Anti-VCAM-1 SAINT-O-Somes enable endothelial-specific delivery of siRNA and downregulation of inflammatory genes in activated endothelium in vivo
Anti-VCAM-1 SAINT-O-Somes enable endothelial-specific delivery of siRNA and downregulation of inflammatory genes in activated endothelium in vivo
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DOI：
10.1016/j.jconrel.2013.12.029
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发表时间：
2014-02-28
影响因子：
10.8
通讯作者：
Kamps, Jan A. A. M.
中科院分区：
文献类型：
--
作者：
Kowalski, Piotr S.;Zwiers, Peter J.;Kamps, Jan A. A. M.
内皮细胞在炎症性疾病病理中的关键作用引起了人们对开发短干扰RNA(SiRNA)递送装置的兴趣，以选择性地对炎症的内皮细胞进行药物干预。目前的研究表明，通过应用一种基于阳离子两亲性SINT-C18(1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride).的新型靶向脂质体，体内可以特异性地递送siRNAs并下调激活的内皮中炎性基因的表达为了对炎症的内皮细胞产生特异性，这些所谓的Saint-O-Somes被利用了抗血管细胞黏附蛋白1(VCAM-1)的抗体。在肿瘤坏死因子α攻击的小鼠中，静脉注射抗VCAM-1 Saint-O-Somes可延长循环时间，并归巢于炎症器官中表达VCAM-1的内皮细胞。这些制剂没有肝脏和肾脏毒性。使用抗VCAM-1 Saint-O-Somes，我们成功地传递了siRNA来击倒炎症的肾脏微血管中的VE-cadherin mRNA，这是在基因表达分析之前使用激光显微解剖不同的微血管床所证明的。使用相同的策略，我们展示了含有核因子kappa B p65特异性siRNA的抗VCAM-1 Saint-O-Somes治疗的小鼠肾脏对内皮炎性反应的局部减弱。这项研究首次证明了一种新型的内皮特异性载体，它适合于在体内选择性地将siRNA输送到炎症的微血管节段，并干扰疾病相关的内皮激活。(C)2014爱思唯尔B.V.保留所有权利。
The pivotal role of endothelial cells in the pathology of inflammatory diseases raised interest in the development of short interfering RNA (siRNA) delivery devices for selective pharmacological intervention in the inflamed endothelium. The current study demonstrates endothelial specific delivery of siRNAs and down-regulation of inflammatory genes in activated endothelium in vivo by applying a novel type of targeted liposomes based on the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride). To create specificity for inflamed endothelial cells, these so-called SAINT-O-Somes were harnessed with antibodies against vascular cell adhesion protein 1 (VCAM-1). In TNF alpha challenged mice, intravenously administered anti-VCAM-1 SAINT-O-Somes exerted long circulation times and homed to VCAM-1 expressing endothelial cells in inflamed organs. The formulations were devoid of liver and kidney toxicity. Using anti-VCAM-1 SAINT-O-Somes we successfully delivered siRNA to knock down VE-cadherin mRNA in inflamed renal microvasculature, as demonstrated by using laser microdissection of different microvascular beds prior to analysis of gene expression. Using the same strategy, we demonstrated local attenuation of endothelial inflammatory response towards lipopolysaccharide in kidneys of mice treated with anti-VCAM-1 SAINT-O-Somes containing NF kappa B p65 specific siRNA. This study is the first demonstration of a novel, endothelial specific carrier that is suitable for selective in vivo delivery of siRNAs into inflamed microvascular segments and interference with disease associated endothelial activation. (C) 2014 Elsevier B. V. All rights reserved.