Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an In Vivo phage display screening
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| Outros Autores: | , , , , , , , , , |
| 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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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 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
MDPI |
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MDPI |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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