L'artémisinine (ART) est un composé antipaludique majeur très actif sur les souches multi-résistantes de Plasmodium falciparum. Cependant, son application clinique est limitée par sa faible solubilité en milieu aqueux et sa faible biodisponibilité par voie orale. La mise en œuvre de cyclodextrines (CDs) bioestérifiées et de dérivés amphiphiles polyoxyéthylénés permet de viser deux objectifs : i) d'une part d'améliorer la concentration aqueuse d'ART à travers son association aux vecteurs colloïdaux de CDs modifiées et ii) d'autre part d'améliorer sa biodisponibilité et son efficacité thérapeutique à travers la décoration de la surface des vecteurs. La décoration surfacique est sensée augmenter le temps de circulation sanguine des nanovecteurs de manière à maintenir des doses plasmatiques efficaces d'ART sur une longue période, suite à une administration intraveineuse. Des suspensions colloïdales stables suffisamment chargées d'ART ont été mises au point permettant de palier le problème d'insolubilité en milieu aqueux de la molécule active et donc d'envisager son administration par voie parentérale. Les essais de lyodisponibilité indiquent que l'ART est libérée des nanosystèmes pendant une période de 4 jours pour les nanoréservoirs et de 11 jours pour les nanosphères. En plus des caractérisations physico-chimiques et pharmacotechniques, les potentialités des nanoparticules décorées en surface ont été évaluées et comparées au cours de tests biologiques. In vitro, l'ART mise en forme a montré une bonne efficacité sur des souches plasmodiales choloroquino-sensibles (3D7) et chloroquino-résistantes (K1) avec des CI50 très faibles de l'ordre de 3 à 6 ng/mL. Le concept de co-nano-assemblage de dérivés amphiphiles de γ-CD-C10 bioestérifiée et de polyéthylène glycol (PEG) dans les conditions de nanoprécipitation semble être une approche intéressante pour conférer des propriétés de furtivité aux nano-systèmes de γ-CD-C10. En effet, les études in vitro mettent en évidence une diminution significativement de la phagocytose par les cellules macrophagiques et/ou de l'adsorption des protéines du complément sérique à la surface des nanoparticules de γ-CD-C10 décorées par le polysorbate 80, le stéarate de PEG1500, et le DMPE-mPEG2000. In vivo, nous observons une augmentation du temps de circulation sanguine des nanoréservoirs γ-CD-C10/polysorbate 80 et des nanosphères γ-CD-C10/DMPE-mPEG2000. Enfin, les études de pharmacocinétique réalisées chez le rat montrent que les paramètres pharmacocinétiques de l'ART sont améliorés lorsqu'elle est associée aux deux systèmes nanoparticulaires précédents. En effet, des valeurs de clairance plasmatique très faibles et de temps de demi-vie plasmatique longs (3 et 5 heures, respectivement) de l'ART ont été enregistrées avec ces deux formulations. Ces formes vectorisées d'ART mises au point ouvrent de perspectives intéressantes pour la prise en charge thérapeutiques des crises de paludisme sévère. / Artemisinin (ART), an endoperoxide sesquiterpene lactone antimalarial drug isolated from a Chinese medicinal herb (Artemisia annua), has a fast action against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, making it very effective in the treatment of multidrug-resistant malaria. However, its poor aqueous solubility, short half-life, and high first-pass metabolism limit its use in therapeutics. The purpose of the present study was to investigate the potential of self-assembled bio-transesterified CD-based nanocarriers as ART delivery systems for an intravenous route. The objective of our study was twofold: (i) to improve the ART dosage through its association with CD esters-based nanocarriers, (ii) to ensure a sufficient blood circulation time of the nanocarriers through their surface decoration, which is a prerequisite to reach infected erythrocytes after systemic administration. Stable colloidal suspensions with good ART association rate were developed to solve the problem of insolubility in aqueous medium of the active molecule and therefore consider its parenteral administration. The γ-CD-C 10 based nanospheres showed a significant sustained release profile of ART extended up to 4 days for nanosphères and 11 days for nanoreservoirs. In addition to the physicochemical characterizations, the potential of nanoparticles decorated on the surface were evaluated and compared in biological tests. The results from this study indicate that ART-loaded nanosystems, mainly PEGylated ones exhibit satisfactory in vitro activity against Chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum with very low IC50 of the order of 3 to 6 ng / mL. The concept of co-assembly of nano-amphiphilic derivatives of γ-CD-C10 bioestérifiée and polyethylene glycol (PEG) under conditions of nanoprecipitation seems to be an interesting approach to impart stealth nano-systems-γ-CD C10. Indeed, in vitro studies show a significant decrease in phagocytosis by macrophages and/or adsorption of serum complement proteins on the surface of nanoparticles of γ-CD-C10 decorated by polysorbate 80, PEG1500 stearate, and mPEG2000-DMPE. In vivo, we observed an increase in blood circulation time of nanoreservoirs γ-CD-C10/polysorbate 80 and nanospheres γ-CD-C10/DMPE-mPEG2000. Finally, pharmacokinetic studies in rats show that the pharmacokinetics of ART are enhanced when combined with previous two nanoparticle systems. Indeed, values of plasma clearance and very low time of long plasma half-life (3 to 5 hours, respectively) of ART were recorded with both formulations. These colloidal forms of ART developed open up interesting prospects for the therapeutic treatment of severe malaria.

Après la mise en évidence de la forte activité antibactérienne à large spectre contre des bactéries Gram (+) et Gram (-) sauvages et résistantes aux antibiotiques des dérivés 3',4',6-tri-naphtylméthyl (2NM) et -trihexyl d'un petit aminoglycoside, la néamine, et de l'activité, contre les bactéries Gram (+) sauvages et résistantes, des 3',4'- et 3',6-di2NM néamines, les travaux réalisés ont cherché à obtenir des dérivés antibactériens plus actifs et moins toxiques que les dérivés trialkylés. Deux approches en séries aminoglycosides amphiphiles ont été développées dans ce but : (1) la synthèse à partir de la néomycine B de nouveaux dérivés de la néamine portant des groupements alkyles de différentes lipophilies de façon à diminuer globalement celle-ci et (2) après les premiers résultats en série néamine, la synthèse à partir de la N-acétyl glucosamine de dérivés amphiphiles d'un des constituants de la néamine, la néosamine.Dans la première approche, après la mise au point de méthodes d'alkylation de la néamine, il a été possible de passer de dérivés trialkylés de la néamine à des dérivés dialkylés, en particulier 3',6- dialkylés, plus actifs et moins cytotoxiques ceci en diminuant la lipophilie globale des composés. Dans la deuxième approche, à partir de la 1-allyl 3,4-dinonyl néosamine, des dérivés amphiphiles antibactériens à large spectre portant en position anomérique des groupements polaires ont été préparés après époxydation de la double liaison. Le dérivé tri2NM de la néamine s'était avéré avoir une forte affinité pour les lipopolysaccharides de la membrane externe de P. aeruginosa et agir à travers son caractère amphiphiles pour dépolariser la membrane bactérienne. L'étude du mode d'action des dérivés de la néamine préparés les plus actifs a suggéré un mécanisme d'action similaire. / In regard to the antibacterial activity of amphiphilic aminoglycosides which are (i) 3',4',6-trinaphtylmethyl (2NM) et -trihexyl neamine derivatives active against wild-type and resistant to antibiotic drugs Gram (+) et Gram (–) bacteria, and (ii) 3',4'- and 3',6-di2NM derivatives active against bacteria Gram (+) bacteria, the works were focused on the search for more active and less toxic derivatives than the trialkyl derivatives. With this aim, two approaches were developed for obtaining antibacterial amphiphilic aminoglycosides: (1) the synthesis from neomycin B of new neamine derivatives carrying alkyl groups of various lipophily in order to decrease the global lipophily and (2) after the first results in the neamine series, the synthesis from N-acetylglucosamine of amphiphilic derivatives of the aminosugar part of the neamine core named neosamine.In the first approach, after optimisation of alkylation methods of neamine, we shifted from active 3',4',6-trialkylated derivatives to less lipophilic more active and less cytotoxic dialkylated derivatives, especially 3',6 derivatives. In the second approach, from 1-allyl 3,4-dinonyl neosamine, large spectrum antibacterial derivatives carrying at the anomeric position polar groups were obtained through epoxidation of the allylic double bond. Previously, the tri2NM neamine derivative has appeared to be able to strongly bind to the lipopolysaccharides of the outer membrane of P. aeruginosa and to destabilize membranes. The study of the mechanism of action of the most active derivatives prepared suggested a similar mode of action.

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

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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.

Six series of cunitic amphiphiles based on benzene sulfonates were synthesized. The molecular characterization was performed by IR and NMR spectroscopy and the purity was determined by elemental analysis and thin layer chromatography. The thermotropic properties of these cunitic sulfonate amphiphiles were subsequently investigated by means of a combination of DSC, polarized microscopy and X-ray scattering. Most of the synthesized sulfonates were found to exhibit hexagonal columnar mesophases, some of them exhibited a complex polymorphism. The polymorphism depended upon variation of the molecular structure. The Six series of cunitic amphiphiles based on benzene sulfonates were synthesized. The molecular characterization was performed by IR and NMR spectroscopy and the purity was determined by elemental analysis and thin layer chromatography. The thermotropic properties of these cunitic sulfonate amphiphiles were subsequently investigated by means of a combination of DSC, polarized microscopy and X-ray scattering. Most of the synthesized sulfonates were found to exhibit hexagonal columnar mesophases, some of them exhibited a complex polymorphism. The polymorphism depended upon variation of the molecular structure. The phase behavior was determined by the nature of headgroup cation Mn+ (n=1, 2), and for the same Mn+ by the carbon number at the hydrophobic tail and by temperature as well. The lyotropic properties of these cunitic sulfonate amphiphiles were also studied by investigating their gelation behavior and gelling capability. A number of the amphiphiles were found to be favorable organogelators that gel various organic solvents of either high or low polarity upon self-aggregation driven by the Coulomb interaction. The morphological results by means of SEM and TEM demonstrate that the organogelators are able to form fibrous network microstructures by self-organization and self-aggregation. The cylindrical aggregates with sulfonated headgroup in the center as well embody the potential to construct ion-selective transport membranes. The cunitic amphiphiles containing polar sulfonate units at their focal point and polymerizable olefin group on their periphery were exploited to prepare functional membranes that contain ion-active transport channels. The ion-selectivity of the formed membranes was investigated by means of ion transport experiments with LiCl, NaCl, KCl solutions of different concentration. By comparison of the ion transport rates across the membranes the ionic permselectivity was demonstrated.

Observing and studying how life forms behave, i.e., their movement, adaptability, and so on, have enabled human beings to develop new technologies or optimize existing ones. One of the more noticeable phenomena in Nature is morphogenesis. Morphogenetic processes exist in different stages of biological development, from cellular division to tissue and organ formation. It is easy to observe shape development during mophogenesis due to emerging imaging techniques. However, it is hard to understand this process due to its complex organization, and the morphogenetic responses can be induced by a variety of chemicals or mechanical stresses and are subject to the stochastic fluctuation of the environment, making it even more difficult to acquire a fundamental understanding. It is natural to think of mimicking the complex biological process using simplified synthetic approaches. Endowing synthetic protocells with the ability to control their shape and motion autonomously would enable them to perform more like a biological system, but with less complexity. Creating synthetic morphogenesis would potentially further our understanding in biological morphogenetic processes. Moreover, we can borrow some of the morphogenetic functions in engineered materials to achieve a variety of applications, including artificial tissues, self-healing materials, controlled drug delivery, manipulation of soft robots, among others. In this dissertation, we used a synthetic cellular system controlled by a reaction regulated network that imitates the genetic control as a minimal model to understand the potential mechanisms of morphogenesis. Different simulation methods were used depending on the length scales of interest in each problem. We studied the following aspects of the minimal model system: (a) catalytic reaction induced local morphological control of amphiphilic diblock copolymer vesicles; (b) non-equilibrium control over the self-assembled structures of amphiphilic surfactants; and (c) diffusiophoretic/self-diffusiophoretic motion of colloidal particles in response to the concentration gradient field. The results obtained in this thesis work will provide a valuable road-map to guide future experiments.

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