O objetivo deste trabalho foi o estudo das propriedades mecânicas e térmicas do PHB e de compósitos de PHB/pó de madeira processados, reprocessados e irradiados. Foram preparados compósitos com PHB e pó de madeira com concentrações de PHB/pó de madeira de 90/10, 80/20 e 70/30 (m/m). Foram realizados ensaios de propriedades mecânicas, HDT, ponto de amolecimento Vicat, TGA e DSC. A incorporação do pó de madeira aumentou o grau de cristalinidade e a temperatura de cristalização do polímero, e nos compósitos PHB/pó de madeira 80/20 e 70/30 a rigidez do material aumentou em relação ao polímero puro. O compósito PHB/pó de madeira 70/30 apresentou os melhores resultados em termos econômicos, de processamento e de estabilidade em relação ao reprocessamento. A irradiação após o processamento, em dose de 30 kGy, provocou aumento da rigidez do PHB puro e dos compósitos PHB/pó de madeira 90/10 e 80/20, embora as outras propriedades tenham decrescido. O compósito PHB/pó de madeira 70/30 apresentou queda de todas as propriedades com a irradiação. / The purpose of this work was the study of the mechanical and thermal properties of processed, reprocessed and irradiated PHB, as well as PHB/wood flour composites. PHB/wood flour composites were prepared with PHB/wood relation of 90/10, 80/20 e 70/30 (w/w). Mechanical properties, HDT, Vicat melting point and thermo analyses (TGA and DSC) tests were carried out. The introduction of the wood flour increased both polymer crystallinity and crystallization temperature. The material stiffness increased in PHB/wood flour composites (80/20 and 70/30) resulting in higher values in some properties when compared with pure PHB. The PHB/wood flour composite 70/30 showed the best results in terms of economy, processing and stability during reprocessing. The irradiation after processing in 30kGy doses led to a stiffness increasing of pure PHB and PHB/wood flour composites (90/10 and 80/20) while other properties have decreased. The PHB/wood flour 70/30 showed decreasing in all properties after irradiation.

This diploma thesis deals with 1) the preparation of biodegradable polymer films based on polyhydroxyalkanoates (PHA) and 2) their modification by lignin as an active additive. The motivation for this work was to prepare active packaging material for food packaging. Polymer films were prepared by blending of neat crystalline poly(3hydroxybutyrate) (P3HB) and amorphous polyhydroxyalkanoate (PHA). The lignin was isolated from grape seeds derived from grape pomace. The solubility of lignin in chloroform was improved by acetylation. The properties of the isolated lignin were determined by elemental analysis, ash content, and infrared spectroscopy (FTIR). Lignin was used as an active additive for the modification of polymeric films prepared by solution casting of P3HB or P3HB blended with amorphous polyhydroxyalkanoate. The effect of different concentrations of lignin in the range of 1 to 10 % was tested. The lignin type and concentration had a different influence on the final thermal and mechanical behaviour of polymeric films. Lignin increased the values of the Young modulus and tensile strength of the prepared films. Differential scanning calorimetry data confirmed that lignin positively modified crystallization kinetics of P3HB. Thermogravimetry was used to analyse the thermal stability of PHA films. Lignin markedly increased the thermal stability of PHA films. However, acetylated lignin harms the mechanical properties of films. Moreover, this work showed that lignin isolated from grape seeds and added into PHA films proved its high antioxidant capacity. PHA films with lignin displayed much better gas barrier properties compared with PHA films without lignin. The prepared bioactive PHA films fulfil the requirements for sustainable food packaging with high antioxidant capacity and excellent gas barrier properties.

Diploma thesis is summarizing sources and technology of PHB and its physical and chemical properties compared to other polymers. Thesis mentions usage and function of certain additives in PHB matrix and their impact on the final product. Practical part of the thesis is concerned with technological parameters and degradation of the PHB during extrusion. The thesis also observes behaviour of nucleating agents on crystallinity and crystallization properties of prepared compounds. Degradation was analyzed by MFI and colour difference against standard material, FTIR was not successfully used for the purpose of degradation. Crystallinity and crystallization behaviour was analysed by DSC and optical microscopy with heated operating table. Graphs were created from results of analysis and suitable usage of each nucleating agent was considered. Boron nitride was selected as the most suitable nucleating agent due to creating higher amount of smaller spherulites.

Background The detrimental impact of malnutrition and cachexia in cancer patients subjected to surgical resection is well established. However, how systemic and local metabolic alterations in cancer patients impact the serum metabolite signature, thereby leading to cancer-specific differences, is poorly defined. In order to implement metabolomics as a potential tool in clinical diagnostics and disease follow-up, targeted metabolite profiling based on quantitative measurements is essential. We hypothesized that the quantitative metabolic profile assessed by 1H nuclear magnetic resonance (NMR) spectroscopy can be used to identify cancer-induced catabolism and potentially distinguish between specific tumour entities. Importantly, to prove tumour dependency and assess metabolic normalization, we additionally analysed the metabolome of patients' sera longitudinally post-surgery in order to assess metabolic normalization. Methods Forty two metabolites in sera of patients with tumour entities known to cause malnutrition and cachexia, namely, upper gastrointestinal cancer and pancreatic cancer, as well as sera of healthy controls, were quantified by 1H NMR spectroscopy. Results Comparing serum metabolites of patients with gastrointestinal cancer with healthy controls and pancreatic cancer patients, we identified at least 15 significantly changed metabolites in each comparison. Principal component and pathway analysis tools showed a catabolic signature in preoperative upper gastrointestinal cancer patients. The most specifically upregulated metabolite group in gastrointestinal cancer patients was ketone bodies (3-hydroxybutyrate, P < 0.0001; acetoacetate, P < 0.0001; acetone, P < 0.0001; false discovery rate [FDR] adjusted). Increased glycerol levels (P < 0.0001), increased concentration of the ketogenic amino acid lysine (P = 0.03) and a significant correlation of 3-hydroxybutyrate levels with branched-chained amino acids (leucine, P = 0.02; isoleucine, P = 0.04 [FDR adjusted]) suggested that ketone body synthesis was driven by lipolysis and amino acid breakdown. Interestingly, the catabolic signature was independent of the body mass index, clinically assessed malnutrition using the nutritional risk screening score, and systemic inflammation assessed by CRP and leukocyte count. Longitudinal measurements and principal component analyses revealed a quick normalization of key metabolic alterations seven days post-surgery, including ketosis. Conclusions Together, the quantitative metabolic profile obtained by 1H NMR spectroscopy identified a tumour-induced catabolic signature specific to upper gastrointestinal cancer patients and enabled monitoring restoration of metabolic homeostasis after surgery. This approach was critical to identify the obtained metabolic profile as an upper gastrointestinal cancer-specific signature independent of malnutrition and inflammation.

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Made available in DSpace on 2017-07-21T14:13:10Z (GMT). No. of bitstreams: 1 Fernanda Malaquias Barbosa.pdf: 3020021 bytes, checksum: d88917643a806ad362e493cbc6e1776b (MD5) Previous issue date: 2013-02-21 / Manidipine is a third-generation calcium channel blocking effective in the treatment of hypertension, which its use has been related to further metabolic effects of potential clinical interest. However, its high lipophilicity results in undesirable physicochemical and biopharmaceutical properties. Thus, a pharmaceutical improvement is necessary to achieve a remarkable advance in its absorption and bioavailability. In that sense, the aim of this paper was to microencapsulate the manidipine in order to avoid its spontaneous compartmentalization in adipocytes and make its intestinal transit longer, with appropriate release rates and duration to generate the desired antihypertensive effect. Poly(ε-caprolactone) (PCL) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microparticles containing manidipine were successfully prepared by simple emulsion/solvent evaporation method. Considering the lack of validated methods for drug quantification in these microparticles, an analytical method by high efficiency liquid chromatography with spectrometric detection in the ultraviolet region was previously developed and validated. This method proved to be selective, linear (r = 0.9992), precise (RSD < 2.08 %) and accurate (recovery capacity between 95.02 and 100.41%) in the range from 10 to 50 μg.mL-1. The chromatography was robust when underwent slight variations in the mobile phase composition and column temperature. All four formulations showed loading efficiency rates greater than 80% and average particle sizes less than 8 μm. Microparticulate systems showed a spherical shape with smooth and porous surface for PCL and PHBV formulations, respectively. According to Fourier-transformed infrared analysis, initial components were not chemically modified during microencapsulation process, whereas X-ray diffraction patterns and differential scanning calorimetry analysis demonstrated that this process led to drug amorphization. In vitro dissolution profile showed that all microparticles prepared were able to sustain manidipine release, especially which one prepared from PCL, that contained 5% of the drug loaded (PCL-M5). Animal studies demonstrated that PCL-M5 formulation was able to hold the mean arterial pressure variation after phenylephrine administration up to 24 hours. These data demonstrate the sustained antihypertensive effect of the proposed microparticles. Results provided an experimental basis for using PCL-M5 formulation as an oral manidipine carrier. / A manidipina é um bloqueador de canal de cálcio de terceira geração, eficaz no tratamento da hipertensão arterial. Seu uso está relacionado a efeitos metabólicos adicionais de potencial interesse clínico. Entretanto, sua extrema lipofilicidade resulta em propriedades físico-químicas e farmacocinéticas indesejáveis. Assim, torna-se necessário um aprimoramento farmacotécnico para alcançar um avanço expressivo na absorção e na biodisponibilidade desse fármaco. Com esse propósito, o objetivo deste trabalho foi microencapsular a manidipina a fim de evitar sua compartimentalização espontânea nos adipócitos e prolongar seu tempo de trânsito intestinal, com taxas de liberação e duração adequadas para gerar o efeito anti-hipertensivo desejado. Micropartículas de poli(ε-caprolactona) (PCL) e poli(3-hidroxibutirato-co-hidroxivalerato) (PHBV) contendo manidipina foram preparadas com êxito pelo método de emulsão simples/evaporação do solvente orgânico. Diante da ausência de métodos validados para quantificação do fármaco encapsulado nestas micropartículas, um método para o doseamento por cromatografia líquida de alta eficiência com detecção espectrométrica na região do ultravioleta foi previamente desenvolvido e validado. Esse método mostrou-se seletivo, linear (r = 0,9992), preciso (DPR < 2,08 %) e exato (capacidade de recuperação entre 95,02 e 100,41%) no intervalo de 10 a 50 μg.mL-1. Além disso, a cromatografia foi robusta quando submetida a pequenas variações na composição da fase móvel e temperatura da coluna. As quatro formulações apresentaram eficiências de encapsulação superiores a 80% e tamanhos médios de partícula inferiores a 8 μm. Os sistemas microparticulados apresentaram uma forma esférica com superfície lisa e porosa para as formulações de PCL e PHBV, respectivamente. De acordo com as análises por espectroscopia na região do infravermelho com transformada de Fourier, os componentes iniciais não foram quimicamente alterados durante o processo de microencapsulação, ao passo que as análises de difratometria de raios-X e de calorimetria exploratória diferencial demonstraram que esse processo levou a amorfização do fármaco. Os perfis de dissolução in vitro confirmaram a capacidade que as micropartículas apresentam de prolongar a liberação da manidipina, especialmente àquelas preparadas a partir da PCL, que continham 5% de fármaco encapsulado (PCL-M5). Os estudos em animais mostraram que a formulação PCL-M5 foi capaz de minimizar a variação da pressão arterial média, frente à administração de fenilefrina, por até 24 horas. Este dado confirma o efeito anti-hipertensivo prolongado da micropartícula proposta. Os resultados forneceram um embasamento experimental que viabiliza o uso da formulação PCL-M5 como um carreador oral da manidipina.

O copolímero biodegradável poli(3-hidroxibutirato-co-3-hidroxihexanoato) P(3HB-co-3HHx) é um polihidroxialcanoato (PHA) que apresenta várias aplicações. A bactéria Burkholderia sacchari acumula P(3HB-co-2mol%3HHx), a partir de glicose e ácido hexanoico. Com o objetivo de obter P(3HB-co-3HHx) com diferentes teores de 3HHx por B. sacchari, foram construídas linhagens recombinantes, contendo genes do operon phaPCJ de Aeromonas spp. Os recombinantes produziram P(3HB-co-3HHx), a partir de ácidos hexanoico, láurico e linoleico, com teores de 3HHx entre 1,88-18 mol%. Experimentos em biorreator com o recombinante, alimentada na fase de acúmulo por glicose 140 g/L e ácido hexanoico entre 0-45 g/L, resultaram copolímeros com composições variando de 0 a 20 mol% de 3HHx. Os copolímeros assim produzidos foram extraídos e analisados quanto às propriedades físicas. A análise de fluxos metabólicos indicou que a produção de PHA pode ser aumentada com mudanças no metabolismo central e deleção/superexpressão de genes. / The biodegradable copolymer poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) P(3HB-co-3HHx) is a polyhydroxyalkanoate (PHA) presenting various applications. The bacterium Burkholderia sacchari accumulated P(3HB-co-2mol%3HHx) from glucose and hexanoic acid. In order to obtain P(3HB-co-3HHx) with different 3HHx amounts by B. sacchari, recombinant strains containing phaPCJ operon genes from Aeromonas spp were constructed. Recombinant strains produced P(3HB-co-3HHx) from hexanoic, lauric and linoleic acids, with contents of 3HHx ranging from 1.88 to 18 mol%. Experiments with the recombinant in bioreactor, fed in the accumulation phase by glucose 140 g.l-1and hexanoic acid 0-45 g.l-1, resulted in copolymers with compositions ranging from 0 to 20 mol% of 3HHx. The copolymers produced were extracted and analyzed for physical properties. The metabolic flux analysis indicated that PHA production can be increased by modifying the central metabolism and deleting/ overexpressing genes.

O copolímero biodegradável poli(3-hidroxibutirato-co-3-hidroxihexanoato) P(3HB-co-3HHx) é um polihidroxialcanoato (PHA) que apresenta várias aplicações. A bactéria Burkholderia sacchari acumula P(3HB-co-2mol%3HHx), a partir de glicose e ácido hexanoico. Com o objetivo de obter P(3HB-co-3HHx) com diferentes teores de 3HHx por B. sacchari, foram construídas linhagens recombinantes, contendo genes do operon phaPCJ de Aeromonas spp. Os recombinantes produziram P(3HB-co-3HHx), a partir de ácidos hexanoico, láurico e linoleico, com teores de 3HHx entre 1,88-18 mol%. Experimentos em biorreator com o recombinante, alimentada na fase de acúmulo por glicose 140 g/L e ácido hexanoico entre 0-45 g/L, resultaram copolímeros com composições variando de 0 a 20 mol% de 3HHx. Os copolímeros assim produzidos foram extraídos e analisados quanto às propriedades físicas. A análise de fluxos metabólicos indicou que a produção de PHA pode ser aumentada com mudanças no metabolismo central e deleção/superexpressão de genes. / The biodegradable copolymer poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) P(3HB-co-3HHx) is a polyhydroxyalkanoate (PHA) presenting various applications. The bacterium Burkholderia sacchari accumulated P(3HB-co-2mol%3HHx) from glucose and hexanoic acid. In order to obtain P(3HB-co-3HHx) with different 3HHx amounts by B. sacchari, recombinant strains containing phaPCJ operon genes from Aeromonas spp were constructed. Recombinant strains produced P(3HB-co-3HHx) from hexanoic, lauric and linoleic acids, with contents of 3HHx ranging from 1.88 to 18 mol%. Experiments with the recombinant in bioreactor, fed in the accumulation phase by glucose 140 g.l-1and hexanoic acid 0-45 g.l-1, resulted in copolymers with compositions ranging from 0 to 20 mol% of 3HHx. The copolymers produced were extracted and analyzed for physical properties. The metabolic flux analysis indicated that PHA production can be increased by modifying the central metabolism and deleting/ overexpressing genes.

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