Cationic lipo-oligomers containing unsaturated oleic acid are potent siRNA carriers based on electrostatic and hydrophobic lipo-polyplex formation and endosomal membrane destabilization. Lipo-oligomers can be produced by solid-phase-supported synthesis in sequence-defined form. However, the trifluoroacetic acid (TFA)-mediated removal of acid-labile protecting groups and cleavage from the resin can be accompanied by side products caused by the addition of TFA to the double bonds of oleic acid. Under aqueous conditions, these TFA adducts of oleic acid are converted into hydroxystearic acid derivatives. The cleavage protocol was optimized to decrease TFA adducts. The pure oleic acid (C18:1) containing lipo-oligomer was compared with analogous structures containing saturated or modified hydrophobic moieties (stearic acid (C18:0), hydroxystearic acid, and 8-nonanamidooctanoic acid). The structure containing intact oleic acid shows favorable pH dependency of lytic activity, efficient gene silencing, and excellent cell tolerability relative to its counterparts.
Keywords: endosomal escape; oleic acid; polyplexes; siRNA delivery; solid-phase synthesis.
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