Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases

Detalhes bibliográficos
Autor(a) principal: Romão, Joana Raquel Aniceto
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Texto Completo: http://hdl.handle.net/10451/57650
Resumo: Tese de mestrado, Biologia Molecular e Genética , 2022, Universidade de Lisboa, Faculdade de Ciências
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spelling Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastasesmetástases encefálicas do cancro da mamabarreira hematoencefálicalipossomafator de crescimento derivado de plaquetassalinomicinaTeses de mestrado - 2023Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética , 2022, Universidade de Lisboa, Faculdade de Ciências15-25 % of breast cancer (BC) patients develop brain metastases (BM), a poor prognosis condition due to the restricted blood-brain barrier (BBB) permeability. Platelet-derived growth factor subunit B (PDGF-B) was associated with BC cells (BCCs) proliferation. Furthermore, salinomycin (SAL) was effective in the eradication of BCCs. Nanoformulations coupled to chlorotoxin (CTX), appear as a strategy to overcome the BBB and achieve target-specific delivery. This prompted us to develop a new nanomedicines platform decorated with CTX for combined drug (SAL) and genetic (siRNA) therapeutic approach to abrogate BC brain metastases (BCBM). Liposomes with siPDGF-B were developed and their biological activity towards triple negative BCCs (4T1 cells) was determined based on cell viability and PDGF-B silencing. SAL incorporation was optimized, and characterized, and SAL encapsulated median lethal dose (LD50) was determined. The efficiency of co-administration was studied based on cell viability, PDGF-B silencing, and proliferation. The safety of both formulations for brain microvascular endothelial cells (b.End5 cells) was studied. BBB transposition efficiency, and efficacy to abrogate BCCs were evaluated in a co-culture model. Finally, the BBB integrity was ensured by transendothelial electrical resistance (TEER) and the βcatenin labeling. siPDGF-B presented no effect on 4T1 cells’ viability, while PDGF-B silencing efficacy achieved 31%. SAL showed around 33% SAL incorporation efficiency, achieving a LD50 of 24.76 µM. Moreover, coadministration treatment modulated 4T1 cells’ proliferation. Importantly, both formulations showed no effect on b.End5 cells’ viability. Using the co-culture model, liposomes’ ability to act on BCCs, decreasing PDGF-B expression was demonstrated. Additionally, liposomes individually lead to cell senescence. Lastly, TEER and β-catenin labeling revealed b.End5 monolayer disruption by SAL. Overall, the delivery of SAL appears to impair the endothelium, while siPDGF-B delivery in a targeted and BBB-permeant platform emerges as a new approach for BCBM treatment.Brito, Maria Alexandra de Oliveira Silva Braga Pedreira de, 1960-Malhó, Rui, 1967-Repositório da Universidade de LisboaRomão, Joana Raquel Aniceto202320222025-12-29T00:00:00Z2023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/57650TID:203486781enginfo:eu-repo/semantics/embargoedAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T14:57:46Zoai:repositorio.ulisboa.pt:10451/57650Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T03:30:21.647523Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
title Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
spellingShingle Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
Romão, Joana Raquel Aniceto
metástases encefálicas do cancro da mama
barreira hematoencefálica
lipossoma
fator de crescimento derivado de plaquetas
salinomicina
Teses de mestrado - 2023
Departamento de Biologia Vegetal
title_short Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
title_full Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
title_fullStr Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
title_full_unstemmed Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
title_sort Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
author Romão, Joana Raquel Aniceto
author_facet Romão, Joana Raquel Aniceto
author_role author
dc.contributor.none.fl_str_mv Brito, Maria Alexandra de Oliveira Silva Braga Pedreira de, 1960-
Malhó, Rui, 1967-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Romão, Joana Raquel Aniceto
dc.subject.por.fl_str_mv metástases encefálicas do cancro da mama
barreira hematoencefálica
lipossoma
fator de crescimento derivado de plaquetas
salinomicina
Teses de mestrado - 2023
Departamento de Biologia Vegetal
topic metástases encefálicas do cancro da mama
barreira hematoencefálica
lipossoma
fator de crescimento derivado de plaquetas
salinomicina
Teses de mestrado - 2023
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética , 2022, Universidade de Lisboa, Faculdade de Ciências
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023-01-01T00:00:00Z
2025-12-29T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/57650
TID:203486781
url http://hdl.handle.net/10451/57650
identifier_str_mv TID:203486781
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/embargoedAccess
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
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