title: Trafficking of Gold Nanoparticles Coated with the 8D3 Anti-Transferrin Receptor Antibody at the Mouse Blood-Brain Barrier.
abstract: Receptor-mediated transcytosis has been widely studied as a possible strategy to transport neurotherapeutics across the blood-brain barrier (BBB). Monoclonal antibodies directed against the transferrin receptor (TfR) have been proposed as potential carrier candidates. A better understanding of the mechanisms involved in their cellular uptake and intracellular trafficking is required and could critically contribute to the improvement of delivery methods. Accordingly, we studied here the trafficking of gold nanoparticles (AuNPs) coated with the 8D3 anti-transferrin receptor antibody at the mouse BBB. 8D3-AuNPs were intravenously administered to mice and allowed to recirculate for a range of times, from 10 min to 24 h, before brain extraction and analysis by transmission electron microscope techniques. Our results indicated a TfR-mediated and clathrin-dependent internalization process by which 8D3-AuNPs internalize individually in vesicles. These vesicles then follow at least two different routes. On one hand, most vesicles enter intracellular processes of vesicular fusion and rearrangement in which the AuNPs end up accumulating in late endosomes, multivesicular bodies or lysosomes, which present a high AuNP content. On the other hand, a small percentage of the vesicles follow a different route in which they fuse with the abluminal membrane and open to the basal membrane. In these cases, the 8D3-AuNPs remain attached to the abluminal membrane, which suggests an endosomal escape, but not dissociation from TfR. Altogether, although receptor-mediated transport continues to be one of the most promising strategies to overcome the BBB, different optimization approaches need to be developed for efficient drug delivery.
authors.affiliation: Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.|Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.
authors.forename: Itsaso
authors.initials: I
authors.lastname: Cabezón
authors.affiliation: Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Manich
authors.affiliation: Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Martín-Venegas
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.|Institut de Biomedicina (IBUB), Universitat de Barcelona , Barcelona, Spain.|CIBERNED Centros de Biomedicina en Red de Enfermedades Neurodegenerativas , 28031 Madrid, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.affiliation: Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.|CIBERNED Centros de Biomedicina en Red de Enfermedades Neurodegenerativas , 28031 Madrid, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Pelegrí
authors.affiliation: Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Spain.|CIBERNED Centros de Biomedicina en Red de Enfermedades Neurodegenerativas , 28031 Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Vilaplana
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D006046:Gold / Q000737:chemistry*; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008813:Mice, Inbred ICR; D021381:Protein Transport; D011990:Receptors, Transferrin / Q000276:immunology*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D011990:Receptors, Transferrin; D006046:Gold
keywords: blood−brain barrier; drug delivery; electron microscopy; monoclonal antibodies; receptor-mediated transport; transferrin receptor