Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases

Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targ...

Descripción completa

Detalles Bibliográficos
Autores: Solomon, Melani, Loeck, Maximilian, Silva Abreu, Marcelle, Moscoso, Ronaldo, Bautista, Ronelle, Vigo, Marco, Muro, Silvia
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/200976
Acceso en línea:https://hdl.handle.net/2445/200976
Access Level:acceso abierto
Palabra clave:Lisosomes
Barrera hematoencefàlica
Lysosomes
Blood-brain barrier
id ES_ce8ecd5e87d187635a92bcb837423e8d
oai_identifier_str oai:recercat.cat:2445/200976
network_acronym_str ES
network_name_str España
repository_id_str
spelling Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseasesSolomon, MelaniLoeck, MaximilianSilva Abreu, MarcelleMoscoso, RonaldoBautista, RonelleVigo, MarcoMuro, SilviaLisosomesBarrera hematoencefàlicaLysosomesBlood-brain barrierTreatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.Copyright © 2022 Elsevier B.V. All rights reserved.Elsevier2023202320222023info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion46 p.application/pdfhttps://hdl.handle.net/2445/200976Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1016/j.jconrel.2022.07.022Journal Of Controlled Release, 2022, vol. 349, p. 1031-1044https://doi.org/10.1016/j.jconrel.2022.07.022cc by-nc-nd (c) Elsevier, 2022http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2009762026-05-29T05:05:01Z
dc.title.none.fl_str_mv Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
title Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
spellingShingle Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
Solomon, Melani
Lisosomes
Barrera hematoencefàlica
Lysosomes
Blood-brain barrier
title_short Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
title_full Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
title_fullStr Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
title_full_unstemmed Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
title_sort Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
dc.creator.none.fl_str_mv Solomon, Melani
Loeck, Maximilian
Silva Abreu, Marcelle
Moscoso, Ronaldo
Bautista, Ronelle
Vigo, Marco
Muro, Silvia
author Solomon, Melani
author_facet Solomon, Melani
Loeck, Maximilian
Silva Abreu, Marcelle
Moscoso, Ronaldo
Bautista, Ronelle
Vigo, Marco
Muro, Silvia
author_role author
author2 Loeck, Maximilian
Silva Abreu, Marcelle
Moscoso, Ronaldo
Bautista, Ronelle
Vigo, Marco
Muro, Silvia
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Lisosomes
Barrera hematoencefàlica
Lysosomes
Blood-brain barrier
topic Lisosomes
Barrera hematoencefàlica
Lysosomes
Blood-brain barrier
description Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.Copyright © 2022 Elsevier B.V. All rights reserved.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/200976
url https://hdl.handle.net/2445/200976
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.jconrel.2022.07.022
Journal Of Controlled Release, 2022, vol. 349, p. 1031-1044
https://doi.org/10.1016/j.jconrel.2022.07.022
dc.rights.none.fl_str_mv cc by-nc-nd (c) Elsevier, 2022
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Elsevier, 2022
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 46 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869420002104311808
score 15,811543

Similares en LA Referencia