Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies

Detalhes bibliográficos
Autor(a) principal: Prata, M. I. M.
Data de Publicação: 2006
Outros Autores: Santos, A. C., Torres, Susana, André, João P., Martins, J. A. R., Neves, M., García Martín, M. L., Rodrigues, T. B., López Larrubia, P., Cerdán, S., Geraldes, Carlos F. G. C.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/1822/5960
Resumo: The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [153Sm]3+ or Gd3+ complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled 153SmDOTAGal2 by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50 % by the presence of its high affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmaco-kinetic studies on Wistar rats using the [153Sm]3+-radiolabeled conjugates show an high uptake in the receptor-rich organ liver of the compounds containing terminal galactosyl groups, but very little uptake for those with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd3+ chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. The maximum concentration/dose ratio attained in the kidneys by the Gd3+- based CAs is considerably lower than for GdDTPA, indicating that part of the injected CAs is T1 contrast-silent, presumably when taken up into the liver. The T1 shortening effect of the Gd3+-labeled Gal-containing compounds is probably strongly diminished upon hepatocyte internalization into an endossomic vesicle via receptor-mediated endocytosis of the ASGP-R.
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spelling Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studiesMagnetic resonance imagingContrast agentsGadoliniumGlycoconjugatesLiver targetingAsialoglycoprotein receptorGamma imaginggamma scintigraphyScience & TechnologyThe characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [153Sm]3+ or Gd3+ complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled 153SmDOTAGal2 by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50 % by the presence of its high affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmaco-kinetic studies on Wistar rats using the [153Sm]3+-radiolabeled conjugates show an high uptake in the receptor-rich organ liver of the compounds containing terminal galactosyl groups, but very little uptake for those with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd3+ chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. The maximum concentration/dose ratio attained in the kidneys by the Gd3+- based CAs is considerably lower than for GdDTPA, indicating that part of the injected CAs is T1 contrast-silent, presumably when taken up into the liver. The T1 shortening effect of the Gd3+-labeled Gal-containing compounds is probably strongly diminished upon hepatocyte internalization into an endossomic vesicle via receptor-mediated endocytosis of the ASGP-R.Fundação para a Ciência e Tecnologia (FCT) -POCTI/QUI/47005/2002.III Instituto de Investigação Interdisciplinar University of Coimbra - III/BIO/45/2005.Institut of Health Carlos III (Spain) - PIO051845.FEDER.WileyUniversidade do MinhoPrata, M. I. M.Santos, A. C.Torres, SusanaAndré, João P.Martins, J. A. R.Neves, M.García Martín, M. L.Rodrigues, T. B.López Larrubia, P.Cerdán, S.Geraldes, Carlos F. G. C.2006-122006-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/1822/5960eng"Contrast Media & Molecular Imaging". ISSN 1555-4309.1 (2006) 246-258.1555-430910.1002/cmmi.111http://www3.interscience.wiley.com/cgi-bin/fulltext/113411803/PDFSTARTwww.interscience.wiley.cominfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T11:55:16Zoai:repositorium.sdum.uminho.pt:1822/5960Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:44:48.411258Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
title Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
spellingShingle Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
Prata, M. I. M.
Magnetic resonance imaging
Contrast agents
Gadolinium
Glycoconjugates
Liver targeting
Asialoglycoprotein receptor
Gamma imaging
gamma scintigraphy
Science & Technology
title_short Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
title_full Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
title_fullStr Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
title_full_unstemmed Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
title_sort Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies
author Prata, M. I. M.
author_facet Prata, M. I. M.
Santos, A. C.
Torres, Susana
André, João P.
Martins, J. A. R.
Neves, M.
García Martín, M. L.
Rodrigues, T. B.
López Larrubia, P.
Cerdán, S.
Geraldes, Carlos F. G. C.
author_role author
author2 Santos, A. C.
Torres, Susana
André, João P.
Martins, J. A. R.
Neves, M.
García Martín, M. L.
Rodrigues, T. B.
López Larrubia, P.
Cerdán, S.
Geraldes, Carlos F. G. C.
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade do Minho
dc.contributor.author.fl_str_mv Prata, M. I. M.
Santos, A. C.
Torres, Susana
André, João P.
Martins, J. A. R.
Neves, M.
García Martín, M. L.
Rodrigues, T. B.
López Larrubia, P.
Cerdán, S.
Geraldes, Carlos F. G. C.
dc.subject.por.fl_str_mv Magnetic resonance imaging
Contrast agents
Gadolinium
Glycoconjugates
Liver targeting
Asialoglycoprotein receptor
Gamma imaging
gamma scintigraphy
Science & Technology
topic Magnetic resonance imaging
Contrast agents
Gadolinium
Glycoconjugates
Liver targeting
Asialoglycoprotein receptor
Gamma imaging
gamma scintigraphy
Science & Technology
description The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [153Sm]3+ or Gd3+ complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled 153SmDOTAGal2 by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50 % by the presence of its high affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmaco-kinetic studies on Wistar rats using the [153Sm]3+-radiolabeled conjugates show an high uptake in the receptor-rich organ liver of the compounds containing terminal galactosyl groups, but very little uptake for those with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd3+ chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. The maximum concentration/dose ratio attained in the kidneys by the Gd3+- based CAs is considerably lower than for GdDTPA, indicating that part of the injected CAs is T1 contrast-silent, presumably when taken up into the liver. The T1 shortening effect of the Gd3+-labeled Gal-containing compounds is probably strongly diminished upon hepatocyte internalization into an endossomic vesicle via receptor-mediated endocytosis of the ASGP-R.
publishDate 2006
dc.date.none.fl_str_mv 2006-12
2006-12-01T00:00:00Z
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/1822/5960
url http://hdl.handle.net/1822/5960
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv "Contrast Media & Molecular Imaging". ISSN 1555-4309.1 (2006) 246-258.
1555-4309
10.1002/cmmi.111
http://www3.interscience.wiley.com/cgi-bin/fulltext/113411803/PDFSTART
www.interscience.wiley.com
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dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
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