25 años de CENTIS. Pandemia y Radiofármacos / 25 years of CENTIS. Pandemic and Radiopharmaceuticals

Resumen Próximo a su 25 aniversario CENTIS reflexiona sobre su quehacer en el contexto de los trastornos que causa la COVID-19. Con ese propósito se examinan el estado de la medicina nuclear y la radiofarmacia antes y durante la epidemia y sus perspectivas de desarrollo. La producción global de radiofármacos continúa siendo una industria consolidada y aunque la pandemia afecta a esta esfera, la presencia de otras enfermedades no cesa, por lo que los servicios de medicina nuclear esenciales y críticos siguen siendo necesarios. Se espera su paulatina reapertura y que se retome con más fuerza la investigación, dado que la COVID-19 es tan compleja y se asocia a tantos factores que constituye, en perspectiva, terreno virgen para las técnicas diagnósticas en medicina nuclear. Ha de permanecer asimismo el papel de los radiofármacos terapéuticos en un grupo importante de enfermedades, en cáncer sobre todo. El Centro de Isótopos pone por ello énfasis tanto en la consolidación, bajo buenas prácticas, de la producción y el suministro de radiofármacos, como en el desarrollo de nuevos productos. Ambos aspectos se basan principalmente en dos radionúclidos: Tc-99m e Y-90.

Abstract Close to its 25th anniversary, CENTIS evaluates its work in the context of the disorders triggered by COVID-19. For this purpose, the situation of nuclear medicine and radiopharmacy, before and during the epidemic and their current development prospects is examined. The production of radiopharmaceuticals continues to be a consolidated global industry and although the pandemic affects this area, the presence of other diseases does not cease, so essential and critical nuclear medicine services are still needed, therefore its gradual reopening is expected. In addition, research will be taken with more strength, given that COVID-19 is so complex and associated with so many factors that it constitutes virgin terrain in perspective for diagnostic techniques in nuclear medicine. The role of therapeutic radiopharmaceuticals in an important set of diseases, especially cancer, will also remain. As a result, the Isotope Center focus its attention under good management practices, on the consolidation of the production and distribution of radiopharmaceuticals and in the development of new products. Both aspects are mainly based on two radionuclides: Tc-99m and Y-90.

Centro de Isótopos: acciones en beneficio de la salud pública / Center of Isotope: actions for the benefit of public health

RESUMEN En tributo a los cinco siglos de ciudad el Centro de Isótopos hace recuento de su actividad. La obtención de compuestos marcados con radionucleidos y otros trabajos radioquímicos en el Instituto de Física Nuclear, inaugurado en 1969, estimularon las aplicaciones de las fuentes radiactivas abiertas, por lo que puede considerarse el antecedente organizado más palpable del centro. Posteriormente en los años 80, la Secretaria Ejecutiva para Asuntos Nucleares aceleró, diversificó y amplió las aplicaciones, desarrolló la formación de cuadros y especialistas y la colaboración internacional. La puesta en operación del Centro de Estudios Aplicados al Desarrollo de la Energía Nuclear coincidió con la consolidación de un grupo de instituciones de investigación y producción biotecnológica y con el auge de las aplicaciones en Medicina Nuclear. Pronto se reconoció que no era posible continuar el manejo de un inventario cada vez mayor de radionucleidos, por lo que se diseñó y construyó un centro especializado a ciclo completo: investigación-desarrollo, producción y comercialización, el CENTIS. Durante su integración en 1994 a la Agencia de Energía Nuclear, se concluyó la inversión y se establecieron las metodologías de producción de los más importantes radiofármacos. En más de 20 años de labor CENTIS se ha convertido en el principal soporte de la Medicina Nuclear del país. Con sus capacidades metrológicas en la magnitud radiactividad y sus investigaciones no clínicas y clínicas, se inserta de forma cada vez más estrecha en la vida socio-económica del país y su capital. En el trabajo se detallan los principales resultados de cada etapa en lo relacionado a la misión del centro y se hace una valoración técnica de hacia dónde se encaminan acciones en favor de sus sectores destino: salud e investigación biomédica. Lustros en favor de siglos.

ABSTRACT To commemorate the 500th anniversary of the city of Havana, the Isotope Center reviews its activity since its creation. The production of radionuclidemarked compounds and other radiochemical work at the Institute of Nuclear Physics, inaugurated in 1969, stimulated the applications of open radioactive sources, which can be considered as the most tangible organized antecedent of the center. Later in the 1980s, the Executive Secretary for Nuclear Affairs accelerated, diversified and expanded nuclear applications, developed the training of highly qualified staff and experts as well as international cooperation. The creation of the Center for Applied Nuclear Development Studies coincided with the consolidation of a group of biotechnological research and production institutions and with these applications gaining importance in Nuclear Medicine. It was soon recognized that it was not possible to continue managing a growing inventory of radionuclides. As a result, CENTIS, a specialized center with a complete cycle, was designed and built, which comprised not only research and development, but also production and marketing. When in 1994 CENTIS became part of the Nuclear Energy Agency, investment was concluded and the production methodologies of the most important radiopharmaceuticals were established. In more than 20 years of work CENTIS has become the main support of Nuclear Medicine in the country. With its metrological capabilities in the magnitude of radioactivity and its non-clinical and clinical research, it is increasingly part of the socio-economic life of the country and its capital. In this paper the main results of each stage are detailed in relation to the mission of the center and a technical assessment is made regarding the actions taken to favor their target sectors: health and biomedical research. Periods of five years in favor of centuries.

[Direct and indirect labeling with 99mTc of an antireceptor monoclonal antibody of EGF]. / Marcaje directo e indirecto con 99mTc de un anticuerpo monoclonal antireceptor del factor de crecimiento epidérmico.

INTRODUCTION: Radiolabeled monoclonal antibodies (MAbs) have been a useful tool for diagnostic imaging and therapy in Oncology. The aim of this study was to carry out the indirect 99mTc radiolabeling of ior egf/r3, monoclonal antibody (MAb) specific for epidermal growth factor (EGF) receptor, and the comparison with a direct 99mTc radiolabeling approach. MATERIAL AND METHODS: Cyclic anhydride of the diethylenetriaminepentaacetic acid (ADTPA) was employed as bifunctional chelating agent in the indirect monoclonal antibody radiolabeling and it was coupled to MAb at molar ratios of 20:1, 50:1 and 200:1 (ADTPA:MAb). For the direct radiolabeling, the reduction of MAb was performed with 2-mercaptoethanol (2ME), based on Schwarz's method. Biological activity was measured by Flow Cytometry. Biodistribution studies were performed at 1, 3 and 24 h after injection of the radiolabeled antibody in Wistar rats. RESULTS: After 30 min of 99mTc radiolabeling of the ior egf/r3 MAb, the radiochemical purity values were between 80.0 +/- 1.8 and 90.0 +/- 1.2 % for the indirect method using ADTPA, while it was 94.8 +/- 1.6 % for the direct approach using 2ME. Stability of the 99mTc-radiopharmaceuticals was similar for both methods. The biological activity was similar for both antibody formulations. There were no significant differences for the biodistribution to normal organs for both radiolabeled antibodies. CONCLUSIONS: Use of ADTPA was shown to be an efficient method for the 99mTc labeling of the monoclonal antibody ior egf/r3. Radiolabeling using 2ME showed higher radiochemical purity.

Marcaje directo e indirecto con 99mTc de un anticuerpo monoclonal antireceptor del factor de crecimiento epidérmico / Direct and indirect labeling with 99mTc of an antireceptor monoclonal antibody of EGF

Introducción: La utilización de anticuerpos monoclonales (AcMs) radiomarcados ha sido una valiosa herramienta dentro de la Oncología, tanto para el diagnóstico por medio de imágenes como para la terapia. Constituye el objetivo fundamental del presente trabajo la radiomarcación indirecta con 99mTc del anticuerpo monoclonal (AcM) ior egf/r3, el cual es específico para el receptor del factor de crecimiento epidérmico (FCE), y la comparación de este procedimiento con un método directo. Material y métodos: Para el marcaje indirecto del anticuerpo se empleó el anhidrido cíclico del ácido dietilentriaminopentaacético (ADTPA) como agente quelantante bifuncional, realizándose la conjugación al AcM ior egf/r3 a relaciones molares de 20:1, 50:1 y 200:1 (ADTPA:AcM). El radiomarcaje directo del anticuerpo se basó en el método de Schwarz, utilizando el 2-mercaptoetanol (2ME) como agente reductor. La actividad biológica se determinó por citometría de flujo. Los estudios de biodistribución se realizaron a 1, 3 y 24 h de inyectado el anticuerpo radiomarcado en ratas Wistar. Resultados: A los 30 minutos de radiomarcado el AcM con 99mTc, se encontraron valores de pureza radioquímica entre 80,0 ± 1,8 y 90,0 ± 1,2 % mediante el ADTPA; mientras que con el 2ME, la pureza radioquímica fue de 94,8 ± 1,6. Se encontró similitud tanto en la estabilidad de los radiofármacos obtenidos por ambos métodos, como en la actividad biológica resultante. Los estudios de biodistribución muestran cierto nivel de captación en hígado, sangre y bazo, que no resultaron significativos. Conclusiones: Se demostró que el AcM ior egf/r3 puede ser radiomarcado de manera eficiente por vía indirecta, utilizando el ADTPA como agente quelatante bifuncional. Se obtuvo una mayor pureza radioquímica mediante el radiomarcaje con 2ME

Introduction: Radiolabeled monoclonal antibodies (MAbs) have been a useful tool for diagnostic imaging and therapy in Oncology. The aim of this study was to carry out the indirect 99mTc radiolabeling of ior egf/r3, monoclonal antibody (MAb) specific for epidermal growth factor (EGF) receptor, and the comparison with a direct 99mTc radiolabeling approach. Material and methods: Cyclic anhydride of the diethylenetriaminepentaacetic acid (ADTPA) was employed as bifunctional chelating agent in the indirect monoclonal antibody radiolabeling and it was coupled to MAb at molar ratios of 20:1, 50:1 and 200:1 (ADTPA:MAb). For the direct radiolabeling, the reduction of MAb was performed with 2-mercaptoethanol (2ME), based on Schwarz's method. Biological activity was measured by Flow Cytometry. Biodistribution studies were performed at 1, 3 and 24 h after injection of the radiolabeled antibody in Wistar rats. Results: After 30 min of 99mTc radiolabeling of the ior egf/r3 MAb, the radiochemical purity values were between 80.0 ± 1.8 and 90.0 ± 1.2 % for the indirect method using ADTPA, while it was 94.8 ± 1.6 % for the direct approach using 2ME. Stability of the 99mTc-radiopharmaceuticals was similar for both methods. The biological activity was similar for both antibody formulations. There were no significant differences for the biodistribution to normal organs for both radiolabeled antibodies. Conclusions: Use of ADTPA was shown to be an efficient method for the 99mTc labeling of the monoclonal antibody ior egf/r3. Radiolabeling using 2ME showed higher radiochemical purityIntroduction: Radiolabeled monoclonal antibodies (MAbs) have been a useful tool for diagnostic imaging and therapy in Oncology. The aim of this study was to carry out the indirect 99mTc radiolabeling of ior egf/r3, monoclonal antibody (MAb) specific for epidermal growth factor (EGF) receptor, and the comparison with a direct 99mTc radiolabeling approach. Material and methods: Cyclic anhydride of the diethylenetriaminepentaacetic acid (ADTPA) was employed as bifunctional chelating agent in the indirect monoclonal antibody radiolabeling and it was coupled to MAb at molar ratios of 20:1, 50:1 and 200:1 (ADTPA:MAb). For the direct radiolabeling, the reduction of MAb was performed with 2-mercaptoethanol (2ME), based on Schwarz's method. Biological activity was measured by Flow Cytometry. Biodistribution studies were performed at 1, 3 and 24 h after injection of the radiolabeled antibody in Wistar rats. Results: After 30 min of 99mTc radiolabeling of the ior egf/r3 MAb, the radiochemical purity values were between 80.0 ± 1.8 and 90.0 ± 1.2 % for the indirect method using ADTPA, while it was 94.8 ± 1.6 % for the direct approach using 2ME. Stability of the 99mTc-radiopharmaceuticals was similar for both methods. The biological activity was similar for both antibody formulations. There were no significant differences for the biodistribution to normal organs for both radiolabeled antibodies. Conclusions: Use of ADTPA was shown to be an efficient method for the 99mTc labeling of the monoclonal antibody ior egf/r3. Radiolabeling using 2ME showed higher radiochemical purity