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

Within this thesis two twin experiments consisting of neutron capture and photon scattering on the neighbour isotopes 77Se / 78Se and 195Pt / 196Pt have been analysed to gain qualitative and quantitative information about the photon strength function and level density in the respective compound nuclei. For the analysis and simulation of both experimental types a new Monte Carlo simulation using a fast and efficient, extreme statistical treatment of radiative nuclear deexcitations, was developed. Furthermore the influence of fluctuations of transition widths on photon scattering were investigated and quantified. It could be shown that those lead to an enhancement of elastic scattering processes. The data analysis of both twin experiments reveals non-Lorentzian extra E1 photon strength below the neutron separation energy.

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.

No description available.

The rapid neutron-capture process, known as the r-process, is responsible for the origin of about half the stable nuclei heavier than iron observed in nature. Though the r-process is believed to take place in explosive stellar environments and to involve a large number (few thousands) of exotic nuclei, this nucleosynthesis process remains poorly understood from the astrophysics as well as nuclear physics points of view. On the nuclear physics side, the nuclei are too exotic to be studied in the laboratory, even though great efforts are constantly made to extend the experimental limits away from the eta-$stability region. Therefore, theoretical models are indispensable to estimate the nuclear properties of interest in the r-process nucleosynthesis modelling. So far, models used to predict the properties of the exotic nuclei were based on parametrized macroscopic-type approaches the reliability of which is questionable when extrapolating far away from the experimentally known region. This work is devoted to the improvement of nuclear predictions, such as the nuclear ground- and excited-state properties, needed as input data to model the r-process. In order to give the predictions a reliable character, we rely on the microscopic mean-field Hartree-Fock theory based on the Skyrme-type interaction. Pairing correlations play an important role in the description of nuclei, and become essential for nuclei located near the drip lines, since the scattering of pairs of quasi-particles into the continuum increases significantly. In this work, we brought to the Hartree-Fock model the self-consistent treatment of the pairing correlations within the Hartree-Fock-Bogoliubov (HFB) theory. Further improvements are made in the restoration of symmetries broken by correlations added in the form of additional degrees of freedom in the wave function. These include the translational invariance restored by calculating the recoil energy, the particle-number symmetry by an exact projection after variation, the rotational symmetry by an approximate cranking correction and the parity symmetry for reflection asymmetric shapes. In addition, the renormalization of the HFB equations has been studied as well and allows to eliminate the dependence of the total energy with respect to the cutoff energy. The effective nucleon-nucleon interaction is determined by adjusting its parameters on all available experimental masses, with some constraints derived from fundamental nuclear matter properties. A systematic study of the influence on mass predictions for each of the above cited improvements as well as of some uncertainties affecting the particle-hole and particle-particle interactions has been conducted. In spite of quite important differences in the input physics, we find a great stability in the mass predictions for exotic neutron-rich nuclei, though local mass differences can be significant. Each of the Skyrme force derived in the present work has been tested on the predictions of basic ground-state properties (including charge radii, quadrupole moments, single-particle levels), fission barriers and electric dipole $gamma-$ray strengths. The HFB predictions globally reproduce experimental data with a level of accuracy comparable with the widely-used droplet-like models. The microscopic character of the approach followed in the present work makes however the predictions for exotic neutron-rich nuclei involved in the r-process more reliable. The influence of such improved nuclear mass predictions on the r-process abundance distribution is studied in the specific scenario of the prompt supernova explosion mechanism.

L’objectif de ce document est de présenter une étude sur la réaction de capture neutronique radiative du noyau instable du ¹⁷³Lu afin de déterminer sa section efficace (n,γ). Si globalement, pour les noyaux stables de nombreuses informations sont à disposition, il reste un véritable manque de données pour les noyaux radioactifs. La première partie de cette thèse se consacre à la présentation des différents formalismes impliqués dans le calcul d’une section efficace ainsi qu’à l’utilisation du code TALYS basé sur ces différents modèles. TALYS nous a permis d’évaluer la section efficace (n,γ) sur le ¹⁷³Lu en s’appuyant sur la connaissance de la réaction de capture sur le ¹⁷⁵Lu. Dans un deuxième temps, la section efficace (n,γ) sur le ¹⁷³Lu a été mesurée sur l’installation LANSCE avec le détecteur 4π DANCE. Cette expérience s’est révélée être un véritable défi tant pour la fabrication de la cible de ¹⁷³Lu que pour l’obtention de données dû à la grande radioactivité de cet isotope. Nous avons pu extraire des informations intéressantes comme le taux de capture total, identifier et caractériser de nouvelles résonances, déterminer des paramètres comme l’espacement moyen, les largeurs neutroniques et les largeurs γ ainsi que la valeur de la fonction densité. Tous ces nouveaux renseignements nous ont permis de reconstruire la section efficace (n,γ) sur le ¹⁷³Lu jusqu’à 200 eV. Grâce à ces différentes informations, nous avons estimé une correction à appliquer sur la section efficace évaluée par TALYS permettant in fine d’obtenir une nouvelle évaluation de cette quantité. La troisième partie de cette thèse est consacrée à apporter des informations supplémentaires sur la réaction ¹⁷³Lu(n,γ)¹⁷⁴Lu en utilisant la méthode de substitution. En premier lieu, nous avons testé la validité de cette méthode sur une réaction connue : ¹⁷⁵Lu(n,γ)¹⁷⁶Lu avec la réaction ¹⁷⁴Yb(³He,p)¹⁷⁶Lu puis dans un second temps nous avons regardé la réaction ¹⁷³Lu(n,γ)¹⁷⁴Lu avec la réaction ¹⁷⁴Yb(³He,t)¹⁷⁴Lu. Pour cela, la probabilité d’émission γ dans ces deux voies a été mesurée et comparée à un calcul TALYS. Cette comparaison a révélé de grandes disparités entre les réactions de transfert utilisées et les réactions induites par des neutrons. Notre investigation s’est alors orientée à regarder de plus près la distribution de spins du noyau composé formé. Celle-ci a pu être extraite grâce à un ajustement de la probabilité d’émission γ mesurée. Cette distribution montre que les réaction (³He,X) peuplent en réalité des spins beaucoup plus grands que ceux issus de la réaction (n,γ). La mesure des rapports des intensités de transitions γ corroborent aussi ce résultat même si les spins peuplés semblent être plus faibles. Cette expérience a mis clairement en évidence qu’une réaction induite par un faisceau d’³He ne pouvait pas se substituer à une réaction (n,γ). Tout au long de ce document, nous avons montré par différents aspects, à quel point il peut être difficile d’obtenir des informations sur les noyaux radioactifs tels que le ¹⁷³Lu et que pour le futur de nombreux défis tant expérimentaux que théoriques sont encore à relever. / This PhD report presents a study of radiative neutron capture reaction of the ¹⁷³Lu to determine the (n,γ) cross section. Contrary to stable nuclei for which a huge amount of data is available, there is a real lack of information for radioactive nuclei. The first part of this PhD focuses on the presentation of different formalisms involved in cross section calculations and on the use of TALYS code based on these models. TALYS allowed us to evaluate the (n,γ) cross section on ¹⁷³Lu with data from the capture reaction on the ¹⁷⁵Lu. In a second step, the (n,γ) cross section on ¹⁷³Lu was measured at the LANSCE facility with the 4π detector DANCE. This experience turned out to be a real challenge for both the target production of ¹⁷³Lu and for obtaining data due to the high radioactivity of this isotope. Interesting informations have been extracted such as the total capture yield, the identification and the characterization of new resonances, the determination of parameters like average spacing, neutron and γ widths and the value of the density function. All these new informations enabled us to reconstruct the (n,γ) cross section on ¹⁷³Lu up to 200 eV. We could then estimate a correction for the cross section evaluated by TALYS in order to obtain a new evaluation. The third part of this PhD deals with getting additionnal information on the ¹⁷³Lu(n,γ)¹⁷⁴Lu reaction by using the surrogate method. Firstly, this technique has been tested on a well-known reaction : ¹⁷⁵Lu(n,γ)¹⁷⁶Lu with the reaction ¹⁷⁴Yb(³He,p)¹⁷⁶Lu. Secondly, we studied the ¹⁷³Lu(n,γ)¹⁷⁴Lu reaction with the ¹⁷⁴Yb(³He,t)¹⁷⁴Lu reaction. The γ decay probability in different ways have been measured and compared with a TALYS calculation. This comparison showed large discrepancies between the transfer reactions and the reactions induced by neutrons. Then our investigation was focused on the spin distribution of the formed compound nucleus. It has been extracted thanks to a fit of the measured γ decay probability. This distribution has shown (³He,X) reactions populate much higher spins than observed in (n,γ) reactions. The measurement of the γ transitions intensities ratios also corroborates this result even if the mean value of the populated spins seem to be lower. This experiment clearly demonstrated a reaction induced by a ³He beam could not to be substituted to a (n,γ) reaction. Throughout this document, we have shown by different aspects on one hand, how it can be difficult to extract information on unstable nuclei such as ¹⁷³Lu and on the other hand that both experimental and theoretical challenges still remain for the future.

Made available in DSpace on 2014-10-09T12:42:01Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:04:33Z (GMT). No. of bitstreams: 1 19174.pdf: 31751 bytes, checksum: 7f1e1ac2bd5fcea7b8edbb1e6ba7a12b (MD5) / Dissertação (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

Submitted by Claudinei Pracidelli (cpracide@ipen.br) on 2016-02-03T12:02:42Z No. of bitstreams: 0 / Made available in DSpace on 2016-02-03T12:02:42Z (GMT). No. of bitstreams: 0 / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP