title: Characterization of a synthetic anionic vector for oligonucleotide delivery using in vivo whole body dynamic imaging.
abstract: 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.
authors.affiliation: INSERM M 0103, CEA-SHFJ, Orsay, France. tavitian@shfj.cea.fr
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tavitian
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marzabal
authors.forename: Valérie
authors.initials: V
authors.lastname: Boutet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kühnast
authors.forename: Salvatore
authors.initials: S
authors.lastname: Terrazzino
authors.forename: Marinette
authors.initials: M
authors.lastname: Moynier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Jean Robert
authors.initials: JR
authors.lastname: Deverre
authors.forename: Alain R
authors.initials: AR
authors.lastname: Thierry
mesh_terms: 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
chemical_list: D000838:Anions; D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense