肝癌细胞靶向性药物与miR-122共传输体系及其协同抗肿瘤作用机制研究

项目名称： 肝癌细胞靶向性药物与miR-122共传输体系及其协同抗肿瘤作用机制研究

项目编号： No.81471777

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 喻翠云

作者单位： 南华大学

项目金额： 72万元

中文摘要： MDR导致肝癌化疗效果不佳。利用miRNA调控肿瘤耐药及凋亡相关基因，增强肿瘤细胞对化疗药物的敏感性已成为当前研究热点。以课题组前期发现的人肝脏特异性miR-122通过调控肝癌耐药细胞基因的表达，增强人肝癌耐药细胞对5-FU敏感性为切入点，构建肝癌细胞靶向性miR-122/GC-FUA纳米体系，该体系将5-FU与miR-122共传输至肝癌细胞，发挥协同抗肿瘤效果，并降低5-FU毒副作用。为此，本项目将5-FU直接偶联到GC上制备大分子前药GC-FUA，并采用GC-FUA包装miR-122。开展体内外实验，证实该纳米体系将miR-122与5-FU共传输至肝癌细胞，揭示miR-122通过调控MDR1、Bcl- 2、Bcl-xL 、Bcl-w和wtp53等基因的表达，阻滞细胞周期，诱导细胞凋亡，抑制侵袭性增殖，发挥协同抗肿瘤作用的机制。本项目将为药物与基因共传递体系用于肿瘤靶向治疗开辟思路。

中文关键词： 基因-药物共传输；微小RNA；抗肿瘤药物；多药耐药；靶向给药系统

英文摘要： Multiple drug resistance (MDR) can lead to hepatocellular carcinoma cells (HCC) resistance to chemotherapy. Using miRNA to regulate the expression of resistance and apoptosis related genes and enhance chemotherapeutic sensitivity in cancer cells is one of the current research hotspots. In our previous work, we addressed that miR-122 can improve sensitivity of HCC to 5-FU by regulation of the hepatic multidrug resistance gene expression. According to that, drug and miR-122 co-delivered by the HCC-targeting system is constructed. Then it can transfer 5-FU and miR-122 to HCC, reduce toxicity of 5-FU, and show a synergistic anti-tumor effect. Therefore, we intend to synthesize macromolecular prodrug GC-FUA by directly couple 5-FU to GC, then load miR-122. Both in vivo and in vitro experiments will be performed to clarify the mechanism of synergistic anti-tumor effect. One is the miR-122 and 5-FU would be transferred to HCC by miR-122/ GC-FUA nanosystems, the other is miR-122 would retard the cell cycle, induce apoptosis and inhibit cell proliferation and invasion by regulating the expression of MDR1, Bcl-2, Bcl-xL, Bcl-w, wtp53 and other related genes. The project about this new drug and gene co-delivery will provide a new approach to targeted cancer therapy.

英文关键词： Co-delivery of gene and drug;miRNA;Antineoplastic;Multidrug resistance;Targeted drug delivery systems