Cationic glycolipids with cyclic and open galactose head groups for the selective targeting of genes to mouse liver
Cationic glycolipids with cyclic and open galactose head groups for the selective targeting of genes to mouse liver
复制标题
DOI：
10.1016/j.biomaterials.2008.12.074
复制
发表时间：
2009-04-01
期刊：
影响因子：
14
通讯作者：
Chaudhuri, Arabinda
中科院分区：
文献类型：
--
作者：
Mukthavaram, Rajesh;Marepally, Srujan;Chaudhuri, Arabinda
为了探索迄今未探索的结构-活性问题，即具有环状和非环状糖头的阳离子糖脂用于将基因靶向肝脏的相对体外和体内功效，我们设计并合成了两个新型的环状阳离子糖脂系列，（脂质1-5）和在糖和带正电荷的氮原子之间含有不同间隔臂长度的开放D-半乳糖头部（脂质6-10）。在环状糖脂中，在季氮原子之间具有六个亚甲基单元间隔物的脂质3和在具有开放糖头的糖脂中，仅具有两个亚甲基单元间隔物的脂质6被发现在将基因靶向培养的HepG 2（人肝癌细胞）和原代肝细胞中是最有效的。在荧光共振能量转移（FRET）的研究结果显示，生物膜荧光作为重要的物理化学参数背后的不同间隔臂的依赖性在两个系列。重要的是，发现血清相容性糖脂3和6在全身环境下在选择性靶向基因至小鼠肝脏方面同样有效。糖脂3和6在分离原代肝细胞以及用脱唾液酸胎球蛋白（脱唾液酸糖蛋白受体的配体）预处理的小鼠中的显著降低的效率支持了由开放和环状糖头系列制备的脂质复合物的细胞摄取通过脱唾液酸糖蛋白受体介导的观点。总之，我们目前的研究结果首次证明，具有环状糖头的阳离子糖脂需要比它们的无环糖头对应物更长的间隔臂以进行有效的基因转染，并且这两个系列在全身环境下对选择性基因靶向肝脏具有同等的希望。(C)2008爱思唯尔有限公司保留所有权利。
Toward probing an hitherto unexplored structure-activity issue namely, the relative in vitro and in vivo efficacies of cationic glycolipids with cyclic and acyclic sugar heads for targeting of genes to liver, we have designed and synthesized two novel series of cationic glycolipids with cyclic (lipids 1-5) and open D-galactose heads (lipids 6-10) containing varying spacer arm lengths in between the sugar and positively charged nitrogen atoms. Among the cyclic glycolipids, lipid 3 with six methylene units spacer in between the quaternary nitrogen atom and among the glycolipids with the open-sugar heads, lipid 6 with only two methylene units spacer were found to be the most efficacious in targeting genes to cultured HepG2 (human hepatocarcinoma cells) and primary hepatocytes. Findings in the fluorescence resonance energy transfer (FRET) Studies revealed biomembrane fusibilities as important physicochemical parameters behind the varying spacer arm dependencies in the two series. Importantly, both the serum compatible glycolipids 3 & 6 were found to be equally efficacious in selectively targeting genes to mouse livers under systemic settings. The significantly reduced efficiencies of the glycolipids 3 & 6 in transfecting primary hepatocytes as well as mice pretreated with asialofetuin (the ligands of asialoglycoprotein receptors) support the notion that the cellular uptake of the lipoplexes prepared from both the open and the cyclic sugar-head series is mediated via asialoglycoprotein receptor. In summary, our present findings demonstrate for the first time that cationic glycolipids with cyclic sugar-head require longer spacer arms than their acyclic sugar-head counterparts for efficient gene transfection and both the series hold equal promise for selective gene targeting to liver under systemic settings. (C) 2008 Elsevier Ltd. All rights reserved.