Titanium-45: development and optimization of the production process in low energy cyclotrons
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2017-02-15
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Introdução: A Medicina praticada atualmente inclui o uso de inovações tecnológicas, tais como a Imagiologia Médica. As técnicas de imagiologia in vivo permitem avaliar estruturas e funções de forma não-invasiva, em quase todos os sistemas biológicos. O tema deste trabalho está centrado na Medicina Nuclear, que é uma modalidade de imagiologia médica com base na medição de uma fonte utilizando um marcador interno. Este método utiliza compostos marcados radioactivamente para estudar processos fisiológicos in vivo, pelo que a Medicina Nuclear está baseada no fornecimento de radionuclídeos.
No contexto específico da imagiologia por Tomografia de Emissão de Positrões (PET), os emissores de positrões são utilizados para radiomarcar vários compostos diferentes que permitem o estudo de praticamente todos os principais sistemas biológicos. Embora existam vários radionuclídeos para ser potencialmente aplicados em imagens de PET, as aplicações clínicas de rotina utilizam apenas um pequeno grupo de nuclídeos, constituído por 18F, 11C, 13N e, mais recentemente, o 68Ga. No entanto, a literatura recente indica que esta tendência está a mudar. Entre outros, 45Ti tem sido proposto como um candidato potencial para geração de imagens PET, uma vez que apresenta algumas propriedades interessantes: emissão eficiente de positrões, reduzida energia dos positrões, semi-vida física de 3,09 h, bem como as suas propriedades químicas relevantes, que permitem a marcação radioativa com quelatos bifuncionais, ligandos diversos ou mesmo para marcar radioactivamente nanopartículas de dióxido de titânio Porém, várias questões devem ser resolvidas antes da real possibilidade de implementar aplicações clínicas de 45Ti.
Objetivo: A produção do radionuclídeo é o primeiro passo técnico fundamental envolvido em PET, contudo a produção de 45Ti é ainda muito pouco explorada na literatura. O projeto relatado neste trabalho foi delineado e implementado de forma a estudar a viabilidade da produção de 45Ti em ciclotrões de baixa energia. Com este objetivo principal desenvolveu-se um programa de pesquisa completo para obter uma caracterização completa das funções de excitação da reação nuclear mais apropriada, determinação dos respetivos rendimentos e desenvolvimento de uma análise crítica para selecionar a metodologia mais apropriada.
Material e Métodos: Para avaliar as reações nucleares foram implementados estudos de ativação nuclear. No entanto, a execução desses estudos merece atenção especial e uma integração cuidadosa de toda a informação disponível já recolhida e publicada. Neste sentido, o primeiro passo desta experiência de ativação foi o planeamento adequado utilizando códigos de simulação Monte Carlo para prever resultados e selecionar os cenários mais prováveis. Os dados calculados foram totalmente integrados na conceção dos estudos experimentais. Ainda antes do estudo experimental de ativação, foram realizados ensaios experimentais preliminares com espectroscopia-gama com fontes calibradas de radionuclídeos, para avaliar a capacidade da técnica para ilustrar fenómenos físicos, tais como o decaimento radioativo e a interação de radiação com a matéria, e refinar a análise da experiência principal.
Finalmente, utilizou-se a técnica da pilha de lâminas num ciclotrão de 18 MeV para estudar a reação nuclear 45Sc(p,n)45Ti e a sua viabilidade para produzir efetivamente 45Ti. A ativação foi medida utilizando espectroscopia-gama com recurso a um detetor HPGe.
Resultados: De acordo com o código TALYS, e também devido a outras considerações práticas, a reação nuclear 45Sc(p, n)45Ti foi selecionada como aquela com mais potencial para obter quantidades significativas de 45Ti para aplicação industrial.
O cálculo com os códigos SRIM permitiu compreender a degradação da energia do feixe ao longo da pilha de lâminas concebida para o estudo da ativação induzida, enquanto que a sub-rotina SSSM foi usada para estudar a implantação do feixe do ciclotrão nos alvos sucessivos na pilha.
Obtiveram-se os dados relativos à função de excitação principal, bem como informações adicionais sobre reações concorrentes que levam à produção de 44mSc, 44Sc e 44Ti. Os resultados experimentais mostraram que a reação nuclear 45Sc(p,n)45Ti parece ser exequível em ciclotrões de baixa energia, com valores de secção eficaz que apresentam um pico para energias do feixe de protões compreendidas entre os 10 e os 14 MeV, enquanto que as energias superiores a 17 MeV devem ser evitadas, devido ao aumento da produção de contaminantes como o 44Ti, o 44Sc e o 44mSc. O rendimento de alvo espesso para uma condição de saturação foi determinado experimentalmente como 433,64 MBq.μA-1sat.
As evidências teóricas recolhidas demonstram que o 45Ti pode proporcionar uma boa qualidade de imagem PET, com algumas aplicações pré-clínicas já testadas em estudos relacionados com uma nova classe de fármacos anticancerígenos à base de complexos de titânio. Outras possíveis aplicações do 45Ti já citadas incluem a radiomarcação de ligandos para teragnóstico e medicina personalizada. Apresenta-se também uma proposta inovadora de uso de 45Ti para a marcação radioativa de nanopartículas de dióxido de titânio.
Conclusão: Existe a possibilidade de obter de forma eficaz quantidades significativas de 45Ti permitindo a sua possível produção comercial, distribuição industrial e utilização clínica. Como o 45Ti tem potencial de proporcionar boas imagens PET, e ser utilizado para a radiomarcação de diferentes compostos, deve ser testado de forma a ser incorporado no desenvolvimento de radiofármacos para imagiologia PET ou na marcação de nanopartículas para estudos aplicados de farmacologia e diferentes aplicações biomédicas.
Introduction: Modern practice of Medicine include the use of technological innovations such as Medical Imaging. In vivo imaging techniques can be used to evaluate biological structures and functions non-invasively in almost all living subjects. In this Thesis it will be highlighted Nuclear Medicine. As a simple definition, Nuclear Medicine is a medical imaging modality based on the measurement of an internal source from an internal tracer, reason why it uses radiolabeled compounds to study in vivo physiologic processes. So, Nuclear Medicine relies on the supply of radionuclides. In the specific context of Positron Emission Tomography (PET) imaging, positron emitters are used to label several different compounds, allowing the study of almost all the major biological systems. Although there are several radionuclides to be potentially applied in PET imaging, routine clinical applications are still based on a small group constituted by 18F, 11C, 13N and, more recently, 68Ga. However, recent literature indicates that this trend is changing. Among others, 45Ti is being proposed as a potential candidate for PET imaging, since it presents some interesting properties: abundant positron emission, reduced positron energy, physical half-life of 3.09h, and relevant chemical properties, that enable radiolabelling with bifunctional chelates, ligands or even to radiolabel titanium dioxide nanoparticles. Given this, several issues should be solved before the real possibility to implement 45Ti clinical applications. Aim: Considering that Radionuclide production is the first crucial technical step involved in PET, and that production of 45Ti is yet very poorly explored in literature, this Project was designed and implemented with the aim to study the viability of the production of 45Ti in low energy cyclotrons, expecting the characterization of the excitation functions of the appropriate nuclear reaction, yield determination and development of a critical analysis to select the best methodology. Materials and Methods: To evaluate nuclear reactions activation studies should be implemented. Nevertheless, the execution of nuclear activation studies deserve special attention and a careful integration of all the available information already collected. In this sense, the first step of this activation experiment was the adequate planning using Monte Carlo simulation codes in the way to obtain several results that were totally integrated in the design of experimental studies. Still before the experimental activation study, some preliminary experimental studies with gamma-spectroscopy were performed with calibrated radionuclide sources as demonstration of the ability of the technique to illustrate physical phenomena such as radioactive decay and radiation interaction with matter, and in the way to refine the analysis of the main experiment. Then, the stacked foil technique was implemented in a 18 MeV cyclotron to study the 45Sc(p,n)45Ti nuclear reaction and its feasibility to effectively produce 45Ti. Activation was measured using HPGe gamma-spectroscopy. Theoretical insight about the potential applications of 45Ti for PET imaging were also reviewed, analyzed, proposed and discussed. Results: According to TALYS code, and also due to other practical considerations, 45Sc(p,n)45Ti nuclear reaction was selected as the one with much more potential for industrial implementation in the way to obtain significant quantities of 45Ti. SRIM code simulations were used to understand the beam energy degradation along the stacked foil designed for the activation study, while SSSM sub-routine was used to study the implantation of the beam in the successive targets. Results on the main excitation function under study were collected, with the addition of information regarding concurrent reactions leading to 44mSc, 44Sc and 44Ti. Experimental results showed that 45Sc(p,n)45Ti nuclear reaction seems to be feasible in low energy cyclotrons, with cross-section values presenting a peak for proton beam energies in the range between 10 and 14 MeV, while energies higher than 17 MeV should be avoided due to the increased production of contaminants such as 44Ti, 44Sc and 44mSc. Thick target yield for a saturation condition was experimentally determined as 433.64 MBq.μA-1sat. Theoretical evidences collected demonstrate that 45Ti could provide good PET image quality, with some preclinical applications already tested in studies related to a new class of anticancer drugs based on titanium complexes. Other possible applications already cited include 45Ti-ligands for theranostics and personalized medicine. An innovative proposal on the use of 45Ti to radiolabel of titanium dioxide nanoparticles will also be presented and discussed. Conclusion: Thus, there is the possibility to effectively obtain significant quantities of 45Ti allowing its possible commercial and industrial production, distribution and use. Given this, 45Ti could then provide good PET images and be used for labeling of different compounds already tested or to be incorporated in the development of nanoparticle-based radiopharmaceuticals.
Introduction: Modern practice of Medicine include the use of technological innovations such as Medical Imaging. In vivo imaging techniques can be used to evaluate biological structures and functions non-invasively in almost all living subjects. In this Thesis it will be highlighted Nuclear Medicine. As a simple definition, Nuclear Medicine is a medical imaging modality based on the measurement of an internal source from an internal tracer, reason why it uses radiolabeled compounds to study in vivo physiologic processes. So, Nuclear Medicine relies on the supply of radionuclides. In the specific context of Positron Emission Tomography (PET) imaging, positron emitters are used to label several different compounds, allowing the study of almost all the major biological systems. Although there are several radionuclides to be potentially applied in PET imaging, routine clinical applications are still based on a small group constituted by 18F, 11C, 13N and, more recently, 68Ga. However, recent literature indicates that this trend is changing. Among others, 45Ti is being proposed as a potential candidate for PET imaging, since it presents some interesting properties: abundant positron emission, reduced positron energy, physical half-life of 3.09h, and relevant chemical properties, that enable radiolabelling with bifunctional chelates, ligands or even to radiolabel titanium dioxide nanoparticles. Given this, several issues should be solved before the real possibility to implement 45Ti clinical applications. Aim: Considering that Radionuclide production is the first crucial technical step involved in PET, and that production of 45Ti is yet very poorly explored in literature, this Project was designed and implemented with the aim to study the viability of the production of 45Ti in low energy cyclotrons, expecting the characterization of the excitation functions of the appropriate nuclear reaction, yield determination and development of a critical analysis to select the best methodology. Materials and Methods: To evaluate nuclear reactions activation studies should be implemented. Nevertheless, the execution of nuclear activation studies deserve special attention and a careful integration of all the available information already collected. In this sense, the first step of this activation experiment was the adequate planning using Monte Carlo simulation codes in the way to obtain several results that were totally integrated in the design of experimental studies. Still before the experimental activation study, some preliminary experimental studies with gamma-spectroscopy were performed with calibrated radionuclide sources as demonstration of the ability of the technique to illustrate physical phenomena such as radioactive decay and radiation interaction with matter, and in the way to refine the analysis of the main experiment. Then, the stacked foil technique was implemented in a 18 MeV cyclotron to study the 45Sc(p,n)45Ti nuclear reaction and its feasibility to effectively produce 45Ti. Activation was measured using HPGe gamma-spectroscopy. Theoretical insight about the potential applications of 45Ti for PET imaging were also reviewed, analyzed, proposed and discussed. Results: According to TALYS code, and also due to other practical considerations, 45Sc(p,n)45Ti nuclear reaction was selected as the one with much more potential for industrial implementation in the way to obtain significant quantities of 45Ti. SRIM code simulations were used to understand the beam energy degradation along the stacked foil designed for the activation study, while SSSM sub-routine was used to study the implantation of the beam in the successive targets. Results on the main excitation function under study were collected, with the addition of information regarding concurrent reactions leading to 44mSc, 44Sc and 44Ti. Experimental results showed that 45Sc(p,n)45Ti nuclear reaction seems to be feasible in low energy cyclotrons, with cross-section values presenting a peak for proton beam energies in the range between 10 and 14 MeV, while energies higher than 17 MeV should be avoided due to the increased production of contaminants such as 44Ti, 44Sc and 44mSc. Thick target yield for a saturation condition was experimentally determined as 433.64 MBq.μA-1sat. Theoretical evidences collected demonstrate that 45Ti could provide good PET image quality, with some preclinical applications already tested in studies related to a new class of anticancer drugs based on titanium complexes. Other possible applications already cited include 45Ti-ligands for theranostics and personalized medicine. An innovative proposal on the use of 45Ti to radiolabel of titanium dioxide nanoparticles will also be presented and discussed. Conclusion: Thus, there is the possibility to effectively obtain significant quantities of 45Ti allowing its possible commercial and industrial production, distribution and use. Given this, 45Ti could then provide good PET images and be used for labeling of different compounds already tested or to be incorporated in the development of nanoparticle-based radiopharmaceuticals.
Descrição
Tese de Doutoramento em Ciências Físicas
Palavras-chave
Ciclotrão , Medicina nuclear , PET , Produção de radionuclídeos