Reynier P, Briane D, Coudert R, Fadda G, Bouchemal N, Bissieres P, Taillandier E, Cao A
Laboratoire de Chimie Structurale et Spectroscopie Biomoléculaire, CNRS UMR, UFR de Médecine, Université Paris XIII, 74 rue Marcel Cachin F93017, Bobigny Cedex, France.
J Drug Target. 2004 Jan;12(1):25-38. doi: 10.1080/10611860410001683040.
A series of four cationic lipids derived from cholesterol was synthesised and their efficiencies to vectorise nucleic acids were compared. The investigation concerns the effects of systematic chemical modifications in the polar head and in the spacer. The cationic lipid molecules used are in the same family of 3beta[N-(N',N',N'-trimethylaminoethane)-carbamoyl] cholesterol iodide (TMAEC-Chol), presenting a spacer of two or three carbons and a quaternary ammonium polar head ramified with methyl or ethyl groups. These lipids formed stable liposomes sizing from 100 to 200 nm when prepared with the colipid dioleoyl phosphatidylethanolamine (DOPE). The goal of this work was to investigate the effect of the chemical structure of these cationic lipids on lipofection. Their ability to form complexes with DNA, their cytotoxicity and their transfection efficiency in vitro and in vivo were studied. Results were compared with those obtained from the well known cholesterol-based cationic lipid DC-Chol. In a melanoma cell line (B16-F10), results showed that either the polar head or the spacer affected the cytotoxicity. Cationic lipids with three ethyl groups in the head are more toxic than those with three methyl groups while cationic lipids with three carbons in the spacer are less toxic than those with two carbons in the spacer. The best transfection level was obtained in vitro and in vivo with cationic lipids having 3C in the spacer. Data indicated that among these lipids, in vivo gene transfer is advantaged by the methylated polar head while in vitro the best level was obtained with the ethylated one. Finally, it was observed that the chemical structure influences the transfection in the presence of serum while the complex charge and the DOPE ratios in liposomes preferentially affect the interaction with erythrocytes. Argumentations are proposed to explain the discrepancies between in vitro and in vivo transfection results concerning the optimal charge ratio and the chemical nature of the cationic lipid head group.
合成了一系列由胆固醇衍生的四种阳离子脂质，并比较了它们将核酸载体化的效率。该研究涉及极性头部和间隔基团中系统化学修饰的影响。所使用的阳离子脂质分子属于3β[N-(N',N',N'-三甲基氨基乙烷)-氨基甲酰基]胆固醇碘化物（TMAEC-Chol）家族，具有两个或三个碳原子的间隔基团和带有甲基或乙基支链的季铵极性头部。当与共脂质二油酰磷脂酰乙醇胺（DOPE）一起制备时，这些脂质形成了大小在100至200纳米之间的稳定脂质体。这项工作的目的是研究这些阳离子脂质的化学结构对脂质转染的影响。研究了它们与DNA形成复合物的能力、细胞毒性以及在体外和体内的转染效率。将结果与从著名的基于胆固醇的阳离子脂质DC-Chol获得的结果进行了比较。在黑色素瘤细胞系（B16-F10）中，结果表明极性头部或间隔基团都会影响细胞毒性。头部带有三个乙基的阳离子脂质比带有三个甲基的毒性更大，而间隔基团中有三个碳原子的阳离子脂质比间隔基团中有两个碳原子的毒性更小。间隔基团中有3个碳原子的阳离子脂质在体外和体内均获得了最佳转染水平。数据表明，在这些脂质中，体内基因转移因甲基化的极性头部而更具优势，而在体外，乙基化的极性头部获得了最佳水平。最后，观察到化学结构在血清存在的情况下会影响转染，而脂质体中的复合物电荷和DOPE比例优先影响与红细胞的相互作用。提出了一些论点来解释关于最佳电荷比和阳离子脂质头部基团化学性质的体外和体内转染结果之间的差异。
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