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Multifunctional Organometallic Compounds for Auger Therapy

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Multifunctional Organometallic Compounds for Auger Therapy Annica de Barros Rosa Graduated in Cellular and Molecular Biology Multifunctional Organometallic Compounds for Auger Therapy Dissertation to obtain Master’s Degree in Biochemistry 2 Supervisor: Dr. António Manuel Rocha Paulo, C TN-IST Jury: President: Prof. Dr. Pedro António de Brito Tavares Examiner: Prof. Dr. Paula Dolores Galhofas Raposinho Supervisor: Prof. Dr. António Manuel Rocha Paulo October 2014 T Multifunctional Organometallic Compounds for Auger Therapy Copyright Annica de Barros Rosa, FCT/UNL-UNL A Faculdade de Ciências e Tecnologia e a Universidade Nova de Lisboa têm o direito, perpétuo e sem limites geográficos, de arquivar e publicar esta dissertação através de exemplares impressos reproduzidos em papel ou de forma digital, ou por qualquer outro meio conhecido ou que venha a ser inventado, e de a divulgar através de repositórios científicos e de admitir a sua cópia e distribuição com objetivos educacionais ou de investigação, não comerciais, desde que seja dado crédito ao autor e editor. Acknowledgments To my mentor, Dr. António Paulo, I thank you for the mentoring, transmitted knowledge and incentives. For the availability and accessibility demonstrated. To Dr. Isabel Rego dos Santos for the opportunity and acceptance in the group Ciências Radiofarmacêuticas of C2TN. To Letícia Alves do Quental for all the support with the laboratory practices, teaching, availability and all the extra help. To Dr. Paula Raposinho, Dr. Sofia Gama and Dr. Célia Fernandes for the studies provided, availability and for all the help. To Dr. Goreti Morais and Dr. Elisa Palma for the teaching and friendship. To Susana, Sofia M., Elisabete R., Inês, Filipe, Maria, Vera, Mariana and Maurício for the NMR spectra, friendship and company. To the rest of the group, I am equally grateful for the welcoming and friendship. To you my parents, I thank you. For the financial support, but essentially, for the emotional support, and for calling me religiously every Friday night during these 5 years I have been away from home. And thank you dad for coming visit me during my writing. To my favorite person in this world, my big brother Yannick. To my grandmothers and to all my relatives, for the calls, and for supporting me from the distance. To my BFF Maira, for the friendship and endless random talking. Thank you to all my other fellow compatriots for bringing a piece of home to this foreign country. In special my relatives, high school buddies and housemates. To all the Portuguese and other PALOP friends I've made, my colleagues, teachers, co-workers and in special my housemates Tânia and Maria. [iii] Abstract Auger emitters gained significant interest in the past years due to the favorable suitability for target therapy at cellular level. Among Auger emitters, 99mTc seems like the most appealing candidate for this task due to its great advantages regarding low cost, high availability and almost ideal radiochemical properties. The short range of Auger electrons demands that the radionuclide must be as close as possible to the target, usually the nuclear DNA, in order to cause significant therapeutic effects. Thus, the search for efficient delivery systems is the major challenge for Auger therapeutic applications. Radioactive complexes capable of entering the cell and target the nucleus showing affinity for the DNA molecule have been reported in the literature. Such compounds comprise efficient multifunctional chelators with the ability to 99m + stabilize the fac-[ Tc(CO)3] core, as well as DNA-intercalating agents that ensure close proximity to the target. Herein we aimed to synthesize 99mTc complexes (Tc1-4) stabilized by multifunctional chelators of the pyrazole-diamine type, containing anthracene (L1 and L2) or acridine orange (L3 and L4) as DNA-binding groups with longer (L2 and L3) or shorter (L1 and L4) spacer between the latter and the chelating agent. The corresponding Re complexes (Re1- 4) were also foreseen for full chemical characterization. Due to the demanding synthesis processes and available time, only Tc1 and Tc2 could be synthesized, characterized and biologically evaluated. The Re congeners showed ability to interact with the CT-DNA molecule trough spectroscopic studies. Tc1 and Tc2 also showed great ability to target the nucleus, once diffused into the cells of B16-F1 murine melanoma and PC3 human prostate cells, but no radio- cytotoxic effect in these cell lines. Although efficient delivery system at subcellular level could be provided in this work, the relevance of the complexes for the design of Auger emitting 99mTc radiopharmaceuticals could not be demonstrated. Keywords Nuclear Medicine Radiotherapy Radiometal Auger electrons Technetium-99m DNA-interaction [v] Resumo A terapia com emissores Auger tem despertado interesse nos últimos anos devido à possibilidade de explorar terapia direccionadas, a nível celular. Entre os emissores Auger conhecidos, o 99mTc oferece diferentes vantagens: baixo custo, elevada disponibilidade e propriedades radioquímicas favoráveis. O curto alcance dos electrões Auger constitui um factor limitante para a sua eficácia biológica exigindo que o radionucídeo se encontre o mais próximo possível do seu alvo, usualmente o DNA nuclear, de modo a exercer os seus efeitos terapêuticos. Assim, o maior desafio para o uso deste tipo de radionuclídeos em procedimentos terapêuticos é o desenho de vectores de entrega eficientes a nível subcelular. Já se encontra descrito um reduzido número de complexos radioactivos com capacidade de se localizar no núcleo das células e com afinidade para o DNA. Para esse efeito, tais compostos possuem em geral um agente quelante multifuncional com capacidade de estabilizar a unidade fac- 99m + [ Tc(CO)3] e, simultaneamente, um agente intercalador do DNA que assegura a proximidade e afinidade para o alvo. Neste trabalho propôs-se a síntese de complexos de tecnécio (Tc1-4) estabilizados por agentes quelantes do tipo pirazolo-diamina contendo os agentes intercaladores antraceno (L1 e L2) ou alaranjado de acridina (L3 e L4), com um espaçador metilénico maior (L2 and L3) ou menor (L1 and L4) entre o agente quelante e intercalador. Perspectivou-se ainda a síntese dos respectivos complexos de rénio (Re1-4) para uma completa caracterização dos compostos. Devido à elevada exigência da síntese dos ligandos e ao tempo disponível, apenas os complexos Tc1 e Tc2 foram sintetizados e caracterizados. Estudos espectroscópicos com os congéneres de Re mostraram que os complexos interagem com o DNA. Tc1 e Tc2 demonstraram elevada capacidade de se localizar no núcleo celular em estudos com células B16-F1 de melanoma de ratinho e células PC3 de cancro de próstata humana. No entanto, não exerceram qualquer efeito radio-citotóxico. Apesar de os complexos apresentarem uma elevada capacidade para atingir o núcleo de células tumorais, não foi possível demonstrar o seu interesse para o desenho de radiofármacos de 99mTc para terapia Auger. Palavras-chave Medicina Nuclear Radioterapia Radiometal Electrões Auger Tecnécio-99m Interacção com DNA [vii] [viii] Index Acknowledgments ...................................................................................................................... iii Abstract ........................................................................................................................................ v Keywords ................................................................................................................................... v Resumo ...................................................................................................................................... vii Palavras-chave ......................................................................................................................... vii List of Figures ........................................................................................................................... xiii List of Schemes ......................................................................................................................... xv List of tables ............................................................................................................................ xvii List of symbols and abbreviations ......................................................................................... xix 1 Introduction .......................................................................................................................... 1 1.1 General aspects about Nuclear Medicine ..................................................................... 1 1.1.1 Diagnosis in Nuclear Medicine .............................................................................. 2 1.1.2 Therapy in Nuclear Medicine ................................................................................. 4 1.1.2.1 Biological effects of ionizing radiation ............................................................... 4 1.1.2.2 Systemic cancer therapy in Nuclear Medicine .................................................. 5 1.2 Auger electrons and cancer therapy ............................................................................. 7 1.2.1 Auger electrons ..................................................................................................... 7 1.2.2 Prospective Auger emitters for cancer therapy ..................................................... 8 1.3 Design of metal-based radiopharmaceuticals ............................................................. 10 1.4 Technetium .................................................................................................................
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