The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis
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...
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| Veröffentlicht in: | Biomedicine & pharmacotherapy 2024-05, Vol.174, p.116573-116573, Article 116573 |
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| creator | Cavaco, Marco Pérez-Peinado, Clara Valle, Javier Silva, Ruben D.M. Gano, Lurdes Correia, João D.G. Andreu, David Castanho, Miguel A.R.B. Neves, Vera |
| description | 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.
[Display omitted]
•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. |
| doi_str_mv | 10.1016/j.biopha.2024.116573 |
| format | Article |
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[Display omitted]
•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.</description><identifier>ISSN: 0753-3322</identifier><identifier>EISSN: 1950-6007</identifier><identifier>DOI: 10.1016/j.biopha.2024.116573</identifier><identifier>PMID: 38613996</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Anticancer peptides ; Antineoplastic Agents - pharmacology ; BBB peptide shuttle ; Blood-brain barrier ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Brain metastasis ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Brain Neoplasms - secondary ; Cell Line, Tumor ; Cell-penetrating peptides ; Endocytosis - drug effects ; Female ; Humans ; PepH3 ; Peptides - pharmacology ; Triple Negative Breast Neoplasms - drug therapy ; Triple Negative Breast Neoplasms - metabolism ; Triple Negative Breast Neoplasms - pathology ; Triple-negative breast cancer ; vCPP2319</subject><ispartof>Biomedicine & pharmacotherapy, 2024-05, Vol.174, p.116573-116573, Article 116573</ispartof><rights>2024 The Authors</rights><rights>Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c357t-bf03bbc933e053ee5ea82885508053640c06aec8b5d1511ff8750a05f16427573</cites><orcidid>0000-0002-2989-7208 ; 0000-0002-0938-9038</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.biopha.2024.116573$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38613996$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cavaco, Marco</creatorcontrib><creatorcontrib>Pérez-Peinado, Clara</creatorcontrib><creatorcontrib>Valle, Javier</creatorcontrib><creatorcontrib>Silva, Ruben D.M.</creatorcontrib><creatorcontrib>Gano, Lurdes</creatorcontrib><creatorcontrib>Correia, João D.G.</creatorcontrib><creatorcontrib>Andreu, David</creatorcontrib><creatorcontrib>Castanho, Miguel A.R.B.</creatorcontrib><creatorcontrib>Neves, Vera</creatorcontrib><title>The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis</title><title>Biomedicine & pharmacotherapy</title><addtitle>Biomed Pharmacother</addtitle><description>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.
[Display omitted]
•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.</description><subject>Animals</subject><subject>Anticancer peptides</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>BBB peptide shuttle</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain metastasis</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain Neoplasms - secondary</subject><subject>Cell Line, Tumor</subject><subject>Cell-penetrating peptides</subject><subject>Endocytosis - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>PepH3</subject><subject>Peptides - pharmacology</subject><subject>Triple Negative Breast Neoplasms - drug therapy</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Triple-negative breast cancer</subject><subject>vCPP2319</subject><issn>0753-3322</issn><issn>1950-6007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtu5CAQRdEo0aTz-INRxDKLuKcwBtObSFGUlxRpNpk1wrg8TcttHMB5_P3QcifLsEEUp-qqDiG_GCwZMPl7s2ycH9dmWUJZLRmTouY_yIKtBBQSoD4gC6gFLzgvyyNyHOMGAITk6ic54koyvlrJBcHnNdIpIvUdNTRijza5V7ykgx-Sf3eWtpPpC5Orwz864phci7TzgTYBTUzUmsFioKNJDocU6ZtL6_xn3EC3mDJhooun5LAzfcSz_X1C_t7dPt88FE9_7h9vrp8Ky0WdiqYD3jR2xTmC4IgCjSqVEgJUfssKLEiDVjWiZYKxrlO1AAOiY7Iq67z_CbmY547Bv0wYk966aLHvzYB-ipoDV1U-bIdWM2qDjzFgp8fgtiZ8aAZ6J1hv9CxY7wTrWXBuO98nTM0W26-mT6MZuJoBzHu-Ogw62mzGYutCdqtb775P-A-AjY3P</recordid><startdate>202405</startdate><enddate>202405</enddate><creator>Cavaco, Marco</creator><creator>Pérez-Peinado, Clara</creator><creator>Valle, Javier</creator><creator>Silva, Ruben D.M.</creator><creator>Gano, Lurdes</creator><creator>Correia, João D.G.</creator><creator>Andreu, David</creator><creator>Castanho, Miguel A.R.B.</creator><creator>Neves, Vera</creator><general>Elsevier Masson SAS</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2989-7208</orcidid><orcidid>https://orcid.org/0000-0002-0938-9038</orcidid></search><sort><creationdate>202405</creationdate><title>The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis</title><author>Cavaco, Marco ; Pérez-Peinado, Clara ; Valle, Javier ; Silva, Ruben D.M. ; Gano, Lurdes ; Correia, João D.G. ; Andreu, David ; Castanho, Miguel A.R.B. ; Neves, Vera</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c357t-bf03bbc933e053ee5ea82885508053640c06aec8b5d1511ff8750a05f16427573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Anticancer peptides</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>BBB peptide shuttle</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Brain metastasis</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain Neoplasms - secondary</topic><topic>Cell Line, Tumor</topic><topic>Cell-penetrating peptides</topic><topic>Endocytosis - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>PepH3</topic><topic>Peptides - pharmacology</topic><topic>Triple Negative Breast Neoplasms - drug therapy</topic><topic>Triple Negative Breast Neoplasms - metabolism</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><topic>Triple-negative breast cancer</topic><topic>vCPP2319</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cavaco, Marco</creatorcontrib><creatorcontrib>Pérez-Peinado, Clara</creatorcontrib><creatorcontrib>Valle, Javier</creatorcontrib><creatorcontrib>Silva, Ruben D.M.</creatorcontrib><creatorcontrib>Gano, Lurdes</creatorcontrib><creatorcontrib>Correia, João D.G.</creatorcontrib><creatorcontrib>Andreu, David</creatorcontrib><creatorcontrib>Castanho, Miguel A.R.B.</creatorcontrib><creatorcontrib>Neves, Vera</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biomedicine & pharmacotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cavaco, Marco</au><au>Pérez-Peinado, Clara</au><au>Valle, Javier</au><au>Silva, Ruben D.M.</au><au>Gano, Lurdes</au><au>Correia, João D.G.</au><au>Andreu, David</au><au>Castanho, Miguel A.R.B.</au><au>Neves, Vera</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis</atitle><jtitle>Biomedicine & pharmacotherapy</jtitle><addtitle>Biomed Pharmacother</addtitle><date>2024-05</date><risdate>2024</risdate><volume>174</volume><spage>116573</spage><epage>116573</epage><pages>116573-116573</pages><artnum>116573</artnum><issn>0753-3322</issn><eissn>1950-6007</eissn><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.
[Display omitted]
•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.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>38613996</pmid><doi>10.1016/j.biopha.2024.116573</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-2989-7208</orcidid><orcidid>https://orcid.org/0000-0002-0938-9038</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ScienceDirect Journals (5 years ago - present) |
| subjects | Animals Anticancer peptides Antineoplastic Agents - pharmacology BBB peptide shuttle Blood-brain barrier Blood-Brain Barrier - drug effects Blood-Brain Barrier - metabolism Brain metastasis Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain Neoplasms - secondary Cell Line, Tumor Cell-penetrating peptides Endocytosis - drug effects Female Humans PepH3 Peptides - pharmacology Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology Triple-negative breast cancer vCPP2319 |
| title | The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis |
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