Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación

La neuroinflamación crónica se caracteriza por un aumento de la permeabilidad de la barrera hematoencefálica (BHE), lo que provoca cambios moleculares en el sistema nervioso central (SNC) que pueden explorarse con biomarcadores de procesos neuroinflamatorios activos. En este contexto la resonancia m...

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Fecha de publicación:: 2024

Institución:: Universidad del Rosario

Repositorio:: Repositorio EdocUR - U. Rosario

Idioma:: spa

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network_acronym_str	EDOCUR2
network_name_str	Repositorio EdocUR - U. Rosario
repository_id_str
dc.title.none.fl_str_mv	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
dc.title.TranslatedTitle.none.fl_str_mv	Validation of peptide conjugated to magnetic iron oxide nanoparticles as a biomarker of molecular changes in the blood-brain barrier under neuroinflammation conditions
title	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
spellingShingle	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación Neuroinflamación Barrera hematoencefálica Nanosondas Resonancia magnética Laminina Nanopartículas de óxido de hierro Neuroinflammation Blood brain barrier Nanoprobe Magnetic resonance Laminin Iron oxide nanoparticles
title_short	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
title_full	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
title_fullStr	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
title_full_unstemmed	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
title_sort	Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación
dc.contributor.advisor.none.fl_str_mv	González Reyes, Rodrigo Esteban Vargas Sánchez, Jeinny Karina
dc.contributor.gruplac.none.fl_str_mv	Grupo de Neurociencias de la Universidad del Rosario (NEUROS)
dc.subject.none.fl_str_mv	Neuroinflamación Barrera hematoencefálica Nanosondas Resonancia magnética Laminina Nanopartículas de óxido de hierro
topic	Neuroinflamación Barrera hematoencefálica Nanosondas Resonancia magnética Laminina Nanopartículas de óxido de hierro Neuroinflammation Blood brain barrier Nanoprobe Magnetic resonance Laminin Iron oxide nanoparticles
dc.subject.keyword.none.fl_str_mv	Neuroinflammation Blood brain barrier Nanoprobe Magnetic resonance Laminin Iron oxide nanoparticles
description	La neuroinflamación crónica se caracteriza por un aumento de la permeabilidad de la barrera hematoencefálica (BHE), lo que provoca cambios moleculares en el sistema nervioso central (SNC) que pueden explorarse con biomarcadores de procesos neuroinflamatorios activos. En este contexto la resonancia magnética nuclear (RMN) ha sido una herramienta clave para detectar tanto las lesiones como la permeabilidad de la BHE. Además, el uso de nanopartículas superparamagnéticas ultrapequeñas de óxido de hierro (USPIO) como agentes de contraste ha permitido mejorar la resolución y precisión de estas observaciones por RMN. Por lo tanto, en esta tesis doctoral se evaluó la interacción del péptido-88 con laminina, mediante la vectorización del péptido 88 con USPIO (NPS-P88), para explorar las alteraciones moleculares de la BHE que ocurren durante la neuroinflamación como una herramienta potencial para su uso en RMN. Para verificar el marcaje específico de NPS-P88 se realizaron experimentos en células endoteliales (hCMEC/D3) y astrocitos (T98G) bajo inflamación inducida por IL-1β durante 3 y 24 horas. En células hCMEC/D3 tratadas con IL-1β durante 3 horas, se observó un aumentó de expresión y colocalización de la laminina con las NPS-P88, en comparación con los controles. Sin embargo, a las 24 horas no se observaron diferencias significativas entre los grupos control y células hCMEC/D3 con IL-1β. Por otro lado, en las células T98G, las NPS-P88 mostraron un etiquetado inespecífico similar al observado en los controles. Estos resultados sugieren que NPS-P88 tiene una mayor afinidad por las células endoteliales cerebrales que por los astrocitos en condiciones de inflamación. Aunque esta afinidad disminuye con el tiempo a medida que la expresión de la laminina se reduce. Los resultados in vivo indicaron que, 30 minutos después de la inyección de las nanosondas, hay una mayor presencia de NPS-P88 en la sangre y el cerebro, pero que disminuye progresivamente con el tiempo. Además, la síntesis de las USPIO por un segundo método permitió obtener nanopartículas con una mayor estabilidad, biocompatibilidad y biodistribución lo que prolongó su permanencia en sangre. En modelos de neuroinflamación animal inducida por LPS por 24 horas se observó un aumento de expresión de la laminina en cerebro durante procesos inflamatorios, lo que se correlaciona con una mayor presencia de NPS-P88. Asimismo, se confirmó una comarcación de la laminina/NPS-P88 en cerebro. En contraste, en médula se encontró una baja presencia de NPS-P88, sin cambios significativos en la expresión de laminina ni comarcación laminina/NPS-P88. Finalmente, en los animales EAE, la RMN reveló una acumulación significativa de NPS-P88 principalmente en la corteza, atribuida a la inflamación y la alteración de la BHE. En conjunto, estos resultados demuestran que NPS-P88 es un biomarcador para evaluar los cambios en la BHE inducidos por la neuroinflamación mediante RMN en modelos biológicos dirigidos a la laminina.
publishDate	2024
dc.date.created.none.fl_str_mv	2024-12-04
dc.date.accessioned.none.fl_str_mv	2025-02-25T15:14:04Z
dc.date.available.none.fl_str_mv	2025-02-25T15:14:04Z
dc.date.embargoEnd.none.fl_str_mv	info:eu-repo/date/embargoEnd/2027-02-28
dc.type.none.fl_str_mv	doctoralThesis
dc.type.coar.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.spa.none.fl_str_mv	Tesis de doctorado
dc.identifier.uri.none.fl_str_mv	https://repository.urosario.edu.co/handle/10336/45030
url	https://repository.urosario.edu.co/handle/10336/45030
dc.language.iso.none.fl_str_mv	spa
language	spa
dc.rights.*.fl_str_mv	Attribution-NonCommercial-ShareAlike 4.0 International
dc.rights.coar.fl_str_mv	http://purl.org/coar/access_right/c_f1cf
dc.rights.acceso.none.fl_str_mv	Restringido (Temporalmente bloqueado)
dc.rights.uri.*.fl_str_mv	http://creativecommons.org/licenses/by-nc-sa/4.0/
rights_invalid_str_mv	Attribution-NonCommercial-ShareAlike 4.0 International Restringido (Temporalmente bloqueado) http://creativecommons.org/licenses/by-nc-sa/4.0/ http://purl.org/coar/access_right/c_f1cf
dc.format.extent.none.fl_str_mv	465 pp
dc.format.mimetype.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Universidad del Rosario
dc.publisher.department.none.fl_str_mv	Escuela de Medicina y Ciencias de la Salud
dc.publisher.program.none.fl_str_mv	Doctorado en Ciencias Biomédicas y Biológicas
publisher.none.fl_str_mv	Universidad del Rosario
institution	Universidad del Rosario
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spelling	González Reyes, Rodrigo Estebanafba3445-a398-49cf-bfda-b11a9e1f1409-1Vargas Sánchez, Jeinny Karina83efbd53-c3ba-43f2-ba6d-9898ef8f4d84-1Grupo de Neurociencias de la Universidad del Rosario (NEUROS)Zapata Acevedo, Juan FelipeDoctor en Ciencias Biomédicas y BiológicasDoctorado0c9293bb-218d-42b0-8b38-d03e0de01885-12025-02-25T15:14:04Z2025-02-25T15:14:04Z2024-12-04info:eu-repo/date/embargoEnd/2027-02-28La neuroinflamación crónica se caracteriza por un aumento de la permeabilidad de la barrera hematoencefálica (BHE), lo que provoca cambios moleculares en el sistema nervioso central (SNC) que pueden explorarse con biomarcadores de procesos neuroinflamatorios activos. En este contexto la resonancia magnética nuclear (RMN) ha sido una herramienta clave para detectar tanto las lesiones como la permeabilidad de la BHE. Además, el uso de nanopartículas superparamagnéticas ultrapequeñas de óxido de hierro (USPIO) como agentes de contraste ha permitido mejorar la resolución y precisión de estas observaciones por RMN. Por lo tanto, en esta tesis doctoral se evaluó la interacción del péptido-88 con laminina, mediante la vectorización del péptido 88 con USPIO (NPS-P88), para explorar las alteraciones moleculares de la BHE que ocurren durante la neuroinflamación como una herramienta potencial para su uso en RMN. Para verificar el marcaje específico de NPS-P88 se realizaron experimentos en células endoteliales (hCMEC/D3) y astrocitos (T98G) bajo inflamación inducida por IL-1β durante 3 y 24 horas. En células hCMEC/D3 tratadas con IL-1β durante 3 horas, se observó un aumentó de expresión y colocalización de la laminina con las NPS-P88, en comparación con los controles. Sin embargo, a las 24 horas no se observaron diferencias significativas entre los grupos control y células hCMEC/D3 con IL-1β. Por otro lado, en las células T98G, las NPS-P88 mostraron un etiquetado inespecífico similar al observado en los controles. Estos resultados sugieren que NPS-P88 tiene una mayor afinidad por las células endoteliales cerebrales que por los astrocitos en condiciones de inflamación. Aunque esta afinidad disminuye con el tiempo a medida que la expresión de la laminina se reduce. Los resultados in vivo indicaron que, 30 minutos después de la inyección de las nanosondas, hay una mayor presencia de NPS-P88 en la sangre y el cerebro, pero que disminuye progresivamente con el tiempo. Además, la síntesis de las USPIO por un segundo método permitió obtener nanopartículas con una mayor estabilidad, biocompatibilidad y biodistribución lo que prolongó su permanencia en sangre. En modelos de neuroinflamación animal inducida por LPS por 24 horas se observó un aumento de expresión de la laminina en cerebro durante procesos inflamatorios, lo que se correlaciona con una mayor presencia de NPS-P88. Asimismo, se confirmó una comarcación de la laminina/NPS-P88 en cerebro. En contraste, en médula se encontró una baja presencia de NPS-P88, sin cambios significativos en la expresión de laminina ni comarcación laminina/NPS-P88. Finalmente, en los animales EAE, la RMN reveló una acumulación significativa de NPS-P88 principalmente en la corteza, atribuida a la inflamación y la alteración de la BHE. En conjunto, estos resultados demuestran que NPS-P88 es un biomarcador para evaluar los cambios en la BHE inducidos por la neuroinflamación mediante RMN en modelos biológicos dirigidos a la laminina.Chronic neuroinflammation is characterized by an increase in the permeability of the blood-brain barrier (BBB), leading to molecular changes in the central nervous system (CNS) that can be explored with biomarkers of active neuroinflammatory processes. In this context, nuclear magnetic resonance (MRI) has been a key tool to detect both lesions and BBB permeability. Furthermore, the use of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) as contrast agents has allowed to improve the resolution and precision of these MRI observations. Therefore, in this PhD thesis, the interaction of peptide-88 with laminin was evaluated, by vectoring peptide-88 with USPIO (NPS-P88), to explore the molecular alterations of the BBB that occur during neuroinflammation as a potential tool for use in MRI. To verify the specific labeling of NPS-P88, experiments were performed in endothelial cells (hCMEC/D3) and astrocytes (T98G) under IL-1β-induced inflammation for 3 and 24 hours. In hCMEC/D3 cells treated with IL-1β for 3 hours, an increase in expression and co-localization of laminin with NPS-P88 was observed, compared to controls. However, at 24 hours, no significant differences were observed between the control groups and hCMEC/D3 cells with IL-1β. On the other hand, in T98G cells, NPS-P88 showed a non-specific labeling similar to that observed in controls. These results suggest that NPS-P88 has a higher affinity for brain endothelial cells than for astrocytes under inflammatory conditions. Although this affinity decreases over time as laminin expression is reduced. In vivo results indicated that 30 minutes after nanoprobes injection, there is a higher presence of NPS-P88 in the blood and brain, but that it progressively decreases over time. In addition, the synthesis of USPIOs by a second method allowed obtaining nanoparticles with greater stability, biocompatibility and biodistribution, which prolonged their permanence in blood. In animal models of neuroinflammation induced by LPS for 24 hours, an increase in laminin expression was observed in the brain during inflammatory processes, which correlates with a higher presence of NPS-P88. Likewise, a laminin/NPS-P88 co-marking was confirmed in the brain. In contrast, a low presence of NPS-P88 was found in the bone marrow, with no significant changes in laminin expression or laminin/NPS-P88 co-marking. Finally, in EAE animals, MRI revealed a significant accumulation of NPS-P88 mainly in the cortex, attributed to inflammation and BBB disruption. 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Adv Drug Deliv Rev. 2019 Jan 1;138:302–25.instname:Universidad del Rosarioreponame:Repositorio Institucional EdocURNeuroinflamaciónBarrera hematoencefálicaNanosondasResonancia magnéticaLamininaNanopartículas de óxido de hierroNeuroinflammationBlood brain barrierNanoprobeMagnetic resonanceLamininIron oxide nanoparticlesValidación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamaciónValidation of peptide conjugated to magnetic iron oxide nanoparticles as a biomarker of molecular changes in the blood-brain barrier under neuroinflammation conditionsdoctoralThesisTesis de doctoradohttp://purl.org/coar/resource_type/c_db06Escuela de Medicina y Ciencias de la SaludBogotáORIGINALValidacion_de_peptido_conjugado_a_nanoparticulas_magneticas_de_oxido_de_hierro_JuanFelipeZapataA.pdfValidacion_de_peptido_conjugado_a_nanoparticulas_magneticas_de_oxido_de_hierro_JuanFelipeZapataA.pdfapplication/pdf14603028https://repository.urosario.edu.co/bitstreams/8f8b5d85-cc42-4799-9304-b67dab9f360f/downloadd70e68c4e5ac2ce00dbe31f1c48a2c4eMD51LICENSElicense.txtlicense.txttext/plain1483https://repository.urosario.edu.co/bitstreams/86951c56-9d85-4116-8261-c30aa8b95b7b/downloadb2825df9f458e9d5d96ee8b7cd74fde6MD52CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-81160https://repository.urosario.edu.co/bitstreams/eeb45942-7468-4499-ac66-9cdadf4423ab/download5643bfd9bcf29d560eeec56d584edaa9MD53TEXTValidacion_de_peptido_conjugado_a_nanoparticulas_magneticas_de_oxido_de_hierro_JuanFelipeZapataA.pdf.txtValidacion_de_peptido_conjugado_a_nanoparticulas_magneticas_de_oxido_de_hierro_JuanFelipeZapataA.pdf.txtExtracted texttext/plain107803https://repository.urosario.edu.co/bitstreams/3d0c7027-ba3a-43d0-ae40-6b2becdd6a06/downloade3f0f9067586e4415aeb55883213a797MD54THUMBNAILValidacion_de_peptido_conjugado_a_nanoparticulas_magneticas_de_oxido_de_hierro_JuanFelipeZapataA.pdf.jpgValidacion_de_peptido_conjugado_a_nanoparticulas_magneticas_de_oxido_de_hierro_JuanFelipeZapataA.pdf.jpgGenerated Thumbnailimage/jpeg2974https://repository.urosario.edu.co/bitstreams/2d472919-269f-4915-8579-901d31eb70ca/download5b1d497d6c98668b58414e7496c09160MD5510336/45030oai:repository.urosario.edu.co:10336/450302025-02-28 13:02:00.309http://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 Internationalhttps://repository.urosario.edu.coRepositorio institucional EdocURedocur@urosario.edu.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

Validación de péptido conjugado a nanopartículas magnéticas de óxido de hierro como biomarcador de cambios moleculares en la barrera hematoencefálica bajo condiciones de neuroinflamación

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