Due to an increased environmental awareness and thus, concerns over the use of fossil-based monomer for polymer production, there is an ongoing effort to find alternatives to non-renewable traditional monomers. This has ushered in the rapid growth in the development of bio-based materials such as green monomers and biodegradable polymers from vegetable and animal resources. Glycerol, as a renewable bio-based monomer, is an interesting candidate for sustainable polymer production. Glycerol is a renewable material that is a by-product of the transesterification of vegetable oils to biodiesel. Utilization of the excess glycerol derived from the growing biodiesel industry is important to oleochemical industries. The main objective of this thesis was to produce high molecular weight polyglycerol from glycerol and synthesize stimuli-responsive polyglycerol hydrogels. The work began with an investigation of the step-growth polymerization of glycerol to relatively high molecular weight polyglycerol using several catalysts. The catalytic reaction mechanisms were compared and the polymer products were fully analyzed. High molecular weight partially branched polyglycerol with multimodal molecular weight distributions was obtained. The polymerization of glycerol proceeded fastest with sulphuric acid as catalyst as indicated by the highest observed conversion of monomer along with the highest molecular weights. Theoretical models were used to predict the gel point and to calculate monomer functionality. High molecular weight polyglycerol was used to synthesize novel stimuli-responsive hydrogels. Real-time monitoring of step-growth polymerization of glycerol was investigated using in-line and off-line Attenuated Total Reflectance/Fourier Transform infrared (ATR-FTIR) technique.

Due to an increased environmental awareness and thus, concerns over the use of fossil-based monomer for polymer production, there is an ongoing effort to find alternatives to non-renewable traditional monomers. This has ushered in the rapid growth in the development of bio-based materials such as green monomers and biodegradable polymers from vegetable and animal resources. Glycerol, as a renewable bio-based monomer, is an interesting candidate for sustainable polymer production. Glycerol is a renewable material that is a by-product of the transesterification of vegetable oils to biodiesel. Utilization of the excess glycerol derived from the growing biodiesel industry is important to oleochemical industries. The main objective of this thesis was to produce high molecular weight polyglycerol from glycerol and synthesize stimuli-responsive polyglycerol hydrogels. The work began with an investigation of the step-growth polymerization of glycerol to relatively high molecular weight polyglycerol using several catalysts. The catalytic reaction mechanisms were compared and the polymer products were fully analyzed. High molecular weight partially branched polyglycerol with multimodal molecular weight distributions was obtained. The polymerization of glycerol proceeded fastest with sulphuric acid as catalyst as indicated by the highest observed conversion of monomer along with the highest molecular weights. Theoretical models were used to predict the gel point and to calculate monomer functionality. High molecular weight polyglycerol was used to synthesize novel stimuli-responsive hydrogels. Real-time monitoring of step-growth polymerization of glycerol was investigated using in-line and off-line Attenuated Total Reflectance/Fourier Transform infrared (ATR-FTIR) technique.

Due to an increased environmental awareness and thus, concerns over the use of fossil-based monomer for polymer production, there is an ongoing effort to find alternatives to non-renewable traditional monomers. This has ushered in the rapid growth in the development of bio-based materials such as green monomers and biodegradable polymers from vegetable and animal resources. Glycerol, as a renewable bio-based monomer, is an interesting candidate for sustainable polymer production. Glycerol is a renewable material that is a by-product of the transesterification of vegetable oils to biodiesel. Utilization of the excess glycerol derived from the growing biodiesel industry is important to oleochemical industries. The main objective of this thesis was to produce high molecular weight polyglycerol from glycerol and synthesize stimuli-responsive polyglycerol hydrogels. The work began with an investigation of the step-growth polymerization of glycerol to relatively high molecular weight polyglycerol using several catalysts. The catalytic reaction mechanisms were compared and the polymer products were fully analyzed. High molecular weight partially branched polyglycerol with multimodal molecular weight distributions was obtained. The polymerization of glycerol proceeded fastest with sulphuric acid as catalyst as indicated by the highest observed conversion of monomer along with the highest molecular weights. Theoretical models were used to predict the gel point and to calculate monomer functionality. High molecular weight polyglycerol was used to synthesize novel stimuli-responsive hydrogels. Real-time monitoring of step-growth polymerization of glycerol was investigated using in-line and off-line Attenuated Total Reflectance/Fourier Transform infrared (ATR-FTIR) technique.

Due to an increased environmental awareness and thus, concerns over the use of fossil-based monomer for polymer production, there is an ongoing effort to find alternatives to non-renewable traditional monomers. This has ushered in the rapid growth in the development of bio-based materials such as green monomers and biodegradable polymers from vegetable and animal resources. Glycerol, as a renewable bio-based monomer, is an interesting candidate for sustainable polymer production. Glycerol is a renewable material that is a by-product of the transesterification of vegetable oils to biodiesel. Utilization of the excess glycerol derived from the growing biodiesel industry is important to oleochemical industries. The main objective of this thesis was to produce high molecular weight polyglycerol from glycerol and synthesize stimuli-responsive polyglycerol hydrogels. The work began with an investigation of the step-growth polymerization of glycerol to relatively high molecular weight polyglycerol using several catalysts. The catalytic reaction mechanisms were compared and the polymer products were fully analyzed. High molecular weight partially branched polyglycerol with multimodal molecular weight distributions was obtained. The polymerization of glycerol proceeded fastest with sulphuric acid as catalyst as indicated by the highest observed conversion of monomer along with the highest molecular weights. Theoretical models were used to predict the gel point and to calculate monomer functionality. High molecular weight polyglycerol was used to synthesize novel stimuli-responsive hydrogels. Real-time monitoring of step-growth polymerization of glycerol was investigated using in-line and off-line Attenuated Total Reflectance/Fourier Transform infrared (ATR-FTIR) technique.

京都大学 / 新制・課程博士 / 博士(人間・環境学) / 甲第23533号 / 人博第1012号 / 新制||人||239(附属図書館) / 2021||人博||1012(吉田南総合図書館) / 京都大学大学院人間・環境学研究科相関環境学専攻 / (主査)教授 小松 直樹, 教授 津江 広人, 准教授 土屋 徹 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DFAM

Gene expression knockdown using RNA interference has dramatically altered the ability to silence target genes without the need for a creation of a genetic knockout. The pitfalls surrounding successful siRNA gene expression knockdown fall in the broad category of delivery. This work focuses on the use of N-isopropyl-acrylamide conjugated polyglycerol (PGNIPAM) as a novel cationic vector of in vitro and possible in vivo delivery of siRNA. The hyper-branched structure of the PGNIPAM molecule bears a biocompatible core with cationic subunits on the surface, providing a less toxic alternative to other cationic polymers used in the past. Further PGNIPAM shows excellent binding and release characteristics over other comparable molecules and systems. Activity of the siRNA requires access to the cell cytoplasm, which in turn requires passage of the siRNA through the cell membrane and release into the internal environment with no degradation. PGNIPAM has shown the ability to traverse the endocytic pathway and release the siRNA directly into the cytoplasm where it can interact with cellular machinery. Knockdown of known oncogene survivin was observed in vitro both through mRNA expression reduction as well as through protein reduction in MDA-MB-231 human breast cancer cells. Additionally, early stage animal work with a human breast cancer model shows positive results for coupled treatment of tumors using siRNA against survivin and doxorubicin, an anticancer drug. PGNIPAM offers a safer alternative to other cationic delivery systems and has shown improvement over standard modes of knockdown from commercial products.

No description available.

Die Analyse der Röntgen- und Neutronenkleinwinkelstreuung stellt ein ideales Werkzeug für Untersuchungen der Struktur submikroskopischer Teilchen und deren Wechselwirkungen dar. Hierbei eröffnet die Variation des Streukontrastes ein zusätzliches Spektrum an Informationen. Wie in der vorliegenden Arbeit gezeigt wird, kann durch die Verwendung komplementäre Verfahren ein detailliertes Bild der untersuchten Systeme erarbeitet werden. Im Fokus der Diskussion stehen Polyethylennanopartikel und Strukturen basierend auf hyperverzweigtem Polyglycerol. Die durchgeführten Untersuchungen liefern beispielsweise Rückschlüsse auf den Mechanismus, der zu einer nahezu idealen Anordnung unverzweigter Polymerketten, während der Bildung der Polyethylennanopartikel, führt. Im amorphen Anteil dieser plättchenförmigen Partikel findet demnach ausschließlich eine Richtungsänderung beim Wiedereintritt der Polymerketten in die kristalline Phase statt, wodurch eine ungehinderte Kettendiffusion möglich ist. Der Einfluss von Defekten entlang der Polymerkette auf die Partikelstruktur konnte durch Untersuchungen eines präzise verzweigten Polyethylens ermittelt werden. Bei weiteren Untersuchungen von wässrigen Dispersionen eines hyperverzweigten Polyglycerols konnte die übergeordnete Struktur als Fraktal beschrieben werden. Der signifikante Beitrag der Mikrostrukturierung des Moleküls zu dessen Kleinwinkelstreuung wurde in den Analysen berücksichtigt. Die Strukturuntersuchungen von Molekülen mit dem polaren hyperverzweigten Kern und einer nahezu vollständigen Funktionalisierung durch bipolare Ketten profitierte von diesen Ergebnissen. Hierbei wurde die Struktur dieser Moleküle in polaren und unpolaren Medien ermittelt. In einer polaren Umgebung wurde die Bildung von Assoziaten beschrieben. Dies liefert wertvolle Hinweise auf die Wirkungsweise als Wirkstofftransportsystem liefert. / The analysis of the small angel X-Ray and neutron scattering is an ideal tool for the discussion of the structure and interactions of submicroscopic particles. Herein, the variation of the scattering contrast enlarges the spectrum of information, additionally. As shown in the presented work, complementary probes give a detailed picture of the investigated systems. The focal point of the discussion is set on polyethylene nanoparticles and structures based on hyperbranched polyglycerol. The analyses provide, for instance, information on the mechanism that leads to an ideal arrangement of the non-branched polymer chains during the formation of the platelet-like polyethylene nanoparticles. The amorphous phase exclusively hosts the redirection of the polymer chains into the crystalline domain. This allows the unimpeded chain diffusion. The effect of defects along the polymer chain on the particle structure was studied by the analyses of polyethylene with precisely placed methyl groups. Analyses of aqueous dispersions of hyperbranched polyglycerol reveal the fractal-like character of the global molecule structure. Additionally, the significant contribution of the molecule’s microstructure to the corresponding small angle scattering was considered. The analyses of molecules composed of the hyperbranched core and a complete functionalisation with bipolar chains profited from these results. Hereby, the molecule structure in polar and non-polar media was identified. In polar surrounding the formation of well-defined aggregates was described. This provides essential information for a further discussion of this type of molecules as drug delivery platform.

Diversos mecanismos celulares estão associados à patogênese do Carcinoma Epidermoide de Cabeça e Pescoço (CECP). Algumas dessas alterações envolvem proteínas pertencentes à via de sinalização do Akt, e o fator de transcrição NF-kB, o qual têm importante papel na fisiologia normal e no câncer. A proteína COX-2, descrita em processos inflamatórios, também participa da carcinogênese e está associada com a via de sinalização do Akt e com o NF-kB. Dendrímeros são uma forma única de nanotecnologia, surgindo como nanotransportadores com a capacidade de penetrar na célula tumoral liberando drogas quimioterápicas em seu interior. Os benefícios desta tecnologia são o aumento da eficicácia do princípio ativo utilizado e a redução dos seus efeitos secundários tóxicos. O Celecoxibe, antiinflamatório não esteroidal, inibidor seletivo da COX-2, tem se mostrado um importante agente anticarcinogênico, no entanto seu mecanismo de ação no CECP não é totalmente compreendido. Neste trabalho, um Dendrímero de Poliglicerol associado ao Celecoxibe (PGLD-celecoxibe) foi sintetizado e caracterizado por técnicas de espectroscopia ¹H-RMN, ¹³C-RMN, Maldi-Tof, TLC e DSC. Além disso, o conjugado foi testado in vitro em três linhagens celulares de CECP. O PGLD-Celecoxibe foi sintetizado com sucesso e promoveu a redução da dose capaz de inibir a proliferação celular, reduzindo o IC 50 do Celecoxibe de forma significativa em todas as linhagens celulares, se aproximando da dose sérica alcançada por este medicamento, resultado corroborado pelo Ensaio de Migração Celular. O mecanismo de morte celular observado foi a apoptose, associada a diminuição significativa da expressão de COX-2 ou por uma via alternativa independente. Alguns dos grupos tratados apresentaram alteração na expressão das proteínas pAkt e NF-kB. / Several cellular mechanisms are associated with the pathogenesis of Head and Neck Squamous Cell Carcinoma (HNSCC). Some of these alterations involve proteins in the Akt signaling pathway and the transcription factor NF-kB, which plays an important role in normal physiology and in cancer. COX-2 protein, described in inflammatory processes, and also involved in the carcinogenesis is associated with the Akt signaling pathway and the NF-kB. Dendrimers are a unique form of nanotechnology, emerging as nanocarriers with the ability to penetrate the tumor cell releasing chemotherapeutic. This technology increases the active substance efficiency and reduces its toxic side effects. Celecoxib, a nonsteroidal anti-inflammatory, selective inhibitor of COX-2 has been shown to be an important anticancer agent, but its action mechanism in HNSCC is not fully understood. A polyglycerol dendrimer linked to celecoxib (PGLD-Celecoxibe) was synthesized and characterized by NMR spectroscopy ¹H-NMR, ¹³C-NMR,TLD, DSC and Maldi-Tof techniques. In addition, in vitro assays were performed in three HNSCC cell lines The PGLD-Celecoxibe was successfully synthesized and provided a decrease in the dose able to inhibit cell proliferation reducing the IC 50 index of Celecoxib significantly in all cell lines, approaching to the serum dose achieved for this product, result supported by Wound Healing Assay. The cell death mechanism observed was apoptosis, which can be associated with significant reduction of expression of COX-2 also may be occurring by a COX-2 independent pathway. Some of the treated groups showed alterations in pAkt and NF-kB proteins expression.

Através de técnicas eletroquímicas (espectroscopia de impedância eletroquímica, resistência à polarização linear e curvas de polarização potenciodinâmica), gravimétrica e analítica, compostos orgânicos foram estudados para avaliar suas possibilidades de emprego como inibidores de corrosão. Poliglicerol hiper-ramificado puro, modificado com dicloro-fosfato, funcionalizado com grupo tiol, funcionalizado com grupo sulfeto e com grupo sulfonato de potássio - foram os compostos sintetizados e testados. Além desses, compostos comerciais, um contendo a função fosfinato e outro a função imidazolina quaternária foram testados com o mesmo intuito. Isotermas de adsorção foram ajustadas aos dados obtidos para imidazolina quaternária. Para simular condições próximas às encontradas na produção de petróleo, água do mar sintética acidificada com ácido clorídrico até pH 3 foi o meio utilizado, tendo o aço carbono 1020 empregado como substrato metálico. O Poliglicerol hiper-ramificado gerou resultados eletroquímicos e gravimétricos que mostraram que em concentrações de até 600 ppm desse composto o processo corrosivo é incentivado ao invés de ser desacelerado, indicando que tal composto não deve ser usado como inibidor de corrosão. O Poliglicerol hiper-ramificado modificado com dicloro-fosfato apresentou resultados insatisfatórios para as condições testadas tanto nos ensaios eletroquímicos como nos gravimétricos. Nas concentrações de 200, 400 e 600 ppm desse composto, a concentração intermediária é a única que diminui ligeiramente a taxa de corrosão, e para as demais concentrações a corrosão é incentivada. Os ensaios eletroquímicos das outras três moléculas obtidas por funcionalização do poliglicerol hiper-ramificado com grupos tiol, sulfonato e sulfeto indicaram aumento da deterioração do substrato. Os resultados de impedância eletroquímica indicaram que o composto à base de fosfinato e na concentração de 2000 ppm e maiores tempos de imersão resultaram em melhores resultados protetores. O ajuste dos dados às isotermas de adsorção para a imidazolina quaternária apresentou melhores resultados para o modelo de Flory-Huggins, porém, os elevados valores de coeficiente de determinação R2 das isotermas de Langmuir e Temkin também permitem dizer que tais modelos de adsorção são seguidos. / Organic compounds were studied by lectrochemical (electrochemical impedance spectroscopy, linear polarization resistance and potenciodynamic polarization curves), analytical and gravimetric techniques, to analyze the possibilities of their use as corrosion inhibitors. Hyper branched polyglycerol only and modified with dichloro-phosphate, functionalized with thiol group, functionalized with sulfide and also with sulphonate group were synthesized and tested as corrosion inhibitors. Furthermore, commercial compounds, one based on phosphinate and a quaternary imidazoline were tested with the same objective. Adsorption isotherms were adjusted to the data obtained for quaternary imidazoline. To simulate the conditions close to those found in petroleum production, synthetic sea water acidified with hydrochloric acid up to pH 3 was the medium used, with 1020 carbon steel used as a metal substrate. The hyper branched polyglycerol generated electrochemical and gravimetric results which showed that, in concentrations up to 600 ppm of this compound, the corrosive process is favored rather than decelerated, indicating that this compound should not be used as a corrosion inhibitor. The hyper branched polyglycerol modified with dichloro-phosphate presented unsatisfactory results for the tested conditions for both electrochemical and gravimetric measurements. At concentrations of 200, 400 and 600 ppm of this compound, the intermediate concentration is the only one that slightly decreases the corrosion rate, and for the other concentrations corrosion is favored. The electrochemical measurements for the other three molecules obtained by functionalization of the hyper branched polyglycerol with thiol, sulphonate and sulfide groups indicated an increase on the substrate deterioration. The electrochemical impedance results showed that the compound based on phosphinate at 2000 ppm concentration and for higher immersion times resulted in better protective results. The adjustment of the data of the adsorption isotherms for quaternary imidazoline presented better results for the Flory-Huggins model. However, the high values of correlation factor R2 of Langmuir and Temkin isotherms show that these adsorption models are also followed.