Lipopolycationic telomers for gene transfer: Synthesis and evaluation of their in vitro transfection efficiency

We report on the synthesis of a series of lipopolyamine telomers I-14,n, I- 18,n, and II-18,n and on their in vitro gene-transfer capability. Their str ucture consists of a polyamine polar moiety, including n primary amine func tions (from 1 to 70), connected to a hydrophobic moiety, including two hydr ocarbon C14 or C18 chains, through a mercaptopropanoyl or mercaptoglyceryl unit and an amide or ether function. They were obtained by telomerization o f N-(2-[(BOC)aminoethyl]})acrylamide with N,N-ditetradecyl- and N,N-dioctad ecylpropanamide-3-thiol and rac-1,2-dioctadecyloxypropane-3-thiol, respecti vely, then BOC deprotection. For NIP ratios (N = number of telomer amine eq uivalents; P = number of DNA phosphates) from 0.8 to 10, these lipopolyamin es condensed DNA, with or without the use of DOPE, forming lipopolyplexes o r teloplexes of mean sizes less than zoo nm. Some trends, structure-activit y and structure-toxicity relationships, were established to achieve both hi ghest in vitro transfection levels and cell viability. Thus, DNA formulatio ns based on telomers I-14,20 and I-18,20 and for NIP ratios lower than 5 le d to the most efficient teloplex formulations for plasmid delivery to lung epithelial A549 cells.