Laboratoire de Conception et Application de Molecules Bioactives, CNRS-Universite de Strasbourg, 74 route du Rhin, BP 60024, 67401 Illkirch Cedex, France.
Bioconjug Chem. 2010 Feb 17;21(2):360-71. doi: 10.1021/bc900469z.
Although a great number of cationic lipids have been designed and evaluated as gene delivery systems, there is still a need for improvement of nonviral vectors. Recently, cationic lipids incorporating terminal fluoroalkyl segments ("FHP" lipids) have been described to display remarkable transfection potency. Here, we describe the synthesis of a new family of fluorinated triblock cationic lipids in which a fluorous segment lays between the cationic and the lipophilic parts of the molecule ("HFP" lipids). The compounds were designed so their self-assembly would offer enhanced resistance toward the host's degradation mechanisms mediated by lipophilic insertion. Self-assembly properties of these cationic lipids were evaluated at the air-water interface where they collapse in a highly ordered liquid phase. The HFP lipids efficiently condense DNA, and the resulting lipoplexes display enhanced resistance to amphiphilic agents when compared to nonfluorinated or FHP cationic lipids. Transfection properties of the fluorinated vectors, alone or as mixtures with different helper lipids (DOPE and a fluorinated analogue of DOPE), were then investigated on different cell lines (BHK-21, HepG2, and HeLa) and compared to those of the reference cationic lipid DOTAP. Data show that impermeabilization of the lipidic phase by fluorous segments alter significantly the gene transfection activities. Remarkably, incorporation of DOPE within the lipoplexes provides the particles with high gene transfection activity without reducing their resistance to amphiphilic agents.
尽管已经设计和评估了大量的阳离子脂质体作为基因传递系统，但仍然需要改进非病毒载体。最近，含有末端氟烷基段的阳离子脂质体（“FHP”脂质）被描述为具有显著的转染效力。在这里，我们描述了一类新型的氟化三嵌段阳离子脂质体的合成，其中氟原子段位于分子的阳离子和亲脂部分之间（“FHP”脂质）。这些化合物的设计使其自组装能够提供增强的抵抗由亲脂性插入介导的宿主降解机制的能力。这些阳离子脂质体的自组装性质在气-水界面进行了评估，在该界面它们在高度有序的液相中坍塌。FHP 脂质能够有效地浓缩 DNA，并且与非氟化或 FHP 阳离子脂质相比，所得的脂质体对两亲性试剂具有增强的抗性。然后研究了氟化载体（单独使用或与不同辅助脂质（DOPE 和 DOPE 的氟化类似物）混合使用）的转染性质，在不同的细胞系（BHK-21、HepG2 和 HeLa）上进行，并与参考阳离子脂质体 DOTAP 进行了比较。数据表明，氟原子段使脂质相的不可渗透性发生显著变化，从而极大地改变了基因转染活性。值得注意的是，DOPE 的掺入使颗粒具有高的基因转染活性，而不会降低其对两亲性试剂的抗性。
