负载miRNA-221-shRNA的双配体修饰壳聚糖纳米颗粒靶向抑制肝细胞癌侵袭转移的作用及机制

项目名称： 负载miRNA-221-shRNA的双配体修饰壳聚糖纳米颗粒靶向抑制肝细胞癌侵袭转移的作用及机制

项目编号： No.81502527

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李民

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 侵袭转移是提高肝细胞癌预后的主要瓶颈，而上皮间质转化(EMT)是肿瘤侵袭转移的关键步骤，故阻断EMT是提高肝癌长期生存的重要手段。但是，目前的靶向药物载体和分子靶点均不理想。在前期研究中，我们成功筛选出肝癌细胞主动靶向配体，并发现miRNA-221下调ADIPOR1介导肝癌EMT过程。为此，我们设想：以ADIPOR1为靶点，用双靶向纳米载体为运载工具，上调其表达可能是一种有效的肝癌靶向药物治疗方案。 . 本项目拟制备负载miRNA-221 shRNA的双靶向壳聚糖纳米药物以上调ADIPOR1表达，干预体外培养的肝癌细胞，检测该纳米药物的靶向性，并探讨对EMT和侵袭转移能力的影响及分子机制；建立高转移肝癌裸鼠模型，静脉给予纳米颗粒，以检测其在体内组织分布及药代动力学，并探讨靶向干预miRNA-221对肝癌生长和转移的抑制作用及机制。本项目旨在探索一种有效的肝癌靶向药物治疗方案。

中文关键词： C09_肝和肝内胆管肿瘤；肿瘤转移；上皮间质转化；靶向治疗；纳米药物载体

英文摘要： Invasion and metastasis mainly limit to improve the prognosis of hepatocellular carcinoma (HCC) and epithelial-mescenchymal transition (EMT) is the essential approach to tumor invasion and metastasis. Therefore, blocking the EMT process is the significant treatment to improve the long-term survival of HCC. However, current targeting drug-carrier and molecular target are not satisfactory. In previous study, we successfully found active targeting ligands and discovered that miRNA-221 downregulated adiponectin receptor 1 (ADIPOR1) to mediate EMT of HCC. Therefore, we hypothesize that upregulation of ADIPOR1, mediated by dual targeting ligand-modified nanoparticles (NPs), perhaps is an efficacious targeting drug for HCC.. In this research, we will attempt to fabricate the dual-ligand modified chitosan NPs loaded with miRNA-221 shRNA to upregulate the level of ADIPOR1 and incubate hepatoma cells with the NPs, then investigate the targeting efficacy to hepatoma cells, and explore the inhibition and molecular mechanism of EMT, invasion and metastasis by the NPs in vitro. Simultaneity, mouse liver cancer model with high metastasis will be prepared and treated with the NPs through intravenous injection. Then we will detect the biodistribution and pharmacokinetics in vivo, and investigate the inhibition and mechanism of liver cancer growth and metastasis through targeted intervention miRNA-221. The research aim at seeking for a novel effective targeting drug treatment method for HCC.

英文关键词： Tumor of liver and intrahepatic bile duct;Tumor metastasis;Epithelial-mesenchymal transition;Targeted therapy;Nano drug carrier