Tesis sobre el tema "Astature"

La chimie supramoléculaire consiste en l’assemblage par des interactions non-covalentes d’architectures moléculaires plus ou moins complexes. A l’état naturel, ces édifices remplissent de nombreuses fonctions telle que le support génétique par la molécule d’ADN. Les anions peuvent aussi être impliqués au niveau radiothérapeutique par le biais de l’iodure. Par opposition, ce même élément peut être associé à certaines catastrophes environnementales (explosion de Fukishima, 2011) voire à certaines pathologies (thyroïdopathie). Face aux problématiques citées, il est donc primordial de développer des outils permettant de lutter face à ces évènements désastreux. Les travaux présentés ici consistent en l’élaboration de macrocycles de type boronium pouvant piéger de manière efficace l’iodure, anion modèle pour l’étude de la capture de l’astature et encore peu connu, en raison de son faible temps de demi-vie. Cette coordination s’effectue par une collaboration de liaisons hydrogène et d’interactions ioniques. Sur la base des travaux antérieurs réalisés au laboratoire, il a été question d’étudier de manière approfondie les propriétés de complexation des cages synthétisées, les Calix-carBIB. Dans un deuxième temps, de nouveaux groupements fonctionnels ont été utilisés afin d’étudier leur potentiel pour différentes applications, notamment pour la purification de l’astature ou encore la vectorisation. Enfin, une nouvelle génération de récepteurs a été étudiée, présentant en théorie une affinité plus importante pour l’astature
Supramolecular chemistry consists of molecular architecture complex organized thanks to a combination of non-covalent interactions. At the natural state, these structures have numerous functions such as cell energy production thanks to the ATP synthase or the genetic support thanks to a polyanion, the DNA molecule. Anions can be involved in radiotherapy through iodide. By opposition, it can also be associated with environmental disasters (Fukushima explosion in 2011) or some diseases (thyroid disease). In front of these troubles, it is a priority to fight against theses disastrous events. This PhD work has focused on the construction of boronium type macrocycle able to strongly trap iodide which is an anion model to study astatide trapping. This coordination is done thanks to hydrogen bonding and ionic interactions collaboration. Based on previous works realized in our laboratory in 2010, complexation properties of Calix-carBIB were studied. In a second time, new functionalized groups were used to study their potential for different applications such as astatide purification, water solubility and vectorization. Finally, a new receptor generation was studied, showing a better affinity for astatide

L'astate (At, Z = 85) est un élément halogène rare, tous ses isotopes étant radioactifs. En raison des quantités disponibles limitées, aucun outil spectroscopique n'est applicable pour identifier la nature moléculaire des espèces d'At. En conséquence, la chimie de l'At reste méconnue. L'un de ses isotopes, ²¹¹At, est un candidat potentiel pour le traitement de cancers par thérapie alpha ciblée. Cependant, la connaissance limitée de ses propriétés chimiques a entravé les tentatives de marquage de ²¹¹At avec des molécules porteuses ciblant la maladie. Cela a conduit au développement d’un programme de recherches sur la chimie de base de At. Cette thèse s’intéresse plus particulièrement au diagramme de Pourbaix de l’astate et à la caractérisation de liaisons halogènes avec l’espèce AtI, au moyen de divers outils expérimentaux (chromatographie ionique, méthode de compétition et électromobilité). Dans une première partie, des études de spéciation de At en milieu alcalin confirment la présence de l'espèce At⁻ en conditions réductrices. Lorsque le potentiel augmente, l’espèce AtO(OH)₂⁻ se forme. Le changement de spéciation entre ces deux espèces est décrit pour la première fois. Dans une deuxième partie, la formation de liaisons halogènes entre l'espèce AtI et divers composés organiques a été étudiée. La réactivité se résume par une échelle de basicité nouvellement établie dont la force entre le donneur (AtI) et l’atome accepteur varie suivant l’ordre C ≤ O ≤ S (≈ Se)
Astatine (At, Z = 85) is a scarce halogen element, all of its isotopes being radioactive. Due to the limited available quantities, no spectroscopic tool is applicable to identify the molecular nature of At species. Consequently, the chemistry of At remains poorly known. One of its isotopes, ²¹¹At, is a potential candidate for the treatment of cancers by targeted alpha therapy. However, the limited knowledge of its chemical properties has hindered attempts to label ²¹¹At with disease targeting carrier molecules. This led to the development of a research program on the basic chemistry of At. This thesis focuses more particularly on the Pourbaix diagram of astatine and the characterization of halogen bonds with the AtI species, by means of various experimental tools (ion chromatography, competition method and electromobility). In the first part, speciation studies of At in alkaline medium confirm the presence of the At⁻ species under reducing conditions. As the potential increases, the AtO(OH)₂⁻ species is formed. The speciation change between these two species is described for the first time. In a second part, the formation of halogen bonds between the AtI species and various organic compounds was studied. The reactivity is summarized by a newly established basicity scale, with the strength between the donor (AtI) and the acceptor atom following the order of C≤ O ≤ S (≈ Se)

Introduction Since 2005, we produce, at academic scale in Orleans, 211At for needs of chemistry and physicians teams of Nantes in research project of alpha immunotherapy. Between 2005 and 2014, several modifications were been made on preparation of target, targetry and radiation to protect personnel. Material and Methods The first target was a molten Bi metal onto a Cu support pre-treated with acid attack. The wished thickness (up to 100 µm) was obtained by mechanical treatment of target. The target is irradiated at 32MeV alpha particle beam for around 2 hours and then delivered by road transport to users. Only a measure of radiation dose was made to evaluate target activity. The second target we have used since 2010 is a electrodeposition of Bi (thickness of around 30 µm) onto AlN backing. We used a beam of 30.5 MeV for reaction 207Bi(α,n)211At (2 h with a current intensity of 2µA). Activity has measured with a detector Ge at 687 keV (γ-branching fraction = 0.26 %) before to be delivered. For all targets, beam energy on target was around 28.7 Mev in order not to produce too much 210At. Results and Conclusion 138 productions with the first target were delivered with an estimated activity of less than 100 MBq. Difficulties with wet extraction1, low yield of radiolabelling (metallic impurities and activation of copper resulting in 66Ga and 67Ga) made necessary to change process of extraction. With support of AlN, dry extraction was used with good yield (75–80 %) and without activation of support. Until today, 46 batchs were delivered with activity of 44 ± 12 MBq/µAh. Yield activity of 211At has been almost doubled compared to first target (25MBq/µAh). The dose burden to personnel was decreased with modification of targetry (outside of blockhouse of cyclotron, in a specific line beam to radionuclide production, cf. FIG. 1). In the case of 211At production, energy of reaction is of major impact. With our versatile accelerator (range of energy in alpha between 10 and 50 MeV) and a low thickness of metal, it’s easy to reach the right energy. This radionuclide production will be continued until ARRONAX, Nantes cyclotron, could take over from us for bigger activity of 211At.

L'alpha-radiothérapie est une technique particulièrement innovante de thérapie des cancers, tout en étant complémentaire des thérapies déjà existantes. Elle repose sur l'utilisation d'un vecteur spécifique (anticorps ou peptide) de la cellule cible à détruire,radiomarqué » par un élément radioactif émetteur alpha. L'astate 211 est un candidat particulièrement intéressant compte tenu de l'énergie des particules  qu'il émet et de sa période physique (7,2 h). L'une des voies de marquage envisagée est l'utilisation de l'astate à un degré d'oxydation supérieur à zéro en tant que cation. En effet, l'astate est supposé présenter un caractère plus métallique que les autres halogènes du fait de son positionnement dans le tableau périodique. Cette voie de marquage a été peu abordée dans la littérature en raison du manque de données sur la chimie de l'astate aux degrés d'oxydation supérieurs à zéro. Le but de ce travail était donc d'explorer cette propriété de l'astate via la construction du diagramme Eh, pH (ou diagramme de Pourbaix) en milieu aqueux non complexant. Pour ce faire, ce travail s'est appuyé sur une double approche expériementale/théorique. L'approche expérimentale utilise des méthodes dites de compétition pour identifier les espèces formées et les constantes thermodynamiques des équilibres étudiés. L'approche théorique utilise des méthodes de chimie computationnelle et fournie des informations à l'échelle moléculaire sur les systèmes étudiés afin de prédire les données thermodynamiques qui servent de support et complément à l'approche expérimentale. Un résultat important de ce travail montre la présence de deux espèces cationiques stables de l'astate en solution aqueuse, At+ et AtO+
Alpha-radiotherapy is an innovative technique for the treatment of cancers complementary to current approaches. The principle is to use tumor-specific vectors labeled with alpha-radioisotopes. Astatine 211 is a very promising candidate if one considers the energy of the  particles emitted as well as its physical half-life (7. 2 h). One of the ways of labeling is to use astatine at a higher oxidation state as a « metal cation ». Indeed, considering its location in the periodic table, astatine is supposed to present a more metallic character than the other halogens. This way of labeling has however never been explored. This can be explained by the fact that the astatine chemistry is nearly unknown. The purpose of this work was therefore to explore this property of astatine and to define its Eh, pH diagram (or Pourbaix diagram) in non complexing aqueous solution. To this end, both experimental and theoretical approaches were used. The experimental approach uses competition methods to identify the formed species and the thermodynamics constants of studied equilibria. The theoretical approach uses methods of computational chemistry and provides information at the molecular scale on the studied systems in order to predict thermodynamic data which are used as support and complement to the experimental approach. The important result of this work shows the presence of two stable cationic forms of astatine in aqueous solution, i. E;, At+ and AtO+

La thérapie alpha ciblée est une technique prometteuse pour le traitement de cancers. L’astate-211, de temps de demi-vie de 7,21 h, est considéré comme un candidat prometteur pour cette application. Une condition pré-requise est de fixer de manière stable l’isotope radioactif sur le vecteur qui va servir à reconnaitre les cellules malades. Ceci demande une connaissance approfondie des propriétés chimiques de l’astate. Compte tenu de sa position dans le tableau périodique des éléments, l’astate peut exister sous la forme At− en cohérence avec les propriétés chimiques des autres halogènes, et possède aussi un caractère plus métallique qui explique l’existence d’espèces cationiques stables. L’objectif de cette thèse est d’identifier et d’étudier les propriétés des différentes espèces de l’astate en solution aqueuse. La prédominance de l’espèce At− en milieu acide réducteur a été confirmée au moyen d’une technique d’électromobilité. Une première valeur de mobilité absolue est ainsi proposée. En milieu plus oxydant, l’espèce At+ domine. La réactivité de cette espèce avec les ions de la série des halogènes a été étudiée/quantifiée. Une espèce exotique IAtBr− a notamment été mise en évidence grâce à l’aide d’outils de modélisation moléculaire. La particularité du compound AtI à former des liaisons de type halogène a été montrée pour la première fois
Targeted alpha therapy is an appealing method for the treatment of cancer as a complement to the current approaches. Astatine-211, with a half-life of 7.21 h, is considered as an exciting prospective candidate for this application. A pre-required condition is to fix in a stable way the radioactive isotope to the vector that is going to serve to recognize cells. This asks for a thorough knowledge of the chemical properties of astatine. Considering its position in the periodic table, it can exist under the form At− in coherence with the chemical properties of the other halogens, and also possesses a more metallic character that explains the existence of stable cationic species. The objective in this work is to identify the properties of different At species in aqueous solution. The predominance of the species At− in reducing acidic conditions was confirmed by means of a technique of electromobility. A first value of absolute mobility is then proposed. In more oxidizing conditions, the species At+ dominates. The reactivity of this species with the ions of the halogens series was studied/quantified. An exotic species IAtBr− was highlighted in particular thanks to the help of modeling tools. The peculiarity of the compound AtI to form halogen-type bonds was shown for the first time

L'astate-211 est un radionucléide émetteur de particules alpha très prometteur pour la thérapie des cancers. Associé à un vecteur immunologique adapté, il pourrait permettre le traitement de différents types de micrométastases ou de cancers résiduels. Cependant, le manque de stabilité des méthodes de radiomarquage des anticorps avec ce radionucléide est un frein au développement d'applications cliniques. Ces travaux ont eu pour but la mise au point d'une nouvelle méthode de radiomarquage des anticorps à l'astate-211. La spécificité de cette méthode est d’utiliser pour la première fois l'astate-211 sous forme hypervalente. Des précurseurs stanniques ont été conçus pour permettre l'introduction de l'astate-211 sous une forme trivalente stabilisée. L'étude de faisabilité du radiomarquage des anticorps par cette méthode ainsi que les tests de stabilité préliminaires ont également été réalisés
Astatine-211 is a promising alpha emitter for the therapy of cancers. In association with a suited immunologic carrier, it could allow the treatment of some micrometastasis or residual cancer diseases. However, the lack of stability of the radiolabelling of the antibodies with this radionuclide is a limitation for the development of clinical applications. This work describes a new approach for the radiolabelling of the antibodies with astatine-211. The specificity of this method is the use for the first time of hypervalent astatine. Tin precursors were designed to allow the introduction of astatine-211 under a stabilised trivalent state. The feasibility study of the radiolabelling of the antibodies with this method and the preliminary stability assesments are also described

Les tentatives menées pour détruire des cellules cancéreuses avec les agents radiothérapeutiques à base de 211 At qui ont été synthétisés jusqu’à présent ne sont pas encore pleinement satisfaisantes car elles sont entachées par une deastatination in vivo. Étant donné que ce problème est lié aux connaissances actuelles qui sont limitées concernant la chimie de base de l’astate et de ses espèces, des recherches fondamentales combinant des expériences à l’échelle des ultra-traces et des études théoriques ont été lancées. Dans cette thèse, une étude théorique de plusieurs espèces de l’astate est réalisée au moyen de méthodes relativistes basées sur la théorie de la fonctionnelle de la densité ou des méthodes à basées sur la fonction d’onde. Tout d'abord, les méthodes qui peuvent être utilisées pour faire des prédictions pertinentes sont établies. A l’aide de ces approches, nous rationaliserons les structures électroniques, géométries et propriétés physicochimiques des différents systèmes d'intérêt théorique ou expérimental, en particulier les espèces AtF3 et AtO+. Finalement, nous identifierons formellement une nouvelle espèce de l’astate à l’aide de résultats expérimentaux et de calculs, ce qui non seulement complète le diagramme de Pourbaix de l’astate en milieu aqueux non complexant, mais aussi donne des informations cruciales pour identifier des conditions expérimentales pour rendre le plus « réactif » possible le précurseur At−, qui est de nos jours impliqué dans la synthèse d’agents radiothérapeutiques innovants
Trials to destroy cancer cells with currently synthesized 211 At-based radiotherapeutic agents are not yet fully satisfactorily since they resume to in vivo deastatination. Since this issue is related to the limited knowledge of the basic chemistry of At and its species, fundamental researches combining ultra-trace experiments and computational studies have been initiated. In this thesis, a computational study of several At species is performed, by means of relativistic density functional theory and wave-function-based calculations. First, the quantum mechanical approaches that can safely be used to make adequate predictions are established. Using these approaches, we attempt to rationalize the electronic structures, geometries, and physico-chemical properties of various systems of theoretical and/or experimental interest, in particular the AtF3 and AtO+ ones. By the end, we firmly identify a new At species by combining outcomes of experiments and calculations. This new species not only completes the Pourbaix diagram of At in aqueous and non-complexing media, but also gives clues of identifying experimental conditions to make best reactive the At– precursor, which is currently involved in the synthesis of promising radiotherapeutic agents

La radio-immunothérapie alpha est une thérapie anticancéreuse prometteuse qui consiste à vectoriser des radionucléides émetteurs de particules alpha à l'aide d'agents immunospécifiques de certaines tumeurs afin de les détruire. La première partie de ce travail présente les différentes caractéristiques conditionnant la réussite de la radio-immunothérapie en replaçant cette approche thérapeutique originale dans l'arsenal anti-cancéreux. Au cours de ces dernières années, l'astate-211 est apparu comme l'un des isotopes émetteurs de particules alpha les plus intéressants, l'ensemble des caractéristiques chimiques, physiques, biologiques ainsi que les différents essais de couplage à des immunovecteurs sont analysés dans cette partie. La seconde partie de ce mémoire a pour but d'évaluer la faisabilité de marquage d'une structure protéique de type immunovecteur (immunoglobuline entière ou fragment de type F(ab’)2) avec de l'astate-211 produit par irradiation cyclotron et extrait de sa cible par une voie originale d'extraction liquide (attaque par de l'acide nitrique). Cette étude expérimentale à permis d'optimiser ce type de marquage en vue d'obtenir un immunovecteur fonctionnel et suffisamment stable in vivo pour envisager une étude pré-clinique
Alpha radio-immunotherapy is a promising cancer therapy that uses alpha-particles vectorized by monoclonal antibody to break down cancerous tumours. The first part of this work presents the different factors that affect the success of radio-immunotherapy in cancer treatment. Specifically we concentrate on astatine-211, an α particle emitting isotope that has shown great promise for cancer treatment. The differents studies of the immuno-vectorisation of this isotope are also presented in this section. The second part of this thesis aims to evaluate the feasibility of immunoglobulin labelling (full or F(ab')2 fragment) with astatine-211. The labelling took place using a cyclotron irradiation to produce astatine-211 which was subsequently extracted by treating the target with nitric acid. This experimental study allowed us to optimize the labelling process to an in vivo stable immunoglobin labelled with astatine-211 such that a pre-clinical study is plausible

L’astate-211 est un radionucléide prometteur pour la thérapie alpha vectorisée des cancers. Cependant, les méthodes actuelles de radiomarquage d’anticorps avec ce radiohalogène présentent de nombreuses limites telles que des rendements non-optimaux ou l’utilisation de précurseurs toxiques, ce qui complique son transfert en clinique. Afin de proposer des alternatives plus viables, l’exploration de nouvelles classes de précurseurs permettant le radiomarquage avec l’astate-211 et l’iode-125 sous forme nucléophile a été menée. Dans un premier temps, la synthèse de composés modèles pour chacune de ces classes et leur comparaison en termes d’efficacité a été réalisée afin d’identifier les plus adaptées pour le radiomarquage avec ces deux radionucléides. Dans une deuxième partie, la faisabilité d’un radiomarquage d’anticorps à l’astate-211 et à l’iode-125 en une seule étape, utilisant les acides arylboroniques, a été investigué. Dans un premier temps, l’étude de réactivité sur un composé modèle simple a été effectuée afin d’identifier des conditions efficaces en milieu aqueux et à basse température avant de transférer cette approche à un anticorps anti- CD138 d’intérêt pour le ciblage du myélome multiple. Le nouveau procédé ainsi développé surpasse les autres méthodes rapportées dans la littérature et a été validé par des études précliniques de biodistributions. Cette nouvelle méthode de radiomarquage devrait faciliter le passage de l’astate-211 en clinique et permettre le développement d’outils théranostiques basés sur la paire astate/iode
Astatine-211 is a promising radionuclide for targeted alpha therapy of cancers. However, current approaches to bind this radiohalogen to an antibody exhibit limitations such as suboptimal radiochemical yields or the use of toxic precursors, which complicates its clinical transfer. In order to find better alternatives, we explored new classes of precursors, which allow the radiolabelling with astatine-211 and iodine-125 in their nucleophilic form. First, the synthesis of model compounds for each class and the comparison of their efficiency were performed to identify the most promising ones for the radiolabelling with both radionuclides. In a second part, the feasibility of the one-step radiolabelling of antibodies with astatine-211 and iodine-125 using arylboronic acids has been investigated. First, the study on a model compound was conducted in order to identify efficient conditions in aqueous medium and at low temperature before transfering this approach to an anti-CD138 antibody of interest for targeting multiple myeloma. The new process developped outperforms others methods reported in the litterature and has been validated in preclinical biodistribution studies. This new radiolabelling method will ease the clinical transfer of astatine-211 as well as the development of theranostic tools based on the astatine/iodine pair

L'alpha-radiothérapie est une technique particulièrement innovante de thérapie des cancers, tout en étant complémentaire des thérapies déjà existantes. Elle repose sur l'utilisation d'un vecteur spécifique (anticorps ou peptide) de la cellule cible à détruire, radiomarqué par un élément radioactif émetteur alpha. L'astate 211 est un candidat particulièrement intéressant compte tenu de l'énergie des particules α qu'il émet et de sa période physique (7,2 h). L'une des voies de marquage envisagée est l'utilisation de l'astate à un degré d'oxydation supérieur à zéro en tant que cation. En effet, l'astate est supposé présenter un caractère plus métallique que les autres halogènes du fait de son positionnement dans le tableau périodique. Cette voie de marquage a été peu abordée dans la littérature en raison du manque de données sur la chimie de l'astate aux degrés d'oxydation supérieurs à zéro. Le but de ce travail était donc d'explorer cette propriété de l'astate via la construction du diagramme Eh, pH (ou diagramme de Pourbaix) en milieu aqueux non complexant. Pour ce faire, ce travail s'est appuyé sur une double approche expérimentale / théorique. L'approche expérimentale utilise des méthodes dites de compétition pour identifier les espèces formées et les constantes thermodynamiques des équilibres étudiés. L'approche théorique utilise des méthodes de chimie computationnelle et fournie des informations à l'échelle moléculaire sur les systèmes étudiés afin de prédire les données thermodynamiques qui servent de support et complément à l'approche expérimentale. Un résultat important de ce travail montre la présence de deux espèces cationiques stables de l'astate en solution aqueuse, At+ et AtO+.

Ce mémoire concerne l'étude par spectrométrie gamma directe du mode de désexcitation des niveaux du radium 225, du francium 221 de l'astate 217 ainsi que du bismuth 213. Pour réduire l'intensité des raies émises lors de la désexcitation des descendants de chaque noyau étudié, nous avons mis au point des procédés d'élution chromatographique continue des produits de filiation. Ceux-ci ont permis d'obtenir des facteurs de décontamination satisfaisants, ce qui a rendu possible l'attribution de transitions non observées précédemment et entraîné une amélioration des connaissances des méthodes de désexcitation électromagnétique des noyaux étudiés. Dans le cas du thorium 229, 169 raies attribuées à sa désintégration ont été observées, dont 97 pour la première fois. La plupart de ces nouvelles transitions se situe dans une zone d'énergies comprises entre 300 et 600 keV, où aucune raie n'avait été observée lors des études antérieures. Un schéma de niveaux est proposé. (. . . ) La structure de niveaux résultante est interprétée en termes de bandes rotationnelles organisées en doublets de parité (. . . ) découlant d'un modèle de couplage fort impliquant une déformation octupolaire stable. 125 transitions attribuées à la désintégration de l'actinium 225 ont été observées, dont 42 pour la première fois. (. . . ) Enfin, 34 raies consécutives à la désintégration du francium 221 ont été observées, dont 13 non observées auparavant, ainsi que 6 raies attribuées à la désexcitation des niveaux du bismuth 213.

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A radioimunoterapia (RIT) faz uso de anticorpos monoclonais conjugados com radionuclídeos emissores α ou β-, ambos para terapia. O tratamento baseia-se na irradiação e destruição do tumor, preservando os órgãos normais quanto ao excesso de radiação. Radionuclídeos emissores β- como 90Y, 131I, 177Lu e 188Re, são úteis para o desenvolvimento de radiofármacos terapêuticos e, quando associados a AcM como o Anti-CD20 são importantes principalmente para o tratamento de Linfomas Não Hodgkins (LNH). 188Re (Eβ- = 2,12 MeV; Eγ= 155 keV; t1/2 = 16,9 h) é um radionuclídeo atrativo para RIT. O Centro de Radiofarmácia do IPEN possui um projeto que visa a produção do radiofármaco 188Re-Anti-CD20. Com isso,este estudo foi proposto para avaliar a eficácia desta técnica de marcação para tratamento em termos compartimentais e dosimétricos. O objetivo deste trabalho consistiu na compararação da marcação do AcM anti-CD20 com 188Re com a marcação do anticorpo com 90Y, 131I, 177Lu e 99mTc (pelas suas características químicas similares) e 211At, 213Bi, 223Ra e 225Ac. Através do estudo de técnicas de marcação relatadas em literatura, foi proposto um modelo compartimental para avaliação de sua farmacocinética e estudos dosimétricos, de alto interesse para a terapia. A revisão de dados publicados na literatura, possibilitou demonstrar diferentes procedimentos de marcação, rendimentos de marcação, tempo de reação, impurezas e estudos de biodistribuição. O resultado do estudo mostra uma cinética favorável para o 188Re, pelas suas características físicas e químicas frente aos demais radionuclídeos avaliados. O estudo compartimental proposto descreve o metabolismo do 188Re-anti-CD20 através de um modelo compartimental mamilar, que pela sua análise farmacocinética, realizada em comparação aos produtos marcados com emissores β-: 131I-antiCD20, 177Lu-anti-CD20, o emissor γ 99mTc-anti-CD20 e o emissor α 211At-Anti-CD20, apresentou uma constante de eliminação de aproximadamente 0,05 horas-1 no sangue do animal. A avaliação dosimétrica do 188Re-Anti-CD20 foi realizada através de duas metodologias: pelo método de Monte Carlo e pelo uso de uma fonte pontual β- através da Fórmula de Loevinger via programa Excel. Através da Fórmula de Loevinger fez-se a validação do método de Monte Carlo para a dosimetria do 188Re-Anti-CD20 e dos demais produtos. As doses e as taxas de doses obtidas pelos dois métodos foram avaliadas em comparação à dosimetria do 90Y-Anti-CD20, 131I-Anti-CD20 e do 177Lu-Anti-CD20, obtidas pela mesma metodologia. O estudo de dose foi realizado utilizando modelos matemáticos considerando um camundongo nude de 25g, simulando diferentes tamanhos de tumor e diferentes formas de distribuição do produto dentro do animal. De acordo com os resultados obtidos, pela energia de emissão β-, 188Re-Anti-CD20 apresenta maior deposição de energia para tumores volumosos em relação aos demais produtos avaliados. Em uma simulação com 100% do produto captado pelo tumor, 89% da dose total manteve-se absorvida pelo tumor, preservando a integridade de ógãos críticos como coração (2%), pulmões (5%), coluna (4%), fígado (0,014%) e rins (0,0007%). Em uma simulação onde há uma biodistribuição do produto no organismo do animal, 38% da dose total é absorvida pelo tumor e >3% é absorvida pela coluna. Nessa situação mais próxima da realidade, a extrapolação dos dados para um humano de 70kg, mostrou que a dose absorvida no tumor corresponde a cerca de 33%; na coluna 7% e o coração receberia uma dose de 35% do total. A análise compartimental e dosimétrica apresentada neste trabalho, realizada através do uso de um modelo animal para o 188Re-Anti-CD20 mostra que o produto desenvolvido e apresentado em literatura é candidato promissor para a RIT.
Tese (Doutorado em Tecnologia Nuclear)
IPEN/T
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

Providing intense, contamination-free beams of rare isotopes to experiments is a challenging task. At isotope separator on-line facilities such as ISAC at TRIUMF, the choice of production target and ion source are key to the successful beam delivery. Due to their element-selectivity, high efficiency and versatility, resonant ionization laser ion sources (RILIS) gain increasingly in importance. The spectroscopic data available are typically incomplete in the region of excited- and autoionizing atomic states. In order to find the most efficient ionization scheme for a particular element, further spectroscopy is often required. The development of efficient laser resonant ionization schemes for yttrium and astatine is presented in this thesis. For yttrium, two ionization schemes with comparable relative intensities were found. Since for astatine, only two transitions were known, the focus was to provide data on atomic energy levels using resonance ionization spectroscopy. Altogether 41 previously unknown astatine energy levels were found.

碩士
國立雲林科技大學
會計系碩士班
101
Through case study and participating the adoption of IFRS by a state-owned enterprise, this study analyzes the adoption project and explores the managerial decisions taken in the process of the first adoption. I also record the adoption process faithfully. The results shows that in the initial stage, helps from outside experts and the support of top management are critical for the success of the project. Moreover, thecompany should build knowledge-sharing mechanism and platform. This study suggests that it would be helpful for a state-owned enterprise to identify the main differences in converting the accounting standards, if it can fully understand its industry, business model and related regulations. However, in learning and identifying the difference of IFRS standards, it needs the cooperation across departments. It is also essential for the state-owned enterprise to use the waiving requirements properly to minimize the effects of financial reporting in the first adoption of the IFRS in 2013.

The need of a stable production of At-211 is necessary to continue research in alpha-particle targeted radionuclide therapy. Our objectives were to establish the production of Astatine-211 at Texas A&M Cyclotron Institute, optimize the production methods to reduce the generation of contaminants and maximize At-211 production, and assess the radiological safety aspects of At-211 production. The production of the alpha-particle emitting radionuclide At-211 was performed at the Texas A&M Cyclotron Institute using the K500 superconducting cyclotron following the production reaction Bi-209(α, 2n)At-211 using a thick bismuth target of 500 μm. We carried out two irradiation experiments where the initial energy of the alpha-particle beam, 80 MeV, was degraded using multiple copper and aluminum foils to 27.8 and 25.3 MeV, respectively. The end of beam time was 4 hours for both experiments. The resulting At-211 yields were 36.0 and 12.4 MBq/μA-h, respectively. Several impurities were produced using the 27.8 MeV, which included At-210 and Po-210. However, when the 25.3 MeV beam was used, the impurities At-210 and Po-210 were resolved and other contaminants were minimized to less than 0.8% of At-211 yield. The production yields were in accordance to previous published results. From the success of these initial experiments, additional steps were taken to produce At-211 in excess quantities for distillation purposes. In order to obtain viable quantities of At-211, the gross yield needed to be increased due to losses that are incurred during distillation and radioactive decay. The ability to produce high yields of this isotope required a redesign of the target and use of the K150 cyclotron using a higher beam intensity.

Resonant ionization laser ion sources are applied worldwide to increase purity and intensity of rare isotopes at radioactive ion beam facilities. Especially for heavy elements the laser wavelengths required for efficient resonant laser ionization are not only element dependent, but also vary to small degrees from isotope to isotope. Since the first operation of an actinide target at ISAC-TRIUMF in 2008, the demand for neutron-rich isotopes far away from stability has steadily increased. Those isotopes often have very low production rates so that often only a few ions per second are released. In order to study isotope shifts and hyperfine structure of silver, actinium and astatine, in-source resonant ionization spectroscopy in combination with radioactive decay detection has been applied. Despite the Doppler limited resolution, it has the advantage that it is ultra-sensitive and the atomic spectrum for the nuclear ground and isomeric states can be investigated individually. An isobaric separation has been demonstrated for 115-119Ag, where the hyperfine structure of one state showed a splitting of 22 GHz to 38 GHz while for the other state only a single peak spectrum can be resolved. For astatine and actinium, the main interest is to measure and study the optical isotope shift, which is for the first excitation step for neutron-rich isotopes in the order of IS_FES≈±3.7GHz/u for both elements, as these observables give insight into nuclear moments and shape. In addition, also the isotope shift of the second excitation step for astatine has been measured to IS_SES,At≈-1.7GHz/u. Laser spectroscopy on astatine has mainly been performed on the neutron-deficient isotopes 199,205At due to high count rates and low isobaric contamination. With the results obtained it is possible to extrapolate the required wavelength for ionizing and delivering the isotopes 221-225At which are of interest to e.g. electric dipole moment studies.
October 2017

The most promising applications for targeted alpha-therapy with astatine-211 (At-211) include treatments of disseminated microscopic disease, the major medical problem for cancer treatment. The primary advantages of targeted alpha-therapy with At-211 are that the alpha-particle radiation is densely ionizing, translating to high relative biological effectiveness (RBE), and short-range, minimizing damage to surrounding healthy tissues. In addition, theranostic imaging with I-123 surrogates has shown promise for developing new therapies with At-211 and translating them to the clinic. Currently, Canada does not have a way of producing At-211 by conventional methods because it lacks alpha-particle accelerators with necessary beam energy and intensity. The work presented here was aimed at studying the Rn-211/At-211 generator system as an alternative production strategy by leveraging TRIUMF's ability to produce rare isotopes. Recognizing that TRIUMF provided production opportunities for a variety of astatine isotopes, this work also originally hypothesized and evaluated the use of At-209 as a novel isotope for preclinical Single Photon Emission Computed Tomography (SPECT) with applications to At-211 therapy research. At TRIUMF's Isotope Separator and Accelerator (ISAC) facility, mass separated ion beams of short­-lived francium isotopes were implanted into NaCl targets where Rn-211 or At-209 were produced by radioactive decay, in situ. This effort required methodological developments for safely relocating the implanted radioactivity to the radiochemistry laboratory for recovery in solution. For multiple production runs, Rn-211 was quantitatively transferred from solid NaCl to solution (dodecane) from which At-211 was efficiently extracted and evaluated for clinical applicability. This validated the use of dodecane for capturing Rn-211 as an elegant approach to storing and shipping Rn-211/At-211 in the future. Po-207 contamination (also produced by Rn-211 decay) was removed using a granular tellurium (Te) column before proceeding with biomolecule labelling. Although the produced quantities were small, the pure At-211 samples demonstrated these efforts to have a clear path of translation to animal studies. For the first time in history, SPECT/CT was evaluated for measuring At-209 radioactivity distributions using high energy collimation. The spectrum detected for At-209 by the SPECT camera presented several photopeaks (energy windows) for reconstruction. The 77-90 Po X­-ray photopeak reconstructions were found to provide the best images overall, in terms of resolution/contrast and uniformity. Collectively, these experiments helped establish guidelines for determining the optimal injected radioactivity, depending on scan parameters. Moreover, At-209-based SPECT demonstrated potential for pursuing image-­based dosimetry in mouse tumour models, in the future. Simultaneous SPECT imaging with At-209 and I-123 was demonstrated to be feasible, supporting the future evaluation of At-209 for studying/validating I-123 surrogates for clinical image-based At-211 dosimetry. This work also pursued a novel strategy for labelling cancer targeting peptides with At-211, using octreotate (TATE, a somatostatin analogue for targeting tumour cells, mostly neuroendocrine tumours) prepared with or without N-terminus PEGylation (PEG2), followed by conjugation with a closo-decaborate linking moiety (B10) for attaching At-211. Binding affinity and in vivo biodistributions for the modified peptides were determined using iodine surrogates. The results indicated that B10-PEG2-TATE retained target binding affinity but that the labelling reaction with iodine degraded this binding affinity significantly, and although having high in vivo stability, no I-123-B10-PEG2-TATE tumour uptake was observed by SPECT in a mouse tumour model positive for the somatostatin receptor (sstr2a). This suggested that further improvements are required for labelling. A new method for producing At-211 at TRIUMF is established, and At-209-­based SPECT imaging is now demonstrated as a new preclinical technology to measure astatine biodistributions in vivo for developing new radiopharmaceuticals with At-211. Combined with the theranostic peptide labelling efforts with iodine, these efforts provide a foundation for future endeavours with At-211-­based alpha-therapy at TRIUMF. All procedures were performed safely and rapidly, suitable for preclinical evaluations. All animal studies received institutional ethics approval from the University of British Columbia (UBC).
Graduate