title: Pharmacokinetics, biodistribution and metabolism of squalenoyl adenosine nanoparticles in mice using dual radio-labeling and radio-HPLC analysis.
abstract: Adenosine is a pleiotropic endogenous nucleoside with potential neuroprotective pharmacological activity. However, clinical use of adenosine is hampered by its extremely fast metabolization. To overcome this limitation, we recently developed a new squalenoyl nanomedicine of adenosine [Squalenoyl-Adenosine (SQAd)] by covalent linkage of this nucleoside to the squalene, a natural lipid. The resulting nanoassemblies (NAs) displayed a dramatic pharmacological activity both in cerebral ischemia and spinal cord injury pre-clinical models. The aim of the present study was to investigate the plasma profile and tissue distribution of SQAd NAs using both Squalenoyl-[(3)H]-Adenosine NAs and [(14)C]-Squalenoyl-Adenosine NAs as respective tracers of adenosine and squalene moieties of the SQAd bioconjugate. This study was completed by radio-HPLC analysis allowing to determine the metabolization profile of SQAd. We report here that SQAd NAs allowed a sustained circulation of adenosine under its prodrug form (SQAd) for at least 1h after intravenous administration, when free adenosine was metabolized within seconds after injection. Moreover, the squalenoylation of adenosine and its formulation as NAs also significantly modified biodistribution, as SQAd NAs were mainly captured by the liver and spleen, allowing a significant release of adenosine in the liver parenchyma. Altogether, these results suggest that SQAd NAs provided a reservoir of adenosine into the bloodstream which may explain the previously observed neuroprotective efficacy of SQAd NAs against cerebral ischemia and spinal cord injury.
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: gaudin.alice@gmail.com.
authors.forename: Alice
authors.initials: A
authors.lastname: Gaudin
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: sinda.lepetre@u-psud.fr.
authors.forename: Sinda
authors.initials: S
authors.lastname: Lepetre-Mouelhi
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: julie.mougin@u-psud.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Mougin
authors.affiliation: BERTIN Pharma, 10 Avenue Claude Guillemin, 45071 Orléans, France. Electronic address: martine.parrod@bertinpharma.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Parrod
authors.affiliation: CEA Saclay, iBiTecS-S/SCBM, Labex LERMIT, 91191 Gif-sur-Yvette, France. Electronic address: gregory.pieters@cea.fr.
authors.forename: Grégory
authors.initials: G
authors.lastname: Pieters
authors.affiliation: CEA Saclay, iBiTecS-S/SCBM, Labex LERMIT, 91191 Gif-sur-Yvette, France. Electronic address: sebastien.garcia-argote@cea.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Garcia-Argote
authors.affiliation: CEA Saclay, iBiTecS-S/SCBM, Labex LERMIT, 91191 Gif-sur-Yvette, France. Electronic address: olivier.loreau@cea.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Loreau
authors.affiliation: BERTIN Pharma, 10 Avenue Claude Guillemin, 45071 Orléans, France. Electronic address: jordan.goncalves@bertinpharma.com.
authors.forename: Jordan
authors.initials: J
authors.lastname: Goncalves
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: helene.chacun@u-psud.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Chacun
authors.affiliation: BERTIN Pharma, 10 Avenue Claude Guillemin, 45071 Orléans, France. Electronic address: yann.courbebaisse@bertinpharma.com.
authors.forename: Yann
authors.initials: Y
authors.lastname: Courbebaisse
authors.affiliation: BERTIN Pharma, 10 Avenue Claude Guillemin, 45071 Orléans, France. Electronic address: pascal.clayette@bertinpharma.com.
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: didier.desmaele@u-psud.fr.
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.affiliation: CEA Saclay, iBiTecS-S/SCBM, Labex LERMIT, 91191 Gif-sur-Yvette, France. Electronic address: bernard.rousseau@cea.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Rousseau
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: karine.andrieux@parisdescartes.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Andrieux
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: patrick.couvreur@u-psud.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013185:Squalene / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D002250:Carbon Radioisotopes; D011355:Prodrugs; D014316:Tritium; D013185:Squalene; D000241:Adenosine
keywords: Biodistribution; Nanoparticle