I denna avhandling studeras elektromagnetisk vågutbredning i graderade materialkompositer med extraordinära egenskaper. Två sådana materialkompositsystem studeras särskilt, med hjälp av både analytiska och beräkningstekniska elektromagnetiska metoder. Det första systemet används för utvecklingen av en lovande icke-invasiv metod för cancerbehandling, som bygger på att tumören med insatta guldnanopartiklar värms upp med hjälp av mikrovågsstrålning. En vågledarstruktur föreslås bestående av ett tunt dielektriskt skikt med en kontinuerlig graderad materialövergång till dess omgivande material till vardera sidan av skiktet. Det tunna lagret består av cancervävnad med insatta guldnanopartiklar som drivs in i elektroforetisk svängning med hjälp av elektromagnetisk strålning. Analytiska lösningar för det givna vågledarproblemet erhålls, vilket möjliggör beräkning av absorptionskoefficienterna endast inom det tunna skiktet, vilket är viktigt för bedömning av genomförbarheten av den tänkta medicinska tillämpningen. De dispersiva dielektriska modellerna som beskriver de elektromagnetiska egenskaperna hos de relevanta biologiska vävnaderna föreslås och diskuteras. Numeriska simuleringar gjorda i COMSOL Multiphysics är i utmärkt överensstämmelse med och validerar de analytiska resultaten. Det andra systemet involverar vågutbredning från ett högerhänt material till ett vänsterhänt metamaterial i fri rymd. De två materialen är impedansmatchade, vilket säkerställer ingen reflektion, och det graderade gränssnittet mellan dem beskrivs av en kontinuerlig funktion. Metamaterialkompositer med rumsligt varierande materialparametrar har fått ett ökande teoretiskt och experimentellt intresse de senaste två decennierna. De är användbara för ett antal tillämpningar, såsom transformationsoptik. I denna uppsats diskuteras egenskaperna hos vänsterhänta material. Fältlösningarna till det impedansmatchade graderade gränssnittet härleds, och en numerisk modell utvecklas i COMSOL. Resultaten bekräftar de extraordinära egenskaperna hos vänsterhänta material. / In this thesis, electromagnetic wave propagation in graded material composites with extraordinary properties are studied. Two such material composite systems are studied in particular, using both analytical and computational electromagnetic methods. The first system is used for the development of a promising non-invasive method of cancer treatment based on heating the tumors with inserted gold nanoparticles by means of microwave radiation. A waveguide structure is proposed consisting of a thin dielectric layer with a continuous graded material transition to its surrounding materials to either side of the layer. The thin layer consists of cancer tissue with inserted gold nanoparticles that are driven into electrophoretic oscillation by means of electromagnetic radiation. Analytical solutions for the given waveguide problem are obtained, allowing the calculation of the absorption coefficients within the thin layer only, which is important for assessment of the feasibility of the envisioned medical application. The dispersive dielectric models describing the electromagnetic properties of the relevant biological tissues are proposed and discussed. Numerical simulations done in COMSOL Multiphysics are in excellent agreement with and validate the analytical results. The second system involves wave propagation from a right-handed material to a left-handed metamaterial in an open boundary system. The two materials are impedance-matched, thus ensuring no reflection, and the graded interface between them is described by a continuous function. Metamaterial composites with spatially varying material parameters have been given an increasing theoretical and experimental interest the last two decades. They are useful for a number of applications, such as transformation optics. In this thesis, the properties of left-handed media are discussed. The field solutions to the impedance-matched graded interface are derived, and a numerical model is developed in COMSOL. The results confirm the extraordinary properties of left-handed media. / <p>QC 20221129</p>

No description available.

Im Rahmen der vorliegenden Dissertationsschrift „Semi-quantitative röntgentomographische Untersuchungen zur Biodistribution von magnetischen Nanopartikeln in biologischem Gewebe“ wurden tomographische Untersuchungen an biologischen Objekten durchgeführt. Bei diesen Objekten handelt es sich um Gewebeproben nach minimal-invasiven Krebstherapien wie zum Beispiel magnetischem Drug Targeting und magnetischer Wärmebehandlung. Der Erfolg dieser Therapien ist sowohl abhängig von der korrekten Verteilung der magnetischen Nanopartikel als auch von der Tatsache, dass diese in der Zielregion in einer ausreichenden Menge vorhanden sind. Das Vorliegen dieser beiden Voraussetzungen ist in der vorliegenden Arbeit untersucht worden. Dabei lag der Schwerpunkt der Arbeit auf der Quantifizierung von magnetischem Material in unterschiedlichen biologischen Gewebeproben mittels Röntgenmikrocomputertomographie (XµCT). Für diesen Zweck wurde ein Kalibrationssystem mit speziellen Phantomen entwickelt, mit dessen Hilfe eine Nanopartikelkonzentration einem Grauwert voxelweise zugewiesen werden kann. Mit Hilfe der Kalibration kann der Nanopartikelgehalt sowohl in monochromatischen als auch in polychromatischen tomographischen Daten im Vergleich zu magnetorelaxometrischen Ergebnissen mit wenigen Prozent Abweichung ermittelt werden. Trotz Polychromasie und damit einhergehenden Artefakten können 3-dimensionale röntgentomographische Datensätze mit einer geringfügigen Konzentrationsabweichung im Vergleich zur quantitativen Messmethode Magnetorelaxometrie semi-quantitativ ausgewertet werden. / The success of the minimal invasive cancer therapies, called magnetic drug targeting and magnetic heating treatment, depends strongly on the correct distribution of the magnetic nanoparticles on one side. On the other side it depends on the fact that a sufficient amount of magnetic nanoparticles carrying drugs is accumulated in the target region. To study whether these two requirements are fulfilled motivates this PhD thesis „Semi-quantitative X-ray-tomography examinations of biodistribution of magnetic nanoparticles in biological tissues“. The analysis of the distribution of the magnetic nanoparticles in tumours and other tissue examples is realized by means of X-ray-micro computer tomography (XμCT). The work focuses on the quantification of the magnetic nanoparticles in different biological tissue samples by means of XµCT. A calibration of the tomographic devices with adequate phantoms, developed in the frame of this work, opens now the possibility to analyze tomographic data in a semi-quantitative manner. Thus, the nanoparticle concentration can be allocated voxel-wise to the grey values of the three-dimensional tomographic data. With the help of calibration of the tomography equipments used, polychromatic as well as monochromatic three-dimensional representations of objects can be analyzed with regard to the biodistribution of magnetic nanoparticles as well as with regard to their quantity. The semi-quantitative results have been compared with results obtained with a quantitative measurement method magnetorelaxometry (MRX). Thereby a good agreement of the semi-quantitative and quantitative data has been figured out.

Im Rahmen der vorliegenden Dissertationsschrift „Semi-quantitative röntgentomographische Untersuchungen zur Biodistribution von magnetischen Nanopartikeln in biologischem Gewebe“ wurden tomographische Untersuchungen an biologischen Objekten durchgeführt. Bei diesen Objekten handelt es sich um Gewebeproben nach minimal-invasiven Krebstherapien wie zum Beispiel magnetischem Drug Targeting und magnetischer Wärmebehandlung. Der Erfolg dieser Therapien ist sowohl abhängig von der korrekten Verteilung der magnetischen Nanopartikel als auch von der Tatsache, dass diese in der Zielregion in einer ausreichenden Menge vorhanden sind. Das Vorliegen dieser beiden Voraussetzungen ist in der vorliegenden Arbeit untersucht worden. Dabei lag der Schwerpunkt der Arbeit auf der Quantifizierung von magnetischem Material in unterschiedlichen biologischen Gewebeproben mittels Röntgenmikrocomputertomographie (XµCT). Für diesen Zweck wurde ein Kalibrationssystem mit speziellen Phantomen entwickelt, mit dessen Hilfe eine Nanopartikelkonzentration einem Grauwert voxelweise zugewiesen werden kann. Mit Hilfe der Kalibration kann der Nanopartikelgehalt sowohl in monochromatischen als auch in polychromatischen tomographischen Daten im Vergleich zu magnetorelaxometrischen Ergebnissen mit wenigen Prozent Abweichung ermittelt werden. Trotz Polychromasie und damit einhergehenden Artefakten können 3-dimensionale röntgentomographische Datensätze mit einer geringfügigen Konzentrationsabweichung im Vergleich zur quantitativen Messmethode Magnetorelaxometrie semi-quantitativ ausgewertet werden. / The success of the minimal invasive cancer therapies, called magnetic drug targeting and magnetic heating treatment, depends strongly on the correct distribution of the magnetic nanoparticles on one side. On the other side it depends on the fact that a sufficient amount of magnetic nanoparticles carrying drugs is accumulated in the target region. To study whether these two requirements are fulfilled motivates this PhD thesis „Semi-quantitative X-ray-tomography examinations of biodistribution of magnetic nanoparticles in biological tissues“. The analysis of the distribution of the magnetic nanoparticles in tumours and other tissue examples is realized by means of X-ray-micro computer tomography (XμCT). The work focuses on the quantification of the magnetic nanoparticles in different biological tissue samples by means of XµCT. A calibration of the tomographic devices with adequate phantoms, developed in the frame of this work, opens now the possibility to analyze tomographic data in a semi-quantitative manner. Thus, the nanoparticle concentration can be allocated voxel-wise to the grey values of the three-dimensional tomographic data. With the help of calibration of the tomography equipments used, polychromatic as well as monochromatic three-dimensional representations of objects can be analyzed with regard to the biodistribution of magnetic nanoparticles as well as with regard to their quantity. The semi-quantitative results have been compared with results obtained with a quantitative measurement method magnetorelaxometry (MRX). Thereby a good agreement of the semi-quantitative and quantitative data has been figured out.

Proton therapy is a relatively new treatment modality for cancer, having recently been incorporated into hospitals in the last two decades. Although proton therapy has much higher start up and treatment costs than traditional methods of radiotherapy, it continues to expand in use today. One reason for this is that proton therapy has the advantage of a more precise localization of dose compared to traditional radiotherapy. Other proposed advantages of proton therapy in the treatment of cancer may lead to a faster expanse in its use if proven to be more effective than traditional radiotherapy. Therefore, much research must be done to investigate the possible negative and positive effects of using proton therapy as a treatment modality. In proton therapy, protons do account for the vast majority of dose. However, when protons travel through matter, secondary particles are created by the interactions of protons and matter en route to and within the patient. It is believed that secondary dose can lead to secondary cancer, especially in pediatric cases. Therefore, the focus of this work is determining both primary and secondary dose. In order to develop relevant simulations, the specifications of the treatment room and beam were based off of real-world facilities as closely as possible. Using available data from proton accelerators and clinical facilities, an accurate proton therapy nozzle was designed. Dose calculations were performed by MCNPX using a simple water phantom, and then beam characteristics were investigated to ensure the accuracy of the model. After validation of the beam nozzle, primary and secondary dose values were tabulated and discussed. By demonstrating the method of these calculations, the purpose of this work is to serve as a guide into the relatively recent field of Monte Carlo methods in proton therapy.

Advances in breast cancer detection and oncology treatment modalities have prolonged the survival time for the cancer population, which is officially the largest group of cancer survivors among women in the western world, including South Africa (Brem & Kumar, 2011; Fisher, Dolbeault, Sultan & Bredart, 2014; Herbst, 2011; Reyes-Gibby, et al., 2012). In the light of shocking statistics and ever rising numbers of cancer, especially breast cancer, the time is ripe for further research in the domain of psycho-oncology and has motivated the researcher, due to her interest and involvement in breast cancer, to make this her field of research. Despite the need for a bio-psycho-social approach when treating cancer patients there is little literature available on the psychological interventions in South Africa where the majority of research studies previously conducted in South Africa have generally focused on the bio-medical aspects of cancer (Albrecht, 2009; Venter, 2014). To comprehend the paradigm of psycho-oncology, which is the backbone of this study, a theoretical framework was attained from Engel’s humanistic or psychological model (caring) and Pasteur’s biomedical model (curing) (Borrel-Carrio, Suchman, & Epstein, 2004). The primary aim of this study was to explore the lived experiences of breast cancer patients concerning their diagnosis, treatment and survivorship and unique needs for psycho-oncological interventions through their own “voices”. The research was conducted within a qualitative framework with a case study method of inquiry employing open-ended style interviews and psychotherapeutic sessions with five purposely sampled breast cancer patients. Two qualitative questionnaires were also used for triangulation purposes. Transcripts of all the therapeutic sessions were analysed using interpretive analysis where categories and themes were developed and described in full. Findings indicated that in spite the extensive proof that breast cancer causes numerous sexual and psychological complications during active treatment and afterwards, patients still feel that they have no “platform” to express their emotions and sexual issues within the oncology framework, or that there is enough and sufficient assistance to attend to their needs. e The researcher hopes that this study will make a valuable contribution to research in the field of psycho-oncology in South Africa and to indicate new realities of the chronicity of breast cancer and treatment complications that demand psychotherapeutic interventions in cancer care and that the study will initiate new ways of understanding the role of psychology and the psychologist in the medical world of cancer. The researcher hopes that by offering an understanding of participants’ unique experiences of this process, practitioners will have insight when working therapeutically with this population and empower them to have a quality of life, even within the boundaries of their illness. / Psychology / D. Litt. et Phil. (Psychology)

Made available in DSpace on 2011-05-04T12:36:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2010 / Corumbá se localiza na fronteira do Brasil com a Bolívia, no estado do Mato Grosso do Sul. As zonas de fronteira apresentam características próprias que influenciam as condições de vida e saúde de seus habitantes. O câncer foi a segunda causa de morte em Corumbá em 2006, respondendo por 14 por cento dos óbitos. A acessibilidade geográfica à rede assistencial exerce grande influência sobre a situação de saúde na região da fronteira e a dificuldade de acesso aos serviços especializados, pode acarretar diagnóstico tardio, demora no tratamento ou não diagnóstico. Os objetivos desta dissertação foram analisar o padrão de mortalidade por câncer entre 1980-2006 e avaliar a assistência oncológica de alta complexidade da população de Corumbá, Mato Grosso do Sul com base nos parâmetros de necessidades de procedimentos normatizados pelo Sistema Único de Saúde (SUS).Dados populacionais e de mortalidade por câncer por sexo, idade, localização e ano de ocorrência foram obtidos no DATASUS/Ministério da Saúde. Taxas de mortalidade por câncer em geral e por tumores específicos foram padronizadas por idade pela população mundial. Estimaram-se modelos de regressão para análise da tendência das taxas de mortalidade. O método das médias móveis foi empregado para suavizar flutuações nas séries, sempre que não se pode ajustar um modelo estatisticamente significativo para as taxas anuais. Razões Padronizadas de Mortalidade (SMR) foram estimadas para comparar a mortalidade por câncer no período 2002-06 em Corumbá e Campo Grande, a capital do estado. Foram obtidas as taxas de incidência de câncer por faixa etária dos Registros de Câncer de Base Populacional (RCBP) da região Centro-Oeste. Os procedimentos de alta complexidade em câncer, realizados por residentes de Corumbá na rede pública de Campo Grande foram obtidos nos Sistemas de Informações Hospitalares e Ambulatorial / Autorização de Procedimentos de Alta Complexidade. As taxas de incidência dos RCBP foram aplicadas ao número de indivíduos de cada grupo etário na população de Corumbá, obtendo-se o número de casos novos esperados por grupo de idade. O seu somatório forneceu o número de casos novos anuais de câncer estimados ajustado por idade. O número estimado de procedimentos de alta complexidade para os residentes da cidade em 2008-2009 foi calculado com base nas estimativas de casos novos e nos parâmetros de necessidades para atenção oncológica. Estimou-se o percentual de cobertura comparando o número de casos que efetivamente realizaram os procedimentos em relação ao número de casos que deveriam tê-los realizado. Os óbitos por câncer demama de mulheres residentes em Corumbá, no período 2004-2008, foram identificados pelas declarações de óbito nominais do município, sendo incluídas somente as que realizaram pelo menos um tipo de tratamento especifico no SUS. Considerou-se idade ao iniciar o tratamento e no óbito, estadiamento clínico, local do tratamento, procedimentos e tipo de serviço que financiou o tratamento, sendo a análise efetuada através de medidas de tendência central e dispersão, distribuições de freqüências e da sobrevida. As taxas de mortalidade de Corumbá passaram de 101,74 para 105,6 por 100.000 no período de estudo. Houve aumento das taxas de mortalidade, principalmente, entre as mulheres e no grupo de 60 ou maisanos. Observou-se declínio constante da mortalidade por câncer de estômago para o conjunto da população e ambos os sexos. Houve tendência de incremento da mortalidade por câncer de cólon/reto na população geral, em homens e mulheres. O comportamento do câncer em Corumbá tende a ser similar ao da região Centro-Oeste e do Brasil, porém com evolução lenta e tardia, predomínio do câncer gástrico e dos tumores de colo uterino e, possivelmente, certo grau de sub-diagnóstico para outras neoplasias. Problemas no acesso ao diagnóstico e tratamento do câncer pela população podem explicar, em parte, esses resultados, assim como diferenças regionais e geracionais nos níveis de exposição a carcinógenos. Entretanto, não existem dados sobre prevalência desses agentes nesta população específica, nem são disponíveis dados de incidência que possibilitem a comparação com a mortalidade, para verificar se as diferenças observadas refletem, efetivamente, tendências da incidência de câncer em Corumbá. Foi evidenciada a baixa cobertura da assistência de alta complexidade em oncologia à população residente em Corumbá e o retardo na instituição do tratamento específico para o câncer de mama. A acessibilidade dos residentes da cidade à rede assistencial de saúde poderia explicar, em parte, esses achados. O Plano Diretor de Regionalização estabelece Campo Grande como referência em alta complexidade em oncologia, às pessoas residentes em Corumbá, porém os resultados indicam dificuldade no cumprimento dessa política e no atendimento às normas de regulação do sistema. Outros estudos, com diferentes abordagens metodológicas, podem contribuir para melhor explicar as razões que permeiam as dificuldades de acesso à assistência em Corumbá. / Corumbá is located on the border between Brazil and Bolivia, Mato Grosso do Sul. Border areas have unique characteristics that influence the living and health conditions of its inhabitants. Cancer was the second leading cause of death in Corumbá in 2006, accounting for 14% of deaths. The geographical accessibility to health care services has great influence on health conditions in the border area and difficulties in access to specialized services, may lead to delayed diagnosis and/or treatment or even to no diagnosis. The objectives of this work were to analyze patterns of cancer mortality during 1980-2006 and to evaluate high-complexity cancer care in the population of Corumbá, Mato Grosso do Sul, based on the parameters of need of established procedures of the Brazilian Unified Health System (SUS). Population data and cancer mortality by sex, age, location and year of occurrence were obtained in DATASUS / Ministry of Health. Mortality rates for cancer in general and for specific tumors were standardized by age using the world population. We estimated regression models to analyze trends in mortality rates. The method of moving averages was used to smooth fluctuations in the series, when it was not possible to adjust a statistically significant model for the annual rates. Standardized Mortality Ratios (SMR) were estimated to compare cancer mortality in Corumbá and Campo Grande, the state capital, in the period 2002-06. Incidence rates of cancer by age were obtained from the Population-Based Cancer Registries (PBCR) of the Midwest region. High-complexity cancer procedures performed in residents of Corumbá at Campo Grande public health services were obtained from the Hospital Information and Outpatient/Authorization Procedures of High Complexity Systems. Incidence rates of PBCRs were applied to the number of individuals in each age group in the Corumbá population, obtaining the number of expected new cases by age group. Their sum provided the annual number of new cases of cancer estimated adjusted for age. The estimated number of high-complexity procedures for residents of the city in 2008-2009 was calculated based on estimates of new cases and the parameters of needs for cancer care. It was estimated the percentage of coverage by comparing the number of cases that actually performed the procedures in relation to the number of cases that should have had them done. Deaths from breast cancer of women living in Corumbá, in the period 2004-2008, were identified through death certificates listed for the city. Only cases that had at least one specific type of treatment in the SUS were selected. Variables considered were age at start of treatment and at death, clinical stage, and place of treatment, procedures and type of service that funded the treatment. Analysis was performed with measures of central tendency and dispersion, frequency distributions and survival. Mortality rates increased in Corumbá from 101.74 to 105.6 per 100,000 during the study period. There was an increase in mortality rates, especially among women and the group of 60 or more years. A steady decline in mortality from stomach cancer was observed for the whole population and both sexes. There was a trend of increasing mortality from colorectal cancer in the general population, men and women. Lung cancer showed a steady decline in the overall population and among men, and cancers of the prostate and cervix tended to decline in most of the period, showing stability at the end. Compared to Campo Grande, Corumbá residents showed excess deaths from stomach and cervical cancers and submortality from other locations. In 2008-2009, 29 cancer surgeries were performed in residents of Corumbá, which corresponds to a coverage between 24.2 and 20.1% of that required to meet only the needs of estimated new cases, based on Campo Grande; and between 12.3 and 10.3%, if the reference was Cuiabá. Considering the lowest estimate, 144 new cases in the biennium would need radiotherapy and 58 received the procedure (40.3% of the total estimate); this value would correspond to 20.6% if the estimate had Cuiaba as its base. For chemotherapy, the lowest estimate indicated that 168 new cases would require the procedure and only 109 received (estimated coverage 64.9%); the same estimate based in Cuiabá would correspond to 33.1%. During 2004-2008, 30 deaths from breast cancer occurred in residents of Corumbá, but it was only possible to obtain information for 26. Of these, 19.2% had less than 40 years at the start of initial treatment and 42.3% died with less than 50 years. Three women underwent initial treatment at other cities than Campo Grande, 23 were treated only in public services and 70.8% had advanced disease at the time of initial treatment. The initial treatment was surgery in 50% and the most frequent sequential treatment was radiotherapy plus chemotherapy. Two women did not receive sequential treatment. The median survival from initial treatment until death was 25.5 months, 25% of the women died within one year ofinitial treatment and 75% within 36 months. Cancer behavior in Corumbá tended to be similar to that of the Midwest region as a whole and of Brazil, with a slow and late evolution, predominance of gastric and cervix cancers and, possibly, some degree of under-diagnosis for other tumors. Problems in access to cancer diagnosis and treatment by the population may partly explain these results, as well as regional and generational differences in the levels of exposure to carcinogens. However, neither data on the prevalence of these agents in this specific population, nor incidence data are available to allow comparison with mortality data, in order to determine whether the observed differences reflect, in fact, trends in cancer incidence in Corumbá. This study showed low coverage of high-complexity oncologic care for the population of Corumbá and a delay in the institution of specific treatment for breast cancer. The access of city residents to health care services could partly explain these findings. The Regionalized Directory Planning established Campo Grande as the reference for high-complexity cancer procedures for people living in Corumbá, but these results indicate difficulties in complying with this policy and with federal guidelines to regulate the system. Other studies with different methodological approaches may contribute to better explain the reasons underlying the difficulties for having access to cancer care in Corumbá.

The present thesis deals with different aspects of the chemistry of oxovanadium(IV) complexes, their interaction with double stranded DNA, photo-induced DNA cleavage, photo-enhanced cytotoxicity in visible light and red light and localisation and cellular uptake to understand the mechanism of cell death. Chapter I presents a general introduction on potential of transition metal complexes as photochemotherapeutic agents. A brief introduction about Photodynamic Therapy (PDT) as a new alternative to chemotherapy for treating cancer has been made. Various modes of interaction of small molecules with duplex DNA are described. Recent reports on metal-based photocytotoxicity, photo-induced DNA cleavage activity and cellular localization are presented in detail. Objective of the present investigation is also dealt in this Chapter. Chapter II of the thesis deals with the synthesis, characterization, DNA binding and photo-induced DNA cleavage activity of ternary oxovanadium(IV) complexes of ONO-donor 2-(2-hydroxybenzylideneamino)phenol (salamp) and phenanthroline bases to explore the photo-induced DNA cleavage activity in UV-A light of 365 nm and photocytotoxicity in visible light. Chapter III deals with the photo-induced DNA cleavage and photocytotoxicity of ternary oxovanadium(IV) complexes containing ONN-donor N-2-pyridylmethylidine-2-hydroxyphenylamine (Hpyamp) Schiff bases and phenanthroline bases. The objective of this work is to investigate the photo-induced DNA cleavage activity in near-IR light. Photocytotoxicity and cell cycle arrest have been studied in HeLa cancer cells. Chapter IV deals serendipitous discovery of planar triazinuim cationic species by vanadyl-assisted novel ring cyclization reaction. The compounds are synthesised, characterized and their DNA binding and anaerobic photoinduced DNA cleavage activity are presented. The importance of the thiazole moiety in the triazinuim species in cellular uptake has been investigated. Photocytotoxicity, localization and cell death mechanism have been studied in HeLa and MCF-7 cells. Chapter V describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of oxovanadium(IV) complexes containing 2-(1H-benzimidazol-2-yl)-N-(pyridin-2-ylmethylene)ethaneamine (Hpy-aebmz) and curcumin as photosensitizer. The effect of conjugating naphthalimide on Hpy-aebmz on photoinduced DNA cleavage and photocytotoxicity has been studied. Cellular uptake, localization and mechanism of cell death induced by complexes have been investigated. Chapter VI presents ternary oxovanadium(IV) complexes having, 2-((1H-benzimidazol-2-yl)methylimino-methyl)phenol (Hsal-ambmz) and phenanthroline bases. The complexes were synthesized, characterized and their DNA binding property studied. Photo-induced DNA cleavage activity and photocytotoxicity in red light has been discussed. Anthracene has been conjugated to a tridentate ligand to investigate cellular uptake, localization and cell death mechanism. Mitochondria targeting property of the complexes having dipeptide has been studied and compared with clinically used drug Photofrin®. The references have been compiled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes, characterized structurally by single crystal X-ray crystallography, are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.

Anticancer active metal complexes such as cisplatin are routinely used for treating various cancers since 1978. However, the side effects of cisplatin overwhelm its therapeutic potential, especially in the latter stages of treatment. The nonspecific cytotoxicity of drugs could be avoided if targeted delivery to cancer cells is achieved using two different methodologies namely, enhanced permeability and retention in solid tumors (EPR) and receptor mediated endocytosis using a homing agent (RME). Ru(II)-arene complexes which are delivered specifically into cancer cells by the transferrin enzyme are less toxic compared to other metal complexes. The thesis describes the synthesis and use of Ru(II)-η6cymene complexes with different ancillary ligands which modulates the anticancer activity and the utility of two macromolecular vehicles in directed drug delivery. Ru(II)-η6cymene complexes with different heterocyclic ancillary ligands are synthesized and their anticancer activity tested against various cancer cell lines. Ruthenium complexes with mercaptobenzothiazoles are found to be quite active against the H460 cell lines that overexpress transferrin receptors and non-cytotoxic to the normal cell line, HEL299. Biophysical studies show that complexes (H1 and H8) can unwind the pBR322 DNA and inhibit the Topo IIα enzyme. A unique biphasic melting curve of CT DNA is observed in the presence of H1 which is attributed to formation of a dinuclear species (H20). Half-sandwich complexes of 6-thioguanine (6-TG) have also been prepared to improve the delivery and efficacy of 6-TG which is used in spite of a deleterious photoreaction. The Ru complexes cytotoxic to several leukemia cell lines. As they are photostable and anticancer active, they are better than 6-TG. Anticancer activity exhibiting piazselenols are used as ancillary ligands to make Ru(II)-arene complexes. Unfortunately, 1H NMR spectra suggests that piazselenol complexes dissociate in solution. However, the nitro substituted piazselenol and its Ru complex show the greatest cytotoxicity (<0.1 µM) against the A2780 cell line. The utility of PAMAM dendrimers and hyper branched polymers (hybramers) conjugated with a homing agent to target cancer cells by EPR and RME is probed. A cytotoxic copper complex (CuATSM) is covalently attached to the macromolecules through a disulfide linker, cleaved in the presence of GSH. Targeting efficacy of the folic acid-dendrimer conjugates is checked against two glioma cell lines. The folic acid-dendrimer conjugate is more active compared to dendrimer conjugate without folic acid against folate-receptor-overexpressing LN18 cell line. Biotin conjugated dendrimer shows better accumulation in HeLa cells, which require high amounts of biotin for growth. In vivo studies demonstrate that the conjugate can cross the blood-brain barrier. These studies suggest that PAMAM dendrimer can be used as a targeted delivery vehicle for cytotoxic metal complexes. Hyperbranched polymers decorated with propargyl groups and hydrophilic OH terminated TEG groups are attached to biotin and a cytotoxic Cu complex. (CuATSM-SS-CONH-N3) through ‘click’ reactions and tested against the HeLa cell line. On the basis of the studies conducted, it is concluded that targeted delivery of cytotoxic metal complexes are possible in the case of Ru(II) half-sandwich complexes and macromolecular vehicles like dendrimers are suitable for specifically delivering copper complexes into cancer cells.

Dans la première partie du travail, nous avons étudié l’expression génique dans les cancers thyroïdiens survenus après l’explosion de la centrale nucléaire de Tchernobyl. L’incidence des cancers thyroïdiens papillaires a fortement augmenté après l’accident de Tchernobyl chez les enfants, offrant l’opportunité exceptionnelle d’étudier les caractéristiques moléculaires des cancers thyroïdiens radioinduits. Contrairement aux études précédentes qui comportaient toutes des facteurs confondants, nous avons pu investiguer l’expression des ARN messagers des tumeurs et de leurs tissus contra-latéraux normaux de patients exposés et de patients non exposés aux retombées radioactives, en utilisant une cohorte de patients appariés pour l’âge et l’ethnicité. L’irradiation d’une population conduit au développement de cancers dans une fraction de cette population. Les individus atteints peuvent l’avoir été de manière stochastique, ou à cause d’une prédisposition ou sensibilité particulière à l’irradiation. La comparaison des tumeurs exposées et non exposées permet d’étudier l’effet de l’irradiation, et celle des tissus normaux contralatéraux offre la possibilité d’étudier la susceptibilité aux radiations dont les implications sont nombreuses en médecine (radio-diagnostic, cancers secondaires) et en radioprotection. L’expression génomique complète a été analysée sur puces Affymetrix pour les tissus de 45 patients. Vingt-deux de ces patients ont été exposés aux retombées de Tchernobyl, vingt-trois autres, appariés selon l'âge et résidant dans les mêmes régions de l'Ukraine, n'ont pas été exposés à l’irradiation. Notre travail a mis en évidence l’existence d’une signature transcriptionnelle permettant de différencier les tissus normaux exposés des non exposés, les gènes qui composent cette signature ayant trait à la prolifération ;nos résultats suggèrent qu’un niveau plus élevé de prolifération dans les tissus normaux pourrait être associé aux cancers radioinduits, soit en tant que facteur prédisposant au cancer, soit en tant que conséquence de la radiation.<p><p>La deuxième partie du travail a été consacrée à la caractérisation in vitro de différentes lignées cellulaires humaines de cancers thyroïdiens. Ces lignées sont souvent employées comme modèles pour l’étude et le développement d’approches thérapeutiques pour ces cancers mais notre laboratoire a démontré que ces lignées s’étaient dédifférenciées au cours de leur propagation in vitro et que leurs profils transcriptionnels se rapprochaient essentiellement des tumeurs les plus dédifférenciées, les cancers anaplasiques. Nous avons tenté de ré-induire dans ces lignées l’expression des marqueurs de différenciation de la thyroïde au moyen d’agents épigénétiques, l’idée étant que ces gènes dont l’expression est caractéristique de la thyroïde ne s’expriment plus suite à l’action de mécanismes épigénétiques comme la méthylation au niveau de leurs promoteurs. Les cancers thyroïdiens dédifférenciés étant les plus agressifs et ayant perdu l’expression des facteurs de différenciation dont le transporteur sodium/iodure (NIS), ils sont inaccessibles au traitement par l’iode radioactif I131. La réexpression des marqueurs de différenciation thyroïdienne permettrait d’une part d’employer plus adéquatement les lignées comme modèle d’étude des cancers différenciés, et d’autre part d’envisager l’emploi de(s) substances(s) qui ont permis cette réexpression en tant que médicaments pour les cancers dédifférenciés. Nos travaux montrent que les traitements épigénétiques des lignées cancéreuses ne permettent pas une réinduction significative de la différenciation mais tendent à démontrer que l’inactivation épigénétique provoque dans ces lignées la perte de l’expression de gènes n’ayant aucun rôle utile pour la cellule au cours des milliers de réplications in vitro / In the first part of the work, we studied gene expression in thyroid cancers following the explosion of the Chernobyl nuclear power plant. The incidence of thyroid papillary cancers rose sharply after the Chernobyl accident in children, providing an exceptional opportunity to study the molecular characteristics of radiation-induced thyroid cancers. Unlike previous studies that included confounding factors, we were able to investigate the expression of messenger RNA from tumors and their normal contra-lateral tissue of patients exposed and not exposed to the fallout using a cohort of patients matched for age and ethnicity. The irradiation of a population leads to the development of cancer in a fraction of the population. Affected individuals may have been stochastically, or because of a particular predisposition or susceptibility to irradiation. Comparison of tumors exposed and unexposed allows to study the effect of irradiation, and the contra-lateral normal tissue offers the possibility to study the susceptibility to radiation whose implications are numerous: medical (radio - diagnosis, secondary cancers ) and radiation protection. The complete gene expression was analyzed on Affymetrix for tissues of 45 patients. Twenty- two of these patients were exposed to fallout from Chernobyl, twenty-three, matched for age and residing in the same regions of Ukraine have not been exposed to radiation. Our work has demonstrated the existence of a transcriptional signature allowing to differentiate exposed and unexposed normal tissues, and the genes that compose the signature are related to proliferation; our results suggest that a higher level of proliferation in normal tissues may be associated with radiation-induced cancers, either as a predisposing factor for cancer,or as a result of the radiation.<p><p>The second part was devoted to the in vitro characterization of different human cell lines of thyroid cancer. These lines are often used as models for the study and development of therapeutic approaches for these cancers, but our laboratory has demonstrated that these cell lines dedifferentiated during their in vitro propagation and their transcriptional profiles are essentially closer to the most dedifferentiated tumors, the anaplastic cancers. We tried to re- induce in these lines the expression of differentiation markers of thyroid using epigenetic agents, the idea being that these genes whose expression is characteristic of thyroid are no longer expressed due to epigenetic mechanisms such as methylation of their promoters. Dedifferentiated thyroid cancers are more aggressive and have lost the expression of differentiation factors including sodium/iodide transporter(NIS), they are inaccessible to treatment with radioactive iodine I131. Re-expression of thyroid differentiation markers could allow in one hand to use more adequately cell lines as models to study differentiated cancers, and secondly to consider the used substances that helped this re-expression as drugs for the dedifferentiated cancers. Our work shows that epigenetic treatments for cancer cell lines do not allow a significant re-induction of differentiation but tend to demonstrate that the epigenetic inactivation in these cell lines causes the loss of expression of genes that have no useful role in the cells over thousands of replication in vitro .<p><p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished