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首页> 外文期刊>Journal of Medicinal Chemistry >Efficient Synthesis and Cell-Transfection Properties of a New Multivalent Cationic Lipid for Nonviral Gene Delivery
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Efficient Synthesis and Cell-Transfection Properties of a New Multivalent Cationic Lipid for Nonviral Gene Delivery

机译：非病毒基因传递的新型多价阳离子脂质的高效合成和细胞转染特性

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摘要

Lipid-mediated delivery of DNA into cells holds great promise both for gene therapy and basic research applications. This paper describes the efficient and facile synthesis and the characterization of a new multivalent cationic lipid with a double-branched headgroup structure for gene delivery applications. The synthetic scheme can be extended to give cationic lipids of different charge, spacer, or lipid chain length. The chemical and physical properties of self-assembled complexes of the cationic liposomes (CLs) with DNA give indications of why multivalent cationic lipids possess superior transfection properties. The lipid bears a headgroup with five charges in the fully protonated state, which is attached to an unsaturated double-chain hydrophobic moiety based on 3, 4-dihydroxybenzoic acid. Liposomes consisting of the new multivalent lipid and the neutral lipid 1,2-dioleoyl-sn-glycerophosphatidylcholine (DOPC) were used to prepare complexes with DNA. Investigations of the structures of these complexes by optical microscopy and small-angle X-ray scattering reveal a lamellar L_α~C phase of CL-DNA complexes with the DNA molecules sandwiched between bilayers of the lipids. Experiments using plasmid DNA containing the firefly luciferase reporter gene show that these complexes efficiently transfect mammalian cells. When compared to the monovalent cationic lipid 2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP), the higher charge density of the membranes of CL-DNA complexes achievable with the new multivalent lipid greatly increases transfection efficiency in the regime of small molar ratios of cationic to neutral lipid. This is desired to minimize the known toxicity effects of cationic lipids.
机译：脂质介导的将DNA传递到细胞中对于基因治疗和基础研究应用都具有广阔的前景。本文介绍了一种高效，简便的合成方法，以及一种具有双分支头基结构的新型多价阳离子脂质的表征，可用于基因传递。可以扩展合成方案以产生具有不同电荷，间隔基或脂质链长度的阳离子脂质。阳离子脂质体（CLs）与DNA的自组装复合物的化学和物理性质提供了为什么多价阳离子脂质具有卓越的转染特性的迹象。脂质在完全质子化的状态下带有一个带有五个电荷的头基，该头基连接至基于3,4-二羟基苯甲酸的不饱和双链疏水部分。由新的多价脂质和中性脂质1,2-二油酰基-sn-甘油磷脂酰胆碱（DOPC）组成的脂质体用于制备与DNA的复合物。通过光学显微镜和小角度X射线散射对这些复合物的结构进行研究，发现CL-DNA复合物的层状L_α〜C相具有夹在脂质双层之间的DNA分子。使用含有萤火虫荧光素酶报道基因的质粒DNA进行的实验表明，这些复合物可以有效地转染哺乳动物细胞。与一价阳离子脂质2,3-环氧乙烷氧基丙基三甲基氯化铵（DOTAP）相比，新的多价脂质可实现的CL-DNA复合物膜更高的电荷密度在阳离子与中性的摩尔比较小的情况下大大提高了转染效率。脂质。希望使阳离子脂质的已知毒性作用最小化。

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