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...
| Autores: | ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Lenguaje: | 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 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | Cell-penetrating peptide Copper Metal complex Intracellular delivery Cancer Redox-active Metallodrug |
| _version_ | 1878733025324302337 |
|---|---|
| author | Peña Aparicio, Joaquim|||0000-0001-6477-8127 |
| 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 |
| author_browse | Bayón, Joan Carles|||0000-0002-2498-1945 Capdevila, Mercè|||0000-0002-2246-0994 Iranzo, Olga|||0000-0001-8542-2429 Lorenzo Rivera, Julia|||0000-0001-5659-6008 Palacios, Òscar|||0000-0002-2987-7303 Peña Aparicio, Joaquim|||0000-0001-6477-8127 Rodriguez-Calado, Sergi|||0000-0002-8849-1101 Simaan, A. Jalila|||0000-0003-2537-0422 |
| 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 |
| collection | Dipòsit Digital de Documents de la UAB |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_4e91e53591dd82c12cdc1a8024debf7e |
| institution | Universitat Autònoma de Barcelona |
| instname_str | Universitat Autònoma de Barcelona |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddd.uab.cat:269563 |
| publishDate | 2022 |
| publishDateSort | 2022 |
| reponame_str | Dipòsit Digital de Documents de la UAB |
| spelling | Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy 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 Cell-penetrating peptide Copper Metal complex Intracellular delivery Cancer Redox-active Metallodrug 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. https://ddd.uab.cat/record/269563 https://dx.doi.org/urn:doi:10.3389/fphar.2022.1060827 |
| 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 | 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_short | Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy |
| title_sort | Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy |
| topic | Cell-penetrating peptide Copper Metal complex Intracellular delivery Cancer Redox-active Metallodrug |
| topic_facet | Cell-penetrating peptide Copper Metal complex Intracellular delivery Cancer Redox-active Metallodrug |
| url | https://ddd.uab.cat/record/269563 https://dx.doi.org/urn:doi:10.3389/fphar.2022.1060827 |