Triggered release of siRNA from poly(ethylene glycol)-protected, pH-dependent liposomes
Triggered release of siRNA from poly(ethylene glycol)-protected, pH-dependent liposomes
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DOI：
10.1016/j.jconrel.2008.06.004
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发表时间：
2008-09-24
影响因子：
10.8
通讯作者：
Langer, Robert
中科院分区：
文献类型：
--
作者：
Auguste, Debra T.;Furman, Kay;Langer, Robert
小干扰RNA （siRNA）调节基因表达的能力具有潜在的治疗应用，但其使用受到低效递送的限制。从pH依赖性（PD）脂质体中触发释放吸附的聚乙二醇(PEG)-b-多阳离子聚合物，可以在循环过程中（pH 7.4）保护免疫识别，并随后在核内体内传递siRNA （pH类似于5.5）。聚阳离子块基于聚[2-（二甲氨基）甲基丙烯酸乙酯]（31或62 DMA重复单元）或聚赖氨酸（21 K重复单元），作为PEG（113乙二醇重复单元）保护块的锚点。1,2-二酰-3-二甲基丙烷（DAP）（一种可滴定的脂质）的掺入增加了脂质体在酸性环境中的净阳离子特性，导致聚合物脱附和膜融合。包裹siRNA的脂质体在转基因表达GFP的HeLa细胞中显示绿色荧光蛋白（GFP）沉默，在人脐静脉内皮细胞（HUVEC）中显示甘油醛-3-磷酸脱氢酶（GAPD）敲低。PEG113-DMA31包被的裸脂质体和PD脂质体的GFP敲除率分别为0.16 +/- 0.2和0.32 +/- 0.3。相比之下，直接施用siRNA和寡聚茶胺复合siRNA分别使GFP表达降低0.06 +/- 0.02和0.14 +/- 0.02个分数。我们的体外数据表明，PD脂质体的聚合物解吸增强了sirna介导的基因敲除。(C) 2008 Elsevier B.V.版权所有
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.