Novel galactosylated polyamine bolaamphiphiles for gene delivery

We describe the synthesis of a series of alpha-galacto-omega-polyamine double-chain bolaamphiphiles (Gal-CL) and report on the gene transfer mediated with lipoplexes they form either when used in conjunction with DOPE or with pcTG90:DOPE. Lipofection was investigated with human HepG2 and murine BNL-CL2 hepatocytes expressing the asialoglycoprotein (ASGP) receptor which displays a high affinity for galactosyl residues, and with A549 cells which do not express ASGP. Our results show that cationic N/P = 5 and 2.5 Gal-CL lipoplexes constitute very efficient nonspecific gene transfer systems. Lipofection experiments performed in the presence of asialofetuin (a high affinity ligand of ASGP) led us to evidence also the involvement of a specific receptor-mediated endocytosis pathway for the transfection of the ASGP(+) HepG2 or BNL-CL2 hepatocytes with some Gal-CL formulations. This work suggests that targetable lipopolyamines presenting a single galactose residue appear as promising synthetic vectors for specific gene delivery to ASGP(+) cells.