Systemic administration of cationic phosphonolipids/DNA complexes and the relationship between formulation and lung transfection efficiency.
Performances of cationic lipid formulations for intravenous gene delivery to mouse lungs have been previously reported. We report in this study that cationic phosphonolipids, when appropriately formulated, can be good synthetic vectors for gene delivery to lung after intravenous administration. One of our reagents, GLB43, was capable of mediating a 500-fold higher expression in the lungs of mice than could be obtained with free pDNA alone (P=0.018). We demonstrate that the most important parameters for cationic phosphonolipid transfection activity after systemic administration are the chemical structure of the cationic phosphonolipid, the lipid to DNA charge ratio and the inclusion of co-lipid in the formulation. We report using a luciferase reporter gene that transfection activity in vivo 24 h after cationic phosphonolipid systemic administration could not be predicted from in vitro analysis. In contrast to in vitro studies, cationic phosphonolipids including the oleyl acyl chains (GLB43) were more effective than its analogue with the myristyl acyl chains (GLB73). Using pathological analysis of animal livers, we demonstrate that the toxicity level was correlated with the lipoplex formulation and the lipid to DNA ratio.
Floch
V
V
Centre de Biogénétique, CHU, ETSBO, 46, rue Félix le Dantec, P.O. Box 454, 29275, Brest, France. virginie.floch@univ-brest.fr
Delépine
P
P
Guillaume
C
C
Loisel
S
S
Chassé
S
S
Le Bolc'h
G
G
Gobin
E
E
Leroy
J P
JP
Férec
C
C
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000633:toxicity*; D015195:Drug Design; D017930:Genes, Reporter; D015316:Genetic Therapy; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008156:Luciferases / Q000032:analysis; D008168:Lung / Q000378:metabolism*; D051379:Mice; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D010957:Plasmids; D014162:Transfection / Q000379:methods
D010714:Phosphatidylethanolamines; D010743:Phospholipids; C028299:phosphonolipids; C094877:dioleoyl phosphatidylethanolamine; D004247:DNA; D002784:Cholesterol; D008156:Luciferases