The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as alpha-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.

Cancer became recently the leading cause of death in industrialized countries. Even though standard treatments achieve significant effects in growth inhibition and tumor elimination, they cause severe side effects as most of the applied drugs exhibit only minor selectivity for the malignant tissue. Hence, specific addressing of tumor cells without affecting healthy tissue is currently a major desire in cancer therapy. Cell surface receptors, which bind peptides are frequently overexpressed on cancer cells and can therefore be considered as promising targets for selective tumor therapy. In this review, the benefits of peptides as tumor homing agents are presented and an overview of the most commonly addressed peptide receptors is given. A special focus was set on the bombesin receptor family and the neuropeptide Y receptor family. In the second part, the specific requirements of peptide-drug conjugates (PDC) and intelligent linker structures as an essential component of PDC are outlined. Furthermore, different drug cargos are presented including classical and recent toxic agents as well as radionuclides for diagnostic and therapeutic approaches. In the last part, boron neutron capture therapy as advanced targeted cancer therapy is introduced and past and recent developments are reviewed.

<p>Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations.</p><p>In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing.</p><p>In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles.</p><p>In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.</p>

O melanoma maligno é a forma mais agressiva dos tumores cutâneos. Sendo o responsável por mais de 75% das mortes relativas á este tipo de câncer. O principal quimioterápico utilizado no tratamento do melanoma é a dacarbazina (DTIC), entretanto, as taxas de resposta são insatisfatórias. O composto DM-1 é um análogo estrutural da curcumina, e por esta razão possui propriedades biológicas semelhantes, como agente antiproliferativo e próapoptótico. A terapia de captura de nêutrons por boro (BNCT) atua por meio da deposição do isótopo 10Boro nas células tumorais e após a irradiação de nêutrons térmicos há produção de partículas alfa e lítio que destroem a célula. Neste trabalho estudou-se o mecanismo de ação destas três terapias, DTIC, DM-1 e BNCT no tratamento do melanoma e seus efeitos em células normais in vitro com a finalidade de obtenção de modalidades terapêuticas diferentes para o tratamento desta neoplasia. A IC50 foi obtida pela metodologia de MTT, além da análise da progressão do ciclo celular e marcadores de morte celular por citometria de fluxo. O composto DM-1 e a BNCT apresentaram efeito citotóxico seletivo para as linhagens de melanoma, com alta produção de radicais livres peroxidados. Nas mesmas condições, estes efeitos foram mínimos em células normais, diferente do tratamento com DTIC. Houve diminuição da proporção de matriz extracelular e colágeno solúvel sintetizado em células de melanoma tratadas com DM-1, BNCT e DTIC, entretanto, o quimioterápico ocasionou isoladamente diminuição também em células normais. O potencial elétrico mitocondrial das células de melanoma foi diminuído nos três protocolos de tratamento, assim como houve aumento na quantidade de DNA fragmentado. Este efeito não foi encontrado em células normais tratadas com DM-1 e BNCT. O composto DM-1 foi capaz de induzir apoptose via intrínseca e extrínseca, avaliado pela Anexina V e por marcadores de cinética e de morte celular. A terapia de BNCT induziu apoptose e necrose, indicando que esta terapia atua por diferentes vias em cada linhagem celular. BNCT e DM-1 induziram aumento na expressão dos marcados próapoptóticos, como Bax, citocromo c, caspase 3 e 8 clivadas, além de diminuir os valores na expressão de ciclina D1 e Ki-67, relacionados com a progressão do ciclo celular e proliferação. O quimioterápico DTIC apresentou alguns indícios de apoptose em células de melanoma, mas seus efeitos em células normais foram extensivos, ocasionando morte e parada do ciclo celular em melanócitos, células endoteliais e fibroblastos. O composto DM-1 apresentou formação de corpos apoptóticos, modificações no citoesqueleto e clivagem de caspase 9 e Parp em linhagens de melanoma humano. Desta forma, o composto DM-1 e a BNCT mostraram-se ferramentas terapêuticas mais eficazes no controle da progressão e no aumento da morte celular em células de melanoma. O poder efetivo da terapia de BNCT e do composto DM-1 faz com que a possibilidade de terapias combinatórias tenha resultados extremamente favoráveis na modulação da resposta proliferativa desses tumores. / Malignant melanoma is the most aggressive skin cancer. It is responsible for more than 75% of deaths. The main and most active chemotherapy in the melanoma treatment is represented by dacarbazine (DTIC), however, response rates are disappointing. The DM-1 compound is a curcumin structural analogue and it has similar biological properties, such as an antiproliferative and pro-apoptotic agent. Boron Neutron Capture Therapy (BNCT) works through the deposition of the isotope 10Boron in tumor cells, with subsequent irradiation of thermal neutrons, which produce alpha particles and lithium that destroy the cell. In this study, the action mechanism of these three therapies, DTIC, DM-1 and BNCT in the melanoma treatment and its effects in vitro on normal cells were studied in order to obtain different therapeutic modalities for cancer treatment. The IC50 was obtained by MTT method, besides the analysis of cell cycle progression and cell death markers by flow cytometry. The DM-1 and BNCT showed selective cytotoxic in melanoma cell lines, with high of free radicals production. In the same conditions, these effects were minimal in normal cells, unlike the treatment with DTIC. There was a decrease in the proportion of extracellular matrix and soluble collagen synthesized in melanoma cells treated with DM-1, BNCT and DTIC, however, only DTIC also resulted in decreased in normal cells. The mitochondrial electrical potential of melanoma cells was decreased in the three treatment protocols, as there was an increase in the amount of fragmented DNA. This effect was not found in normal cells treated with DM-1 and BNCT. The compound DM-1 was able to induce apoptosis by the intrinsic and extrinsic pathways, as assessed by Annexin V, cell death and kinetic markers. BNCT induced apoptosis and necrosis, indicating that this therapy acts through different pathways in each cell line. DM-1 and BNCT induced an increase of pro-apoptotic markers, such as Bax, cytochrome c, cleaved caspase 3 and 8 expression, and they reduced cyclin D1 and Ki-67, expression related to the progression of the cell cycle and proliferation. The DTIC has shown some signs of apoptosis in melanoma cells, but its effect on normal cells were extensive, causing death and cell cycle arrest in melanocytes, fibroblasts and endothelial cells. The DM-1 showed apoptotic bodies formation, cytoskeleton changes and caspase 9 and Parp cleavage in human melanoma cell lines. Thus, the DM-1 and BNCT showed as therapeutic tools more with high effectiveness in controlling the cell cycle progression and cell death increase in melanoma cells. The effectiveness of BNCT and DM-1 makes the possibility of combinatorial therapies, with extremely favorable results in the modulation of the proliferative response of these tumors.

Orientadores: Sandro Guedes de Oliveira, Jörg Kobarg / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-09-02T02:16:09Z (GMT). No. of bitstreams: 1 Smilgys_Barbara_D.pdf: 17430152 bytes, checksum: 82ba0350f1128e5f264b9ee314a4fef6 (MD5) Previous issue date: 2017 / Resumo: BNCT (do inglês, Boron Neutron Capture Therapy) é uma terapia para tratamento de cânceres que tem se mostrado efetiva em casos de metástases e tumores inoperáveis. Sua base física é a reação de captura de nêutrons pelo boro resultando na produção de uma partícula 'alfa' e de um íon de recuo de lítio: 10B(n,'alfa')7Li. O objetivo principal deste trabalho foi verificar a viabilidade de monitoração de taxa de reações de interesse em BNCT e estimar, a partir das taxas de reações medidas, quantidades probabilísticas que descrevam o campo de irradiação, utilizando-se filmes finos de boro e detectores plásticos de traços nucleares (PADC). Além disto, pretendia-se realizar estudos biológicos de sobrevivência celular, para então, com a descrição detalhada do campo de irradiação e medidas de efeitos radiobiológicos, avaliar possíveis correlações entre os efeitos de heterogeneidade de deposição de energia (quantidades probabilísticas) e as frações de sobrevivência celular. Assim, o trabalho foi dividido em três partes experimentais fundamentais: a calibração do conjunto de filmes finos de boro acoplados a detectores PADC, cuja importância é a quantificação de átomos de 10B presentes nos filmes finos utilizados para a medida da taxa da reação 10B(n,'alfa')7Li, a realização de experimentos in vitro com irradiações com partículas 'alfa' que visavam o desenvolvimento da metodologia de quantificação de sobrevivência celular, que seriam utilizadas posteriormente, quando realizados os experimentos in vitro com nêutrons, os quais unem os resultados obtidos das calibrações dos filmes finos de boro e os métodos aplicados nas análises de resposta biológica de irradiações de células com partículas 'alfa'. A partir das fluências de partículas 'alfa' e das taxas da reação 10B(n,'alfa')7Li, calculou-se as médias da distribuição de eventos poissonianos em uma célula de área A e com estas médias foram feitas simulações de distribuição de eventos em uma matriz de células, para quantificação da formação de clusters de células (primeiras vizinhas) atingidas. Por se tratar de um problema de muitas variáveis (sobrevivência celular, média de eventos, eventos por célula, células por cluster e total de clusters), escolheu-se fazer uma análise de componentes principais, na tentativa de se determinar quais destas variáveis introduzem as maiores variabilidades no problema. Mostrou-se que a formação de clusters de células vizinhas influencia a inativação das células, embora não tenha sido possível estabelecer modelos quantitativos. Portanto, com este trabalho, foi possível estabelecer uma metodologia segura para a quantificação da taxa de reação de interesse na BNCT, e a partir desta, calcular descritores que levam em conta a heterogeneidade da distribuição de energia durante as irradiações. A partir de dados de experimentos in vitro, tanto de irradiações com partículas 'alfa' quanto com nêutrons térmicos, foi possível encontrar correlações com estes descritores de heterogeneidade e conclui-se, então, que eles podem ser usados como descritores de efeitos biológicos / Abstract: BNCT (Boron Neutron Capture Therapy) is a therapy for the treatment of cancers that has been proven to be effective in cases of metastases and inoperable tumors. Its physical basis is the boron neutron capture reaction resulting in the production of an 'alpha' particle and a lithium recoil ion: 10B(n,'alpha')7Li. The main objective of this work was to verify the feasibility of monitoring the main reactions rates in BNCT using boron thin films and nuclear tracks plastic detectors (PADC) and to estimate, from the reactions rates measured, probabilistic quantities that describe the irradiation field. In addition, it was intended to carry out biological studies of cell survival, and with the detailed description of the field of irradiation and measurements of radiobiological effects, to evaluate possible correlations between the effects of heterogeneity of energy deposition (probabilistic quantities) and fractions of cell survival. Thus, the work was divided into three fundamental experimental parts: the calibration of the setup of boron thin films coupled to PADC detectors (whose importance is the quantification of the 10B atoms present in the thin films used for the measurement of 10B(n,'alpha')7Li reaction rate), the in vitro experiments carried out with irradiations with particles 'alpha' aiming to develop the methodology for cell survival quantification, which would later be used when performing the in vitro experiments with neutrons, which combine the results obtained from the calibrations of the boron thin films and the methods applied for cell survival quantification. From the 'alpha' particles fluences and the 10B(n,'alpha')7Li reaction rates, it was possible to calculate the mean of the Poisson distribution for events happening inside a cell of area A. Simulations were performed for quantifying the number of clusters formed by neighbor cells that were hit by an incident particle. Since this is a problem of many variables (cell survival, poissonian mean, events per cell, cells per cluster and total number of clusters), it was performed a principal components analysis in an attempt to determine which of these variables introduce the greatest variabilities to the problem. It was shown that the cells clusters formation influences cell inactivation, though it was not possible to establish quantitativy models. Therefore, with this work, it was possible to establish a safe methodology for the quantification of the reaction rate of interest in BNCT, and from this, to calculate descriptors that take into account the heterogeneity of energy distribution during irradiation. From data from both in vitro experiments of cells irradiation with 'alpha' particles and with thermal neutrons, it was possible to find correlations with these descriptors of heterogeneity and it is concluded, then, that they can be used as descriptors for biological effects / Doutorado / Física / Doutora em Ciências

Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations. In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing. In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles. In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.

O melanoma maligno é a forma mais agressiva dos tumores cutâneos. Sendo o responsável por mais de 75% das mortes relativas á este tipo de câncer. O principal quimioterápico utilizado no tratamento do melanoma é a dacarbazina (DTIC), entretanto, as taxas de resposta são insatisfatórias. O composto DM-1 é um análogo estrutural da curcumina, e por esta razão possui propriedades biológicas semelhantes, como agente antiproliferativo e próapoptótico. A terapia de captura de nêutrons por boro (BNCT) atua por meio da deposição do isótopo 10Boro nas células tumorais e após a irradiação de nêutrons térmicos há produção de partículas alfa e lítio que destroem a célula. Neste trabalho estudou-se o mecanismo de ação destas três terapias, DTIC, DM-1 e BNCT no tratamento do melanoma e seus efeitos em células normais in vitro com a finalidade de obtenção de modalidades terapêuticas diferentes para o tratamento desta neoplasia. A IC50 foi obtida pela metodologia de MTT, além da análise da progressão do ciclo celular e marcadores de morte celular por citometria de fluxo. O composto DM-1 e a BNCT apresentaram efeito citotóxico seletivo para as linhagens de melanoma, com alta produção de radicais livres peroxidados. Nas mesmas condições, estes efeitos foram mínimos em células normais, diferente do tratamento com DTIC. Houve diminuição da proporção de matriz extracelular e colágeno solúvel sintetizado em células de melanoma tratadas com DM-1, BNCT e DTIC, entretanto, o quimioterápico ocasionou isoladamente diminuição também em células normais. O potencial elétrico mitocondrial das células de melanoma foi diminuído nos três protocolos de tratamento, assim como houve aumento na quantidade de DNA fragmentado. Este efeito não foi encontrado em células normais tratadas com DM-1 e BNCT. O composto DM-1 foi capaz de induzir apoptose via intrínseca e extrínseca, avaliado pela Anexina V e por marcadores de cinética e de morte celular. A terapia de BNCT induziu apoptose e necrose, indicando que esta terapia atua por diferentes vias em cada linhagem celular. BNCT e DM-1 induziram aumento na expressão dos marcados próapoptóticos, como Bax, citocromo c, caspase 3 e 8 clivadas, além de diminuir os valores na expressão de ciclina D1 e Ki-67, relacionados com a progressão do ciclo celular e proliferação. O quimioterápico DTIC apresentou alguns indícios de apoptose em células de melanoma, mas seus efeitos em células normais foram extensivos, ocasionando morte e parada do ciclo celular em melanócitos, células endoteliais e fibroblastos. O composto DM-1 apresentou formação de corpos apoptóticos, modificações no citoesqueleto e clivagem de caspase 9 e Parp em linhagens de melanoma humano. Desta forma, o composto DM-1 e a BNCT mostraram-se ferramentas terapêuticas mais eficazes no controle da progressão e no aumento da morte celular em células de melanoma. O poder efetivo da terapia de BNCT e do composto DM-1 faz com que a possibilidade de terapias combinatórias tenha resultados extremamente favoráveis na modulação da resposta proliferativa desses tumores. / Malignant melanoma is the most aggressive skin cancer. It is responsible for more than 75% of deaths. The main and most active chemotherapy in the melanoma treatment is represented by dacarbazine (DTIC), however, response rates are disappointing. The DM-1 compound is a curcumin structural analogue and it has similar biological properties, such as an antiproliferative and pro-apoptotic agent. Boron Neutron Capture Therapy (BNCT) works through the deposition of the isotope 10Boron in tumor cells, with subsequent irradiation of thermal neutrons, which produce alpha particles and lithium that destroy the cell. In this study, the action mechanism of these three therapies, DTIC, DM-1 and BNCT in the melanoma treatment and its effects in vitro on normal cells were studied in order to obtain different therapeutic modalities for cancer treatment. The IC50 was obtained by MTT method, besides the analysis of cell cycle progression and cell death markers by flow cytometry. The DM-1 and BNCT showed selective cytotoxic in melanoma cell lines, with high of free radicals production. In the same conditions, these effects were minimal in normal cells, unlike the treatment with DTIC. There was a decrease in the proportion of extracellular matrix and soluble collagen synthesized in melanoma cells treated with DM-1, BNCT and DTIC, however, only DTIC also resulted in decreased in normal cells. The mitochondrial electrical potential of melanoma cells was decreased in the three treatment protocols, as there was an increase in the amount of fragmented DNA. This effect was not found in normal cells treated with DM-1 and BNCT. The compound DM-1 was able to induce apoptosis by the intrinsic and extrinsic pathways, as assessed by Annexin V, cell death and kinetic markers. BNCT induced apoptosis and necrosis, indicating that this therapy acts through different pathways in each cell line. DM-1 and BNCT induced an increase of pro-apoptotic markers, such as Bax, cytochrome c, cleaved caspase 3 and 8 expression, and they reduced cyclin D1 and Ki-67, expression related to the progression of the cell cycle and proliferation. The DTIC has shown some signs of apoptosis in melanoma cells, but its effect on normal cells were extensive, causing death and cell cycle arrest in melanocytes, fibroblasts and endothelial cells. The DM-1 showed apoptotic bodies formation, cytoskeleton changes and caspase 9 and Parp cleavage in human melanoma cell lines. Thus, the DM-1 and BNCT showed as therapeutic tools more with high effectiveness in controlling the cell cycle progression and cell death increase in melanoma cells. The effectiveness of BNCT and DM-1 makes the possibility of combinatorial therapies, with extremely favorable results in the modulation of the proliferative response of these tumors.

Orientador: Sandro Guedes de Oliveira / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-20T00:29:22Z (GMT). No. of bitstreams: 1 Smilgys_Barbara_M.pdf: 13526183 bytes, checksum: 6bc7b12944024ced8153260711197b5f (MD5) Previous issue date: 2012 / Resumo: O princípio de funcionamento da Terapia por Captura de Nêutrons pelo Boro (BNCT, Boron Neutron Capture Therapy) é a entrega seletiva de uma maior quantidade de átomos de boro às células cancerígenas do que àquelas saudáveis, seguida da irradiação com nêutrons que irá induzir a emissão de partículas a e íons de recuo de 7Li através da reação nuclear 10B(n,a)7Li. O objetivo deste trabalho é desenvolver uma metodologia para quantificar a taxa da reação de interesse através do uso da montagem de filmes finos de boro acoplados a detectores CR-39, que detectam as partículas a e os íons de recuo de 7Li. Este detector é composto por átomos de hidrogênio, carbono e oxigênio, os quais interagem com nêutrons rápidos e as partículas resultantes destas reações (de espalhamentos e de captura de nêutrons) também são detectadas pelo próprio detector. Deste modo, é possível quantificar, ao mesmo tempo, a reação 10B(n,a)7Li e a contribuição de nêutrons rápidos do fluxo. Essas medidas são fundamentais para os estudos de biodistribuição de átomos de 10B e de microdosimetria dos tecidos irradiados com nêutrons, levando ao planejamento da terapia em si. Os filmes finos de boro foram confeccionados por dois métodos, Deposição de Solução Química (CSD, Chemical Solution Deposition) e deposição por sputtering, e irradiados com nêutrons no reator nuclear IEA-R1 localizado no IPEN/CNEN. Os resultados obtidos para a caracterização e a calibração dos filmes finos de boro, além da calibração dos detectores CR-39 são aqui analisados. Foi possível confeccionar, por ambos os métodos, filmes finos de boro homogêneos e calibrar o sistema de filme fino de boro acoplado a detector CR-39 para a medida da taxa da reação 10B(n,a)7Li e para a determinação da componente rápida do fluxo de nêutrons através do uso de filmes finos de urânio e tório, respectivamente / Abstract: The working principle of the Boron Neutron Capture Therapy (BNCT) is the selective delivery of a greater amount of 10B atoms to the tumor cells than to the healthy ones, followed by neutron irradiation that will induce the emission of a particles and 7Li recoil ions through the nuclear reaction 10B(n,a)7Li. The goal of this work is to develop a methodology to quantify the reaction rate of interest using an assembly of boron thin film coupled to CR-39 detector, which detects the a particles and the 7Li recoil ions. This detector is composed of atoms of hydrogen, carbon and oxygen, which interacts with fast neutrons and the resulting particles from these scattering and capture processes are also detected by the CR-39 detector. In this way, it is possible to quantify, at the same time, the reaction 10B(n,a)7Li and the fast neutrons contribution to the flux. Those measurements are fundamental to the 10B biodistribution studies and tissue microdosimetry, leading to the therapy planning itself. The boron thin films were manufactured using two methods, Chemical Solution Depostion and sputtering deposition, and irradiated with neutrons at the nuclear reactor IEA-R1 located at IPEN/CNEN. The results obtained for the boron thin films characterization and calibration, as well as the CR-39 detectors calibration are analyzed here. It was possible to manufacture with both methods homogeneous boron thin films and to calibrate the assembly of boron thin film coupled to CR-39 detector for measuring the 10B(n,a)7Li reaction rate and determining the fast component of the neutron flux through the use of uranium and thorium thin films, respectively / Mestrado / Física / Mestra em Física

Orientador: Sandro Guedes de Oliveira / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin / Made available in DSpace on 2018-08-26T18:12:34Z (GMT). No. of bitstreams: 1 Vasconcellos_HerminianeLuizade_M.pdf: 4238996 bytes, checksum: 69965aad9e9748e349be6894c6ebf385 (MD5) Previous issue date: 2015 / Resumo: Este trabalho baseia-se na analise de descritores de heterogeneidade de dose atraves de programas desenvolvidos em linguagem C++ com base na estatistica de Poisson e probabilidades de ocorrencia de heterogeneidade fundamentadas na teoria de percolacao. A finalidade deste trabalho e obter descritores que possam ser uteis no estudo de efeitos biologicos da radiacao caracteristicos de situacoes em que ha heterogeneidade de dose. Os suportes iniciais deste trabalho se encontram em um relatorio da International Comission on Radiation Units and Measurements, que aborda as questoes de heterogeneidade de dose. Particulas ¿¿ e reacoes envolvendo interacao com neutrons sao as radiacoes que foram focadas na dissertacao e base da aplicacao dos programas desenvolvidos, atraves de resultados obtidos de um experimento em um acelerador linear Elekta Synergy, inter-calibrado com simulacoes de calculo de Monte Carlo. A teoria de percolacao que estuda o comportamento de aglomerados em redes bidimensionais e tridimensionais e baseada em processos randomicos, e pode ser aplicada porque eventos gerados pelas reacoes nucleares ou espalhamentos com neutrons que obedecem a estatistica de Poisson. Os eventos gerados podem ser mapeados a procura de aglomerados, celulas que sao vizinhas nas quais tenham ocorrido eventos. Os aglomerados sao a base da construcao dos descritores. Os resultados encontrados demonstram que os indices de heterogeneidades utilizados fornecem informacoes importantes a respeito da formacao destes aglomerados. Foram comparados os resultados obtidos para os casos 2D e 3D de distribuicao de celulas hipoteticas e foi possivel estudar as relacoes entre os dois casos. Os descritores de heterogeneidade possibilitarao associacoes de dano biologico com a distribuicao de eventos em culturas celulares (caso 2D) e tecidos (caso 3D) / Abstract: The goal of this study is the analysis of dose heterogeneity descriptors through programs developed in C ++ language based on Poisson statistics and probabilities for the occurrence of heterogeneity based on percolation theory. The purpose of this study is to obtain descriptors that may be useful in the study of radiobiological effects characteristic of the situations in which there is dose heterogeneity. The initial support for this work is the report by the International Commission on Radiation Units and Measurements, which describes the dose heterogeneity issues. Álpha particles and reactions involving interaction with neutrons were focused on this thesis are the base of application programs developed from results of an experiment at a linear accelerator Elekta Synergy, inter-calibrated with Monte Carlo simulation. The percolation theory, a theory that studies cluster behavior in two and three-dimensional lattices, is based on random processes, can be applied because the events generated by nuclear reactions with neutrons follow the Poisson statistics. Generated events can be mapped in the search for clusters, neighbor cells in which events occurred. The clusters are the basis for construction of descriptors. The results show that the heterogeneity descriptors provide important information about clusters formation. The results for 2D and 3D cases were compared for distribution of hypothetical cells. and it was possible to study the relations between the two cases. The descriptors of heterogeneity enable biological damage associations with the distribution of events in cell culture (2D case) and tissues (3D case) / Mestrado / Física / Mestra em Física

Background: Boron Neutron Capture Therapy (BNCT) is a binary approach to cancer therapy that requires accumulation of boron atoms preferentially in tumour cells. This can be achieved by using nanoparticles as boron carriers and taking advantage of the enhanced permeability and retention (EPR) effect. Here, we present the preparation and characterization of size and shape-tuned gold NPs (AuNPs) stabilised with polyethylene glycol (PEG) and functionalized with the boron-rich anion cobalt bis(dicarbollide), commonly known as COSAN. The resulting NPs were radiolabelled with 124I both at the core and the shell, and were evaluated in vivo in a mouse model of human fibrosarcoma (HT1080 cells) using positron emission tomography (PET). Methods: The thiolated COSAN derivatives for subsequent attachment to the gold surface were synthesized by reaction of COSAN with tetrahydropyran (THP) followed by ring opening using potassium thioacetate (KSAc). Iodination on one of the boron atoms of the cluster was also carried out to enable subsequent radiolabelling of the boron cage. AuNPs grafted with mPEG-SH (5 Kda) and thiolated COSAN were prepared by ligand displacement. Radiolabelling was carried out both at the shell (isotopic exchange) and at the core (anionic absorption) of the NPs using 124I to enable PET imaging. Results: Stable gold nanoparticles simultaneously functionalised with PEG and COSAN (PEG-AuNPs@[4]) with hydrodynamic diameter of 37.8 0.5 nm, core diameter of 19.2 1.4 nm and -potential of 18.0 0.7 mV were obtained. The presence of the COSAN on the surface of the NPs was confirmed by Raman Spectroscopy and UV-Vis spectrophotometry. PEG-AuNPs@[4] could be efficiently labelled with 124I both at the core and the shell. Biodistribution studies in a xenograft mouse model of human fibrosarcoma showed major accumulation in liver, lungs and spleen, and poor accumulation in the tumour. The dual labelling approach confirmed the in vivo stability of the PEG-AuNPs@[4]. Conclusions: PEG stabilized, COSAN-functionalised AuNPs could be synthesized, radiolabelled and evaluated in vivo using PET. The low tumour accumulation in the animal model assayed points to the need of tuning the size and geometry of the gold core for future studies.