Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy
Peña, Quim (Universitat Autònoma de Barcelona. Departament de Química)
Rodríguez-Calado, Sergi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Simaan, A. Jalila (Aix-Marseille Université)
Capdevila Vidal, Mercè (Universitat Autònoma de Barcelona. Departament de Química)
Bayón, Joan Carles (Universitat Autònoma de Barcelona. Departament de Química)
Palacios Bonilla, Òscar (Universitat Autònoma de Barcelona. Departament de Química)
Lorenzo Rivera, Julia (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Iranzo, Olga (Aix-Marseille Université)

Data:	2022
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad BIO2015-67358-C2-2-P Ministerio de Economía y Competitividad CTQ2015-70371-REDT Agencia Estatal de Investigación RTI2018-098027-B-C22 Ministerio de Ciencia e Innovación PID2021-127983OB-C22 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-864 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-01584
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cell-penetrating peptide ; Copper ; Metal complex ; Intracellular delivery ; Cancer ; Redox-active ; Metallodrug
Publicat a:	Frontiers in Pharmacology, Vol. 13 (November 2022) , art. 1060827, ISSN 1663-9812

DOI: 10.3389/fphar.2022.1060827
PMID: 36467097

15 p, 2.0 MB

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