双靶向纳米化miRNA-204治疗心肌缺血再灌注损伤的机制研究

项目名称： 双靶向纳米化miRNA-204治疗心肌缺血再灌注损伤的机制研究

项目编号： No.81470390

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： 何斌

作者单位： 上海交通大学

项目金额： 73万元

中文摘要： 缺血性心脏病的基因治疗是生命医学界的热点，而miRNA是很有临床应用前景的一类基因。我们前期研究发现：miRNA-204在心肌缺血再灌注（IR）损伤中发挥重要的调控作用。但由于miRNA体内的稳定性差且无心肌靶向性，极大限制了疗效，而近年新兴的纳米载体有望解决此问题。鉴于磁靶向与生物靶向的互补性，我们拟在前期研制的磁纳米载体基础上，引入聚乙二醇（提高稳定性和缓释性）、聚亮氨酸（包裹磁纳米）和聚赖氨酸（装载miRNA），再耦联特异性靶向缺血心肌的AT1多肽，组装出双靶向纳米载体。其中磁靶向结合磁共振成像示踪技术，可动态评估miRNA对心肌IR损伤的靶向性治疗效果；而生物靶向将进一步增强miRNA的心肌靶向性和缓释性，提高疗效。并深入研究miRNA-204如何通过调控心肌自噬和凋亡靶基因，发挥心肌保护作用。本项目有望研发具有自主知识产权的新型基因治疗药物，并具备诊疗一体化临床优势。

中文关键词： 缺血再灌注损伤；诊疗一体化；双靶向；微小RNA；纳米

英文摘要： Gene therapy for ischemic heart disease is a research hotspot in the biomedical field, and miRNA is a very promising gene therapy drug in clinic. Our previous study found that miRNA-204 played an important regulatory role in myocardial ischemia-reperfusion (IR) injury. However, the fact of miRNA-204 lacking in vivo myocardial targeting and poor stability greatly limited the therapeutic effect. The emerging nanotechnology in recent years is expected to address this issue. On the basis of the previously studies on magnetic nanoparticle,combined with the consideration of stong complementary effect between magnetic targeting and biotargeting. we intend to introduce polyethylene glycol(enhance the stability), poly(leucine)(load magnetic nanoparticles), and poly(lysine) (load miRNA-204) into the nanoparticle, and coupling ischemic myocardium specific targeting oligopeptide AT1 on the surface of nanoparticle, thus assembled a novel dual-targeted miRNA-204 nanocarrier. Magnetic target combined with bio-target can further enhance the myocardial targeting,which eventually resulted in improved therapeutic effect. With paramagnetic nanoparticles, magnetic resonance imaging (MRI) and simultaneously visualization tracer can be realized, which facilitate the evaluation of the targeting therapeutic effect of miRNA on myocardial IR injury. and the protective effects of miRNA-204 on myocardial IR injury via regulating myocardial autophagy or apoptosis-related target genes will be further investigated. This project is expected to develop new gene therapy drug with independent intellectual property rights, and have great potential in clinical theranostics.

英文关键词： ischemia reperfusion injury;theranostics;dual-target;miRNA;nano