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阳离子脂质混合物在脂质转染中的协同作用:在凝胶 - 液晶相转变时具有卓越活性。

Synergy in lipofection by cationic lipid mixtures: superior activity at the gel-liquid crystalline phase transition.

作者信息

Koynova Rumiana, Wang Li, MacDonald Robert C

机构信息

Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208, USA.

出版信息

J Phys Chem B. 2007 Jul 12;111(27):7786-95. doi: 10.1021/jp071286y. Epub 2007 Jun 16.

Abstract

Some mixtures of two cationic lipids including phospholipid compounds (O-ethylphosphatidylcholines) as well as common, commercially available cationic lipids, such as dimethylammonium bromides and trimethylammonium propanes, deliver therapeutic DNA considerably more efficiently than do the separate molecules. In an effort to rationalize this widespread "mixture synergism", we examined the phase behavior of the cationic lipid mixtures and constructed their binary phase diagrams. Among a group of more than 50 formulations, the compositions with maximum delivery activity resided unambiguously in the solid-liquid crystalline two-phase region at physiological temperature. Thus, the transfection efficacy of formulations exhibiting solid-liquid crystalline phase coexistence is more than 5 times higher than that of formulations in the gel (solid) phase and over twice that of liquid crystalline formulations; phase coexistence occurring at physiological temperature thus appears to contribute significantly to mixture synergism. This relationship between delivery activity and physical property can be rationalized on the basis of the known consequences of lipid-phase transitions, namely, the accumulation of defects and increased disorder at solid-liquid crystalline phase boundaries. Packing defects at the borders of coexisting solid and liquid crystalline domains, as well as large local density fluctuations, could be responsible for the enhanced fusogenicity of mixtures. This study leads to the important conclusion that manipulating the composition of the lipid carriers so that their phase transition takes place at physiological temperature can enhance their delivery efficacy.

摘要

一些包含磷脂化合物(O - 乙基磷脂酰胆碱)以及常见市售阳离子脂质(如二甲基溴化铵和三甲基丙烷铵)的两种阳离子脂质混合物,在递送治疗性DNA方面比单独的分子效率要高得多。为了合理解释这种普遍存在的“混合物协同作用”,我们研究了阳离子脂质混合物的相行为并构建了它们的二元相图。在一组50多种配方中,具有最大递送活性的组合物在生理温度下明确位于固 - 液晶两相区域。因此,呈现固 - 液晶相共存的配方的转染效率比凝胶(固体)相配方高5倍以上,比液晶配方高两倍以上;在生理温度下发生的相共存似乎对混合物协同作用有显著贡献。基于脂质相变的已知结果,即固 - 液晶相边界处缺陷的积累和无序度的增加,可以合理解释递送活性与物理性质之间的这种关系。共存的固体和液晶域边界处的堆积缺陷以及大的局部密度波动,可能是混合物融合性增强的原因。这项研究得出了一个重要结论,即通过控制脂质载体的组成,使其相变在生理温度下发生,可以提高其递送效率。

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