Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer's disease

被引：122
作者：
Park, Tae-Eun [1 ,2 ]
Singh, Bijay [1 ,2 ]
Li, Huishan [1 ,2 ]
Lee, Jun-Yeong [1 ,2 ]
Kang, Sang-Kee [3 ]
Choi, Yun-Jaie [1 ,2 ]
Cho, Chong-Su [1 ,2 ]
机构：
[1] Seoul Natl Univ, Dept Agr Biotechnol, Seoul 151921, South Korea
[2] Seoul Natl Univ, Res Inst Agr & Life Sci, Seoul 151921, South Korea
[3] Seoul Natl Univ, Inst Green Bio Sci & Technol, Pyeongchanggun 232916, Gangwondo, South Korea
来源：
BIOMATERIALS | 2015年 / 38卷
基金：
新加坡国家研究基金会;
关键词：
RNA interference; Caveolae-mediated endocytosis; Blood-brain barrier; Mannitol; Polyethylenimine; Alzheimer's disease; BLOOD-BRAIN-BARRIER; NICOTINIC ACETYLCHOLINE-RECEPTOR; LUNG-CANCER CELLS; GENE-DELIVERY; MEDIATED ENDOCYTOSIS; IN-VITRO; ENDOTHELIAL-CELLS; DRUG-DELIVERY; NANOPARTICLES; SIRNA;
D O I：
10.1016/j.biomaterials.2014.10.068
中图分类号：
R318 [生物医学工程];
学科分类号：
0831 ;
摘要：
RNA interference (RNAi) holds one of the promising tools for Alzheimer's disease (AD) treatment by directly arresting the causative genes. For successful RNAi therapeutics for AD, limited access of therapeutic genes to the brain needs to be overcome by developing siRNA delivery system that could cross the blood brain barrier (BBB). Here, we report a non-viral vector, rabies virus glycoprotein (RVG)-modified poly(mannitol-co-PEI) gene transporter (PMT), R-PEG-PMT. The RVG ligand directed the PMT/siRNA complexes toward the brain through binding to nicotinic acetylcholine receptors expressed on BBB. In mechanistic study using in vitro BBB model, we observed that osmotically-active PMT enhanced the receptor-mediated transcytosis by stimulating the caveolar endocytosis. The potential of RNAi therapeutics for AD using R-PEG-PMT/siBACE1 complexes was demonstrated in vitro and in vivo. Our results suggest that R-PEG-PMT is a powerful gene carrier system for brain targeted RNAi therapeutics with synergistic effect of RVG ligand and PMT on well-modulated receptor-mediated transcytosis through BBB. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码：61 / 71
页数：11
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