Activation of the complement system by synthetic DNA complexes: A potential barrier for intravenous gene delivery
Activation of the complement system by synthetic DNA complexes: A potential barrier for intravenous gene delivery
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DOI：
10.1089/hum.1996.7.12-1437
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发表时间：
1996-08-01
影响因子：
4.2
通讯作者：
Wagner, E
中科院分区：
文献类型：
--
作者：
Plank, C;Mechtler, K;Wagner, E
我们已经研究了合成阳离子分子及其与DNA的复合物的补体激活特性。常用的基因递送载体包括DNA与各种链长的聚赖氨酸的复合物、转铁蛋白-聚赖氨酸、第五代聚酰胺胺（PAMAM）树枝状聚合物、聚乙烯亚胺和几种阳离子脂质（DOTAP、DC-Chol/DOPE、DOGS/DOPE和DOTMA/DOPE）。这些试剂在不同程度上激活补体系统。用长链聚赖氨酸、树枝状聚合物、聚（乙烯亚胺）和DOGS观察到强补体激活（在所用测定中，在约3 μ M胺含量下达到半最大值）。与这些化合物相比，其它阳离子脂质（在脂质体制剂中）是补体系统的弱激活剂（在测定中，半最大值约为50-100 μ M正电荷）。多聚赖氨酸的补体激活强烈依赖于链长。短链寡聚赖氨酸在其补体激活方面与阳离子脂质相当。将这些化合物与DNA孵育以形成复合物在几乎所有情况下都降低了补体激活。DNA复合物的补体激活程度强烈依赖于聚赖氨酸、树枝状聚合物、聚（乙烯亚胺）和DOGS的聚阳离子和DNA的比率（表示为电荷比）。在较小程度上，电荷比也影响单价阳离子脂质-DNA复合物的补体激活。对于聚赖氨酸-DNA复合物，通过用聚乙二醇修饰预先形成的DNA复合物的表面（半最大值约为20 μ M胺含量），可以显著降低补体激活。数据表明，通过适当配制DNA复合物，可以最小化甚至避免补体激活。这些研究结果应有利于寻找DNA复合物配方适合可重复的静脉内基因传递。
We have examined the complement-activating properties of synthetic cationic molecules and their complexes with DNA. Commonly used gene delivery vehicles include complexes of DNA with polylysine of various chain lengths, transferrin-polylysine, a fifth-generation poly(amidoamine) (PAMAM) dendrimer, poly(ethyleneimine), and several cationic lipids (DOTAP, DC-Chol/DOPE, DOGS/DOPE, and DOTMA/DOPE).* These agents activate the complement system to varying extents. Strong complement activation is seen with long-chain polylysines, the dendrimer, poly(ethyleneimine), and DOGS (half-maximal at about 3 mu M amine content in the assay used). Compared to these compounds, the other cationic lipids (in liposome formulations) are weak activators of the complement system (half-maximal approximate to 50-100 mu M positive charge in assay). Complement activation by polylysine is strongly dependent on the chain length. Short-chain oligolysines are comparable to cationic lipids in their activation of complement. Incubation of these compounds with DNA to form complexes reduces complement activation in virtually all cases. The degree of complement activation by DNA complexes is strongly dependent on the ratio of polycation and DNA (expressed as the charge ratio) for polylysine, dendrimer, poly(ethyleneimine), and DOGS. To a lesser degree, charge ratio also influences complement activation by monovalent cationic lipid-DNA, complexes. For polylysine-DNA complexes, complement activation can be considerably reduced by modifying the surface of preformed DNA complexes with polyethyleneglycol (half-maximal approximate to 20 mu M amine content). The data suggests that, by appropriate formulation of DNA complexes, complement activation can be minimized or even avoided. These findings should facilitate the search for DNA complex formulations appropriate for reproducible intravenous gene delivery.