Publication: Bis-Cyclometalated Iridium(III) Complexes Derived from Benzazole Scaffolds: Innovative Applications in Anticancer Photodynamic Therapy and Chemotherapy
Authors
Linero Artiaga, Antonio
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Escuela Internacional de Doctorado
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Rodríguez Hernández, Venancio ; Ruiz López, José
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
Objetivos de la tesis. La presente Tesis Doctoral se ha centrado en el diseño, la síntesis, la caracterización fotofísica, la evaluación fotoquímica y la determinación de la actividad biológica de nuevos complejos ciclometalados de iridio derivados de fragmentos benzazol como posibles fármacos en el tratamiento mediado por PDT y quimioterapia frente a diversas líneas celulares cancerígenas metastásicas o resistentes a fármacos convencionales.
Metodología. En el Capítulo 2 se ha abordado el problema de la baja selectividad frente a células tumorales mediante el diseño racional de un novedoso complejo ciclometalado de iridio, caracterizado por su elevada afinidad hacia la seroalbúmina humana y por su notable potencial como agente en terapia fotodinámica dirigida selectivamente a tumores. A partir de la estructura química de este complejo inicial, se ha desarrollado en los Capítulos 3 y 4 un compuesto análogo, cuya conjugación a la albúmina y su encapsulación en nanopartículas polimérica han permitido demostrar la activación fotoinducida de una vía de muerte celular no convencional, la oncosis. El Capítulo 5 se centra en la síntesis de una serie de complejos de iridio emisores en la región del rojo, manteniendo constante el ligando auxiliar, con el propósito de aplicar la PDT en el tratamiento de tumores de pulmón y colon. Finalmente, en el Capítulo 6 se describe la preparación de una familia de compuestos quimioterapéuticos de iridio, diseñados para el diagnóstico y la eliminación de células madre cancerígenas.
Resultados. El diseño racional del Capítulo 2 mostró la elevada afinidad del complejo hacia la albúmina, mientras que los cálculos DFT revelaron propiedades fotofísicas excelentes que podrían facilitar mecanismos eficaces de transferencia de energía y electrones, esenciales para PDT de tipo I y II. Estudios experimentales verificaron que el compuesto genera oxígeno singlete y oxida a NADH tras su irradiación con luz azul. El respectivo conjugado con albúmina demostró una respuesta fototóxica significativa en células cancerosas CT26 de colon. Por su parte, el conjugado de albúmina del Capítulo 3 demostró una potente actividad fotocatalítica tras su irradiación con luz. Esto resultó en una fuerte respuesta citotóxica contra diversas líneas celulares cancerosas en cultivos 2D y esferoides multicelulares. Estudios biológicos posteriores revelaron que el conjugado condujo a la muerte celular por oncosis, un mecanismo poco explorado en terapia anticancerígena. Las nanopartículas poliméricas del Capítulo 4 mostraron excelentes propiedades fotosensibilizadoras, presentando una potente respuesta fotocitotóxica contra células de cáncer colorrectal CT26 y esferoides tumorales multicelulares. Estudios mecanísticos adicionales revelaron que las nanopartículas también indujeron la vía de muerte celular oncótica. Por otro lado, los complejos del Capítulo 5 mostraron un perfil emisivo desplazado al rojo en disoluciones acuosas, convirtiéndolos en agentes de diagnóstico idóneos. La evaluación fotobiológica demostró que los complejos poseen una actividad fototóxica elevada en las líneas celulares de carcinoma pulmonar A549 y HCC827, así como en la de adenocarcinoma HCT116 de colon. Este comportamiento fototóxico se asoció notablemente con un aumento en los niveles de ROS. Notablemente, el efecto fototerapéutico mostrado por uno de los complejos fue reproducible en modelos 3D. Por último, los complejos del Capítulo 6 mostraron su capacidad para oxidar NADH e inhibir varias proteínas involucradas en las rutas metabólicas asociadas a las células madre cancerígenas. Ensayos posteriores de citotoxicidad revelaron la notable eficacia terapéutica de los complejos contra células madre de cáncer de mama HMLERshEcad y modelos 3D celulares de mama, alcanzando valores de citotoxicidad en el rango micromolar.
Thesis objectives. This Doctoral Thesis has focused on the design, synthesis, photophysical characterization, photochemical evaluation, and determination of the biological activity of novel cyclometalated iridium complexes derived from benzazole fragments as potential drugs for photodynamic therapy (PDT) and chemotherapy against various metastatic or resistant cancer cell lines. Methodology. Chapter 2 addresses the issue of low selectivity toward tumor cells through the rational design of a cyclometalated iridium complex, characterized by its strong affinity for human serum albumin and its remarkable potential as a photosensitizing agent selectively targeting tumor tissues. Based on the chemical structure of this initial complex, an analogous compound was developed in Chapters 3 and 4, whose conjugation to albumin and encapsulation in polymeric nanoparticles demonstrated the photoinduction of a nonconventional cell death pathway, oncosis. Chapter 5 focuses on the synthesis of a series of red emitting iridium complexes, maintaining the auxiliary ligand constant, with the aim of applying PDT to the treatment of lung and colon tumors. Finally, Chapter 6 describes the preparation of a family of iridium chemotherapeutic compounds designed for the diagnosis and eradication of cancer stem cells. Results. The rational design described in Chapter 2 revealed the high affinity of the complex for albumin, while DFT calculations indicated excellent photophysical properties that could facilitate efficient energy and electron transfer mechanisms, essential for both type I and type II PDT. Experimental studies verified that the compound generates singlet oxygen and oxidizes NADH upon blue light irradiation. The corresponding albumin conjugate exhibited a significant phototoxic response in CT26 colon cancer cells. The albumin conjugate described in Chapter 3 demonstrated strong photocatalytic activity under light irradiation, leading to a potent cytotoxic response against various cancer cell lines in both 2D cultures and multicellular tumor spheroids. Subsequent biological studies revealed that the conjugate induced cell death via oncosis, rarely explored in anticancer therapy. The polymeric nanoparticles described in Chapter 4 displayed excellent photosensitizing properties, producing a strong phototoxic response against CT26 colorectal cancer cells and multicellular tumor spheroids. Additional mechanistic studies confirmed that the nanoparticles also induced oncotic cell death. Meanwhile, the complexes in Chapter 5 exhibited red emission profiles in aqueous solutions, making them promising diagnostic agents. Photobiological evaluation demonstrated that these complexes possess a favorable phototoxicity profile in A549 and HCC827 lung carcinoma cell lines, as well as in the colon HCT116 adenocarcinoma line. This phototoxic behavior was strongly associated with increased ROS levels. Remarkably, the phototherapeutic effect of one of the complexes was reproducible in 3D models. Finally, the complexes described in Chapter 6 showed the ability to oxidize NADH and inhibit several proteins involved in metabolic pathways associated with cancer stem cells. Subsequent cytotoxicity assays revealed the outstanding therapeutic efficacy of these complexes against HMLERshEcad breast cancer stem cells and 3D breast cellular models, achieving cytotoxicity values in the micromolar range
Thesis objectives. This Doctoral Thesis has focused on the design, synthesis, photophysical characterization, photochemical evaluation, and determination of the biological activity of novel cyclometalated iridium complexes derived from benzazole fragments as potential drugs for photodynamic therapy (PDT) and chemotherapy against various metastatic or resistant cancer cell lines. Methodology. Chapter 2 addresses the issue of low selectivity toward tumor cells through the rational design of a cyclometalated iridium complex, characterized by its strong affinity for human serum albumin and its remarkable potential as a photosensitizing agent selectively targeting tumor tissues. Based on the chemical structure of this initial complex, an analogous compound was developed in Chapters 3 and 4, whose conjugation to albumin and encapsulation in polymeric nanoparticles demonstrated the photoinduction of a nonconventional cell death pathway, oncosis. Chapter 5 focuses on the synthesis of a series of red emitting iridium complexes, maintaining the auxiliary ligand constant, with the aim of applying PDT to the treatment of lung and colon tumors. Finally, Chapter 6 describes the preparation of a family of iridium chemotherapeutic compounds designed for the diagnosis and eradication of cancer stem cells. Results. The rational design described in Chapter 2 revealed the high affinity of the complex for albumin, while DFT calculations indicated excellent photophysical properties that could facilitate efficient energy and electron transfer mechanisms, essential for both type I and type II PDT. Experimental studies verified that the compound generates singlet oxygen and oxidizes NADH upon blue light irradiation. The corresponding albumin conjugate exhibited a significant phototoxic response in CT26 colon cancer cells. The albumin conjugate described in Chapter 3 demonstrated strong photocatalytic activity under light irradiation, leading to a potent cytotoxic response against various cancer cell lines in both 2D cultures and multicellular tumor spheroids. Subsequent biological studies revealed that the conjugate induced cell death via oncosis, rarely explored in anticancer therapy. The polymeric nanoparticles described in Chapter 4 displayed excellent photosensitizing properties, producing a strong phototoxic response against CT26 colorectal cancer cells and multicellular tumor spheroids. Additional mechanistic studies confirmed that the nanoparticles also induced oncotic cell death. Meanwhile, the complexes in Chapter 5 exhibited red emission profiles in aqueous solutions, making them promising diagnostic agents. Photobiological evaluation demonstrated that these complexes possess a favorable phototoxicity profile in A549 and HCC827 lung carcinoma cell lines, as well as in the colon HCT116 adenocarcinoma line. This phototoxic behavior was strongly associated with increased ROS levels. Remarkably, the phototherapeutic effect of one of the complexes was reproducible in 3D models. Finally, the complexes described in Chapter 6 showed the ability to oxidize NADH and inhibit several proteins involved in metabolic pathways associated with cancer stem cells. Subsequent cytotoxicity assays revealed the outstanding therapeutic efficacy of these complexes against HMLERshEcad breast cancer stem cells and 3D breast cellular models, achieving cytotoxicity values in the micromolar range
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29-nov-2026
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