Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier

Autores
Pascual-Pasto, Guillem; Olaciregui, Nagore G.; Opezzo, Javier A. W.; Castillo Ecija, Helena; Cuadrado Vilanova, Maria; Paco, Sonia; Rivero, Ezequiel Mariano; Vila Ubach, Monica; Restrepo Perdomo, Camilo A.; Torrebadell, Montserrat; Suñol, Mariona; Schaiquevich, Paula Susana; Mora, Jaume; Bramuglia, Guillermo Federico; Chantada, Guillermo Luis; Carcaboso, Angel M.
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P = 0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P = 0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.
Fil: Pascual-Pasto, Guillem. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Olaciregui, Nagore G.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Castillo Ecija, Helena. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Cuadrado Vilanova, Maria. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Paco, Sonia. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Rivero, Ezequiel Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Vila Ubach, Monica. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Restrepo Perdomo, Camilo A.. Hospital Sant Joan de Deu Barcelona; España
Fil: Torrebadell, Montserrat. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; España
Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Carcaboso, Angel M.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Materia
ABC TRANSPORTERS
ABCB1/P-GP
ABCG2/BCRP
BCRP
BLOOD-RETINAL BARRIER
DELIVERY
DISTRIBUTION
MICRODIALYSIS
P-GP
PANTOPRAZOLE
PEDIATRIC CANCER
RABBIT
RETINA
RETINOBLASTOMA
TOPOTECAN
VITREOUS
XENOGRAFT
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/85225
Acceder
id CONICETDig_6da335314b437802459eff6147ba40ab
oai_identifier_str oai:ri.conicet.gov.ar:11336/85225
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrierPascual-Pasto, GuillemOlaciregui, Nagore G.Opezzo, Javier A. W.Castillo Ecija, HelenaCuadrado Vilanova, MariaPaco, SoniaRivero, Ezequiel MarianoVila Ubach, MonicaRestrepo Perdomo, Camilo A.Torrebadell, MontserratSuñol, MarionaSchaiquevich, Paula SusanaMora, JaumeBramuglia, Guillermo FedericoChantada, Guillermo LuisCarcaboso, Angel M.ABC TRANSPORTERSABCB1/P-GPABCG2/BCRPBCRPBLOOD-RETINAL BARRIERDELIVERYDISTRIBUTIONMICRODIALYSISP-GPPANTOPRAZOLEPEDIATRIC CANCERRABBITRETINARETINOBLASTOMATOPOTECANVITREOUSXENOGRAFThttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P = 0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P = 0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.Fil: Pascual-Pasto, Guillem. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Olaciregui, Nagore G.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Castillo Ecija, Helena. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Cuadrado Vilanova, Maria. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Paco, Sonia. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Rivero, Ezequiel Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vila Ubach, Monica. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Restrepo Perdomo, Camilo A.. Hospital Sant Joan de Deu Barcelona; EspañaFil: Torrebadell, Montserrat. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Carcaboso, Angel M.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaElsevier Science2017-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85225Pascual-Pasto, Guillem; Olaciregui, Nagore G.; Opezzo, Javier A. W.; Castillo Ecija, Helena; Cuadrado Vilanova, Maria; et al.; Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier; Elsevier Science; Journal of Controlled Release; 264; 10-2017; 34-440168-3659CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.jconrel.2017.08.018info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S016836591730785Xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:02:48Zoai:ri.conicet.gov.ar:11336/85225instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:02:49.105CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
title Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
spellingShingle Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
Pascual-Pasto, Guillem
ABC TRANSPORTERS
ABCB1/P-GP
ABCG2/BCRP
BCRP
BLOOD-RETINAL BARRIER
DELIVERY
DISTRIBUTION
MICRODIALYSIS
P-GP
PANTOPRAZOLE
PEDIATRIC CANCER
RABBIT
RETINA
RETINOBLASTOMA
TOPOTECAN
VITREOUS
XENOGRAFT
title_short Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
title_full Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
title_fullStr Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
title_full_unstemmed Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
title_sort Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier
dc.creator.none.fl_str_mv Pascual-Pasto, Guillem
Olaciregui, Nagore G.
Opezzo, Javier A. W.
Castillo Ecija, Helena
Cuadrado Vilanova, Maria
Paco, Sonia
Rivero, Ezequiel Mariano
Vila Ubach, Monica
Restrepo Perdomo, Camilo A.
Torrebadell, Montserrat
Suñol, Mariona
Schaiquevich, Paula Susana
Mora, Jaume
Bramuglia, Guillermo Federico
Chantada, Guillermo Luis
Carcaboso, Angel M.
author Pascual-Pasto, Guillem
author_facet Pascual-Pasto, Guillem
Olaciregui, Nagore G.
Opezzo, Javier A. W.
Castillo Ecija, Helena
Cuadrado Vilanova, Maria
Paco, Sonia
Rivero, Ezequiel Mariano
Vila Ubach, Monica
Restrepo Perdomo, Camilo A.
Torrebadell, Montserrat
Suñol, Mariona
Schaiquevich, Paula Susana
Mora, Jaume
Bramuglia, Guillermo Federico
Chantada, Guillermo Luis
Carcaboso, Angel M.
author_role author
author2 Olaciregui, Nagore G.
Opezzo, Javier A. W.
Castillo Ecija, Helena
Cuadrado Vilanova, Maria
Paco, Sonia
Rivero, Ezequiel Mariano
Vila Ubach, Monica
Restrepo Perdomo, Camilo A.
Torrebadell, Montserrat
Suñol, Mariona
Schaiquevich, Paula Susana
Mora, Jaume
Bramuglia, Guillermo Federico
Chantada, Guillermo Luis
Carcaboso, Angel M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ABC TRANSPORTERS
ABCB1/P-GP
ABCG2/BCRP
BCRP
BLOOD-RETINAL BARRIER
DELIVERY
DISTRIBUTION
MICRODIALYSIS
P-GP
PANTOPRAZOLE
PEDIATRIC CANCER
RABBIT
RETINA
RETINOBLASTOMA
TOPOTECAN
VITREOUS
XENOGRAFT
topic ABC TRANSPORTERS
ABCB1/P-GP
ABCG2/BCRP
BCRP
BLOOD-RETINAL BARRIER
DELIVERY
DISTRIBUTION
MICRODIALYSIS
P-GP
PANTOPRAZOLE
PEDIATRIC CANCER
RABBIT
RETINA
RETINOBLASTOMA
TOPOTECAN
VITREOUS
XENOGRAFT
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P = 0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P = 0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.
Fil: Pascual-Pasto, Guillem. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Olaciregui, Nagore G.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Castillo Ecija, Helena. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Cuadrado Vilanova, Maria. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Paco, Sonia. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Rivero, Ezequiel Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Vila Ubach, Monica. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Restrepo Perdomo, Camilo A.. Hospital Sant Joan de Deu Barcelona; España
Fil: Torrebadell, Montserrat. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; España
Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
Fil: Carcaboso, Angel M.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; España
description Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P = 0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P = 0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.
publishDate 2017
dc.date.none.fl_str_mv 2017-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/85225
Pascual-Pasto, Guillem; Olaciregui, Nagore G.; Opezzo, Javier A. W.; Castillo Ecija, Helena; Cuadrado Vilanova, Maria; et al.; Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier; Elsevier Science; Journal of Controlled Release; 264; 10-2017; 34-44
0168-3659
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85225
identifier_str_mv Pascual-Pasto, Guillem; Olaciregui, Nagore G.; Opezzo, Javier A. W.; Castillo Ecija, Helena; Cuadrado Vilanova, Maria; et al.; Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier; Elsevier Science; Journal of Controlled Release; 264; 10-2017; 34-44
0168-3659
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jconrel.2017.08.018
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S016836591730785X
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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