The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis
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- dc.contributor.author Cavaco, Marco
- dc.contributor.author Pérez-Peinado, Clara, 1991-
- dc.contributor.author Valle, Javier
- dc.contributor.author Silva, Rúben D.M.
- dc.contributor.author Gano, Lurdes
- dc.contributor.author Correia, João D.G.
- dc.contributor.author Andreu Martínez, David
- dc.contributor.author Castanho, Miguel A.R.B.
- dc.contributor.author Neves, Vera
- dc.date.accessioned 2024-06-05T06:15:42Z
- dc.date.available 2024-06-05T06:15:42Z
- dc.date.issued 2024
- dc.description.abstract Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of commonly targeted receptors. Unspecific chemotherapy is currently the main therapeutic option, with poor results. Another major challenge is the frequent appearance of brain metastasis (BM) associated with a significant decrease in patient overall survival. The treatment of BM is even more challenging due to the presence of the blood-brain barrier (BBB). Here, we present a dual-acting peptide (PepH3-vCPP2319) designed to tackle TNBC/BM, in which a TNBC-specific anticancer peptide (ACP) motif (vCPP2319) is joined to a BBB peptide shuttle (BBBpS) motif (PepH3). PepH3-vCPP2319 demonstrated selectivity and efficiency in eliminating TNBC both in monolayers (IC50≈5.0 µM) and in spheroids (IC50≈25.0 µM), with no stringent toxicity toward noncancerous cell lines and red blood cells (RBCs). PepH3-vCPP2319 was also able to cross the BBB in vitro and penetrate the brain in vivo, and was stable in serum with a half-life above 120 min. Tumor cell-peptide interaction is fast, with quick peptide internalization via clathrin-mediated endocytosis without membrane disruption. Upon internalization, the peptide is detected in the nucleus and the cytoplasm, indicating a multi-targeted mechanism of action that ultimately induces irreversible cell damage and apoptosis. In conclusion, we have designed a dual-acting peptide capable of brain penetration and TNBC cell elimination, thus expanding the drug arsenal to fight this BC subtype and its BM.
- dc.format.mimetype application/pdf
- dc.identifier.citation Cavaco M, Pérez-Peinado C, Valle J, Silva RDM, Gano L, Correia JDG, et al. The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis. Biomed Pharmacother. 2024 May;174:116573. DOI: 10.1016/j.biopha.2024.116573
- dc.identifier.doi http://dx.doi.org/10.1016/j.biopha.2024.116573
- dc.identifier.issn 0753-3322
- dc.identifier.uri http://hdl.handle.net/10230/60350
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof Biomed Pharmacother. 2024 May;174:116573
- dc.rights © 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
- dc.subject.keyword Anticancer peptides
- dc.subject.keyword BBB peptide shuttle
- dc.subject.keyword Blood-brain barrier
- dc.subject.keyword Brain metastasis
- dc.subject.keyword Cell-penetrating peptides
- dc.subject.keyword PepH3
- dc.subject.keyword Triple-negative breast cancer
- dc.subject.keyword vCPP2319
- dc.title The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion