title: Use of LDL receptor-targeting peptide vectors forin vitroandin vivocargo transport across the blood-brain barrier.
abstract: The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study,in vitroBBB models that were derived from wild-type and LDLR-knockout animals (ldlr-/-) were used to validate the specific LDLR-dependent transcytosis of LDLviaa nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayersviathe same route as LDL. Finally, we demonstratedin vivothat LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug deliveryviareceptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors forin vitroandin vivocargo transport across the blood-brain barrier.
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Molino
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Marion
authors.initials: M
authors.lastname: David
authors.affiliation: Aix Marseille Université, Centre National de la Recherche Scientifique, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, Marseille, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Varini
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Françoise
authors.initials: F
authors.lastname: Jabès
authors.affiliation: Aix Marseille Université, Centre National de la Recherche Scientifique, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gaudin
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Aude
authors.initials: A
authors.lastname: Fortoul
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Karima
authors.initials: K
authors.lastname: Bakloul
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Maxime
authors.initials: M
authors.lastname: Masse
authors.affiliation: Aix Marseille Université, Centre National de la Recherche Scientifique, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bernard
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Lucile
authors.initials: L
authors.lastname: Drobecq
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Lécorché
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Jamal
authors.initials: J
authors.lastname: Temsamani
authors.affiliation: Vect-Horus S.A.S., Faculté de Médecine, Marseille, France; and.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquot
authors.affiliation: Aix Marseille Université, Centre National de la Recherche Scientifique, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, Marseille, France michel.khrestchatisky@univ-amu.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D051379:Mice; D051381:Rats; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000906:Antibodies; C573412:LDLR protein, human; D011973:Receptors, LDL
keywords: CNS drug delivery; endosome; intracellular trafficking; lysosome; receptor-mediated transcytosis