Ilies Marc Antoniu, Seitz William A, Ghiviriga Ion, Johnson Betty H, Miller Aaron, Thompson E Brad, Balaban Alexandru T
Department of Marine Sciences, Texas A & M University at Galveston, 5007 Avenue U, Galveston, TX 77551, USA.
J Med Chem. 2004 Jul 15;47(15):3744-54. doi: 10.1021/jm0499763.
Three series of pyridinium cationic lipids useful as nonviral gene delivery agents were prepared by reaction of pyrylium salts with aminodiols, followed by acylation with fatty acyl chlorides. On the basis of this set of compounds, we undertook a comprehensive structure-activity relationship study at the level of the linker, hydrophobic anchor, and counterion in order to identify the structural elements that generate the highest transfection efficiency for this new type of cationic lipid. The results revealed that when formulated with cholesterol at a 1:1 molar ratio, the 1-(1,3-dimyristoyloxyprop-2-yl)-2,4,6-trimethylpyridinium, under the form of hexafluorophosphate (5AMyr) or chloride (5DMyr), was able to transfect NCI-H23 lung carcinoma with efficiencies surpassing classic DOTAP-based formulations and with lower cytotoxicity. Subsequent tests on other malignancies yielded similarly promising results.
通过将吡喃鎓盐与氨基二醇反应，然后用脂肪酰氯进行酰化反应，制备了三类用作非病毒基因传递剂的吡啶鎓阳离子脂质。基于这组化合物，我们在连接基团、疏水锚定基团和抗衡离子层面进行了全面的构效关系研究，以确定对这类新型阳离子脂质产生最高转染效率的结构元件。结果表明，当与胆固醇以1:1摩尔比配制时，六氟磷酸盐（5AMyr）或氯化物（5DMyr）形式的1-(1,3-二肉豆蔻酰氧基丙-2-基)-2,4,6-三甲基吡啶鎓能够转染NCI-H23肺癌细胞，其效率超过基于经典DOTAP的制剂，且细胞毒性较低。随后对其他恶性肿瘤的测试也产生了类似的良好结果。
