title: Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26.
abstract: The inhibition of the caspase-3 enzyme is reported to increase neuronal cell survival following cerebral ischemia. The peptide Z-DEVD-FMK is a specific caspase inhibitor, which significantly reduces vulnerability to the neuronal cell death. However, this molecule is unable to cross the blood-brain barrier (BBB) and to diffuse into the brain tissue. Thus, the development of an effective delivery system is needed to provide sufficient drug concentration into the brain to prevent cell death. Using the avidin (SA)-biotin (BIO) technology, we describe here the design of chitosan (CS) nanospheres conjugated with poly(ethylene glycol) (PEG) bearing the OX26 monoclonal antibody whose affinity for the transferrin receptor (TfR) may trigger receptor-mediated transport across the BBB. These functionalized CS-PEG-BIO-SA/OX26 nanoparticles (NPs) were characterized for their particle size, zeta potential, drug loading capacity, and release properties. Fluorescently labeled CS-PEG-BIO-SA/OX26 nanoparticles were administered systemically to mice in order to evaluate their efficacy for brain translocation. The results showed that an important amount of nanoparticles were located in the brain, outside of the intravascular compartment. These findings, which were also confirmed by electron microscopic examination of the brain tissue indicate that this novel targeted nanoparticulate drug delivery system was able to translocate into the brain tissue after iv administration. Consequently, these novel nanoparticles are promising carriers for the transport of the anticaspase peptide Z-DEVD-FMK into the brain.
authors.affiliation: Physico-Chimie, Pharmacotechnie, Biopharmacie, Faculté de Pharmacie, Université Paris Sud, UMR CNRS 8612, 92296 Chatenay Malabry, France.
authors.forename: Yeşim
authors.initials: Y
authors.lastname: Aktaş
authors.forename: Muge
authors.initials: M
authors.lastname: Yemisci
authors.forename: Karine
authors.initials: K
authors.lastname: Andrieux
authors.forename: R Neslihan
authors.initials: RN
authors.lastname: Gürsoy
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Alonso
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernandez-Megia
authors.forename: Ramón
authors.initials: R
authors.lastname: Novoa-Carballal
authors.forename: Emilio
authors.initials: E
authors.lastname: Quiñoá
authors.forename: Ricardo
authors.initials: R
authors.lastname: Riguera
authors.forename: Mustafa F
authors.initials: MF
authors.lastname: Sargon
authors.forename: H Hamdi
authors.initials: HH
authors.lastname: Celik
authors.forename: Ayhan S
authors.initials: AS
authors.lastname: Demir
authors.forename: A Atilla
authors.initials: AA
authors.lastname: Hincal
authors.forename: Turgay
authors.initials: T
authors.lastname: Dalkara
authors.forename: Yilmaz
authors.initials: Y
authors.lastname: Capan
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D048271:Chitosan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D005456:Fluorescent Dyes; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D009842:Oligopeptides / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D011990:Receptors, Transferrin / Q000276:immunology; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D005456:Fluorescent Dyes; D009842:Oligopeptides; D011990:Receptors, Transferrin; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D011092:Polyethylene Glycols; D048271:Chitosan; C505409:Casp3 protein, mouse; D053148:Caspase 3