Gene Transfer with a Series of Lipophilic DNA-Binding Molecules

Abstract

Synthetic gene transfer vectors could be an attractive alternative to biological vehicles for gene therapy. In an effort to improve the previously developed lipopolyamine-mediated transfection technique, various amphiphilic DNA-binding molecules have been synthesized. Besides Transfectam, several lipospermines display very high gene delivery levels. The structure-activity relationship obtained points to the central role played by the polyamine headgroup in condensing the plasmid and binding it to the cell surface, provided the hydrophobic moiety is capable to generate nonmicellar mesomorphic structures. It also highlights other favorable (albeit more speculative) properties shared by protonable lipospermines as compared to quaternary ammonium-bearing lipids, such as their ability to act as a buffer and their strong affinity for chromatin. The former property may prevent the pH decrease along the degradative lysosomial pathway. The ability to bind to chromatin even in the presence of endogeneous polyamines should have two consequences: a nuclear tropism of the transfecting particles and plasmid uncoating in the nucleus by competitive dilution of the lipopolyamine into an ocean of DNA.

On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids

“…29,43,44 Here, we only point out that differing cationic headgroups can lead to different abilities to promote H II organization as indicated by the T BH parameter. In particular, it was found that both DOTAP/DOPS and DOTMA/DOPS mixtures exhibited similar T BH values between 7 and 13°C ( Table 1).…”

Co-polymer of histidine and lysine markedly enhances transfection efficiency of liposomes

“…Cationic liposomes are the most commonly used nonviral delivery system for delivery of plasmids into cells in vitro [1][2][3] and in vivo. [4][5][6] A significant problem associated with cationic liposomes is their low in vivo transfection efficiency, 7,8 possibly due to inactivation of the liposomes by serum.…”

Development of plasmid and oligonucleotide nanometric particles

“…Upon addition to cells, their fast exchange with the medium or the cell membrane leads to DNA unfolding, hence their poor transfection properties. 6,7 Correspondence: E Dauty We have succeeded in combining the advantages of cationic detergents with those of lipids, through a twostep process. First, DNA molecules were individually condensed with a cationic cysteine-based detergent.…”