Ligand density at the surface of a nanoparticle and different uptake mechanism: Two important factors for successful siRNA delivery to liver endothelial cells
Ligand density at the surface of a nanoparticle and different uptake mechanism: Two important factors for successful siRNA delivery to liver endothelial cells
复制标题
DOI：
10.1016/j.ijpharm.2014.08.048
复制
发表时间：
2014-11-20
影响因子：
5.8
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Akhter, Afsana;Hayashi, Yasuhiro;Harashima, Hideyoshi
将基因特异性递送至肝窦内皮细胞（LSEC）可能成为治疗与此类细胞相关的各种肝脏疾病的有用策略。我们之前报道过，静脉注射后，KLGR 肽修饰脂质体通过肝窦血管的积累增强。在此，我们报告了开发 LSEC 靶向纳米载体系统的尝试，该系统可传递 siRNA，以成功敲低 LSEC 特异性基因表达。该系统涉及开发一种用 KLGR 肽修饰的多功能包膜型纳米装置 (MEND)，用于靶向 LSEC 的 siRNA 递送。我们开发的载体成功降低了 LSEC 中的特定基因表达。体内研究表明，MEND 表面配体密度较低时，LSEC 中基因表达的敲低程度最高。这是第一份成功将 siRNA 递送至 LSEC 的报告。进一步的实验表明，不仅更高的内体逃逸效率进入细胞质，而且作为配体密度函数的摄取机制是靶向 LSEC 需要考虑的两个重要因素。 (C) 2014 Elsevier B.V. 保留所有权利。
The specific delivery of a gene to liver sinusoidal endothelial cells (LSEC) could become a useful strategy for treating various liver diseases associated with such cells. We previously reported that the accumulation of KLGR peptide modified liposomes through liver sinusoidal blood vessels was enhanced after an intravenous administration. Here, we report on an attempt to develop an LSEC targeted nanocarrier system to deliver siRNA for the successful knockdown of LSEC specific gene expression. The system involved the development of a multifunctional envelop-type nano device (MEND) modified with the KLGR peptide for siRNA delivery targeting LSEC. Our developed carrier successfully lowered specific gene expression in LSEC. An in vivo study showed that at a lower density of ligand at the surface of the MEND resulted in the highest knockdown of gene expression in LSEC. This is the first report of the successful delivery of siRNA to LSECs. Further experiments suggest that not only a higher endosomal escape efficiency into the cytosol but also the uptake mechanism as a function of ligand density are two important factors to be considered for targeting LSEC. (C) 2014 Elsevier B.V. All rights reserved.