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Development and characterization of an innovative drug delivery platform targeting breast cancer brain metastases
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Resumo(s)
15-25 % 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.
Descrição
Tese de mestrado, Biologia Molecular e Genética , 2022, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
metástases encefálicas do cancro da mama barreira hematoencefálica lipossoma fator de crescimento derivado de plaquetas salinomicina Teses de mestrado - 2023