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Development and biological characterization of a drug delivery system for brain metastatic breast cancer
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Resumo(s)
Triple-negative breast cancer (TNBC) has no receptors and high Ki-67 levels, being a highly
invasive subtype, prone to develop metastasis, with limited treatment options due to most therapeutic
agents’ inability to effectively cross the blood-brain barrier (BBB), posing a significant global health
challenge. This study aimed to develop a targeted drug delivery system capable of bypassing the BBB
to deliver a promising compound (Mol. X) to metastatic cells in the brain. Two long-circulating
liposomal formulations coated with polyethylene glycol (PEG) were developed: a non-targeted [Mol.
X-Lip], and a TNBC-targeted formulation relying on the use of chlorotoxin (CTX) [Mol. X-Lip-CTX].
CTX was covalently coupled to the distal end of PEG using the direct coupling method. Both
formulations were characterized in terms of mean size, polydispersity index, zeta potential, and total
lipid and Mol. X contents allowing the determination of incorporation efficiency (IE). For the Mol. XLip-CTX, the covalently linked CTX was quantified, and the attachment capacity (AC) was calculated.
Mol. X-Lip exhibited an IE of 85 %, a mean size of 128 nm, a polydispersity index of 0.049, and a zeta
potential of -3 mV, as expected for pegylated liposomes. The Mol. X-Lip-CTX showed an IE of 69 %,
a CTX AC of 4.5 nmol per µmol of lipids, a mean size of 247 nm, a polydispersity index of 0.288, and
a zeta potential of -5 mV. In cell viability assay using the TNBC brain-tropism cell line (MDA-MB-231
Br4), Mol. X-Lip showed no toxicity at any concentration. Additionally, immunocytochemistry analysis
targeting the biomarker Ki-67 revealed inconclusive results. Finally, a cell viability assay was conducted
using the Mol. X-Lip-CTX, where no cytotoxicity was observed. In conclusion, successful incorporation
of the hydrophobic compound Mol. X, and anchoring CTX into liposomes were achieved, without detect
toxicity on the cells at any Mol. X concentration.
Descrição
Tese de mestrado, Bioquímica e Biomedicina, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Metástases encefálicas de cancro da mama barreira hematoencefálica lipossoma clorotoxina sistema de entrega de medicamentos direcionado Teses de mestrado - 2025