Depuis plusieurs dizaines d'années, les matériaux hybrides organiques-inorganiques constituent une classe de matériaux particulièrement bien adaptée aux applications en optique intégrée. Le réseau minéral, élaboré par procédé sol-gel, confère au matériau la tenue mécanique. Quant au réseau organique, qui est réticulable par voie photochimique, il permet la formation des systèmes guidants. Des travaux antérieurs réalisés au sein de notre laboratoire ont montré le potentiel d'un matériau à base d'un précurseur hybride 2-(3,4 epoxycyclohexylethyltrimethoxysilane) (EETMOS) pour l'application en optique intégrée. Bien que la qualité des composants réalisés à 1,31µm se soit révélée satisfaisante, un problème subsiste : une trop forte atténuation à 1,55 µm. La transmission optique autour de ces longueurs d'ondes est limitée par la présence des groupements OH et CH aliphatiques.L'objectif principal de ce travail est de développer une nouvelle génération de matériaux hybrides avec une très grande réactivité et de diminuer la quantité de groupements impliqués dans l'atténuation. Nous avons choisi la fonction vinyl éther comme fonction organique grâce à sa grande réactivité par voie cationique en comparaison avec la fonction époxyde. Nous avons étudié la double fonctionnalité de polymérisation du nouveau matériau hybride à base d'un vinyl éther silane. En premier lieu, les réactions d'hydrolyse et de polycondensation du sol ont été suivies par la spectroscopie RMN liquide du Si-29 en fonction du temps, de la température et du pH de l'eau impliquée dans l'hydrolyse. Le but était d'obtenir le plus haut taux d'oligomère multifonctionnel possible et le minium de groupement OH. La photopolymérisation de type cationique de la fonction vinyl éther a ensuite été étudiée, en utilisant la spectroscopie d'absorption dans l'infrarouge moyen. En présence du photoamorceur diaryliodonium, la photopolymérisation a été étudiée en suivant l'évolution de la bande d'absorption de la double liaison vinyl éther avant et après irradiation. La photopolymérisation cationique est rapidement initiée dès le début de l'exposition aux UV, ce qui prouve la réactivité important de la fonction vinyl éther. En utilisant la spectroscopie d'absorption dans le proche infrarouge, les résultats montrent des niveaux d'atténuation très prometteurs pour l'utilisation de ce matériau en optique intégré à 1,31 et 1,55 µm. / In the last few years, organic-inorganic hybrid materials were particularly attractive for integrated optical circuits. Hybrid network could be prepared by the formation of inorganic and organic network simultaneously through sol-gel technique and photopolymerization process.A composition based on [2-(3, 4 epoxycyclohexylethyltrimethoxysilane)] has already allowed the fabrication of optical integrated devices. The organic polymerization is on a cationic way. Results show the contributions of OH and aliphatic CH groups to the attenuation in the third telecommunication window located at 1,55 µm.The main objective of this work is to remove this difficulty by developing a new generation of hybrid materials with a very high reactivity and low amount of groups involved in the attenuation. We have chosen vinyl ether function as an organic part because of their well known high polymerization rates via cationic way which are faster than the epoxide function and which lead to no OH groups generation and a very low aliphatic CH groups introduction.In this work, we study the dual functional structure of a new vinyl ether alkoxysilane hybrid precursor. Firstly, hydrolysis and polycondensation of vinyl ether based solution are followed by liquid and solid Si-NMR spectroscopy. The kinetic reaction is followed as a function of time, temperature and pH of the water involved in the hydrolysis, in order to obtain the highest reactive multifunctional oligomer and the lowest OH groups. Secondly, results of the cationic photopolymerization of vinyl ether- based monomers are also reported, using middle infrared spectroscopy. In the presence of diaryliodonium photoinitator, the photopolymerization is studied by monitoring the absorption band of vinyl ether double bond before and after irradiation. The cationic photopolymerization occurs rapidly upon UV-exposure and vinyl ether monomers proved to be very effective monomers. Using near infrared spectroscopy, results show promising attenuation for the use of this material in integrated optic at 1,31 µmand 1,55 µm.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Complexos de bipiridinas de rutÃnio sÃo bastante estudados na literatura por apresentarem propriedades de interesse em diversas Ãreas como estudos fotoquÃmicos e fotofÃsicos, aplicaÃÃo em sistemas biolÃgicos e como fotosensibilizadores em cÃlulas solares. No presente trabalho, os complexos do tipo cis-[Ru(bpy)(dcbH2)(L)Cl], onde L = Azul do Nilo (NB), Azul de Toluidina (TBO), 9-Aminoacridina (9AA), Azure B (AB) e Violeta de Cresila (VC) foram sintetizados e caracterizados por tÃcnicas espectroscÃpicas e eletroquÃmica para aplicaÃÃo em cÃlulas solares sensibilizadas por corante (DSCs). AlÃm destes, o complexo cis-[Ru(dcbH2)(bpy)(TCNE)Cl] (Ru-TCNE) tambÃm foi testado como sensibilizador em DSC. Estes compostos apresentaram bandas de transferÃncia de carga do tipo MLCT na regiÃo do visÃvel e potenciais redox termodinamicamente favorÃveis para as reaÃÃes de transferÃncia de carga que ocorrem no dispositivo fotoeletroquÃmico. A adsorÃÃo quÃmica dos complexos sensibilizadores na superfÃcie do TiO2 foi evidenciada pelo deslocamento das bandas de MLCT para regiÃes de menor energia quando comparadas aos espectros em soluÃÃo. Os desempenhos fotovoltaicos dos complexos como sensibilizadores em DSC foram avaliados atravÃs das curvas corrente versus potencial, obtidas em condiÃÃes padrÃo AM 1,5. As DSCs contendo os sensibilizadores Ru-TBO e Ru-AB apresentaram os menores desempenhos fotovoltaicos com eficiÃncia global de 0,02 e 0,06%, respectivamente. JÃ as cÃlulas solares sensibilizadas pelos corantes Ru-NB e Ru-VC obtiveram um rendimento de 0,11% com baixos valores de eficiÃncia de incidÃncia de conversÃo de fÃtons a corrente, IPCE. Os melhores resultados foram para as cÃlulas contendo os corantes Ru-9AA e Ru-TCNE, as quais apresentaram rendimentos de 0,54 e 2,01%, respectivamente, com valores de IPCE iguais a 10% para Ru-9AA e 48% para Ru-TCNE. Todos os complexos apresentaram eficiÃncia global de conversÃo de energia solar em elÃtrica inferiores ao complexo padrÃo N3. / Bipyridines ruthenium complexes are widely studied in the literature for presenting interesting properties in various fields such as photochemical and photophysical studies, applications in biological systems and as photosensitizers in solar cells. In this work, the complexes of the type cis-[Ru(bpy)(dcbH2)(L)Cl], where L = Nile blue (NB), Toluidine blue (TBO), 9-aminoacridine (9AA), Azure B (AB) and Cresyl Violet (VC) were synthesized and characterized by spectroscopic and electrochemical techniques for application in dye-sensitized solar cells (DSC). In addition, the complex cis-[Ru(dcbH2)(bpy)(TCNE)Cl] (Ru-TCNE) was also tested as a sensitizer DSC. These compounds showed bands of charge transfer type MLCT in the visible region and thermodynamically favorable redox potentials for the charge transfer reactions which occur in the photoelectrochemical device. The adsorption of the chemical sensitizers complexes on the surface of TiO2 was evidenced by displacement of MLCT bands to lower-energy when compared to the spectra in solution. The photovoltaic performances of the complexes as sensitizers in DSC were evaluated through current versus potential curves obtained in standard AM 1.5 conditions. The DSC sensitizers containing Ru-TBO and Ru-AB had the lowest overall efficiency with photovoltaic performances of 0.02 and 0.06%, respectively. As for the dye-sensitized solar cells by Ru-NB and Ru-VC obtained a yield of 0.11% with low efficiency values of incident conversion of photon to current, IPCE. The best results were for cells containing the dyes Ru-9AA and Ru-TCNE, with energy conversion efficiency of 0.54 and 2.01%, respectively, with IPCE values equal to 10% for Ru-9AA and 48% for Ru-TCNE moieties. All complexes showed overall efficiency of converting solar energy into electricity below the N3 complex pattern.

Nesta tese serão discutidos alguns aspectos químicos, fotoquímicos e fotofísicos importantes no desenvolvimento de fotossensibilizadores para aplicação em terapia fotodinâmica (TFD). Os estudos abrangeram a investigação de 29 espécies, sendo que 20 delas continham um anel porfirínico convencional e 9 eram porfirinas duplamente N-confusas. As primeiras foram sintetizadas para apresentarem diferentes números e tipos de substituintes catiônicos coordenados à posição meso do anel porfirínico, mais especificamente as meso(N-4-piridil)fenilporfirinas e as meso(N-3-piridil)fenilporfirinas contendo um, dois (em trans), dois (em cis), três e quatro grupos [Ru(bipy)2Cl]+ ou CH3+ (figura 1). Em contraste com as porfirinas convencionais. as outras 9 estruturas consistiram das formas protonadas, neutras e desprotonadas de porfirinas que exibem dois anéis pirrólicos adjacentes voltados para fora do anel porfirínico, mais especificamente a base livre (H2N2CP) e os respectivos complexos de prata (AgHN2CP) e de cobre (CuHN2CP). Esta peculiaridade estrutural permite coordenar metais de transição por meio de dois átomos de carbono e dois de nitrogênio, estabilizando fortemente íons metálicos em estados de oxidação anormalmente elevados como Ag3+ e Cu3+. Os dois nitrogênios pirrólicos externos ao anel são susceptíveis tanto a protonação quanto a desprotonação, possibilitando a modulação das propriedades eletrônicas desses compostos por simples alteração no pH do meio. De um modo geral, a acidificação das amostras perturbou mais significativamente suas propriedades fotoquímicas que a desprotonação. Em especial, as espécies neutras metaladas apresentaram bandas bastante intensas na região fototerapêutica de 600 a 750 nm, além de um elevado rendimento quântico de formação de oxigênio singlete (ΦΔ > 0,90 para o complexo Ag(III)). Todavia, um processo de fotodecomposição atribuído ao ataque do 1O2 formado, também foi observado. Ambos os processos, ΦΔ e fotodecomposição, parecem ser modulados pelo metal coordenado no centro do anel. Tanto a coordenação de Ag(lII) como Cu(lII) aumentou o ΦΔ, provavelmente devido ao efeito do metal pesado sobre o cruzamento interssistema. Todavia, verificou-se que o derivado AgHN2CP é muito menos reativo que o CuHN2CP e a base livre. Os motivos deste comportamento ainda não são completamente compreendidos, mas é evidente que o complexo de Ag(lII) apresenta melhores propriedades fotodinâmicas que as demais. Em comparação com as porfirinas duplamente N-confusas, as demais 20 porfirinas catiônicas são muito mais solúveis em água. Neste caso, o enfoque dos experimentos foi direcionado às aplicações biológicas propriamente ditas. Assim, além das propriedades fotofísicas associadas à formação de oxigênio singlete (1O2), também foram exploradas a influência do número dos substituintes periféricos sobre a ligação e danos fotooxidativos provocados em eritrócitos, lipossomos, mitocôndrias e células cancerígenas. Os resultados de ΦΔ mostraram ser inversamente proporcionais ao número de cargas positivas, para as porfirínas contendo grupos N-4metilpiridíniom. Estas diferenças foram consistentes com os efeitos de agregação, causados pela formação de dímeros ou oligômeros, no caso das espécies mais hidrofóbicas. Os coeficientes de partição em n-octanol/água (logPOA) corroboraram estes resultados, apresentando uma dependência inversamente proporcional ao número de cargas positivas ou proporcional ao número de resíduos fenila. As eficiências de ligação à bicamada lipídica mitocondrial, lipossomal e celular e os processos de peroxidação lipídica fotoinduzidos mostraram uma dependência proporcional aos valores de logPOA, exceto para as porfirinas contendo complexos de rutênio. O comportamento não linear neste último caso pode estar associada a dissociação da ligação rutênio-porfirina, devido a elevada força iônica das soluções fisiológicas utilizadas. Neste caso, a descoordenação dos complexos periféricos deve promover uma drástica diminuição da solubilidade do composto. Por este motivo os experimentos foram conduzidos somente com as espécies metiladas. No caso, de mitocôndrias isoladas verificou-se que a interação também apresenta uma razoável participação do potencial de membrana. De fato, quando a mitocôodria estava energizada foi observado um acréscimo de 15% no acúmulo da 3P2cMe em comparação com à mitocôndria desacoplada. Para as demais porfirinas houve um menor acúmulo com o aumento do número de resíduos N-3-metilpirídínio. Em todos os experimentos, um comportamento diferenciado foi observado no caso dos isômeros dicatiônicos. A espécie com cargas dispostas nas posições cis (3P2cMe) apresentou praticamente o dobro de eficiência que o correspondente isômero trans (3P2tMe). Este comportamento parece consistente com uma maior penetração da primeira espécie na bicamada lipídica, proporcionado pelo caráter antipático de sua estrutura química. Os resultados apresentados neste estudo mostraram que estas séries de meso-porfirinas catiônicas constituem sistemas bastante interessantes para a compreensão dos efeitos estruturais envolvidos na ação fotodinâmica dos compostos sobre membranas lipídicas, devido à possibilidade de modulação da relação hidrofilicidade/lipofilicidade, sem alterar significativamente a eficiência na formação de 1O2. Além disso, a disposição espacial das cargas positivas na estrutura do fotossensibilizador demonstrou ser extremamente crítica no processo de ancoragem do mesmo na membrana celular ou mitocondrial e consequentemente em causar efeitos fotooxidativos mais eficientemente. As porfirinas contendo grupos 3-metilpiridínio apresentam vantagens sobre as 4-metilpiridínio, normalmente estudas, por serem mais hidrofílicas, terem menor tendência de agregação e possuírem similar atividade fotodinâmica. Em especial, a estrutura anfipática da 3P2cMe associada a sua elevada formação de 1O2 e estabilidade lhe conferem uma interessante potencialidade como agente fototerapêutico. / In this thesis the chemical, photochemical and photophysical relevant aspects for the development of new photosensitizers for photodynamic therapy applications are discussed. 20 conventional porphyrins species and 9 doubly Nconfused porphyrins species were investigated. The first series contains variable number (1 to 4) of cationic groups, [Ru(bipy)2CI]+ or CH3+ (figure 1), bound to the meta or para-pyridil N-atoms of meso-phenylpyridylporphyrins. On the other hand, the protonated, neutral and deprotonated doubly N-confused porphyrins possess two rotated adjacent pyrrol rings, such that they have two coordinating camon atoms. Consequently, transition metal ions in unusually high oxidation states such as Ag(lII) and Cu(lII) can be stabilized by this structure, while the outer pyrrol N-atoms are susceptible to protonation and deprotonation reactions, allowing the modulation of their electronic properties simply by controlling the pH of the solution. In general, the protonation perturbed more significantly the photochemical properties than the deprotonation. The neutral species exhibit intense absorption bands in the phototherapeutical range (600 to 750 nm), associated with a high singlet oxygen sensitization quantum yield (ΦΔ> 0,90 for the Ag(lII) complex). Furthermore, a photodecomposition process due to the reaction with 1O2 was also identified. Both ΦΔ and photodecomposition are influenced by the metal ion coordinated to the doubly N-confused porphyrin ring. The coordination of Ag(lIl) and Cu(lII) increased ΦΔ, probably due to the enhancement of intersystem crossing quantum yield associated with the heavy atom effects. However, AgHN2CP is much more stable than CuHN2CP or the free-base, but the reasons are not clear and should be further investigated. The above results clearly evidence the superior properties of the Ag(lIl) complex as photosensitizer for PDT applications. The 20 cationic pyridylporphyrin derivatives are much soluble in water and experiments directed to biological applications could be carried out. Accordingly, in addition to the quantum yield for singlet oxygen generation(1O2), the effect of the stereochemistry and number and position of the electrically charged substituents on the binding constants and photooxidative damage on erythrocytes, lipossomes, mitochondria and HeLa cells were evaluated. The ΦΔ values were constant in the case of the N-3-methylpyridinium derivatives but inversely proportional to the number of positive charges for the N-4-methylpyridinium derivatives. This was assigned to an increase of aggregation of the sensitizers as the number of meso-phenyl rings and the lipophylicity increase. The partition coefficients in n-octanol/water (logPOA) corroborate that assertion showing a linear correlation with increasing of the number of phenyl groups. The binding efficiency towards the mitochondrial, lipossomal and cellular membrane and the photo-induced lipidic peroxidation processes were directly proportional to the logPOA, except for the ruthenated porphyrins. This last behavior may be associated with the dissociation reactions of the rutheniumpyridylporphyrin bond in the physiologic solution. Accordingly, those experiments were carried out only with the methylpyridynium derivatives. For the first time, we showed inequivocally that the interaction of the methyllated porphyrins with mitochondria are significantly influenced by the membrane potential. In fact, when the mitochondria was energized a 15% increase was observed in the binding constants of 3P2cMe in comparison with teh results with decoupled mitochondria. Also, the amount of bond porphyrin sensitizer decreased as the number of methylpyridynium groups was increased, following the same tendency as above. The behavior of the cis (3P2cMe) and trans (3P2tMe) isomers didn\'t follow the general tendency for the other derivatives in a series, such that the binding constants of the cis isomers were always about twice higher than for the trans, which were much higher than predicted by the general behavior. This means that they can associate more strongly and penetrate deeper in the membrane than the more charged porphyrin derivatives. In particular, the cis species is amphiphilic, i.e. possess an adequate structure for that interaction. The results presented in this thesis showed conclusively that the two series of meso-phenylpyridylporphyrins are adequate for the investigation of the effect of the stereochemistry on the bonding ability and photodynamic properties of those photosensitizers. This is particularly true due to the possibility of modulating the ratio between hydrophobicitylhydrophylicity and the stereochemistry without influencing significantly the quantum yield for 1O2 generation. The meta- series showed an advantage over the conventionally used para- series of methylpyridynium porphyrins because it is more soluble and shows lesser tendency to aggregate. In condusion, the amphiphilic 3P2cMe is the species with the highest potentiallity as por sensitizer because of its high binding constants, low tendency to associate and high ΦΔ.

Foram sintetizadas duas novas classes de porfirinas aquosolúveis pela quaternização dos resíduos piridínicos da TPyP empregando halelos de benzila e alila. Os produtos dessas reações de quaternização TBzPyP e TAlPyP. são mais facilmenle obtidos que a TMPyP, exingindo menores tempos de reação e menores quantidades de agente alquilante para que a quaternização total da TPyP seja efetuada. Esse procedimento surge como uma rota alternativa para a obtenção de porfirinas aquosolúvei s e vale-se da alta estabilidade dos cátions benzílicos e alílicos. Os respectivos complexos de zinco e paládio foram obtidos da reação de quaternização de ZnTPyP e PdTPyP ou por reações de metalação de TBzPyP e TAlPyP. As bases livres e os metalocomplexos foram estudados quanto às suas propriedades espectroscópicas, eletroquímicas e fotoquímicas. Os novos derivados apresentam deslocamentos batocrômicos das posições dos máximos de absorção e emissão se comparados com a série metil-piridil substituída, indicando a existência de efeitos eletrônicos e vibracionais dos substituintes sobre o sistema Π do macrociclo. Os dados espectroscópicos mostram evidências de que as bases livres encontram-se em solução aquosa no estado agregado, provavelmenle formando dímeros em concentrações superiores a cerca de 6.0 x 10-7 M. A presença de detergentes aniônicos altera significamente tanto a posição dos máximos de absorção como de emissão mostrando que além dos aspectos eletrostáticos fatores hidrofôbicos-hidrofílicos fazem-se presentes na interação de surfactantes com os derivados porfirínicos. C comportamento eletroquímico dos derivados benzílicos e alílicos também é diferenciado com relação aos derivados metílicos, sendo observadas maiores separações entre os picos anódico e catódico. Estas diferenças devem-se, provavelmente ao maior caráter hidrofóbico destes derivados, que originam interações específicas nos processos eletródicos. Os tempos de vida do estado excitado triplete das zinco porfirinas, ZnTMPyP, ZnTBzPyP e ZnTAlPyP foram medidos utilizando-se a técnica de flash-photolysis, sendo que todas apresentam tempos de vida da ordem de 1 ms. A fim de estudar reações de transferência de elétrons fotoinduzidas entre os novos derivados porfirínicos e aceptores adequados em sistemas de clivagem da água (p. ex. metilviologênio), catalisadores coloidais de platina foram preparados pela redução de Pt(IV) ou Pt(II) a Pt(O), e as dimensões do colóide foram estimadas por microscopia eletrônica, sendo obtidas partículas coloidais de 30-40 Å. A concentração de platina foi determinada por emissão atômica, ou por complexiometria. Estudou-se a interação de porfirinas e metaloporfirinas com o polímero sintético da melanina, utilizando-se a técnica de emissão de fluorescência. Verificou-se que a presença de metais coordenados à porfirina assim como a presença de grupos com maior caráter hidrofôbico acentuam a interação implicando em maior especificidade destes derivados, característica essa apropriada para a utilização destas moléculas em terapia fotodinâmica. Foi determinada a CMC em pH = 1,00 de um derivado porfirínico surfactante, sendo que a partir de 1,0 x 10-4 M ocorre a micelização. Este é o primeiro exemplo de auto-agregação de uma porfirina sintética em um meio onde não participam solventes orgânicos. / In the present work two new classes of water soluble porphyrins were prepared by the quaternization of the TPyP pyridynic groups employng benzyl and allyl halides. The products of these quaternization reactions, TBzPyP and TAlPyP, are easier to obtain than TMPyP because they require smaller amounts of alkylating agents and a less period of reaction to achive the pyridinic quaternization. This method is an alternative route in obtaining water soluble porphyrins and is based on the high stability of the benzylic and allylic cation. The corresponding zinc and palladium complexes were obtanained by quaternization reactions of ZnTPyP and PdTPyP or by metallation reactions of TBzPyP and TAlPyP. The free bases and metallocomplexes studies were carried out taking to account their spectroscopic electrochemical and photochemical properties. The new derivatives exhibit bathocromic shifts in the absorption and emission position bands when compared with the methyl-pyridynium derivatives these data indicate the existence of elect.ronic and vibrational effects of the substituents on the macrociclic Π system. The espectroscopic data show evidences that the free bases are like aggregates in aqueous solution, probably forming dimers in the concentration range of 5,0 x 10-7 M. The presence of anionic detergents alter deeply the spectroscopic properties, showing that hidrophobic-hidrophylic factors in addition of eletrostatic factors are present, in the interaction of the surfactant with the porphyrinic derivatives. The electrochemical behavior of the benzylic and allylic derivatives are different when compared with the methylic derivatives, were it was observed greater separation between the anodic and cathodic peaks. The observed differences are probably due to specific interactions of the more hidrophobic derivatives in eletrode processes. The triplet excited state lifetimes of the zinc derivatives, ZnTMPyP, ZnTBzPyP e ZnTAlPyP mesured employng f\'lash-photolysis thecnics were c.a. 1 ms. The synthesis of coloidal platinum catalyst was achived by slight modification of the literature methods, and the size of the majority particules determined by electron microscopy are around 30-40 A. The int.eract.ion between porphyrins and metalloporphyrins wilh the synthetic melanin polymer was studied employng fluorescence emisson. The presence of coordinate metals and the presence of more hidrophobic groups attached at the porphyrin ring originate greater specificity by the polymer, which make them possible photosensitizers in photodynamic therapy. It was also determined the CMC of a surfactant funtionalyzed zinc porphyrin in aqueous medium at. pH = 1,00. This derivative form micellar assemblies at 1,0 x 10-4 M, and is the first example of self aggregation of a synthetic porphyrin in a non-organic medium.

<p>Over the past decade, the development of macromolecular drugs based on peptides, proteins and nucleic acids has increased the interest in microparticulate drug delivery, i.e., the delivery of drug systems in the nanometer and micrometer ranges. However, little is known so far about the effect that microparticulate systems have on various tissues after administration. Additionally, the knowledge of mechanisms responsible for the uptake and transport of microparticles across the human intestine is incomplete and requires further investigation to improve both the safety profiles and the efficiency of these drug delivery systems.</p><p>This thesis is comprised of two parts. The first one investigates gene expression responses obtained from DNA arrays in local and distal tissues after microparticulate drug delivery. The second part focuses on the mechanisms responsible for the transport of microparticles across epithelial cells lining the intestine.</p><p>The results presented in the first part demonstrated that gene expression analysis offers a detailed picture of the tissue responses after intramuscular or pulmonary administration of microparticulate drug delivery systems compared to the traditional techniques used for such evaluations. In addition, DNA arrays provided a useful and sensitive tool for the initial characterization and evaluation of both local and distal tissue responses, making it possible to distinguish between gene expression patterns related to each studied delivery system.</p><p>The results presented in the second part demonstrated that the surface properties of the microparticle were important for the extent of transport across an <i>in vitro</i> model of the follicle-associated epithelium (FAE), comprised of intestinal epithelial cells specialized in particle transport (M cells). Another important finding was that the enteropathogen bacterium, <i>Yersinia pseudotuberculosis</i>, induced microparticle transport across the normal intestinal epithelium, represented by Caco-2 cells and excised human ileal tissue. This transport was most probably mediated by an increased capacity for macropinocytosis in the epithelial cells.</p>

<p>Collagenous colitis (CC) is an inflammatory bowel disease of unknown etiology. It is characterized by watery diarrhoea without blood, normal endoscopic findings but microscopically colonic mucosal inflammation and increased thickness of the subepithelial collagen band, the latter being a pathognomonic sign. The inflammatory infiltrate in the mucosa of CC contains lymphocytes, plasma cells, eosinophils, mast cells but few neutrophils. The pathophysiological roles of the thickened collagen band and the inflammatory infiltrate in CC are not fully understood. The aims of the present study were to develop a colonoscope based segmental perfusions technique and to analyze local intestinal secretion of inflammatory mediators: Eosinophilic Cationic Protein (ECP), Myeloperoxidase (MPO), Basic Fibroblast Growth Factor (bFGF), Vascular Endothelial Growth Factor (VEGF) and permeability marker albumin in CC patients without medication and also during steroid treatment. Furthermore, the colonic mucosal distribution of bFGF and VEGF were studied by immunohistochemical methods.</p><p>Colonoscope-based segmental perfusions were performed in totally 22 patients and the success rate was 76% in both rectal and descending colon segments. The analysis showed high intraluminal concentrations of ECP, bFGF, VEGF and albumin in ten CC patients compared to 10 control patients. Further, albumin had correlations with ECP and VEGF. However, elevated concentrations of MPO, an important feature of ulcerative colitis, were only observed in a few CC patients. Immunohistochemistry visualized bFGF and VEGF in the colonic epithelium but also deeper in the lamina propria. The steroid treatment study (including 12 patients) showed that the perfusate concentrations of ECP, bFGF and VEGF declined significantly in parallel with decreased frequency of diarrhoea. </p><p>In conclusion, a safe colonoscope-based, segmental perfusion technique was developed and perfusions of the rectum and descending colon were performed. CC patients had elevated perfusate concentrations of ECP, VEGF and bFGF. There was a marked reduction of these mediators during steroid treatment supporting the hypothesis that these inflammatory mediators separately or synergistically participate in the inflammatory reaction and tissue remodelling in CC patients. The finding of correlations between albumin and ECP or VEGF implies that permeability is increased in CC and may be triggered by ECP and VEGF. </p>

Over the past decade, the development of macromolecular drugs based on peptides, proteins and nucleic acids has increased the interest in microparticulate drug delivery, i.e., the delivery of drug systems in the nanometer and micrometer ranges. However, little is known so far about the effect that microparticulate systems have on various tissues after administration. Additionally, the knowledge of mechanisms responsible for the uptake and transport of microparticles across the human intestine is incomplete and requires further investigation to improve both the safety profiles and the efficiency of these drug delivery systems. This thesis is comprised of two parts. The first one investigates gene expression responses obtained from DNA arrays in local and distal tissues after microparticulate drug delivery. The second part focuses on the mechanisms responsible for the transport of microparticles across epithelial cells lining the intestine. The results presented in the first part demonstrated that gene expression analysis offers a detailed picture of the tissue responses after intramuscular or pulmonary administration of microparticulate drug delivery systems compared to the traditional techniques used for such evaluations. In addition, DNA arrays provided a useful and sensitive tool for the initial characterization and evaluation of both local and distal tissue responses, making it possible to distinguish between gene expression patterns related to each studied delivery system. The results presented in the second part demonstrated that the surface properties of the microparticle were important for the extent of transport across an in vitro model of the follicle-associated epithelium (FAE), comprised of intestinal epithelial cells specialized in particle transport (M cells). Another important finding was that the enteropathogen bacterium, Yersinia pseudotuberculosis, induced microparticle transport across the normal intestinal epithelium, represented by Caco-2 cells and excised human ileal tissue. This transport was most probably mediated by an increased capacity for macropinocytosis in the epithelial cells.

Collagenous colitis (CC) is an inflammatory bowel disease of unknown etiology. It is characterized by watery diarrhoea without blood, normal endoscopic findings but microscopically colonic mucosal inflammation and increased thickness of the subepithelial collagen band, the latter being a pathognomonic sign. The inflammatory infiltrate in the mucosa of CC contains lymphocytes, plasma cells, eosinophils, mast cells but few neutrophils. The pathophysiological roles of the thickened collagen band and the inflammatory infiltrate in CC are not fully understood. The aims of the present study were to develop a colonoscope based segmental perfusions technique and to analyze local intestinal secretion of inflammatory mediators: Eosinophilic Cationic Protein (ECP), Myeloperoxidase (MPO), Basic Fibroblast Growth Factor (bFGF), Vascular Endothelial Growth Factor (VEGF) and permeability marker albumin in CC patients without medication and also during steroid treatment. Furthermore, the colonic mucosal distribution of bFGF and VEGF were studied by immunohistochemical methods. Colonoscope-based segmental perfusions were performed in totally 22 patients and the success rate was 76% in both rectal and descending colon segments. The analysis showed high intraluminal concentrations of ECP, bFGF, VEGF and albumin in ten CC patients compared to 10 control patients. Further, albumin had correlations with ECP and VEGF. However, elevated concentrations of MPO, an important feature of ulcerative colitis, were only observed in a few CC patients. Immunohistochemistry visualized bFGF and VEGF in the colonic epithelium but also deeper in the lamina propria. The steroid treatment study (including 12 patients) showed that the perfusate concentrations of ECP, bFGF and VEGF declined significantly in parallel with decreased frequency of diarrhoea. In conclusion, a safe colonoscope-based, segmental perfusion technique was developed and perfusions of the rectum and descending colon were performed. CC patients had elevated perfusate concentrations of ECP, VEGF and bFGF. There was a marked reduction of these mediators during steroid treatment supporting the hypothesis that these inflammatory mediators separately or synergistically participate in the inflammatory reaction and tissue remodelling in CC patients. The finding of correlations between albumin and ECP or VEGF implies that permeability is increased in CC and may be triggered by ECP and VEGF.

Els polímers són una sèrie de compostos que troben un ampli ventall d'aplicacions en la indústria actual. Un exemple són les espumes de poliuretà, estructures de tipus cel·lular obtingudes mitjançant la reacció química entre compostos de tipus isocianat i compostos de tipus poliol (polièters amb diferent nombre de grups hidroxil). És imprescindible l'ús d'additius d'estructura tensioactiva (surfactants de silicona) per estabilitzar el procés d'espumació i per proporcionar una estructura cel·lular ordenada i homogènia en mida i distribució. La síntesis i caracterització de les molècules precursores (polihidrosiloxans i polièters al·lílics), l'estudi de la reacció d'hidrosililació com a via d'obtenció dels diferents surfactants per reacció d'addició entre els polihidrosiloxans i els polièters al·lílics i la caracterització i avaluació en formulacions comercials de poliuretà dels surfactants sintetitzats han constituït els objectius del present treball.MEMÒRIALa Tesi Doctoral ha estat presentada seguint el següent esquema:CAPÍTOL I. INTRODUCCIÓ A LA QUÍMICA DEL POLIURETÀ.Es presenten els principis de la química del poliuretà, fent esment dels recents avenços en la síntesis i caracterització d'aquests compostos polimèrics, així com un apartat concret centrat en els surfactants de silicona. Es presenten les estructures habituals d'aquests compostos comercials i es detallen les reaccions de síntesi i les característiques físiques que aquests compostos proporcionen a les espumes de poliuretà.CAPÍTOL II. OBJECTIUS.1.- Síntesis y caracterització d'una àmplia gamma de poliglicols al·lílics i de polihidrosiloxans amb grups hidrur reactius, ambdós precursors d'estructures polimèriques de tipus surfactant.2.- Estudi de la reacció d'hidrosililació com a via de formació d'enllaços Si-C no hidrolitzables, mitjançant la reacció d'addició entre els substrats al·lílics insaturats i els polisiloxans amb grups hidrur reactius.3.- Caracterització de les estructures polimèriques de tipus surfactant sintetitzades i avaluació d'aquestes en formulacions de poliuretà, a fi de relacionar l'estructura química d'aquests oligómers amb els efectes físics que originen en l'espuma de poliuretà.CAPÍTOL III. SÍNTESI I CARACTERITZACIÓ DE SUBSTRATS AL·LÍLICS INSATURATS DE TIPUS POLIGLICOL.S'han caracteritzat per HPLC-UV una sèrie de polietilenglicols comercials. S'ha estudiat la reacció de derivatització al·lílica sobre els grups hidroxil dels polièters comercials (PEG, PPG i copolímers PEG-PPG) i s'han caracteritzat exhaustivament els productes sintetitzats (1H,13C-RMN, GC, GC-MS, FTIR, ESI-MS, HPLC-UV). S'ha iniciat un estudi de polimerització aniònica sobre nous epòxids amb un punt de diversitat molecular, sintetitzant-se i caracteritzant-se els corresponents nous polièters obtinguts. CAPÍTOL IV. SÍNTESI I CARACTERITZACIÓ DE POLIHIDROSILOXANS REACTIUS.S'estudia la síntesis de polihidrosiloxans amb grups hidrur reactius, mitjançant la reacció de polimerització aniònica d'obertura d'anell ("AROP, anionic ring opening polimerization") i mitjançant la reacció de polimerització per equilibració catiònica. Es presenta una caracterització exhaustiva dels productes sintetitzats i es descriu la naturalesa de la microestructura polimèrica a partir de la distribució bivariant dels copolímers PDMS-co-PHMS (poli(dimetilsiloxà)-co-poli(hidrometilsiloxà)).CAPÍTOL V. ESTUDI SISTEMÀTIC DE LA REACCIÓ D'HIDROSILILACIÓ.S'ha estudiat la reacció d'hidrosililació amb la finalitat de sintetitzar estructures copolimèriques poliglicol-polisiloxà a partir de la reacció de polisiloxans hidrur reactius i polièters al·lílics. S'han provat diferents catalitzadors (Pt/C 5%, cat. de Speier i cat. de Karstedt), s'han sintetitzat diferents estructures tensoactives (lineals i ramificades) i s'ha modelitzat les diferents reaccions secundàries observades, per presentar un estudi mecanístic de la reacció d'hidrosililació aplicada a la síntesis de molècules d'elevat PM a partir de la reacció entre substrats al·lílics insaturats i polihidrosiloxans.CAPÍTOL VI. AVALUACIÓ DELS SURFACTANTS EN FORMULACIONS DE POLIURETÀ.S'ha estudiat la idoneïtat dels surfactants de silicona sintetitzats en diferents formulacions de poliuretà comercials. S'ha relacionat el comportament físic d'aquests surfactants en les espumes de poliuretà amb la seva estructura química a partir de l'anàlisi per microscòpia electrònica de rastreig.CAPÍTOL VII. CONCLUSIONS.S'han esposat les conclusions extretes de cada capítol. / The present review has been structured in three parts, firstly a general introduction to polyurethane chemistry and the specific role that silicone surfactants develop, secondly a memory that contents a concise description of the PhD Thesis structure and finally the presentation of the results obtained and their discussion.1.- INTRODUCTIONPolyurethane is one of the most important polymers used in the industry worldwide. The reaction, discovered in 1937 by Otto Bayer, consists in a polyaddition reaction between hydroxyl compounds and isocyanate groups. This reaction forms the new urethane group (strictly a carbamat group) that provide the chemical structure of the polymer. In the presence of different amounts of water, another reaction is involved, between isocyanate groups and water, in order to obtain urea groups. This reaction is very important because, besides generates new polyurea structures it generates carbon dioxide (CO2), the blowing aggent mostly used in the formulations of polyurethane.Actually, a lot of applications of polyurethane products take advantage on the specific cellular structure that presents, specially flexible foams in mattresses, sofas, seats, rigid foams as insulation panels and semi-rigid foams in the automotive industry. The cellular structure is obtained in the foaming process of the reaction, which involves the generation of a gas (usually CO2 although other compounds like pentane, HCFC's and external CO2 had been used) and the growing of the cell because of the exothermic process. The foaming process is usually an unstable state that needs the participation of a surfactant, a silicone structure that provides the necessary stabilizing capacity in the foaming process. Moreover, another important feature of silicone surfactants is to improve the order and distribution of the cells in the foam.Generally, the chemical structure of silicone surfactants is co polymeric, consisting in an hydrophobic part composed by the polysiloxane group and an hydrophilic part, usually being made up of different types of polyether structures. This different physical behaviour in the same molecule provides the specific characteristics of silicone surfactants. In order to obtain commercially available surfactants, it has been necessary to study the synthesis and the characterization of the components in the surfactant molecule (the polyether and the polysiloxane groups) and to perform a study of the hydrosilylation, the chemical reaction that generates the co polymeric structure by the reaction between the polyether and the polysiloxane constituents.2.- PhD THESIS STRUCTUREThe thesis has been organized in seven chapters, being the first of them the introduction to polyurethane chemistry. In the second chapter are exposed the aims of the work. The third chapter is the synthesis and characterization of polyether type unsaturated substrates, the fourth is the synthesis and characterization of reactive polyhydrosiloxanes and the fifth is the systematic study on the hydrosilylation reaction. The evaluation of surfactants in different polyurethane formulations is described in the sixth chapter whereas the concluding remarks have been reported in the seventh chapter.3.- RESULTS AND DISCUSSIONThe first part of this study details the synthesis and characterization of unsaturated polyethers, substrates of the hydrosilylation reaction. Thus, the allylic modification of commercial monohidroxy polyethers has allowed the synthesis of this unsaturated substrates that can react through hydrosilylation reaction with Si-H bonds. In order to obtain new polyether structures, an investigation about the anionic polymerisation of new epoxies has been developed. These new polyether structures have been extensively characterized to estimate the polymerization degree and their molecular weight.The synthesis and characterization of reactive polysiloxane compounds (containing Si-H bonds in their structure) has been the second aim of this work. In order to obtain these polysiloxane structures, both anionic polymerization of cyclic trisiloxane compounds and cationic polymerization have been studied. Its interesting to emphasize that the results have shown that the microstructure of the copolymeric poly(dimethylsiloxane)-co-poly(hidromethylsiloxane) is statistical in the monomeric distribution (based on MALDI-TOF-MS and 29Si-RMN results), thus the chemical composition along the polymer chain become constant.Little information has been reported in the literature about the hydrosilylation as source of polymer structures. In order to clarify the synthetic behaviour of the reaction between polysiloxanes with Si-H bonds and allylic polyethers, an exhaustive study of the hydrosilylation as been developed. Different catalysts (Speier's, Karstedt's and an heterogeneous Pt/C 5% have been studied), concluding that the Karstedt catalyst has given the better behaviour.Finally, the evaluation of the surfactant structures synthesized in different commercially available polyurethane formulations as allowed obtaining a relation between the chemical structure of the silicone surfactant and the physical behavior in the foaming process. SEM has been the technique of choice to better characterize the otained foams.

I present a new approach to stable n-type doping of organic matrices using organic dopants. In order to circumvent stability limitations of strong organic donors, I produce the donor from a stable precursor compound in situ. As an example, the cationic dye pyronin B chloride is studied as a dopant in an 1,4,5,8-naphthalene tetracarboxylic dianhydride (NTCDA) matrix. A field effect and conductivity study of a series of doped NTCDA samples is carried out. It proves the increase of the electron density with the doping concentration. Conductivities up to 1.9*10^-4 S/cm are obtained for doped NTCDA, which is two orders of magnitude higher than the conductivity of NTCDA doped with (bis(ethylenedithio)-tetrathiafulvalene (BEDT- TTF) as investigated previously [A. Nollau, M. Pfeiffer, T. Fritz, K. Leo, J. Appl. Phys. 87, 4340 (2000)], and four orders of magnitude higher than nominally undoped NTCDA films. The experimental trends in the field effect study are interpreted in terms of transport in disordered solids. Detailed mass spectroscopic investigation are carried out to investigate the sublimation behaviour of the organic salt pyronin B chloride. We conclude that mainly HCl and the leuco base of pyronin B is present in the gas phase. Optical absorption spectroscopy shows that the leuco base is transformed to the pyronin B cation in air. A similar reaction is observed for mixed thin films of pyronin B and tetracyano quinodimethane. This supports the image of the doping process being due to an electron transfer from the pyronin to the matrix molecules. The formation of the leuco base and subsequent oxidation to the pyronin B cation is supported by Fourier transform infrared (FTIR) absorption spectroscopy. Doping experiments with other matrices reveal that the doping effect is universal for all materials of moderate acceptor strength. Matrices such as perylene-3,4,9,10-tetracarboxylic dimethyl diimide (Me-PTCDI) and fullerene C60 can be successfully doped. These compounds are frequently employed electron transport materials in organic solar cells. Therefore, such devices can be improved by this new doping approach. / In dieser Arbeit wird ein neuer Ansatz zur n-Dotierung organischer Dünnschichten mit organischen Dotanden vorgestellt. Die bisher zur n-Dotierung benötigten starken Donormoleküle zeigen eine hohe Reaktivität. Dies erschwert die Synthese und weiterhin die Verwendung solcher Verbindungen als Dotanden. Zur Vermeidung dieser Stabilitätsprobleme wird in dieser Arbeit der reaktive Dotand in situ aus einer stabilen Vorläüuferverbindung erzeugt. Beispielhaft wird der kationische Farbstoff Pyronin B Chlorid als Dotand in einer 1,4,5,8-Naphthalen Tetracarbonsäure Dianhydrid (NTCDA)-Matrix untersucht. Feldeffekt- und Leitfähigkeitsuntersuchungen an einer Serie von dotierten Dünnschichten werden durchgeführt. Eine Erhöhung der Elektronendichte mit der Dotierkonzentration wird gefunden. Dies führt zu Leitfähigkeiten von bis zu 1.9*10^-4 S/cm, d.h. vier Größenordnungen höher als undotiertes NTCDA und zwei Größenordnungen höher als das früher untersuchte NTCDA, dotiert mit Bis(Ethylendithio)-Tetrathiafulvalen (BEDT- TTF) [A. Nollau, M. Pfeiffer, T. Fritz, K. Leo, J. Appl. Phys. 87, 4340 (2000)]. Die Abhängigkeiten der elektrischen Kenngrößen Leitfähigkeit, Beweglichkeit und Ladungsträgerdichte werden anhand eine Modells erklärt, das den Transport in ungeordneten Systemen beschreibt. Massenspektrometrische Untersuchungen werden zur Untersuchung des Verdampfungsverhaltens des organischen Salzes Pyronin B Chlorid eingesetzt. Es wird gefunden, daß Pyronin B Chlorid durch Bildung von HCl und der Leukobase des Pyronins in die Gassphase übergeht. In der optische Absorptionsspektroskopie ist die Transformation der Leukobase unter Lufteinfluß in das Pyronin B-Kation zu beobachten. Das gleiche Verhalten wird für Mischschichten aus Pyronin B und Tetracyano Chinodimethan gefunden. Dies bestätigt die Vorstellung des Dotierprozesses als Elektronentransfer vom Pyronin B zum Matrixmolekül. Die Bildung der Leukobase und die anschlie\ss ende Oxidierung zum Pyronin B-Kation ist auch in der Infrarotspektroskopie sichtbar. Der Dotiereffekt ist nicht auf NTCDA beschränkt, sondern wird auch für andere Matrizen mit genügend hoher Elektronenaffinität gefunden. Matrixmaterialien wie z.B. Perylen-3,4,9,10-Tetracarbonsäure Dimethyldiimid (Me-PTCDI) und Fulleren C60 werden erfolgreich dotiert. Sie werden üblicherweise in organischen Solarzellen eingesetzt. Durch den hier demonstrierten Ansatz können folglich solche Bauelemente verbessert werden.