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

Abstract

Cationic amphiphiles featuring ramified lipid chains self-organized in water as inverted hexagonal aggregates. They demonstrated high gene delivery efficiencies.

Phosphonodithioester–Amine Coupling as a Key Reaction Step for the Design of Cationic Amphiphiles Used for Gene Delivery

“…This structural feature introduces a kink in the lipid chain that disturbs the lipid packing and increases fluidity, as previously reported [39]. In the case of branched lipid chains, the ramification results in a larger volume of hydrophobic chains that contribute to the formation of a cone-shaped amphiphilic structure that favors non-lamellar self-assemblies and produces efficient gene carriers [23]. Their synthesis starts with a transesterification reaction involving a lipid alcohol and diphenylphosphite.…”

“…The synthesis of the new cationic lipids is depicted in Figure 2. Regarding the choice of the lipid chains, we selected oleyl chains or the branched lipid chain 2-decyl-tetradecanyl because they proved their efficacy when incorporated in the structure of other cationic amphiphiles [23,35]. Previous publications have indeed observed that oleyl chains increase the fluidity of self-assemblies thanks to the presence of their carbon-carbon double bond possessing a Z-configuration.…”

“…This negative charge could be due to a different type of supramolecular assembly. Branched lipid chains are indeed prone to adopting inverted hexagonal assemblies [23]. The complexation properties of these formulations were evaluated using gel electrophoresis of the lipoplexes, prepared in water at different charge ratios (from 0.7 to 4; Figure 3).…”

“…Other type of cationic amphiphiles have been designed with the aim of controlling their molecular shape, which is, according to the Israelachvili theory [22], a key parameter for controlling the type of supramolecular self-assembly. Following this line, we have reported the synthesis of phospholipids using commercially available branched lipid chains [23] or including branched lipid chains prepared via the photo-thiol-ene reaction [24]. These cationic amphiphiles form inverted hexagonal aggregates that promote lipid fusion and favor the transfection process.…”

“…the type of supramolecular self-assembly. Following this line, we have reported the synthesis of phospholipids using commercially available branched lipid chains [23] or including branched lipid chains prepared via the photo-thiol-ene reaction [24]. These cationic amphiphiles form inverted hexagonal aggregates that promote lipid fusion and favor the transfection process.…”