Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy

Metal-based chemotherapeutics like cisplatin are widely employed in cancer treatment. In the last years, the design of redox-active (transition) metal complexes, such as of copper (Cu), has attracted high interest as alternatives to overcome platinum-induced side-effects. However, several challenges...

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Autores: Peña Aparicio, Joaquim|||0000-0001-6477-8127, Rodriguez-Calado, Sergi|||0000-0002-8849-1101, Simaan, A. Jalila|||0000-0003-2537-0422, Capdevila, Mercè|||0000-0002-2246-0994, Bayón, Joan Carles|||0000-0002-2498-1945, Palacios, Òscar|||0000-0002-2987-7303, Lorenzo Rivera, Julia|||0000-0001-5659-6008, Iranzo, Olga|||0000-0001-8542-2429
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:269563
Acceso en línea:https://ddd.uab.cat/record/269563
https://dx.doi.org/urn:doi:10.3389/fphar.2022.1060827
Access Level:acceso abierto
Palabra clave:Cell-penetrating peptide
Copper
Metal complex
Intracellular delivery
Cancer
Redox-active
Metallodrug
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spelling Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapyPeña Aparicio, Joaquim|||0000-0001-6477-8127Rodriguez-Calado, Sergi|||0000-0002-8849-1101Simaan, A. Jalila|||0000-0003-2537-0422Capdevila, Mercè|||0000-0002-2246-0994Bayón, Joan Carles|||0000-0002-2498-1945Palacios, Òscar|||0000-0002-2987-7303Lorenzo Rivera, Julia|||0000-0001-5659-6008Iranzo, Olga|||0000-0001-8542-2429Cell-penetrating peptideCopperMetal complexIntracellular deliveryCancerRedox-activeMetallodrugMetal-based chemotherapeutics like cisplatin are widely employed in cancer treatment. In the last years, the design of redox-active (transition) metal complexes, such as of copper (Cu), has attracted high interest as alternatives to overcome platinum-induced side-effects. However, several challenges are still faced, including optimal aqueous solubility and efficient intracellular delivery, and strategies like the use of cell-penetrating peptides have been encouraging. In this context, we previously designed a Cu(II) scaffold that exhibited significant reactive oxygen species (ROS)-mediated cytotoxicity. Herein, we build upon the promising Cu(II) redox-active metallic core and aim to potentiate its anticancer activity by rationally tailoring it with solubility- and uptake-enhancing functionalizations that do not alter the ROS-generating Cu(II) center. To this end, sulfonate, arginine and arginine-rich cell-penetrating peptide (CPP) derivatives have been prepared and characterized, and all the resulting complexes preserved the parent Cu(II) coordination core, thereby maintaining its reported redox capabilities. Comparative in vitro assays in several cancer cell lines reveal that while specific solubility-targeting derivatizations (i.e., sulfonate or arginine) did not translate into an improved cytotoxicity, increased intracellular copper delivery via CPP-conjugation promoted an enhanced anticancer activity, already detectable at short treatment times. Additionally, immunofluorescence assays show that the Cu(II) peptide-conjugate distributed throughout the cytosol without lysosomal colocalization, suggesting potential avoidance of endosomal entrapment. Overall, the systematic exploration of the tailored modifications enables us to provide further understanding on structure-activity relationships of redox-active metal-based (Cu(II)) cytotoxic complexes, which contributes to rationalize and improve the design of more efficient redox-mediated metal-based anticancer therapy. 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/269563https://dx.doi.org/urn:doi:10.3389/fphar.2022.1060827reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 BIO2015-67358-C2-2-PMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 CTQ2015-70371-REDTAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-098027-B-C22Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-127983OB-C22Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-864Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-01584open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2695632026-06-06T12:50:31Z
dc.title.none.fl_str_mv Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
title Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
spellingShingle Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
Peña Aparicio, Joaquim|||0000-0001-6477-8127
Cell-penetrating peptide
Copper
Metal complex
Intracellular delivery
Cancer
Redox-active
Metallodrug
title_short Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
title_full Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
title_fullStr Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
title_full_unstemmed Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
title_sort Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
dc.creator.none.fl_str_mv Peña Aparicio, Joaquim|||0000-0001-6477-8127
Rodriguez-Calado, Sergi|||0000-0002-8849-1101
Simaan, A. Jalila|||0000-0003-2537-0422
Capdevila, Mercè|||0000-0002-2246-0994
Bayón, Joan Carles|||0000-0002-2498-1945
Palacios, Òscar|||0000-0002-2987-7303
Lorenzo Rivera, Julia|||0000-0001-5659-6008
Iranzo, Olga|||0000-0001-8542-2429
author Peña Aparicio, Joaquim|||0000-0001-6477-8127
author_facet Peña Aparicio, Joaquim|||0000-0001-6477-8127
Rodriguez-Calado, Sergi|||0000-0002-8849-1101
Simaan, A. Jalila|||0000-0003-2537-0422
Capdevila, Mercè|||0000-0002-2246-0994
Bayón, Joan Carles|||0000-0002-2498-1945
Palacios, Òscar|||0000-0002-2987-7303
Lorenzo Rivera, Julia|||0000-0001-5659-6008
Iranzo, Olga|||0000-0001-8542-2429
author_role author
author2 Rodriguez-Calado, Sergi|||0000-0002-8849-1101
Simaan, A. Jalila|||0000-0003-2537-0422
Capdevila, Mercè|||0000-0002-2246-0994
Bayón, Joan Carles|||0000-0002-2498-1945
Palacios, Òscar|||0000-0002-2987-7303
Lorenzo Rivera, Julia|||0000-0001-5659-6008
Iranzo, Olga|||0000-0001-8542-2429
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cell-penetrating peptide
Copper
Metal complex
Intracellular delivery
Cancer
Redox-active
Metallodrug
topic Cell-penetrating peptide
Copper
Metal complex
Intracellular delivery
Cancer
Redox-active
Metallodrug
description Metal-based chemotherapeutics like cisplatin are widely employed in cancer treatment. In the last years, the design of redox-active (transition) metal complexes, such as of copper (Cu), has attracted high interest as alternatives to overcome platinum-induced side-effects. However, several challenges are still faced, including optimal aqueous solubility and efficient intracellular delivery, and strategies like the use of cell-penetrating peptides have been encouraging. In this context, we previously designed a Cu(II) scaffold that exhibited significant reactive oxygen species (ROS)-mediated cytotoxicity. Herein, we build upon the promising Cu(II) redox-active metallic core and aim to potentiate its anticancer activity by rationally tailoring it with solubility- and uptake-enhancing functionalizations that do not alter the ROS-generating Cu(II) center. To this end, sulfonate, arginine and arginine-rich cell-penetrating peptide (CPP) derivatives have been prepared and characterized, and all the resulting complexes preserved the parent Cu(II) coordination core, thereby maintaining its reported redox capabilities. Comparative in vitro assays in several cancer cell lines reveal that while specific solubility-targeting derivatizations (i.e., sulfonate or arginine) did not translate into an improved cytotoxicity, increased intracellular copper delivery via CPP-conjugation promoted an enhanced anticancer activity, already detectable at short treatment times. Additionally, immunofluorescence assays show that the Cu(II) peptide-conjugate distributed throughout the cytosol without lysosomal colocalization, suggesting potential avoidance of endosomal entrapment. Overall, the systematic exploration of the tailored modifications enables us to provide further understanding on structure-activity relationships of redox-active metal-based (Cu(II)) cytotoxic complexes, which contributes to rationalize and improve the design of more efficient redox-mediated metal-based anticancer therapy.
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/269563
https://dx.doi.org/urn:doi:10.3389/fphar.2022.1060827
url https://ddd.uab.cat/record/269563
https://dx.doi.org/urn:doi:10.3389/fphar.2022.1060827
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 BIO2015-67358-C2-2-P
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 CTQ2015-70371-REDT
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-098027-B-C22
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-127983OB-C22
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-864
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-01584
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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