title: Intranasal administration as a route for drug delivery to the brain: evidence for a unique pathway for albumin.
abstract: A variety of compounds will distribute into the brain when placed at the cribriform plate by intranasal (i.n.) administration. In this study, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the blood-brain barrier, to distribute into the brain after i.n. administration. We labeled bovine serum albumin with [(125)I] ([(125)I]Alb) and studied its uptake into 11 brain regions and its entry into the blood from 5 minutes to 6 hours after i.n. administration. [(125)I]Alb was present throughout the brain at 5 minutes. Several regions showed distinct peaks in uptake that ranged from 5 minutes (parietal cortex) to 60 minutes (midbrain). About 2-4% of the i.n. [(125)I]Alb entered the bloodstream. The highest levels occurred in the olfactory bulb and striatum. Distribution was dose-dependent, with less taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid-phase stimulator PMA (phorbol 12-myristate 13-acetate), but inhibitors to receptor-mediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered the distribution of radioactive leptin given by i.n. administration, decreasing uptake into the blood and by the cerebellum and increasing uptake by the hypothalamus. We conclude that [(125)I]Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid-phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration.
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Falcone
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.).
authors.forename: Therese S
authors.initials: TS
authors.lastname: Salameh
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.).
authors.forename: Xiang
authors.initials: X
authors.lastname: Yi
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.).
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Cordy
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.).
authors.forename: William G
authors.initials: WG
authors.lastname: Mortell
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.).
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine (J.A.F., T.S.S., W.A.B.) and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (J.A.F., T.S.S., X.Y., B.J.C., W.G.M., W.A.B.); Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina (X.Y., A.V.K.); and Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia (A.V.K.) wabanks1@uw.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000187:drug effects*; D020738:Leptin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D020738:Leptin; D014677:Pharmaceutical Vehicles; D012710:Serum Albumin, Bovine; D013755:Tetradecanoylphorbol Acetate