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oai:riubu.ubu.es:10259/74442026-02-06T12:53:36Zcom_10259_4363com_10259_5086com_10259_2604com_10259_3924com_10259.4_2516com_10259_3592com_10259_3591com_10259.4_106col_10259_4364col_10259_3925col_10259.4_2517col_10259_3930

Rational design of mitochondria targeted thiabendazole-based Ir(III) biscyclometalated complexes for a multimodal photodynamic therapy of cancer Echevarría Poza, Igor Zafon, Elisenda Barrabés, Sílvia Martínez, María Ángeles Ramos Gómez, Sonia Ortega Santamaría, Natividad Manzano, Blanca R. Jalón Sotés, Félix Ángel Quesada Pato, Roberto Espino Ordóñez, Gustavo Massaguer Vall-Llovera, Anna Photodynamic therapy Iridium Cyclometalated complexes Cancer Mitochondria DNA Química orgánica Química analítica Química inorgánica Medicina Chemistry, Organic Chemistry, Analytic Chemistry, Inorganic Medicine Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)2(N^N′ )]Cl (N^N′ = thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines. Furthermore, the cytotoxic activity of derivatives of Series A is enhanced upon irradiation, particularly for complexes [1a]Cl and [3a]Cl, which show phototoxicity indexes (PI) above 20. Endocytosis was established as the uptake mechanism for [1a]Cl and [3a]Cl in prostate cancer cells by flow cytometry. These derivatives mainly accumulate in the mitochondria as shown by colocalization confocal microscopy experiments. Presumably, [1a]Cl and [3a]Cl induce death on cancer cells under irradiation through apoptosis triggered by a multimodal mechanism of action, which likely involves damage over mitochondrial DNA and mitochondrial membrane depolarization. Both processes seem to be the result of photocatalytic oxidation processes. We acknowledge the financial support provided by the Spanish Ministerio de Ciencia, Innovacion ´ y Universidades (RTI2018-100709-BC21, RTI2018-100709-B-C22) and CTQ (QMC)-RED2018-102471-T), Junta de Castilla y Leon ´ (BU087G19), Junta de Comunidades de CastillaLa Mancha-FEDER (JCCM) (grant SBPLY/19/180501/000260) and UCLM-FEDER (grants 2019-GRIN-27183 and 2019-GRIN-27209). I. Echevarría wants to acknowledge his fellowship to both the European Social Fund and Consejería de Educacion ´ de la Junta de Castilla y Leon ´ (EDU/1100/2017). E. Zafon wants to acknowledge her predoctoral fellowship to the Generalitat de Catalunya (AGAUR; 2021 FI_B 01036). We are also indebted to Jacinto Delgado, Pilar Castroviejo and Marta Mansilla (PCT of the Universidad de Burgos) for technical support and Jos´e Vicente Cuevas Vicario for advice and support with theoretical calculations and Gabriel García-Herbosa for providing us access to CV equipment. 2023-02-13T11:43:03Z 2023-02-13T11:43:03Z 2022-06 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 0162-0134 http://hdl.handle.net/10259/7444 10.1016/j.jinorgbio.2022.111790 eng Journal of Inorganic Biochemistry. 2022, V. 231, 111790 https://doi.org/10.1016/j.jinorgbio.2022.111790 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-100709-B-C21/ES/NUEVOS METALOFARMACOS DISEÑADOS PARA INCREMENTAR LA SELECTIVIDAD EN TRATAMIENTOS CONTRA EL CANCER. USO DE FOTOTERAPIA Y VEHICULIZACION CON LIGANDOS DIRIGIDOS A TUMORES/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-100709-B-C22/ES/NUEVOS METALOFARMACOS DISEÑADOS PARA INCREMENTAR LA SELECTIVIDAD. USO DE FOTOTERAPIA Y VEHICULIZACION CON LIGANDOS DIRIGIDOS A TUMORES/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RED2018-102471-T/ES/METALOFARMACOS MULTIFUNCIONALES PARA DIAGNOSIS Y TERAPIA/ info:eu-repo/grantAgreement/Junta de Castilla y León//BU087G19//Compuestos organometálicos de ir(iii) en terapias antiproliferativas y como sondas químicas deaminas biógenas/ info:eu-repo/grantAgreement/JCCM//SBPLY%2F19%2F180501%2F000260/ info:eu-repo/grantAgreement/UCLM//2019-GRIN-27183/ info:eu-repo/grantAgreement/UCLM//2019-GRIN-27209/ info:eu-repo/grantAgreement/AGAUR//2021 FI_B 01036/ Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf Elsevier https://riubu.ubu.es/bitstream/10259/7444/4/Echevarria-jib_2022.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by-nc-nd/4.0/ RIUBU. Repositorio Institucional de la Universidad de Burgos http://hdl.handle.net/10259/7444