LIPITOIDS - NOVEL CATIONIC LIPIDS FOR CELLULAR DELIVERY OF PLASMID DNA IN-VITRO

Background: Although synthetic nonviral vectors hold promise for the d elivery of plasmid DNA, their gene-transfer efficiencies are far from matching those of viruses. To systematically investigate the structure -activity relationship of cationic lipids, a small library of cationic lipid-peptoid conjugates (lipitoids) was synthesized. The compounds w ere evaluated for their ability to form complexes with plasmid DNA and to mediate DNA transfer in vitro. Results: Lipid-peptoid conjugates w ere conveniently prepared in high yield using solid-phase synthesis. S everal lipitoids condensed plasmid DNA int 100 nm spherical particles and protected the DNA from DNase digestion, A subset of lipitoids with a repeated (aminoethyl, neutral, neutral) sidechain trimer motif conj ugated with dimyristoyl phosphatidyl-ethanolamine (DMPE) mediate DNA t ransfer with high efficiency. Conclusions: Automated solid-phase synth esis of cationic lipids allowed the rapid synthesis of a diverse set o f transfection reagents. The most active compound DMPE-(Nae-Nmpe-Nmpe) (3) (Nae, N-aminoethyl glycine; Nmpe, N-p-methoxyphenethyl-glycine) is more efficient than lipofectin or DMRIE-C (two commercial cationic li pid transfection reagents) and is active in the presence and absence o f serum. The activity in the presence of serum suggests potent at for applications in vivo.