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利用指数富集的配体系统进化技术发现肝星状细胞的适配体配体

Discovery of Aptamer Ligands for Hepatic Stellate Cells Using SELEX.

作者信息

Chen Zhijin, Liu Hao, Jain Akshay, Zhang Li, Liu Chang, Cheng Kun

机构信息

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States.

出版信息

Theranostics. 2017 Jul 21;7(12):2982-2995. doi: 10.7150/thno.19374. eCollection 2017.

DOI:10.7150/thno.19374
PMID:28839458
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5566100/
Abstract

Insulin like growth factor II receptor (IGFIIR) is a transmembrane protein overexpressed in activated hepatic stellate cells (HSCs), which are the major target for the treatment of liver fibrosis. In this study, we aim to discover an IGFIIR-specific aptamer that can be potentially used as a targeting ligand for the treatment and diagnosis of liver fibrosis. Systematic evolution of ligands by exponential enrichment (SELEX) was conducted on recombinant human IGFIIR to identify IGFIIR-specific aptamers. The binding affinity and specificity of the discovered aptamers to IGFIIR and hepatic stellate cells were studied using flow cytometry and Surface Plasmon Resonance (SPR). Aptamer-20 showed the highest affinity to recombinant human IGFIIR protein with a K of 35.5 nM, as determined by SPR. Aptamer-20 also has a high affinity (apparent K 45.12 nM) to LX-2 human hepatic stellate cells. Binding of aptamer-20 to hepatic stellate cells could be inhibited by knockdown of IGFIIR using siRNA, indicating a high specificity of the aptamer. The aptamer formed a chimera with an anti-fibrotic PCBP2 siRNA and delivered the siRNA to HSC-T6 cells to trigger silencing activity. biodistribution study of the siRNA-aptamer chimera also demonstrated a high and specific uptake in the liver of the rats with CCl-induced liver fibrosis. These data suggest that aptamer-20 is a high-affinity ligand for antifibrotic and diagnostic agents for liver fibrosis.

摘要

胰岛素样生长因子II受体（IGFIIR）是一种跨膜蛋白，在活化的肝星状细胞（HSC）中过表达，而肝星状细胞是肝纤维化治疗的主要靶点。在本研究中，我们旨在发现一种IGFIIR特异性适配体，其有可能用作肝纤维化治疗和诊断的靶向配体。通过指数富集的配体系统进化技术（SELEX）对重组人IGFIIR进行操作，以鉴定IGFIIR特异性适配体。使用流式细胞术和表面等离子体共振（SPR）研究了所发现适配体对IGFIIR和肝星状细胞的结合亲和力和特异性。通过SPR测定，适配体-20对重组人IGFIIR蛋白表现出最高亲和力，解离常数K为35.5 nM。适配体-20对LX-2人肝星状细胞也具有高亲和力（表观K为45.12 nM）。使用小干扰RNA（siRNA）敲低IGFIIR可抑制适配体-20与肝星状细胞的结合，表明该适配体具有高特异性。该适配体与抗纤维化的PCBP2 siRNA形成嵌合体，并将siRNA递送至HSC-T6细胞以触发沉默活性。对siRNA-适配体嵌合体的生物分布研究还表明，在四氯化碳诱导的肝纤维化大鼠肝脏中，其具有高特异性摄取。这些数据表明，适配体-20是用于肝纤维化抗纤维化治疗和诊断药物的高亲和力配体。

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