Unsaturated cationic ortho esters for endosome permeation in gene delivery
Unsaturated cationic ortho esters for endosome permeation in gene delivery
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DOI：
10.1021/jm060128c
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发表时间：
2007-09-06
影响因子：
7.3
通讯作者：
Guo, Xin
中科院分区：
文献类型：
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作者：
Chen, Haigan;Zhang, Huizhen;Guo, Xin
设计了两种可切割的阳离子脂质，通过形成倒六边形相（Hit）来触发它们在核内体中的脂质体的熔原性和膜渗透。两种脂质都含有一个阳离子头基团和一个不饱和疏水性二油基甘油部分，由一个线性或环状邻位酯连接剂连接在一起。在pH 7.4时，脂质与质粒DNA形成稳定的复合物，并与锥状辅助脂质1,2-二油基-sn-甘油-3-磷酸乙醇胺（DOPE）形成稳定的复合物。pH的降低促进了邻位酯连接物的水解，使阳离子头基团被去除，导致脂丛聚集。在pH 5.5下，阳离子脂质N-[2-甲基-2-（1',2'-二油基甘油氧基）二恶唑兰-4-基]甲基-N，N。具有环邻位酯连接物的n -三甲基碘化铵(2)表现出异常的ph敏感性，并在溶酶体降解前的内核体加工时间内触发其脂质体渗透模型生物膜。与ph不敏感的对照脂质1,2-二酰-3-三甲基氨基丙烷（DOTAP）相比，脂质2显著改善了培养细胞中的基因转染。
Two cleavable cationic lipids were designed to trigger the fusogenicity and membrane permeation of their lipoplexes in endosomes via the formation of inverted hexagonal phases (Hit). Both lipids contain a cationic head group and an unsaturated hydrophobic dioleylglycerol moiety joined together by a linear or a cyclic ortho ester linker. At pH 7.4, the lipids formed stable complexes with plasmid DNA together with the conelike helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The decrease of pH enhanced the hydrolysis of the ortho ester linkers, which removed the cationic head groups and caused the aggregation of the lipoplexes. At pH 5.5, the cationic lipid N-[2-methyl-2-(1',2'-dioleylglyceroxy)dioxolan-4-yl]methyl-N,N.N-trimethyl-ammonium iodide (2) with a cyclic ortho ester linker showed exceptional pH-sensitivity and triggered its lipoplex to permeate model biomembranes within the time span of endosome processing prior to lysosomal degradation. Lipid 2 significantly improved gene transfection in cultured cells compared to the pH-insensitive control lipid 1,2-dioleoyl-3-trimethylammoniopropane (DOTAP).