The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis - 27/04/24
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | The combo peptide PepH3-vCPP2319 has a brain-penetration and an anticancer sequence. |
• | PepH3-vCPP2319 is selective, nontoxic, and has high stability. |
• | PepH3-vCPP2319 crosses blood-brain barrier models and penetrates the brain in vivo. |
• | The combo peptide efficiently eliminates cancer cells by a multi-target mechanism. |
• | Overall, the dual-acting peptide shows potential for brain metastasis elimination. |
Abbreviations : ACN, ACPs, AF, cAMP, AMT, BBB, BBBpS, BC, BDNF, BSA, BM, CF, CPZ, DCM, DIEA, DIPCI, DMEM, DMF, DODT, ECGS, ECM, EMEM, ER/PR, FCCP, F12, FBS, FD4, HBTU, HER2+, HOBt, NAC, NODA-GAtBu3, RBC, RMT, ROS, SPPS, TFA, TAT, TBHP, TIS, TMRE, TNBC
Keywords : Anticancer peptides, BBB peptide shuttle, Blood-brain barrier, Brain metastasis, Cell-penetrating peptides, PepH3, Triple-negative breast cancer, vCPP2319
Plan
Vol 174
Article 116573- mai 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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