Aminoglycoside-derived cationic lipids as efficient vectors for gene transfection in vitro and in vivo.
BACKGROUND
Cationic lipids are at present very actively investigated for gene transfer studies and gene therapy applications. Basically, they rely on the formation of DNA/lipid aggregates via electrostatic interactions between their cationic headgroup and the negatively charged DNA. Although their structure/activity relationships are not well understood, it is generally agreed that the nature of the positive headgroup impacts on their transfection activity. Thus, we have directed our efforts toward the development of cationic lipids with novel cationic moieties. In the present work, we have explored the transfection potential of the lipophilic derivatives of the aminoglycoside kanamycin A. Indeed, aminoglycosides, which are natural polyamines known to bind to nucleic acids, provide a favorable scaffold for the synthesis of a variety of cationic lipids because of their structural features and multifunctional nature.


RESULTS
We report here the synthesis of a cationic cholesterol derivative characterized by a kanamycin A headgroup and of its polyguanidinylated derivative. The amino-sugar-based cationic lipid is highly efficient for gene transfection into a variety of mammalian cell lines when used either alone or as a liposomal formulation with the neutral phospholipid dioleoylphosphatidylethanolamine (DOPE). Its polyguanidinylated derivative was also found to mediate in vitro gene transfection. In addition, colloidally stable kanamycin-cholesterol/DOPE lipoplexes were found to be efficient for gene transfection into the mouse airways in vivo.


CONCLUSIONS
These results reveal the usefulness of cationic lipids characterized by headgroups composed of an aminoglycoside or its guanidinylated derivative for gene transfection in vitro and in vivo.
Belmont
Philippe
P
Laboratoire de Chimie des Interactions Moléculaires, Collège de France, 11 place Marcelin Berthelot, 75005 Paris, France.
Aissaoui
Abderrahim
A
Hauchecorne
Michelle
M
Oudrhiri
Noufissa
N
Petit
Laure
L
Vigneron
Jean-Pierre
JP
Lehn
Jean-Marie
JM
Lehn
Pierre
P
D000617:Aminoglycosides / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005822:Genetic Vectors; D066298:In Vitro Techniques; D007612:Kanamycin / Q000378:metabolism; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D051381:Rats; D014162:Transfection
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D000617:Aminoglycosides; D008081:Liposomes; D010714:Phosphatidylethanolamines; D007612:Kanamycin; D002784:Cholesterol