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

人类基因组绘图计划已使人们得以鉴定与许多遗传性疾病有关的基因和基因缺陷。基因治疗代表了这些疾病中蛋白质表达缺陷的修复，这些疾病没有足够的治疗方法。其基本思想是用一个“健康”的基因取代“生病”的基因，或者添加一个新的基因来促进治疗性蛋白质的合成。 基因（质粒DNA）穿过细胞膜转移到靶，即转染，主要使用天然DNA已被所需DNA取代的病毒载体进行。使用这种载体的程序是复杂的、危险的和昂贵的。最近，非病毒载体已被研究作为替代剂。我们已经发现，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剂（肥皂样），通过烃间隔基团连接，可以作为有效的非病毒载体。在“辅助脂质”的存在下，它们与DNA形成的复合物已经被我们证明能够在某些细胞系中表达治疗性蛋白质。下一阶段研究的目标是提高这些非病毒载体的转染效率;（i）通过修饰表面活性剂的化学结构，使所得复合物与DNA的形态更好地适应通过细胞膜转移，以及（ii）提高我们对DNA一旦进入细胞内就从内体释放的机制的认识。治疗剂的局部递送系统的开发是全世界公共和动物卫生机构的优先领域。然而，在这个时候，似乎很少有以马达加斯加为基础的研究集中在这一活动。这里描述的项目将是使加拿大保持在这一研究领域前沿的重要一步。

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the cell membrane to the target, transfection, has been mainly pursued using viral vectors with native DNA having been replaced by the required DNA.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.