京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19010号 / 工博第4052号 / 新制||工||1623(附属図書館) / 31961 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 田畑 泰彦, 教授 岩田 博夫, 教授 木村 俊作 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19408号 / 工博第4124号 / 新制||工||1636(附属図書館) / 32433 / 京都大学大学院工学研究科合成・生物化学 / (主査)教授 北川 進, 教授 松田 建児, 教授 濵地 格 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第19668号 / 薬科博第56号 / 新制||薬科||7(附属図書館) / 32704 / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 髙倉 喜信, 教授 橋田 充, 教授 佐治 英郎 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19746号 / 工博第4201号 / 新制||工||1648(附属図書館) / 32782 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 田畑 泰彦, 教授 秋吉 一成, 教授 木村 俊作 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21045号 / 薬科博第88号 / 新制||薬科||10(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 髙倉 喜信, 教授 山下 富義, 教授 小野 正博 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21421号 / 医博第4411号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 瀬原 淳子, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Die Forschung an porösen Hybridmaterialien hat sich rasch entwickelt, und in letzter Zeit ist die Anzahl neuer Strukturen und Zusammensetzungen aufgrund ihrer vielfältigen Anwendungsmöglichkeiten im Bereich des Kristall-Engineering von großem Interesse. Metall-organische Gerüste (metal-organic frameworks, MOFs) sind eine aufstrebende Klasse von Nanomaterialien, deren Eigenschaften durch Variation der Bausteine, die aus Metallionen und organischen Liganden bestehen und sich koordinativ zu einer dreidimensionale Struktur verbinden lassen, leicht angepasst werden können. Eigenschaften wie eine große Oberfläche und eine hohe Porosität verleihen diesen Materialien vielversprechende Eigenschaften, um als Wirtsmaterial verwendet zu werden. Die vorliegende Arbeit konzentriert sich auf die Synthese der Verbindung [Fe3O(H2O)2(OH)(bdc)3]n (bcd = 1,4-Benzoldicarboxylat; MIL-101(Fe), MIL = Materials of Institut Lavoisier), die aus einem carboxylato-verbrückten, oxido-zentriertem, dreikernigen Fe3+-Komplex besteht. Die Struktur besitzt große Poren (Ø: 29 und 34 Å) und eine große Oberfläche mit der Fähigkeit, zahlreiche Moleküle einzuschließen. In der vorliegenden Arbeit wird MIL-101(Fe) als Arzneimittelabgabesystem verwendet. Curcumin, Capecitabin und 5-Fluorouracil (5-FU) wurden als Modellarzneimittel für die Verkapselung in der MIL-101(Fe)-Struktur ausgewählt. Es wurden verschiedene Freisetzungsregime in unterschiedlichen biologischen Medien untersucht. Nach vielversprechenden ersten Ergebnissen bei der Freisetzung dieser Medikamente aus der MIL-101(Fe)-Struktur wurde anschließend die selektive Lasersintertechnik (SLS) verwendet. Die SLS ist ein additives Schichtbauverfahren, das sich in dieser Arbeit als ressourcenschonende Technologie für die schnelle Herstellung erwiesen hat. Die Möglichkeit, die Größe, Form und Geometrie der hergestellten Proben individuell anzupassen, bot die Gelegenheit, die Wirkstofffreisetzung zu modulieren und den Freisetzungszeitraum zu verlängern. / The field of porous hybrid materials has grown rapidly; recently the number of new structures and compositions are of great interest in the crystal-engineering field, due to their various possible applications. Metal-organic frameworks (MOFs) are an emerging class of nanomaterials, whose properties can be easily adjusted by varying the molecular building blocks, obtained from metal ions and organic ligands that can be combined to three-dimensional structures. Properties such as high surface area and high porosity give these materials promising characteristics to be used as host materials. The present work focuses on the synthesis of [Fe3O(H2O)2(OH)(bdc)3]n (bcd = 1,4-benzenedicarboxylate; MIL-101(Fe), MIL = Materials of Institut Lavoisier), composed of carboxylate-bridged, oxido-centered, trinuclear Fe3+ complexes. The iron-based structure features large pore sizes (Ø: 29 and 34 Å) and high surface area with the ability to encapsulate numerous molecules, for use as a drug delivery system in the present work. The curcumin, capecitabine, and 5-fluorouracil (5-FU) were chosen as model drugs for the encapsulation into the MIL-101(Fe) structure. Different delivery regimes were studied in different biological media. After promising initial results with the release of these drugs from the MIL-101(Fe) structure, the selective laser sintering technique (SLS) was introduced subsequently. The SLS is an additive layer manufacturing technique that has emerged in this work as a resourceful technology for rapid manufacturing, the possibility to customize the size, shape, and geometry of the manufactured samples, thus providing the opportunity to modulate the drug release extending it for even longer periods of time.

The objective of this thesis is to develop a method by which antimicrobials are delivered into a food product as a concentrated dose to the specific area in which the microorganism is growing without interference from the food matrix. More specifically, we plan to achieve this by delivering the antimicrobials nisin and lysozyme attached to nanoparticles and emulsion droplets. We hypothesize that (a) the attachment to a delivery vessel may increase the local concentration of the antimicrobial in the vicinity of the bacterial pathogens and (b) that the size and charge of the nanoparticle following attachment of the antimicrobials will be critical to its efficacy against pathogens. This thesis is designed to test this hypothesis using silver nanoparticles with well defined sizes and surface chemistry that allow control over the loading of the particle and oil droplets to which nisin is a secondary layer attached to pork gelatin which acts as the primary emulsifier.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24586号 / 工博第5092号 / 新制||工||1975(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 秋吉 一成, 教授 大塚 浩二, 教授 田中 一生 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

The increase in obesity and overweight in many countries has led to an upsurge of interest in the development of reduced fat food products. However, the development of these products is challenging because of the many roles that fat droplets normally plays in these food products, including contributing to flavor, texture, appearance, and bioactivity. The goal of this research was to develop novel reduced-fat emulsions based on hetero-aggregation of oppositely charged food-grade colloidal particles or polymers. Initially, lactoferrin (LF) and β-lactoglobulin (β-Lg) were selected as emulsifiers to form protein-coated fat droplets (d43 ≈ 0.38 μm) with opposite charges at neutral pH: pKaβ-Lg ≈ 5 < pH 7 < pKaLF ≈ 8.5. Droplet aggregation occurred when these two emulsions were mixed together due to electrostatic attraction. The structural organization of the droplets in these mixed emulsions depended on the positive-to-negative particle ratio, particle concentration, pH, ionic strength, and temperature. The nature of the structures formed influenced the rheology, stability, and appearance of the mixed emulsions, which enabled some control over emulsion functionality. The largest microclusters were formed at particle ratios of 40% LF-coated and 60% β-Lg-coated fat droplets, which led to mixed emulsions with the highest apparent viscosity or gel strength. At low total particle concentrations (0.1%), there was a relatively large distance between microclusters and the mixed emulsions were fluid. At high particle concentrations (>20%), a three-dimensional network of aggregated droplets formed that led to gel-like or paste-like properties. The influence of environmental stresses on the physicochemical stability of the microclusters formed by hetero-aggregation was investigated: pH (2-9); ionic strength (0-400 mM NaCl); and temperature (30-90 ºC). Large microclusters were obtained at pH 7 (d43 ≈ 10 μm) with the absence of salt at room temperature. More acidic (< pH 6) or alkaline (> pH 8.5) solutions resulted in smaller aggregates by minimizing the electrostatic attraction between the protein-coated fat droplets. Microclusters dissociated upon addition of intermediate levels of salt, which was attributed to screening of attractive electrostatic interactions. Heating the microclusters above the thermal denaturation temperature of the proteins led to an increase in gel-strength, which was attributed to increased hydrophobic attraction. The influence of hetero-aggregation of lipid droplets on their potential biological fate was studied using a simulated gastrointestinal tract (GIT). Results showed that the mixed emulsions had high viscosity in the simulated oral environment but exhibited similar rheological properties and particle characteristics as single-protein emulsions in the simulated gastric and small intestinal tract regions. The mixed emulsions also had similar lipid digestion rates in the simulated small intestine as single-protein emulsions suggesting that they could be used as delivery systems for bioactive lipophilic compounds in reduced fat food products. The possibility of using more practical food ingredients to promote heteroaggregation system was also examined. Whey protein isolate (positive) and modified starch (negative) were selected as building blocks due to their opposite charges at pH 3.5. The largest aggregates and highest viscosities occurred at a particle ratio of 70% MS and 30% WPI, which was attributed to strong electrostatic attraction between the oppositely charged droplets. Particle aggregation and viscosity decreased when the pH was changed to reduce the electrostatic attraction between the droplets. Finally, the influence of interfacial properties on the chemical stability of bioactive components in emulsion-based delivery systems containing mixed proteins was studied. Lactoferrin (LF: pI ≈ 8) and β-lactoglobulin (β-Lg: pI ≈ 5) were selected to engineer the interfacial properties. Interfaces with different structures were formed: LF only; β-Lg only; LF-β-Lg (laminated); β-Lg -LF (laminated); β-Lg /LF (mixed). The influence of pH, ionic strength, and temperature on the physical stability of β-caroteneenriched emulsions was then investigated. LF- emulsions were stable to the pH change from 2 to 9 but the aggregation was occurred in intermediate pH for other emulsions. β- Lg- emulsions aggregated at low salt concentration (≥ 50mM NaCl), however other emulsions were stable (0 - 300mM NaCl). β-Lg /LF (mixed) emulsions were unstable to heating (≥ 60 ºC), but all other emulsions were stable (30 to 90 ºC). Color fading due to β-carotene degradation occurred relatively quickly in β-Lg-emulsions (37 ºC), but was considerably lower in all other emulsions, which was attributed to the ability of LF to bind iron or interact with β-carotene. Overall, this study shows that hetero-aggregation may be a viable method of creating novel structures and rheological properties that could be used in the food industry.