellular microvesicles function as vehicles for transporting miRNAs between cells under physiological conditions. Based on intrinsic role of exosomes in endogenous miRNA shuttling, we hypothesize that exosome-mediated intercellular RNA transportation can serve as a potent mechanism for targeted miRNA delivery.

上皮性卵巢癌（EOC）病患具有高复发率，高抗药和高死亡率；因而我们迫切需要探索更为特异、有效、安全的新方法。let-7是近年来被广泛证实具有肿瘤抑制作用的miRNA家族，前期研究中我们发现let-7作用于细胞周期，控制肿瘤转移，对肿瘤干细胞特性有促进分化的作用; 并且let7在EOC中表达失调。为此我们需要设计新型免疫靶向性外泌体运载系统，来特异性运送外源miRNA到肿瘤细胞。本课题利用外泌体（exosome）固有的RNA运载并实现细胞间沟通的功能，并加以基因工程改造来实现对肿瘤细胞表面高表达的叶酸受体（FRa）的靶向并运送let7 mimics到胞内，从而抑制肿瘤，促进干细胞分化并增加对顺铂类化疗药的敏感性。内源的外泌体不具有免疫原性，因而可能为卵巢癌的临床治疗提供新的突破点。