Pyridinium cationic lipids in gene delivery: an in vitro and in vivo comparison of transfection efficiency versus a tetraalkylammonium congener
Pyridinium cationic lipids in gene delivery: an in vitro and in vivo comparison of transfection efficiency versus a tetraalkylammonium congener
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DOI：
10.1016/j.abb.2004.12.010
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发表时间：
2005-03-01
影响因子：
3.9
通讯作者：
Balaban, AT
中科院分区：
文献类型：
--
作者：
Ilies, MA;Johnson, BH;Balaban, AT
阳离子脂质提供了一个有前途的替代使用病毒的基因治疗。在这几类介体中，那些带有杂环阳离子头的介体显示出重要的优势。例如低细胞毒性和在不同细胞系中提高的效率。我们最近报道了一种简单而有效的策略，用于获得吡啶阳离子脂质，从吡喃盐和伯胺开始。本研究的目的是比较的细胞毒性和转染效率产生的吡啶极性头与四甲基铵一对几种肿瘤细胞系，也在实验动物。通过瘤内注射递送。因此，以各种摩尔比与不同辅助脂质共配制的先导化合物1-（2，3-二油酰氧基丙基）-2，4，6-三甲基吡啶鎓脂质（20 c）针对其铵同类物DOTAP-标准转染试剂进行测试。结果显示，当与胆固醇以1：1摩尔比配制时，吡啶钥脂质20 c能够以与其四烷基维氨钥同类物DOTAP相似或更好的效率抑制几种癌细胞系。同时产生较低的细胞毒性。发现NCI-H23肺癌细胞系是最易被转染的。因此，我们设计了一种基于裸鼠中这种类型的癌的体内测定法，该裸鼠瘤内注射基于2 Oc和DOTAP的脂质复合物。红色荧光蛋白报告显示，吡啶阳离子脂质上级其四烷基铵同类物，在更高的面积上以更高的效率对组织进行切割。这些令人鼓舞的发现，以及简单有效的合成策略。为进一步开发具有提高的体内转染效率和甚至进一步降低的细胞毒性的用于基因治疗的吡啶鎓脂质奠定了基础。(C)2004年爱思唯尔公司All rights reserved.
Cationic lipids provide a promising alternative to the use of viruses for delivering genes therapeutically. Among the several classes of lipidic vectors, those bearing a heterocyclic cationic head have shown important advantages. such as low cytotoxicity and improved efficiency across different cell lines. We recently reported a simple and efficient strategy for obtaining pyridinium cationic lipids, starting from pyrylium salts and primary amines. The present study is aimed to compare the cellular toxicity and transfection efficiency generated by the pyridinium polar head versus the tetramethylammonium one on several tumor cell lines and also in experimental animals. delivered via intratumor injections. Thus, the lead compound 1-(2,3-dioleoyloxypropyl)-2,4,6-trimethylpyridinium lipid (2Oc), coformulated with different helper lipids in various molar ratios, was tested against its ammonium congener DOTAP-a standard transfection reagent. The results revealed that when formulated with cholesterol at 1:1 molar ratio, the pyridinium lipid 2Oc was able to transfect several cancer cell lines with similar or better efficiency than its tetraalkvilarrimonium congener DOTAP. while producing lower cytotoxicity. The NCI-H23 lung cancer cell line was found to be the most susceptible to be transfected. Therefore, we designed an in vivo assay based on this type of carcinoma in nude mice, which were injected intratumoral with 2Oc- and DOTAP-based lipoplexes. The red fluorescent protein reporter revealed that the pyridinium cationic lipid was superior to its tetra-alkylammonium congener, transfecting the tissue on a higher area and with higher efficiency. These encouraging findings, together with the simple and efficient synthetic strategy. lay the foundation for further development of pyridinium lipids for gene therapy with improved transfection efficiency in vivo and even further reduced cytotoxicity. (C) 2004 Elsevier Inc. All rights reserved.