Triggered release of siRNA from poly(ethylene glycol)-protected, pH-dependent liposomes

JOURNAL OF CONTROLLED RELEASE

卷:130

Article

Auguste, Debra T.¹  Furman, Kay²  Wong, Andrew³  Fuller, Jason¹  Armes, Steven P.⁴  Deming, Timothy J.⁵  Langer, Robert¹ 

[1] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[2] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA

[3] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA

[4] Univ Sheffield, Dept Chem, Sheffield S3 7HF, S Yorkshire, England

[5] Univ Calif Santa Barbara, Dept Mat Sci, Santa Barbara, CA 93106 USA

关键词: RNAi;    siRNA;    Genedelivery;    Liposome;    pH-dependent;    PEG;   

DOI  :  10.1016/j.jconrel.2008.06.004

来源: Elsevier

【 摘 要 】

The ability of small interfering RNA (siRNA) to regulate gene expression has potential therapeutic applications, but its use is limited by inefficient delivery. Triggered release of adsorbed poly(ethylene glycol) (PEG)-b-polycation polymers from pH-dependent (PD) liposomes enables protection from immune recognition during circulation (pH 7.4) and subsequent intracellular delivery of siRNA within the endosome (pH similar to 5.5). Polycationic blocks, based on either poly[2-(dimethylamino)ethyl methacrylate] (31 or 62 DMA repeat units) or polylysine (21 K repeat units), act as anchors for a PEG (113 ethylene glycol repeat units) protective block. Incorporation of 1,2-dioleoyl-3-dimethylammonium-propane (DAP), a titratable lipid, increases the liposome's net cationic character within acidic environments, resulting in polymer desorption and membrane fusion. Liposomes encapsulating siRNA demonstrate green fluorescent protein (GFP) silencing in genetically-modified, GFP-expressing HeLa cells and glyceraldehyde-3-phosphate dehydrogenase (GAPD) knockdown in human umbilical vein endothelial cells (HUVEC). Bare and PD liposomes coated with PEG113-DMA31 exhibit a 0.16 +/- 0.2 and 0.32 +/- 0.3 fraction of GFP knockdown, respectively. In contrast, direct siRNA administration and Oligofectamine complexed siRNA reduce GFP expression by 0.06 +/- 0.02 and 0.14 +/- 0.02 fractions, respectively. Our in vitro data indicates that polymer desorption from PD liposomes enhances siRNA-mediated gene knockdown. (C) 2008 Elsevier B.V. All rights reserved.

【 授权许可】

Free