Les polysaccharides amphiphiles possèdent des propriétés rhéologiques et interfaciales singulières dues aux interactions attractives entres les groupements hydrophobes greffés le long du squelette hydrophile. Leurs propriétés sont modulables suivant certains paramètres bien identifiés (nature des groupements hydrophobes, densité de greffage, etc.). Néanmoins, peu d’études s’intéressent à l’impact de la conformation du squelette sur le comportement de ces systèmes. L’objectif de ce mémoire est de déterminer l’influence de la rigidité du squelette sur les propriétés en solution d’un polysaccharide amphiphile à base de xanthane. En solution, ce polymère peut adopter deux conformations distinctes suivant les conditions opératoires : une forme ordonnée hélicoïdale rigide ou une forme désordonnée de type pelote flexible. Deux protocoles de greffage ont été développés afin de modifier le xanthane sous ces deux formes. Les xanthanes greffés sous forme ordonnée conservent une conformation hélicoïdale rigide, qui gouverne l’organisation globale des macromolécules. Au contraire, pour les polymères greffés sous forme désordonnée, l’organisation des chaînes est principalement contrôlée par les interactions attractives entre les groupements hydrophob / Hydrophobically modified polysaccharides show unusual rheological and interfacial properties in solution due to the self association of hydrophobic entities grafted onto their hydrophilic backbone. Their properties are tunable according to some well known parameters, such as the length of the hydrophobic moieties or the grafting density. However, very few studies deal with the influence of the backbone conformation on the properties of such systems in solution. Therefore, the objective of this work is to determine the impact of the backbone rigidity on the behavior of an amphiphilic polysaccharide based on xanthan. Indeed, in solution, this polymer can adopt two different conformations depending on the experimental conditions: an ordered, rigid helix or a disordered, flexible coil. Hydrophobic moieties have been grafted on xanthan either under its ordered and disordered conformation. Chains modified under the ordered conformation remain ordered and rigid after grafting and the overall properties are controlled by the high rigidity of the polymer backbone. On the contrary, macromolecules grafted under the disordered form show a more flexible conformation in solution. As a result, the organization of these derivatives is mainly controlled by the attractive interactions between the grafted moieties

Trois architectures de copolymères (dibloc, tribloc et hétérogreffé) amphiphiles photo-stimulables à base de polyoxazoline et de groupements photo-sensibles de type coumarine sont étudiées dans ce travail. Ces copolymères s’auto-assemblent en milieu aqueux sous forme de nanoparticules de morphologies sphériques, ovales mais également de nanofibres hélicoïdales de plusieurs micromètres de longueur. Selon les cas, les morphologies sont induites par de la cristallisation des motifs coumarine entre eux ou bien des interactions polyoxazoline-coumarine. Par ailleurs, la photo-réponse des nanoparticules a été examinée après irradiation UV des groupements coumarine, capables de dimériser de manière réversible selon la longueur d’onde utilisée. Elle diffère selon l’architecture du copolymère qui constitue les nanoparticules et donne lieu à des phénomènes de (pré-)photo-dimérisation ou photo-réticulation du cœur de celles-ci avec des réversibilités sous UV variables et un maximum d'efficacité dans le cas des copolymères triblocs. La stabilité de ces auto-assemblages a également été examinée avant et après exposition UV. Dans tous les cas, l’irradiation des nanoparticules améliore leur stabilité en température et dans le temps avec un effet maximal dans le cas de la pré-photodimérisation (tribloc). Enfin, la réticulation et la cristallisation se sont révélées être des freins au piégeage de molécules hydrophobes, illustrées ici avec le Nile Red, alors que les copolymères diblocs se sont révélés être les systèmes les plus efficaces. En somme, les nanoparticules de copolymères triblocs présentent le meilleur compromis entre stabilité, efficacité UV et piégeage. / Three photo-responsive amphiphilic copolymer architectures (diblock, triblock and heterografted) based on polyoxazoline and coumarin photo-sensitive units are studied in this work. These copolymers self-assemble in water into spherical or ovalic nanoparticles and also supramicrometer helicoidal nanofibers. Depending on the macromolecular architectures, these morphologies are induced by crystallization of coumarin units or polyoxazoline-coumarin interactions. Moreover, the nanoparticle photo-response is examinated after the UV-exposure of coumarin units, that are able to reversibly dimerize according to the wavelength used. This photo-response varies with the copolymer structure and leads to (previous) photo-dimerization or photo-crosslinking phenomena. These latters present various photo-reversibility behaviors under UV and a maximal efficiency for triblock copolymers. The nanoparticle stability was additionally studied before and after UV-irradiation. In both cases, the nanoparticle stability is improved towards time and temperature with a maximal impact for the previous photo-dimerization (triblock). Finally, the crosslinking and the crystallization appear as brakes for the hydrophobic molecule entrapment, illustrated here by Nile Red, whereas diblock copolymers seem to be the most efficient systems. To conclude, previously photo-dimerized nanoparticles (triblock) are the best way combining stability, UV-efficiency and entrapment.

L’objectif de cette thèse était d'étudier les propriétés physico-chimiques de réseaux interpénétrés formés par auto-assemblage de copolymères à blocs amphiphiles stimulables. La première partie du travail a consisté à élaborer des hydrogels interpénétrés IPSAN (InterPenetrated Self-Assembled Network) à partir d’un simple mélange de copolymères triblocs associatifs. Ainsi, l’IPSAN correspond à une combinaison des deux réseaux polymères. Le premier réseau est formé par un copolymère tribloc à base de poly(oxyde d'éthylène) (tPOE) porteur de blocs hydrophobes polymérisables sous UV. Le deuxième réseau est constitué d’un copolyélectrolyte tribloc pH sensible à base de poly(acide acrylique) (TH50).L’influence des concentrations en copolymères et du pH sur la structure et les propriétés mécaniques des hydrogels IPSAN a été systématiquement étudiée. Dans une deuxième partie, nous nous sommes intéressés à l'influence de la formation d'un réseau transitoire sur la séparation de phases dans des mélanges de tPOE et de polymères linéaires en solution aqueuse. Cette étude a mis en évidence une augmentation de l'incompatibilité entre les deux polymères induite par l’association du copolymère tribloc. Ce système a permis l'élaboration d'hydrogels macroporeux photo-réticulables.Enfin, la diffusion de polymères linéaires et de particules solides micrométriques dans des réseaux de copolymères pH-sensibles a été étudiée par des techniques de recouvrement de fluorescence après photobleaching (FRAP) et de diffusion dynamique de la lumière. La formation du réseau transitoire ralentit le mouvement de traceurs linéaires de petite taille de la même manière que dans le cas d'hydrogels covalents. Le contrôle de la structure et de la dynamique du réseau par le pH est un levier puissant pour contrôler la diffusion dans ces hydrogels. / The objective of this thesis was to investigate the physical chemical properties of interpenetrating networks formed by self-association of responsive amphiphilic block copolymers. The first part of the work was to develop IPSAN hydrogels(InterPenetrated Self-Assembled Network) simply by mixing two triblock copolymers. Thus, the IPSAN corresponds to a combination of the two polymer networks. The first network is formed by a triblock copolymer based on poly(ethylene oxide) (tPEO) bearing UV-cross-linkable hydrophobic blocks. The second network consists of a pH-sensitive triblock polyelectrolyte based on poly(acrylic acid) (TH50). The influence of the concentration of the copolymers and of the pH on the structure and the mechanical properties of the IPSAN has been systematically studied. In the second part we investigated the influence ofthe formation of a transient network on the phase separation in mixtures of tPEO and linear polymers in aqueous solution. This study revealed an increase of the incompatibility between the two polymers induced by the association of the triblock copolymer. This system enabled the elaboration of photo-cross-linked macroporous hydrogels. Finally, the diffusion of linear polymers and solid particles in pH-sensitive networks was studied by fluorescence recovery after photobleaching (FRAP)and dynamic light scattering. The formation of a transient network restricts the movement of small linear tracers in the same way as a covalent hydrogel would. The control of the structure and dynamics of the network by the pH is a powerful tool to control the diffusion in this hydrogels.

Cette thèse s’inscrit dans une thématique de recherche visant à synthétiser des moléculesamphiphiles présentant des propriétés bioactives, pouvant être mises à profit dans diversesapplications biomédicales ou encore dans le domaine de l’agrochimie. Les molécules amphiphilessont alors les propres actrices de leur formulation de par leurs propriétés d’auto-association et debioactivité (concept dit « d’économie moléculaire »). Dans ce contexte, la première partie de cetravail a été consacrée à la synthèse de molécules amphiphiles modèles dérivées de D-glucose etde N-acétyl-D-glucosamine. La voie de synthèse choisie pour les obtenir a été une aminationréductrice régiosélective à partir de chaînes alkylamine de différentes longueurs (6, 12 et 16atomes de carbone). Leur caractérisation a été réalisée par RMN et spectrométrie de masse. Ladeuxième partie de ce travail a été orientée vers l’étude du comportement auto-associatif desmolécules à base de D-glucose en solution aqueuse, seules, ou en mélange avec un phospholipidemodèle. Une organisation à différentes échelles de taille a été mise en évidence par les techniquesde diffusion de la lumière, microscopie électronique en transmission et grâce à la modélisation dedonnées expérimentales obtenues en diffusion des rayons X aux petits angles. / This work is part of a research program on the synthesis of amphiphilic molecules havingbioactive properties, which could be used in biomedical applications or in agrochemistry.Amphiphilic molecules could be the own actor of their formulation because of the dual propertyof bioactivity and self-assembly. In this context, the first part of this work concerns the synthesisof model amphiphilic molecules derived from D-glucose and N-acetyl-D-glucosamine. The chosenway to synthesize these molecules was a regioselective reductive amination from alkylaminechains of different lengths (6, 12 and 16 carbon atoms). Compounds were characterized by NMRand Mass Spectrometry. The second part of this work was oriented towards the study of the selfassemblyproperties of molecules derived from D-glucose in an aqueous solution, alone, or mixedwith a model phospholipid. An organization with different sizes was shown with severaltechniques: light diffusion, transmission electronic microscopy, and thanks to the establishment ofa model from experimental small-angle X-ray scattering data. When the amphiphilic moleculewith 12 atoms of carbon on this hydrocarbonated chain is studied alone in a solution, ellipsoidalmicelles seem to be present, mixed with bigger aggregates (~100 nm). However, when this sameamphiphilic molecule is used in a mix with a model phospholipid, a size diminution of theassembly was observed with the increase of amphiphilic molecules in the formulations.

Polymers that undergo dramatic changes in structural conformations in response to numerous stimuli such as temperature, pH, electric and magnetic fields, light inten- sity, biological molecules, and solvent polarity, are known as stimuli-responsive or ”smart” polymers. There is a broad range of very promising applications of these materials in catalysis, environmental remediation, sensors or actuator systems, and as delivery systems of therapeutic agents. Researchers have been trying to mimic smart polymers based on properties of polymers found in nature such as proteins, carbohydrates and nucleic acids. Novel bio-compatible polymers with a variety of chemical functional groups, diverse topologies, and cross-linking patterns with the ability to self-assemble in vivo are being engineered. Experimental and theoretical studies indicate that the thermodynamic properties relating to the hydrophobic effects play a pivotal role in determining the self-assembly process in smart polymers. At the same time, computational approaches based on simulation and modeling provide an understanding of this phenomenon on the micro- scopic level. Building empirical models based on statistical mechanics methods and simulation data helps to design polymeric materials with desirable traits. My research is mainly focused on investigating physicochemical characteristics of stimuli-responsive polymers under different conditions. I used atomistic molecular dynamics simulations to investigate these effects on polymer conformation. Given the size and complexity of our polymeric systems, we employed Graphical Process- ing Units (GPU) and enhanced sampling techniques such as REDS2 to increase the sampling time. These methods allow for the study of polymeric structural dynamics in solvents of varying polarity and in human skin epidermis. Our constant pH simulation of poly(methacrylic acid) revealed that the overall response is made up of local and global structural changes. The local structural re- sponse depends on the tacticity of the polymer, which leads to distinct cooperative effects for polymers with varying stereochemistry. Such simulations help to under- stand the principal driving forces behind the mechanism of self-assembly processes.

Orientador: Maria Isabel Felisberti / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T10:02:17Z (GMT). No. of bitstreams: 1 Camilo_AnaPaulaRodrigues_D.pdf: 5133828 bytes, checksum: 99ef787814cdea2e327eb67879a8eec7 (MD5) Previous issue date: 2015 / Resumo: Neste trabalho foram sintetizados copolímeros anfifílicos dibloco baseados em 1¿-O-metacrilato de sacarose (SMA) e metacrilato de metila (MMA) por RAFT (Reversible Addition-Fragmentation Chain Transfer) e ATRP (Atom Transfer Radical Polymerization) com diferentes composições (balanço hidrofílico/hidrofóbico diferenciado). O MMA é um monômero hidrofóbico, enquanto, o SMA apresenta caráter fortemente hidrofílico. Primeiramente, foi realizado um estudo referente aos parâmetros reacionais utilizados na síntese do bloco de MMA, tanto via RAFT quanto ATRP. Para a polimerização RAFT, avaliou-se a influência da razão molar entre os reagentes, da temperatura e do solvente sobre a eficiência na polimerização. Na polimerização ATRP estudou-se sistemas reacionais contendo diferentes iniciadores, ligantes e catalisadores. A partir desse estudo, adotou-se os sistemas catalisador/iniciador, brometo de cobre (I)/ 2,2,2-tribrometanol (CuBr/TriBrEt), e agente de transferência/iniciador, ditiobenzoato de 2-cianopropila/2,2?-azoisobutironitrila (CPDB/AIBN), para a polimerização ATRP e RAFT, respectivamente. Estes sistemas mostraram ser eficazes tanto para a obtenção do homopolímero PMMA, quanto para os copolímeros em bloco P(MMA-b-SMA), com polidispersidade controlada. Os homopolímeros (PMMA) e os copolímeros dibloco P(MMA-b-SMA) foram caracterizados estruturalmente por ressonância magnética nuclear de 13C (RMN 13C) e cromatografia de permeação em gel (GPC). As propriedades físico-químicas dos copolímeros no estado sólido foram avaliadas por análise termogravimétrica (TGA), análise dinâmico-mecânica (DMA), difratometria de raios-X de alto ângulo (DRX) e espalhamento de raios-X de baixo ângulo (SAXS). A morfologia foi estudada por microscopia de força atômica (AFM) e microscopia eletrônica de transmissão (TEM). O comportamento de soluções dos copolímeros em DMF foi estudado por SAXS. Todos os polímeros sintetizados se apresentaram solúveis em DMF, evidenciando que tratam-se de macromoléculas não-reticuladas, revelando que o caráter anfifílico é fortemente dependente da composição, tal como era esperado. As propriedades físico-químicas dos copolímeros sólidos e em solução, assim como a morfologia, mostraram-se dependentes da composição. A combinação dos resultados das análises de RMN 13C, DMA, AFM e TEM, para os copolímeros, permitiu concluir que o bloco de PMMA constitui-se a fração majoritária, que os blocos PSMA e PMMA são imiscíveis, e que a morfologia é a de uma matriz constituída predominantemente por PMMA, na qual a fase PSMA minoritária encontra-se dispersa, respectivamente. Resultados de estudos por RMN 13C e SAXS mostraram que, dependendo da composição, os copolímeros tendem a se organizar em solução ou na forma sólida. Os resultados de SAXS e de AFM de filmes dos copolímeros também indicaram que a dispersão da fase PSMA na matriz de PMMA ocorre de forma distinta, de acordo com o solvente utilizado no processo casting / Abstract: In this work, amphiphilic diblock copolymers based on sucrose 1'-O-methacrylate (SMA) and methyl methacrylate (MMA) with different compositions (differentiated hydrophilic/hydrophobic balance) were synthesized by RAFT (Reversible Addition-Fragmentation Chain Transfer) and ATRP (Atom Transfer Radical Polymerization). Methyl methacrylate (MMA) is a hydrophobic monomer, while the 1'-O-sucrose methacrylate (SMA) is strongly hydrophilic. The first step of the studies concerned the influence of the reaction parameters on the synthesis of the MMA block, using both RAFT and ATRP. For RAFT polymerization, the influence of the molar ratio between the reactants, temperature and solvent on the efficiency of polymerization was evaluated. For the ATRP polymerization four different combinations of initiators/ligants/catalysts were studied and their efficiency were compared. From this study, systems catalyst/initiator, copper (I) bromide/2,2,2-tribromethanol (CuBr/TriBrEt), and transfer agent/initiator, (2-cyanopropyl) dithiobenzoate/2,2?-azobis(2-methylpropionitrile) (CPDB/AIBN), were used for ATRP and RAFT polymerization, respectively. These systems showed to be effective to obtain PMMA homopolymer and block copolymers P(MMA-b-SMA) with controlled polydispersity. The homopolymers (PMMA) and diblock copolymers P(MMA-b-SMA) were structurally characterized by 13C nuclear magnetic ressonance (13C NMR) and gel permeation chromatography (GPC). The physico-chemical properties of the copolymers in the solid state was evaluated by thermogravimetric analysis (TGA), dynamic mechanical analysis (DMA), X-ray diffraction (XRD) and small-angle X-ray scattering (SAXS). The morphology was studied by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The behavior of copolymers in solutions of the DMF was studied by SAXS. All copolymers were soluble in DMF, showing that they are non-crosslinked macromolecules, revealing that the amphiphilic character is strongly dependent of the composition, as expected. From 13C NMR, DMA, AFM and TEM analysis of the copolymers it was possible conclude that PMMA block is a majority component, PSMA and PMMA blocks are miscible and the morphology is predominantly composed of a PMMA matrix, in which the minority PSMA phase is dispersed, respectively. The results of studies by 13C NMR and SAXS showed that some compositions of the copolymers are self-organized in solution and in solid state. The results of SAXS and AFM indicated that the dispersion of the PSMA phase in the PMMA matrix occurs differently, according with the solvent used in the casting process / Doutorado / Físico-Química / Doutora em Ciências

Recent pharmaceutical developments have investigated using supramolecular nanoparticles in order to increase the bioavailability and solubility of drugs delivered in various methods. Modification of the carbohydrate cyclodextrin increases the ability to encapsulate hydrophobic pharmaceutical molecules by forming a carrier with a hydrophobic core and hydrophilic exterior. Guest molecules are commonly added to these inclusion complexes in order to add stability and further increase targeting abilities of the carriers. One such guest molecule is adamantine combined with a poly(ethylene glycol) chain. Vesicles are formed by hydrating a thin film of amphiphilic cyclodextrin and guest molecules in buffer solution that mimics physiological conditions. The solution is subject to freeze-thaw cycles and extrusion, and the complexes are separated out via size exclusion chromatography. Dynamic Light Scattering instrumentation is used to observe the particle size distribution. Cargo release can be observed in fluorescent dye-loaded vesicles by addition of a membrane-cleaving agent under a fluorimeter instrument. Future work involving this drug delivery technology includes synthesizing a chemically sensitive guest that will cleave in the presence of an intra-cellular anti-oxidant, and finally observing the uptake of these vesicles into live cells and testing the delivery of cargo in vitro under physiological conditions.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22846号 / 工博第4786号 / 新制||工||1748(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 大内 誠, 教授 竹中 幹人, 教授 秋吉 一成 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Amphiphilic kanamycin is one of the promising class of compounds for the treatment of fungal infections in plants and animal. Factor that lead to the restricting of compounds for commercialization includes, the higher cost of production and poor stability of the compound. However, the new lead, identified from the synthesis and biological testing, can be synthesized on a large scale with a cost comparable to commercial antifungals. The newly reported lead is stable at the acidic and basic conditions. Additionally, this compound has an excellent activity towards Candida auris, a multidrug-resistant superbug. Heart disease is the leading cause of death in the United States most of which are caused by cardiac ischemia and arrhythmias. Abnormal opening of Cx43 hemichannel can damage the heart muscles and lead to these conditions. A compound which can selectively inhibit the opening of Cx43 hemichannel may pave the way to reducing the mortality rate of heart disease. A selective inhibitor towards Cx43 hemichannel is explored from the synthesis and biological testing of kanamycin derivatives. The synthesis of the new inhibitor is scalable and cost-effective.

This thesis focuses on the self-assembly of the boron cluster compounds and the coassembly of metallacaborane cobalt bis(dicarbollide), COSAN, with hydrophilic polymers. The research was motivated by the discovery of HIV inhibition by COSAN and its conjugates. Therefore, we decided to study in detail the behavior of boron cluster compounds in water. We demonstrated the amphiphilic character of several boranes and carboranes by the study of surface tension and self-assembly despite the absence of classical amphiphilic topology. The behavior of COSAN showed similarities with classical surfactants, such as SDS, whereas the behavior of smaller clusters with high charge density reminded of hydrotropes or chaotropes. Furthermore, we searched for the most suitable carriers of COSAN for drug delivery. Based on the earlier findings that COSAN interacts with both poly(ethylene oxide), PEO, and poly(2-oxazoline), POX, we prepared nanoparticles by mixing COSAN with block copolymers of various types of POX. Comparing linear and star-like block copolymers, we showed that the polymer architecture has a crucial role in the morphology of nanoparticles. In addition, we proved different selectivity of alkaline cations towards PEO and POX, resulting in the different structures of nanoparticles depending on the present...