Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening

Detalhes bibliográficos
Autor(a) principal: Aguiar, Sandra Isabel
Data de Publicação: 2021
Outros Autores: Dias, Joana N. R., S. André, Ana, Silva, Lisete M., Martins, Diana, Carrapiço, Belmira, Castanho, Miguel, Carriço, João, Cavaco, Marco, Aires da Silva, Frederico, [et al.]
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.5/22940
Resumo: Research Areas: Pharmacology & Pharmacy
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spelling Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screeningBrain targeting antibodiesBlood-brain barrierIn vivo phage displaySingle-domain antibodiesDrug deliveryResearch Areas: Pharmacology & PharmacyA major bottleneck in the successful development of central nervous system (CNS) drugs is the discovery and design of molecules that can cross the blood-brain barrier (BBB). Nano-delivery strategies are a promising approach that take advantage of natural portals of entry into the brain such as monoclonal antibodies (mAbs) targeting endogenous BBB receptors. However, the main selected mAbs rely on targeting broadly expressed receptors, such as the transferrin and insulin receptors, and in selection processes that do not fully mimic the native receptor conformation, leading to mistargeting and a low fraction of the administered dose effectively reaching the brain. Thus, there is an urgent need to identify new BBB receptors and explore novel antibody selection approaches that can allow a more selective delivery into the brain. Considering that in vitro models fail to completely mimic brain structure complexity, we explored an in vivo cell immunization approach to construct a rabbit derived single-domain antibody (sdAb) library towards BBB endothelial cell receptors. The sdAb antibody library was used in an in vivo phage display screening as a functional selection of novel BBB targeting antibodies. Following three rounds of selections, next generation sequencing analysis, in vitro brain endothelial barrier (BEB) model screenings and in vivo biodistribution studies, five potential sdAbs were identified, three of which reaching >0.6% ID/g in the brain. To validate the brain drug delivery proof-of-concept, the most promising sdAb, namely RG3, was conjugated at the surface of liposomes encapsulated with a model drug, the pan-histone deacetylase inhibitor panobinostat (PAN). The translocation efficiency and activity of the conjugate liposome was determined in a dual functional in vitro BEB-glioblastoma model. The RG3 conjugated PAN liposomes enabled an efficient BEB translocation and presented a potent antitumoral activity against LN229 glioblastoma cells without influencing BEB integrity. In conclusion, our in vivo screening approach allowed the selection of highly specific nano-antibody scaffolds with promising properties for brain targeting and drug delivery.MDPIRepositório da Universidade de LisboaAguiar, Sandra IsabelDias, Joana N. R.S. André, AnaSilva, Lisete M.Martins, DianaCarrapiço, BelmiraCastanho, MiguelCarriço, JoãoCavaco, MarcoAires da Silva, Frederico[et al.]2022-01-07T15:06:35Z2021-10-022021-10-02T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.5/22940engAguiar SI, Dias JNR, André AS, Silva ML, Martins D, Carrapiço B, Castanho M, Carriço J, Cavaco M, Gaspar MM [et al.]. Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening. 2021. Pharmaceutics 13(10):1598. Doi: 10.3390/ pharmaceutics1310159810.3390/pharmaceutics131015981999-4923info: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:RCAAP2023-03-06T14:52:28Zoai:www.repository.utl.pt:10400.5/22940Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T17:07:16.696456Repositório 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 Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
title Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
spellingShingle Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
Aguiar, Sandra Isabel
Brain targeting antibodies
Blood-brain barrier
In vivo phage display
Single-domain antibodies
Drug delivery
title_short Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
title_full Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
title_fullStr Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
title_full_unstemmed Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
title_sort Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
author Aguiar, Sandra Isabel
author_facet Aguiar, Sandra Isabel
Dias, Joana N. R.
S. André, Ana
Silva, Lisete M.
Martins, Diana
Carrapiço, Belmira
Castanho, Miguel
Carriço, João
Cavaco, Marco
Aires da Silva, Frederico
[et al.]
author_role author
author2 Dias, Joana N. R.
S. André, Ana
Silva, Lisete M.
Martins, Diana
Carrapiço, Belmira
Castanho, Miguel
Carriço, João
Cavaco, Marco
Aires da Silva, Frederico
[et al.]
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Aguiar, Sandra Isabel
Dias, Joana N. R.
S. André, Ana
Silva, Lisete M.
Martins, Diana
Carrapiço, Belmira
Castanho, Miguel
Carriço, João
Cavaco, Marco
Aires da Silva, Frederico
[et al.]
dc.subject.por.fl_str_mv Brain targeting antibodies
Blood-brain barrier
In vivo phage display
Single-domain antibodies
Drug delivery
topic Brain targeting antibodies
Blood-brain barrier
In vivo phage display
Single-domain antibodies
Drug delivery
description Research Areas: Pharmacology & Pharmacy
publishDate 2021
dc.date.none.fl_str_mv 2021-10-02
2021-10-02T00:00:00Z
2022-01-07T15:06:35Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.5/22940
url http://hdl.handle.net/10400.5/22940
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Aguiar SI, Dias JNR, André AS, Silva ML, Martins D, Carrapiço B, Castanho M, Carriço J, Cavaco M, Gaspar MM [et al.]. Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening. 2021. Pharmaceutics 13(10):1598. Doi: 10.3390/ pharmaceutics13101598
10.3390/pharmaceutics13101598
1999-4923
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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