Novel Cationic Lipids with Enhanced Gene Delivery and Antimicrobial Activity

Cationic lipids facilitate plasmid delivery and some cationic sterol-based compounds have antimicrobial activity due to their amphiphilic character. These dual functions are relevant in the context of local chronic infection during intrapulmonary gene transfer for cystic fibrosis. The transfection activities of two cationic lipids, dexamethasone spermine (DS) and disubstituted spermine (D₂S), were tested in bovine aortic endothelial cells and A549 cells. The results showed a 3 to 7-fold improvement in transgene expression for mixtures of DS with 20 to 40 mol% D₂S. D₂S was a potent bactericidal agent against E. coli MG1655, B. subtilis, and P. aeruginosa PAO1 with complete killing demonstrated at 5 μM and a two order of magnitude higher tolerance before eukaryotic membrane disruption (erythrocyte hemolysis). D₂S also exhibited LPS scavenging activity resulting in significant inhibition of LPS-mediated activation of human neutrophils with 85 and 65% lower IL-8 released at 12 and 24 hrs respectively. In addition, mixtures of DS and D₂S were effective gene delivery vectors for transfection in lung and D₂S demonstrated in vivo antibacterial activity. Mixtures of DS and D₂S can improve transfection activity over common lipofection reagents, and D₂S has strong antimicrobial action suited for suppression of bacterial-mediated inflammation.