Imaging and therapy of liver fibrosis using bioreducible polyethylenimine/siRNA complexes conjugated with N-acetylglucosamine as a targeting moiety
Imaging and therapy of liver fibrosis using bioreducible polyethylenimine/siRNA complexes conjugated with N-acetylglucosamine as a targeting moiety
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DOI：
10.1016/j.biomaterials.2013.05.013
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发表时间：
2013-09-01
期刊：
影响因子：
14
通讯作者：
Chung, Bong Hyun
中科院分区：
文献类型：
--
作者：
Kim, Sun-Jung;Ise, Hirohiko;Chung, Bong Hyun
早期肝纤维化的诊断和治疗对于治疗致命性肝病至关重要。在这里，我们报告了使用N-乙酰葡萄糖胺（GlcNAc）-和吲哚菁绿色（ICG）-共轭PEI/siRNA复合物对活化的肝星状细胞（HSC）和纤维化肝组织的靶向成像和治疗。通过迈克尔加成实现二硫键与PEI（PEI-D）的缀合。我们使用EDC偶联方法，用N-乙酰葡糖胺（PEI-D-GlcNAc）修饰PEI，其可以特异性地与活化的HSC上的结蛋白相互作用。共聚焦显微镜分析显示PEI-D-GlcNAc/siRNA在与表面结蛋白相互作用后被HSC内化。体外western blot分析证实，PEI-D-GlcNAc在用TGF β 1 siRNA转染HSC后提供了强的蛋白质敲低。在尾静脉注射ICG缀合的复合物后，PEI-D-GlcNAc-ICG/siRNA复合物在纤维化小鼠的肝脏中比在正常小鼠中在延长的持续时间内积累更大程度。此外，荧光分析证实，PEI-D-GlcNAc-ICG/siRNA复合物与纤维化肝组织中的HSC特异性共定位，HSC是结蛋白阳性细胞。当使用PEI-D-GlcNAc复合物时，体内TGF β 1 siRNA递送也导致上级蛋白质敲低。这些结果表明，PEI-D-GlcNAc-ICG/TGF β 1 siRNA复合物是用于成像和治疗肝纤维化的有用工具。(C)2013爱思唯尔有限公司保留所有权利。
Diagnosis and therapy of early stage liver fibrosis is very important for the treatment of fatal liver diseases. Here, we report on the targeted imaging and therapy of activated hepatic stellate cells (HSCs) and fibrotic liver tissue using N-acetylglucosamine (GlcNAc)- and indocyanine green (ICG)-conjugated PEI/siRNA complexes. The conjugation of a disulfide bond to PEI (PEI-D) was achieved by Michael addition. We modified PEI with N-acetylglucosamine (PEI-D-GlcNAc), which can specifically interact with desmin on activated HSCs, using the EDC coupling method. Confocal microscopic analysis showed that the PEI-D-GlcNAc/siRNA was internalized by HSCs upon interaction with surface desmin. In vitro western blot analysis confirmed that PEI-D-GlcNAc provided strong protein knock-down after transfection with TGF beta 1siRNA into HSCs. After a tail vein injection of ICG-conjugated complexes, the PEI-D-GlcNAc-ICG/siRNA complex accumulated to a greater extent in the livers of fibrotic mice than in normal mice over an extended duration. Moreover, immunohistofluorescence analysis confirmed that the PEI-D-GlcNAc-ICG/siRNA complex specifically colocalized with HSCs, which are desmin-positive cells, in fibrotic liver tissues. In vivo TGF beta 1siRNA delivery also resulted in superior protein knock-down when using the PEI-D-GlcNAc complex. These results demonstrate that the PEI-D-GlcNAc-ICG/TGF beta 1siRNA complex is a useful tool for imaging and treatment of liver fibrosis. (C) 2013 Elsevier Ltd. All rights reserved.