siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.
siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.
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DOI：
10.1089/nat.2014.0505
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发表时间：
2015-03
影响因子：
4
通讯作者：
J. Zuckerman;A. Gale;Peiwen Wu;R. Ma;Mark E. Davis
中科院分区：
文献类型：
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作者：
J. Zuckerman;A. Gale;Peiwen Wu;R. Ma;Mark E. Davis
迫切需要新的治疗方法，可以停止或逆转慢性肾脏疾病的进程，对患者的副作用负担最小。小干扰RNA（siRNA）纳米颗粒是临床开发中的新的治疗实体，其可用于慢性肾病治疗，因为它们将纳米颗粒的组织特异性靶向性质与siRNA的基因特异性沉默效应结合联合收割机。最近的报告已经出现，表明肾脏，特别是肾小球，是一个容易接近的网站的纳米粒子靶向。在这里，我们探讨的假设，静脉内给药的聚阳离子环糊精纳米粒子含有siRNA（siRNA/CDP-NPs）可用于交付的siRNA肾小球系膜。我们证明siRNA/CDP-NPs定位于肾小球系膜，静脉注射后在肾脏其他区域的沉积有限。此外，我们报告说，小鼠和人类肾小球系膜细胞迅速内化siRNA/CDP-NPs在体外和纳米颗粒的摄取可以通过连接靶向配体甘露糖或转铁蛋白的纳米颗粒表面增强。最后，我们展示了用siRNA/CDP-NPs静脉内处理后，在报告小鼠品系中肾小球系膜增强的绿色荧光蛋白表达的敲低。总之，这些数据证明了使用静脉内施用的siRNA/CDP-NP靶向系膜的可行性。
There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.