Characterization of a synthetic anionic vector for oligonucleotide delivery using in vivo whole body dynamic imaging.
OBJECTIVE
To compare the pharmacokinetics and bioavailability of an oligonucleotide delivered in a free form or using cationic or anionic synthetic carrier systems.


METHODS
Whole body dynamic quantitative imaging and metabolism of a HIV antisense oligonucleotide intravenously administered either free or incorporated into synthetic carriers were compared in baboons. using non invasive positron emission tomography and an enzyme-based competitive hybridization assay, respectively.


RESULTS
In its free form, the oligonucleotide showed high liver and kidney concentration, rapid plasmatic degradation and elimination from the body. Use of a cationic vector slightly protected the oligonucleotide against degradation and enhanced uptake by the reticulo-endothelial system. In contrast, the anionic vector dramatically enhanced the uptake in several organs, including the lungs, spleen and brain, with a prolonged accumulation of radioactivity in the brain. Using this vector, intact oligonucleotide was detected in plasma for up to two hours after injection. and the T 1/2beta and distribution volume increased by 4- and 7-fold, respectively. No evidence of toxicity was found after a single dose administration.


CONCLUSIONS
The anionic vector improves significantly the bioavailability and the pharmacokinetics of the oligonucleotide, and is a promising delivery system for in vivo administration of therapeutic nucleic acids.
Tavitian
Bertrand
B
INSERM M 0103, CEA-SHFJ, Orsay, France. tavitian@shfj.cea.fr
Marzabal
Stéphane
S
Boutet
Valérie
V
Kühnast
Bertrand
B
Terrazzino
Salvatore
S
Moynier
Marinette
M
Dollé
Frédéric
F
Deverre
Jean Robert
JR
Thierry
Alain R
AR
D000818:Animals; D000838:Anions / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008081:Liposomes; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010215:Papio; D014055:Tomography, Emission-Computed / Q000379:methods*; D014915:Whole-Body Counting / Q000379:methods
D000838:Anions; D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense