Branched lipid chains to prepare cationic amphiphiles producing hexagonal aggregates: supramolecular behavior and application to gene delivery

Abstract

A ramified lipid alcohol, 2-hexyldecanol, was used as hydrophobic moiety to prepare at a gram scale in 3 to 4 steps, cationic amphiphiles featuring either a trimethylammonium 5, dimethylhydroxyethylammonium 6 or N-methylimidazolium 7 polar head group. Compression isotherms at the air-water interface reveal that all these cationic amphiphiles collapse at a relatively low pressure indicating a weak stabilization of the monolayer via hydrophobic interactions. Ellipsometry measurements point out the presence of thin monolayer at low lateral pressure whereas its thickening occurs at higher pressure with a high percentage of variation of the thickness, thus demonstrating an adaptability to the constraints. 31P NMR of the hydrated cationic amphiphiles clearly shows that these cationic amphiphiles self-assemble in water to form hexagonal phases, irrespective of the nature of their polar head group. Furthermore, the comparison of molecular structures suggests that compounds 5-7 self-organize in inverted hexagonal phase (HII). These cationic amphiphiles, alone or in presence of DOPE, were evaluated for the transfection of three human-derived cell lines (i.e. A549, 16HBE, HeLa). The three compounds demonstrate high transfection efficacies in every cell line tested, 7/DOPE being the most efficient