title: Improved brain uptake and pharmacological activity of dalargin using a peptide-vector-mediated strategy.
abstract: The blood-brain barrier restricts the passage of substances into the brain. Neuropeptides, such as enkephalins, cannot be delivered into the brain when given systemically because of this barrier. Therefore, there is a need to develop efficient transport systems to deliver these drugs to the brain. Recently, we have demonstrated that conjugation of doxorubicin or penicillin to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated the enkephalin analog dalargin with two different peptide vectors, SynB1 and SynB3, to improve its brain delivery and its pharmacological effect. We show by in situ brain perfusion that vectorization markedly enhances the brain uptake of dalargin. We also show using the hot-plate model that this enhancement in brain uptake results in a significant improvement in the observed antinociceptive effect of dalargin. These results support the usefulness of peptide-mediated strategies for improving the availability and efficacy of central nervous system drugs.
authors.affiliation: Synt:em, Parc Scientifique Georges Besse, 30000 Nimes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousselle
authors.forename: Philippe
authors.initials: P
authors.lastname: Clair
authors.forename: Maria
authors.initials: M
authors.lastname: Smirnova
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kolesnikov
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gac-Breton
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Rees
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Jamal
authors.initials: J
authors.lastname: Temsamani
mesh_terms: D000698:Analgesia; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D010455:Peptides; D016308:Enkephalin, Leucine-2-Alanine; C040996:enkephalin-Leu, Ala(2)-Arg(6)-