Influence of Minor Backbone Structural Variations in Modulating the in Vitro Gene Transfer Efficacies of α-Tocopherol Based Cationic Transfection Lipids

Toward probing the influence of backbone structural variation in cationic lipid mediated gene delivery of alpha-tocopherol based lipids, two novel alpha-tocopherol based lipids 1 and 2 have been designed and synthesized. The only structural difference between the cationic amphiphiles 1 and 2 is the backbone structure, where lipid 1 has a non-glycerol backbone and lipid 2 has a glycerol backbone. The lipids 1 and 2 showed contrasting transfection efficiencies: lipid 1 showed high gene transfer efficacy in multiple cultured animals cell lines, whereas lipid 2 is transfection incompetent. In summary, the present findings demonstrate that in the case of alpha-tocopherol based lipids even minor structural variations like backbone can profoundly influence size, DNA binding characteristics, cellular uptake, and consequently gene delivery efficacies.