期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 106, 期 9, 页码 2420-2427出版社
WILEY
DOI: 10.1016/j.xphs.2017.04.075
关键词
biomaterials; DNA/oligonucleotide delivery; endothelial; gene delivery; nanoparticles; nanotechnology; PEGylation; siRNA
资金
- JSPS KALENHI [15H01806, 15K15315]
- Kanae Foundation for the promotion of medical science
- Takeda Science Foundation
- Asahi Glass Foundation
- TAIHO Pharmaceutical Co., Ltd., Hokkaido University
- TAIHO Pharmaceutical Co., Ltd.
A alpha-helical GALA peptide (WEAALAEALAEALAEHLAEALAEALEALAA) has been found to possess dual functions: a pH-dependent inducer of endosomal escape, and a ligand that targets lung endothelium. In the present study, the flexibility of GALA was improved by modifying the edge with polyethylene glycol linker, to increase lung-targeting activity. We first investigated the uptake of the GALA-modified liposomes in which GALA was directly conjugated to the lipid (Cholesterol: GALA/Chol) or the phospholipid-PEG (GALA/PEG(2000)). The liposomes that were modified with GALA/PEG(2000) (GALA/PEG(2000)-LPs) were taken up at a higher level by human lung endothelial cells (HMVEC-L), in comparison with particles that were modified with GALA/Chol (GALA/Chol-LPs). Small-interfering RNA-encapsulating liposomal-based nanocarriers (multifunctional envelope-type nano device: MEND) that were formulated with a vitamin E-scaffold SS-cleavable pH-activated lipid-like material, namely GALA/PEG(2000)-MENDssPalmE were also modified with GALA/PEG(2000). Gene silencing activity in the lung endothelium was then evaluated against an endothelial marker; CD31. In comparison with the unmodified MENDssPalmE, GALA/PEG(2000)-MENDssPalmE exhibited a higher silencing activity in the lung. Optimization of GALA/PEG(2000)-MENDssPalmE resulted in silencing activity in the lung with an ED50 value of 0.21 mg/kg, while non-specific gene silencing in liver was marginal. Collectively, PEGylated GALA is a promising device for use in targeting the lung endothelium. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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