title: Systemically administered brain-targeted nanoparticles transport peptides across the blood-brain barrier and provide neuroprotection.
abstract: Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood-brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.
authors.affiliation: Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Muge
authors.initials: M
authors.lastname: Yemisci
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
authors.forename: Secil
authors.initials: S
authors.lastname: Caban
authors.affiliation: Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Gursoy-Ozdemir
authors.affiliation: Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Sevda
authors.initials: S
authors.lastname: Lule
authors.affiliation: Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Novoa-Carballal
authors.affiliation: Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Riguera
authors.affiliation: Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernandez-Megia
authors.affiliation: Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud XI, Chátenay-Malabry, France.
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 XI, Chátenay-Malabry, France.
authors.forename: Partick
authors.initials: P
authors.lastname: Couvreur
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
authors.forename: Yilmaz
authors.initials: Y
authors.lastname: Capan
authors.affiliation: Department of Neurology, Faculty of Medicine, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Turgay
authors.initials: T
authors.lastname: Dalkara
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D058726:Nanoconjugates / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009842:Oligopeptides / Q000008:administration & dosage*; D020521:Stroke / Q000473:pathology*
chemical_list: D058726:Nanoconjugates; D018696:Neuroprotective Agents; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D016222:Fibroblast Growth Factor 2