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

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the cell membrane to the target, transfection, has been mainly pursued using viral vectors with native DNA having been replaced by the required DNA.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