PEI-based vesicle-polymer hybrid gene delivery system with improved biocompatibility
PEI-based vesicle-polymer hybrid gene delivery system with improved biocompatibility
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DOI：
10.1016/j.ijpharm.2003.12.029
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发表时间：
2004-04-15
影响因子：
5.8
通讯作者：
Schätzlein, AG
中科院分区：
文献类型：
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作者：
Brownlie, A;Uchegbu, IF;Schätzlein, AG
转染试剂聚合物聚乙烯亚胺（PEI）在体内的广泛应用因其毒性而受阻。为了检验兼具聚合物和脂质类载体特性的材料是否具有更优的特性，合成了四种PEI衍生物：支链PEI（25 kDa）的甲基化产生了一种永久带电荷的季铵衍生物。使用棕榈酸侧链对这些主链进行酰化，产生了两亲性PEI变体，其形成纳米颗粒或囊泡。最后通过聚乙二醇化向聚合物主链添加亲水基团。对这些材料进行了表征，并测试了它们的体外和体内特性。与起始材料相比，这些修饰显著提高了材料的生物相容性，但也降低了转染效率。带有铵基和棕榈酰基的材料毒性降低了10倍，同时在体外保留了约30%的转染效率。在小鼠模型中静脉注射后，这些材料还在肝脏中引起了绿色荧光蛋白转基因的表达。这种合成策略改变了复杂的物理化学性质，提高了生物相容性，同时对大多数配方保持了体外基因表达。将阳离子脂质和聚合物的互补特性组合到一种杂化材料中的策略也可能适用于其他材料。（C）2004爱思唯尔公司。保留所有权利。
Wider use of the transfection agent polymer polyethylenimine (PEI) in vivo has been hampered by its toxicity. In order to examine whether material combining properties of polymers and lipid type of carriers would have improved characteristics, four PEI derivatives were synthesised: The methylation of the branched PEI (25 kDa) created a permanently charged quaternary ammonium derivative. Acylation of these backbones using pendant palmitic acid chains created amphiphilic PEI variants which formed nanoparticles or vesicles. Finally hydrophilic groups were added to the polymer backbone by PEGylation. The materials were characterised and their in vitro and in vivo properties were tested. The modifications improved the materials biocompatibility markedly when compared to the starting material but also reduced transfection efficiency. The material bearing ammonium and palmitoyl groups was 10x less toxic while retaining about 30% of the transfection efficiency in vitro. After intravenous administration in a mouse model the materials also gave rise to GFP transgene expression in the liver. The synthetic strategy altered complex physicochemistry and improved biocompatibility while maintaining in vitro gene expression for most formulations. The strategy of combination of complementary properties of cationic lipids and polymers into a hybrid material may also be applicable to other materials. (C) 2004 Elsevier B.V. All rights reserved.