Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells

The gut microbial-derived metabolites of ellagitannins and ellagic acid, urolithins (Uros) are well-established anti-cancer metabolites according to preclinical studies. However, their efficacy is limited in systemic tissues, including the brain, by phase-II metabolism. Exosomes (EXOs), extracellula...

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Autores: Ávila-Gálvez, María Ángeles, Romero-Reyes, Salvador, López de las Hazas, María del Carmen, del Saz-Lara, Andrea, Dávalos, Alberto, Espín de Gea, Juan Carlos, González-Sarrías, Antonio
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2024
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/392688
Acesso em linha:http://hdl.handle.net/10261/392688
https://api.elsevier.com/content/abstract/scopus_id/85200568170
Access Level:Acceso aberto
Palavra-chave:Apoptosis | Brain cancer | Exosome | Nanocarrier | Perfused brain | Polyphenol | Urolithins
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spelling Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cellsÁvila-Gálvez, María ÁngelesRomero-Reyes, SalvadorLópez de las Hazas, María del Carmendel Saz-Lara, AndreaDávalos, AlbertoEspín de Gea, Juan CarlosGonzález-Sarrías, AntonioApoptosis | Brain cancer | Exosome | Nanocarrier | Perfused brain | Polyphenol | UrolithinsThe gut microbial-derived metabolites of ellagitannins and ellagic acid, urolithins (Uros) are well-established anti-cancer metabolites according to preclinical studies. However, their efficacy is limited in systemic tissues, including the brain, by phase-II metabolism. Exosomes (EXOs), extracellular vesicles involved in cell signaling with the ability to cross the blood-brain barrier (BBB), could protect polyphenols from metabolism. Therefore, we loaded milk EXOs with Uro-A, Uro-B or IsoUro-A to evaluate their brain delivery and anticancer effects compared to non-encapsulated Uros. In Sprague-Dawley rats, perfused brain tissue analyses by UPLC-ESI-QTOF-MS showed higher Uro levels (∼3−4-fold) at 5 min following intravenous administration of EXO-Uros compared to non-encapsulated Uros, except for Uro-B, using similar Uro concentrations (17−30 μM). Experiments on neuroblastoma SH-SY5Y cells revealed dose-dependent antiproliferative effects for all EXO-Uros (0.3−1.2 μM), but not with non-encapsulated Uros (10 μM). Flow cytometry analyses indicated that only EXO-Uros arrested the cell cycle and induced apoptosis. Finally, using fluorescent-labeled EXOs and selective inhibitors, the primary endocytic pathway was revealed to be clathrin-dependent. Overall, encapsulating Uros into EXOs is promising for enhancing brain delivery and anticancer activity.This work was supported by the by the grants TED 2021-130962B–C21 and TED 2021-130962B–C22 funded by MICIU/AEI/10.13039/501100011033 and by the “European Union” or by the “European Union NextGenerationEU/PRTR”, PID 2022-136419OB-I00, and PID 2022-143100OB-I00 funded by MICIU/AEI/10.13039/501100011033 and “ERDF A way of making Europe”, the grant 22030/PI/22 funded by the Programa Regional de Fomento de la Investigación Científica y Técnica (Plan de Actuación 2022) de la Fundación Séneca-Agencia de Ciencia y Tecnología de la Región de Murcia (Murcia, Spain), and the AGROALNEXT program supported by MCIN with funding from the European Union NextGenerationEU (PRTR-C17. I1) and Fundación Séneca. M.C.L.-H. is a recipient of a Juan de la Cierva Grant IJC 2020-044353-/MCIN/AEI/10.13039/501100011033/EU/PRTR. A.S.-L. is supported by a predoctoral fellowship (Nº 2021–01- PhD GRANT) from the International Olive Council. CIBEROBN (CB22/03/00068) is an initiative of the Instituto de Salud Carlos III, SpainPeer reviewedElsevierEspín de Gea, Juan Carlos [0000-0002-1068-8692]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/392688https://api.elsevier.com/content/abstract/scopus_id/85200568170reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésFood Biosciencehttps://doi.org/10.1016/j.fbio.2024.104888Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3926882026-05-22T06:33:51Z
dc.title.none.fl_str_mv Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
title Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
spellingShingle Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
Ávila-Gálvez, María Ángeles
Apoptosis | Brain cancer | Exosome | Nanocarrier | Perfused brain | Polyphenol | Urolithins
title_short Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
title_full Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
title_fullStr Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
title_full_unstemmed Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
title_sort Loading milk exosomes with urolithins boosts their delivery to the brain: Comparing the activity of encapsulated vs. free urolithins in SH-SY5Y neuroblastoma cells
dc.creator.none.fl_str_mv Ávila-Gálvez, María Ángeles
Romero-Reyes, Salvador
López de las Hazas, María del Carmen
del Saz-Lara, Andrea
Dávalos, Alberto
Espín de Gea, Juan Carlos
González-Sarrías, Antonio
author Ávila-Gálvez, María Ángeles
author_facet Ávila-Gálvez, María Ángeles
Romero-Reyes, Salvador
López de las Hazas, María del Carmen
del Saz-Lara, Andrea
Dávalos, Alberto
Espín de Gea, Juan Carlos
González-Sarrías, Antonio
author_role author
author2 Romero-Reyes, Salvador
López de las Hazas, María del Carmen
del Saz-Lara, Andrea
Dávalos, Alberto
Espín de Gea, Juan Carlos
González-Sarrías, Antonio
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Espín de Gea, Juan Carlos [0000-0002-1068-8692]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Apoptosis | Brain cancer | Exosome | Nanocarrier | Perfused brain | Polyphenol | Urolithins
topic Apoptosis | Brain cancer | Exosome | Nanocarrier | Perfused brain | Polyphenol | Urolithins
description The gut microbial-derived metabolites of ellagitannins and ellagic acid, urolithins (Uros) are well-established anti-cancer metabolites according to preclinical studies. However, their efficacy is limited in systemic tissues, including the brain, by phase-II metabolism. Exosomes (EXOs), extracellular vesicles involved in cell signaling with the ability to cross the blood-brain barrier (BBB), could protect polyphenols from metabolism. Therefore, we loaded milk EXOs with Uro-A, Uro-B or IsoUro-A to evaluate their brain delivery and anticancer effects compared to non-encapsulated Uros. In Sprague-Dawley rats, perfused brain tissue analyses by UPLC-ESI-QTOF-MS showed higher Uro levels (∼3−4-fold) at 5 min following intravenous administration of EXO-Uros compared to non-encapsulated Uros, except for Uro-B, using similar Uro concentrations (17−30 μM). Experiments on neuroblastoma SH-SY5Y cells revealed dose-dependent antiproliferative effects for all EXO-Uros (0.3−1.2 μM), but not with non-encapsulated Uros (10 μM). Flow cytometry analyses indicated that only EXO-Uros arrested the cell cycle and induced apoptosis. Finally, using fluorescent-labeled EXOs and selective inhibitors, the primary endocytic pathway was revealed to be clathrin-dependent. Overall, encapsulating Uros into EXOs is promising for enhancing brain delivery and anticancer activity.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/392688
https://api.elsevier.com/content/abstract/scopus_id/85200568170
url http://hdl.handle.net/10261/392688
https://api.elsevier.com/content/abstract/scopus_id/85200568170
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Food Bioscience
https://doi.org/10.1016/j.fbio.2024.104888
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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