Gemini surfactants: behaviour at interfaces and interaction with synthetic and biological macromolecules

人类基因组图谱项目已经能够识别出与一些遗传性疾病有关的基因和基因缺陷。基因治疗代表着修复这些疾病中有缺陷的蛋白质表达，而这些疾病没有足够的治疗方法可用。其基本思想是用“健康”基因取代“有病”的基因，或增加一个新的基因来促进治疗性蛋白质的合成。通过细胞膜将基因(质粒DNA)转移到靶基因，即转染法，主要是利用病毒载体，用所需的DNA取代原生DNA。使用这种载体的过程复杂、危险和昂贵。近年来，非病毒载体已被作为替代药物进行研究。我们发现，由两个带正电荷的头部基团和两个烷基尾部组成的表面活性物质(类肥皂)，通过碳氢化合物间隔基连接，可以作为有效的非病毒载体。我们已经证明，在“辅助脂质”的存在下，它们与DNA形成的复合体能够在某些细胞系中表达一种治疗性蛋白质。下一阶段的研究目标是提高这些非病毒载体的转染效率；(I)通过改变表面活性剂的化学结构，使得到的与DNA的复合体的形态更适合通过细胞膜转移；(Ii)提高我们对DNA进入细胞内体后从内体释放的机制的了解。开发治疗剂的局部给药系统是公共和动物卫生机构在世界范围内的优先领域。然而，目前似乎几乎没有加拿大的研究集中在这一活动上。这里描述的项目将是保持加拿大在这一研究领域的领先地位的重要一步。

The Human Genome Mapping Project has allowed the identification of genes and gene defects implicated in a number of inherited diseases. Gene therapy represents the repair of defective protein expression in these diseases where there are no adequate therapies available. The basic idea is to replace the "sick" gene with a "healthy" one or to add a new gene to promote the synthesis of a therapeutic protein.  The transfer of the gene (plasmid DNA) across the cell membrane to the target, transfection, has been mainly pursued using viral vectors with native DNA having been replaced by the required DNA. The procedures using such vectors are complex, hazardous, and expensive. Recently, nonviral vectors have been studied as alternate agents. We have found that surface active agents (soap-like) consisting of two positively charged head groups and two alkyl tails, connected by a hydrocarbon spacer group, can act as effective nonviral vectors. The complexes they form with DNA, in the presence of a "helper-lipid," have been shown by us to be able to express a therapeutic protein within certain cell lines. The objective of the next stage of research is to improve the transfection efficiency of these nonviral vectors; (i) by modifying the chemical structure of the surfactant so that the morphology of the resulting complex with DNA is better adapted to transfer through the cell membrane and (ii) to improve our insight of the mechanism of release of the DNA from the endosome once it is within the cell. The development of topical delivery systems for therapeutic agents is a priority area, worldwide, for public and animal health agencies. However, at this time there appears to be little Canadian-based research focusing on this activity. The project described here will be an important step in keeping Canada at the forefront of this research area.