Nanotubos de TiO2 reducido como potencial plataforma para fotoquimioterapia del cáncer.
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Date
2024
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Universidad de Concepción
Abstract
El cáncer es un conjunto de enfermedades que ha causado una alta tasa de mortalidad alrededor del mundo, por lo que es de vital importancia el desarrollo de diversas estrategias de tratamiento debido al gran impacto que tiene sobre la sociedad. En ese sentido, el uso de nanomateriales ha surgido como un enfoque prometedor para el desarrollo de sistemas con la capacidad de propiciar modalidades de tratamiento combinadas para mejorar la eficacia y superar limitaciones relacionadas a los tratamientos convencionales. Por lo anterior, en la presente tesis doctoral se prepararon nanotransportadores basados en dióxido de titanio (TiO2) sin reducir y reducido, funcionalizados superficialmente con los fotosensibilizadores Chlorin e6 (Ce6) y Toluidine Blue O (TBO), con capacidad de adsorber fármacos quimioterapeuticos con el propósito de combinar los efectos de la administración de fármacos, mediada por nanomateriales, y la producción de especies reactivas de oxígeno (ROS), esenciales para la terapia fotodinámica (PDT–Photodynamic Therapy), como estrategias para inducir muerte de células cancerosas. La caracterización realizada en las diferentes etapas de preparación de los nanomateriales confirman la obtención de nanorods de TiO2 que tras ser sometidos al tratamiento térmico con NaBH4 dan lugar a nanorods de TiO2 negro (NRTN). Los sistemas que poseen fotosensibilizadores unidos covalentemente a su superficie evidenciaron la generación de ROS, específicamente 1O2 y HO•, bajo irradiación con luz LED visible, las cuales fueron detectadas a través de un método fluorimétrico empleando hidroxifenilfloresceína (HPF) y Sensor de Oxígeno Singlete Verde (SOSG), como sensores de HO• y 1O2, respectivamente.
Los experimentos de viabilidad celular in vitro con células HeLa mostraron que los nanomateriales preparados exhiben actividad fotodinámica cuando se irradian con luz LED visible (150 W m-2), y no son citotóxicos en oscuridad bajo las condiciones evaluadas. Además, los experimentos de encapsulación de doxorrubicina (DOX), como fármaco quimioterapéutico modelo, demostraron que las nanoestructuras encapsulan eficazmente DOX y las formulaciones de nanomateriales/DOX muestran efectos quimiocitotóxicos en las células HeLa.
Los experimentos combinados de quimio-fototoxicidad muestran efectos mejorados en cuanto a la reducción de la viabilidad de las células HeLa, indicando que los NRTN conjugados con fotosensibilizadores son plataformas prometedoras para su uso en terapia combinada inducida por irradiación de luz visible.
Cancer is a group of diseases with a high mortality rate worldwide, making the development of various treatment strategies vital due to its significant impact on society. In this sense, nanomaterials have emerged as a promising approach for developing systems that can promote combined treatment modalities to improve efficacy and overcome the limitations of conventional treatments. In this work, nanocarriers based on unreduced and reduced titanium dioxide (TiO2) were prepared and superficially functionalized with the photosensitizers Chlorin e6 (Ce6) and Toluidine Blue O (TBO). These nanocarriers can adsorb chemotherapeutic drugs, combining the effects of nanomaterial-mediated drug delivery with the production of reactive oxygen species (ROS), essential for photodynamic therapy (PDT) to induce cancer cell death. The characterization during the preparation stages confirmed the formation of TiO2 nanorods; precursors used to produce black TiO2 nanorods (NRTN) after thermal treatment with NaBH4. The systems covalently conjugated with photosensitizers generated 1O2 and HO• under visible LED light irradiation. These species were detected using a fluorimetric method with Hydroxyphenyl fluorescein (HPF) and Singlet Oxygen Sensor Green (SOSG) as sensors for HO• and 1O2, respectively. In vitro cell viability experiments with HeLa cells showed that the prepared nanomaterials exhibited photodynamic activity when irradiated with visible LED light (150 W m-2) and were non-cytotoxic in darkness under the tested conditions. Furthermore, encapsulation experiments with doxorubicin (DOX), a model chemotherapeutic drug, demonstrated that the nanostructures effectively encapsulated DOX. The nanomaterials/DOX formulations exhibited chemocytotoxic effects on HeLa cells. Combined chemo-phototoxicity experiments showed enhanced effects in reducing HeLa cell viability, indicating that NRTNs conjugated with photosensitizers are promising platforms for combined therapy induced by visible light irradiation.
Cancer is a group of diseases with a high mortality rate worldwide, making the development of various treatment strategies vital due to its significant impact on society. In this sense, nanomaterials have emerged as a promising approach for developing systems that can promote combined treatment modalities to improve efficacy and overcome the limitations of conventional treatments. In this work, nanocarriers based on unreduced and reduced titanium dioxide (TiO2) were prepared and superficially functionalized with the photosensitizers Chlorin e6 (Ce6) and Toluidine Blue O (TBO). These nanocarriers can adsorb chemotherapeutic drugs, combining the effects of nanomaterial-mediated drug delivery with the production of reactive oxygen species (ROS), essential for photodynamic therapy (PDT) to induce cancer cell death. The characterization during the preparation stages confirmed the formation of TiO2 nanorods; precursors used to produce black TiO2 nanorods (NRTN) after thermal treatment with NaBH4. The systems covalently conjugated with photosensitizers generated 1O2 and HO• under visible LED light irradiation. These species were detected using a fluorimetric method with Hydroxyphenyl fluorescein (HPF) and Singlet Oxygen Sensor Green (SOSG) as sensors for HO• and 1O2, respectively. In vitro cell viability experiments with HeLa cells showed that the prepared nanomaterials exhibited photodynamic activity when irradiated with visible LED light (150 W m-2) and were non-cytotoxic in darkness under the tested conditions. Furthermore, encapsulation experiments with doxorubicin (DOX), a model chemotherapeutic drug, demonstrated that the nanostructures effectively encapsulated DOX. The nanomaterials/DOX formulations exhibited chemocytotoxic effects on HeLa cells. Combined chemo-phototoxicity experiments showed enhanced effects in reducing HeLa cell viability, indicating that NRTNs conjugated with photosensitizers are promising platforms for combined therapy induced by visible light irradiation.
Description
Tesis presentada para optar al grado académico de Doctora en Ciencias con mención en Química
Keywords
Fotoquimioterapia, Nanotecnología, Oncología médica