title: Evaluation of New Fluorescent Lipophosphoramidates for Gene Transfer and Biodistribution Studies after Systemic Administration.
abstract: The objective of lung gene therapy is to reach the respiratory epithelial cells in order to deliver a functional nucleic acid sequence. To improve the synthetic carrier's efficacy, knowledge of their biodistribution and elimination pathways, as well as cellular barriers faced, depending on the administration route, is necessary. Indeed, the in vivo fate guides the adaptation of their chemical structure and formulation to increase their transfection capacity while maintaining their tolerance. With this goal, lipidic fluorescent probes were synthesized and formulated with cationic lipophosphoramidate KLN47 (KLN: Karine Le Ny). We found that such formulations present constant compaction properties and similar transfection results without inducing additional cytotoxicity. Next, biodistribution profiles of pegylated and unpegylated lipoplexes were compared after systemic injection in mice. Pegylation of complexes led to a prolonged circulation in the bloodstream, whereas their in vivo bioluminescent expression profiles were similar. Moreover, systemic administration of pegylated lipoplexes resulted in a transient liver toxicity. These results indicate that these new fluorescent compounds could be added into lipoplexes in small amounts without perturbing the transfection capacities of the formulations. Such additional properties allow exploration of the in vivo biodistribution profiles of synthetic carriers as well as the expression intensity of the reporter gene.
authors.affiliation: Unité INSERM 1078, Faculté de Médecine, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 avenue Camille Desmoulins, 29238 Brest cedex 3, France. nawal.belmadi@univ-brest.fr.
authors.forename: Nawal
authors.initials: N
authors.lastname: Belmadi
authors.affiliation: Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. mathieu.berchel@univ-brest.fr.|UMR CNRS 6521, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté des Sciences, 6 avenue Victor Le Gorgeu, 29238 Brest, France. mathieu.berchel@univ-brest.fr.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Berchel
authors.affiliation: Unité INSERM 1078, Faculté de Médecine, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 avenue Camille Desmoulins, 29238 Brest cedex 3, France. caroline.denis@chu-brest.fr.|Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. caroline.denis@chu-brest.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Denis
authors.affiliation: Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. wilfried.berthe@univ-brest.fr.|UMR CNRS 6521, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté des Sciences, 6 avenue Victor Le Gorgeu, 29238 Brest, France. wilfried.berthe@univ-brest.fr.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Berthe
authors.affiliation: Unité INSERM 1078, Faculté de Médecine, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 avenue Camille Desmoulins, 29238 Brest cedex 3, France. yann.sibiril@univ-brest.fr.|Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. yann.sibiril@univ-brest.fr.
authors.forename: Yann
authors.initials: Y
authors.lastname: Sibiril
authors.affiliation: Unité INSERM 1078, Faculté de Médecine, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 avenue Camille Desmoulins, 29238 Brest cedex 3, France. tony.legall@univ-brest.fr.|Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. tony.legall@univ-brest.fr.
authors.forename: Tony
authors.initials: T
authors.lastname: Le Gall
authors.affiliation: Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. jeanpierre-haelters@bbox.fr.|UMR CNRS 6521, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté des Sciences, 6 avenue Victor Le Gorgeu, 29238 Brest, France. jeanpierre-haelters@bbox.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Haelters
authors.affiliation: Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. paul-alain.jaffres@univ-brest.fr.|UMR CNRS 6521, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté des Sciences, 6 avenue Victor Le Gorgeu, 29238 Brest, France. paul-alain.jaffres@univ-brest.fr.
authors.forename: Paul-Alain
authors.initials: PA
authors.lastname: Jaffres
authors.affiliation: Unité INSERM 1078, Faculté de Médecine, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 avenue Camille Desmoulins, 29238 Brest cedex 3, France. tristan.montier@univ-brest.fr.|Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France. tristan.montier@univ-brest.fr.|Laboratoire de génétique moléculaire et d'histocompatibilité, CHRU de Brest, 5 Avenue du Maréchal Foch, 29609 Brest cedex, DUMG, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 rue Camille Desmoulins, CS 93837-29238 Brest cedex 3, France. tristan.montier@univ-brest.fr.
authors.forename: Tristan
authors.initials: T
authors.lastname: Montier
mesh_terms: D000577:Amides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D018014:Gene Transfer Techniques; D006801:Humans; D008081:Liposomes; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D057054:Molecular Imaging; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D010957:Plasmids / Q000737:chemistry; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D000577:Amides; D005456:Fluorescent Dyes; D008081:Liposomes; D010756:Phosphoric Acids; D004247:DNA; C011067:phosphoramidic acid
keywords: administration way; cationic lipids; in situ biodistribution; in vivo fluorescence; pegylated formulations