Hydrogen sulfide (H2S) is an endogenously produced signaling gas involved in numerous cellular functions. At the appropriate concentration, exogenous administration of this gasotransmitter regulates vasodilation, promotes angiogenesis of endothelial cells, and generally exhibits beneficial effects as an anti-inflammatory and antioperoxidative agent. H2S is also capable of acting as a gaseous chemotherapeutic agent. Therefore, the therapeutic potential of exogenous delivery of H2S is vast. The delivery of H2S is complicated by its gaseous nature. Under physiologically relevant conditions, H2S is rapidly depleted from solution by oxidation and/or degassing. Therefore, direct exogenous delivery is difficult. To date, most studies have employed Na2S as a convenient H2S source. However, the rapid surge in H2S concentration upon Na2S dissolution followed by its rapid decline poorly mimics the sustained production of low concentrations of H2S that occurs in biological systems. We synthesized a library of S-aroylthiooximes (SATOs)—H2S-releasing compounds that more aptly mimic in vivo H2S concentrations. SATOs are synthesized via reaction of a S-aroylthiohydroxylamine and an aldehyde or ketone. SATOs release H2S in response to a thiol functionality. H2S release from SATOs could be controlled, with H2S release half-lives on the order of minutes to hours. SATO chemistry was utilized to prepare H2S-releasing polymers. Copolymers prepared using RAFT polymerization could be functionalized with SATOs with conversions > 99%, and these polymers released H2S on a similar timescale to our small molecule donors, confirming the viability of SATO formation as a post-polymerization modification strategy. SATO-functionalized polymer amphiphiles were prepared that self-assembled into micelles or vesicles based on their composition. H2S was released from these polymer assemblies more slowly than from the small molecules and statistical polymers. These H2S-releasing micelles were employed in in vitro cytotoxicity studies. H2S released from the micelles was found to be selectively toxic to human colon cancer cells compared with healthy fibroblasts. These polymeric micelle donors outperformed existing H2S donors in terms of their toxicity towards cancer cells. The observed enhanced toxicity was suspected to arise from the slow and sustained release of H2S from the micelles. / Ph. D.

Yes / We report the effect of low-energy thermal neutron irradiation on the antiproliferative activities of a highly hydrophobic organometallic arene ruthenium dithiolatoecarborane complex [Ru(p-cymene) (1,2- dicarba-closo-dodecarborane-1,2-dithiolato)] (1), and of its formulation in Pluronic® triblock copolymer P123 coreeshell micelles (RuMs). Complex 1 was highly active, with and without neutron irradiation, towards human ovarian cancer cells (A2780; IC50 0.14 mM and 0.17 mM, respectively) and cisplatinresistant human ovarian cancer cells (A2780cisR; IC50 0.05 and 0.13 mM, respectively). Complex 1 was particularly sensitive to neutron irradiation in A2780cisR cells (2.6 more potent after irradiation compared to non-irradiation). Although less potent, the encapsulated complex 1 as RuMs nanoparticles resulted in higher cellular accumulation (2.5 ), and was sensitive to neutron irradiation in A2780 cells (1.4 more potent upon irradiation compared to non-irradiation). / We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RD14102 to NPEB), the University of Birmingham/EPSRC Follow-on- Fund (Grant No UOBFOF026 to BP), the ERC (Grant No. 247450 to PJS), EPSRC (EP/F034210/1 to PJS).

Tableau d'honneur de la Faculté des études supérieures et postdorales, 2015-2016 / La microfiltration (MF) est un procédé membranaire permettant de séparer les micelles de caséines (CN) des protéines sériques (PS) du lait grâce à des pores ayant un diamètre de 0,1 μm. Le rétentat obtenu est enrichi en CN, tandis que le perméat contient des PS sous forme native. La membrane céramique à gradient de perméabilité (GP) a été développée récemment dans le but de réduire l’encrassement à long terme, ce qui permet des flux de perméation élevés et une meilleure séparation des protéines. À ce jour, les conditions opératoires les plus efficientes pour réaliser la MF du lait n’ont pas été déterminées pour ce type de membrane. L’objectif de cette étude était donc de caractériser l’effet de différentes pressions transmembranaires (PTM), différents facteurs de concentration volumique (FCV) et de la diafiltration (DF) sur l’efficience du procédé. Un bilan de matière a été réalisé à la suite du dosage des solides totaux, ainsi que de l’azote total, non caséique et non protéique. La consommation énergétique du système de MF a également été mesurée in situ. Les résultats obtenus démontrent qu’un FCV de 1,5X permet d’obtenir la meilleure séparation des protéines, tout en ayant un flux de perméation plus élevé et une plus faible consommation énergétique. Lorsque le FCV est plus élevé, les pertes totales de CN dans le perméat et la consommation énergétique deviennent plus importantes, ce qui réduit la rentabilité du procédé. Les étapes de DF réduisent l’efficience du procédé en augmentant la durée de filtration et la quantité de perméat généré de façon considérable, sans permettre d’obtenir une quantité satisfaisante de PS supplémentaires dans le perméat. Les résultats obtenus pourront bénéficier aux transformateurs laitiers lors de la prise de décision quant à la pertinence d’effectuer la MF du lait avec la membrane céramique GP. / Microfiltration (MF) is a membrane process used to separate casein (CN) micelles from serum proteins (SP) of milk using 0.1 μm pore diameter membranes. The resulting retentate is enriched in CN, while the permeate contains native SP. The graded permeability (GP) ceramic membrane has been recently developed to reduce long-term fouling, which improves permeation flux and protein separation. To date, the most efficient operating conditions to achieve MF of milk have not been determined for this type of membrane. The objective of this study was to characterize the effect of different transmembrane pressures (TMP), volumetric concentration factors (VCF) and diafiltration (DF) on the process efficiency. Mass balance measurements were carried out following the determination of total solids, total nitrogen, non-casein nitrogen and non-protein nitrogen. The in situ energy consumption of the MF system was also measured. Results obtained showed that a VCF of 1.5X provided the best separation of proteins, while allowing the highest permeation flux and the lowest energy consumption. When the VCF was higher, the total losses of CN in the permeate increased, as well as energy consumption, which reduces the process profitability. DF steps reduced the process efficiency by increasing the filtration time and the amount of permeate generated, without increasing significantly the transmission of additional SP in the permeate. Results will benefit dairy processors in decision making about the potential of MF of skim milk with GP membrane.

L'écoulement des fluides complexes à l'échelle micrométrique est une problématique qui intéresse notamment la récupération assistée du pétrole. Ici, les fluides sont des solutions de polymères et de tensioactifs capables de s'auto-assembler en micelles géantes. Nous étudions ces écoulements au sein d'outils microfluidiques fabriqués en résine SU-8 selon un protocole développé pendant cette thèse. Nous avons réalisé des expériences de drainage d'huile en milieux poreux et montré que la rhéofluidification et le glissement promeuvent le phénomène de digitation pendant l'invasion. Nos expériences montrent que ces solutions peuvent être élastiquement turbulentes à de faibles nombre de Reynolds. Ces instabilités de vitesse ont des conséquences sur la rhéologie locale du fluide dans un simple canal droit et sont une source de dissipation additionnelle dans des géométries plus complexes. / The flow of complex fluids in confined geometries is an issue of interest notably in the field of oil recovery. In this work, the fluids are polymer solutions of high molecular weight and surfactant solutions enable to form wormlike micelles. We study the flow in microfluidic devices made-up with Su-8 resin following a protocol that has been set during this PhD. We carried out experiences of oil drainage in porous media and show that shear-thinning and slippage are propoting the fingering during the invasion. our experiences also show that these solutions can be turbulent at low reynods numbers. These instabilities have consequences on the local rheology in a simple straight channel and are source of additional dissipation in more complex geometries.

L’étude des fluides complexes présente un grand intérêt de par la richesse des phénomènes que font intervenir leur écoulement. Une étude de rhéologie locale de systèmes de micelles géantes en microcanal droit est effectuée. L’expérience montre que les propriétés du fluide soumis à un fort gradient de contrainte ne peuvent être décrites que par une équation rhéologique comportant des termes non locaux. Nous montrons alors l’influence du système de micelles géantes, du confinement ainsi que de la nature des surfaces du microcanal sur ces effets non locaux. Une étude des phénomènes temporels intervenant dans ces écoulements en microcanaux est alors proposée, ainsi qu’une étude préliminaire concernant les écoulements dans des milieux poreux modèles. / The study of complex fluids flows is of great interest according to the diversity of phenomenon it involves. A study of the local rheology of wormlike micelles flowing in a simple straight microchannel is proposed. Experiments show that the properties of such a fluid undergoing a strong shear stress gradient can only be described by an equation including non local terms. We thereafter show the influence of the wormlike micelles system, of the confinement and of the nature of the microchannel walls on those non local effects. A study of the temporal phenomenon occurring in microfluidic flows of wormlike micelles is then proposed, as well as a preliminary study concerning flows in porous media.

Nanoparticles have important applications in ceramics, metal catalysts, semiconductors etc. They are normally required to be of small size (~ nm) and monodisperse. The aim of the present work is to model the formation of nanoparticles, obtained by precipitation in reverse micellar microreactors. These are dispersions of tiny water drops in a surfactant laden oil medium. Two systems were investigated: (i) Reverse micelles, having nanometer sized spherical water droplets in the micellar core and (ii) Water-in-oil emulsions, having micron-sized aqueous drops. Two modes of precipitation, namely, gas-liquid (g-1) and liquid-liquid (1-1) were studied. In each case, the models could predict the number, average size and size distribution of the particles reported in literature. Two groups have obtained widely divergent number and size of CaCO3 nanoparticles, formed by g-1 precipitation in reverse micelles. These particles are used as a fine suspension in lube-oil additives, where they serve to neutralize acid produced during combustion in engines. Kandori et al. (J. Colloid Interface Sci, 122,1988, 78) obtained particles of about 100 nm size, by passing CO2 through a reverse micellar solution, containing dissolved Ca(OH)2 in the micellar core. Roman et al. (J. Colloid Interface Sci., 144,1991, 324), instead of using lime solution; added micron-sized solid lime particles in the oil and generated the reverse micelles by in situ reaction. This is a commercial process known as overbasing. It led to a higher amount of lime in the micelles as well as unreacted lime particles in oil, at the beginning of the experiment Upon passing CO2, they got particles of only 6 nm in size, compared to 100 nm reported by Kandori et al.. Furthermore, while Kandori et al. found that one particle formed from 108 micelles, Roman et al. got one particle out of only ten micelles. We have modelled the two processes in a common framework to explain the reported disparity in particle characteristics. A time scale analysis of CO2 mass transfer, reaction, collision-fusion of micelles, nucleation, and growth of particles was carried out It showed that, in the experiments of Kandori et al., the rate limiting steps are nucleation and fusion. The analysis also indicates that the contents of a particular micelle are well mixed and reaction of lime and incoming CO2 can be treated as instantaneous. In the process of Kandori et al., the amount of lime taken initially being very small, the average number of product molecules in a micelle is well below one. Rapid Brownian coalescence and exchange of micellar contents leads to Poisson distribution of CaCO3(l) molecules formed by reaction. The low occupancy therefore suggests that most of the micelles are empty. Nucleation in a particular micelle is much slow and occurs when it has a critical number of molecules. Thus only very few micelles can nucleate. Comparison of nucleation and growth time scales - both intrinsic growth in a micelle and growth during fusion of nucleated and non-nucleated micelles - show that growth is much faster than both nucleation and collision. Hence a micelle can have only one nucleus, with subsequent growth during collisions. A population balance equation (PBE) is written involving the above steps. Solution of the moments of the distribution yields the number of CaCO3 particles, its size, coefficient of variance (COV) etc. The model not only predicts the ratio of number of micelles to particles, obtained experimentally as 108, but also captures the maxima in this quantity with increasing micellar size. The increase in average particle size with micellar size is also predicted well. The process of of Roman et ai, in addition, involves the time scale of solubilization of solid lime into micelles. Its comparison with other time scales demarcates their experiments into two distinct phases. Phase I consists of reaction of lime initially present in micelles. Time scale analysis also suggests that, as the lime content in the micelles is large, a high degree of supersaturation is rapidly generated. This results in a burst of nuclei. The other conclusions, like, well-mixed micelle, Poisson distribution of CaCO3(l) molecules, instantaneous growth and mono-nucleated micelles are found to hold good. Once the pre-existing lime is finished, relative time scales indicate that, further precipitation is controlled entirely by fresh solubilization of lime. This marks the beginning of phase II. However, solubilization being the slowest step, CaCO3(l) in micelles never builds up for any further nucleation. Phase II thus consists of pure growth of the particles formed in phase I. On developing more general PBEs and with solution of resulting moment equations - written separately for the two phases - the experimental data on number of particles and temporal evolution to the final particle size of 6 nm could be predicted very well. The model also captures the qualitative trend in COV of particle radius with time. Thus within the same framework we could successfully predict both the results, differing by seven orders of magnitude. The above analysis indicates that relative rates of nucleation, fusion-growth and mass transfer of gas controls the carbonation process. We further simplify the process and obtain an analytical solution in the limit of instantaneous mass transfer. The solution gives close first estimates for both the experiments and also indicates the smallest panicle size that could be obtained for a given experimental condition. In contrast to g-1 mode, precipitation in 1-1 mode - using two reverse micellar solutions having two reactants- occurs only on coalescence of two micelles. To obviate the solution of multivariate PBEs, we have developed a general Monte Carlo (MC) simulation scheme for nanoparticle formation, using the interval of quiescence technique (IQ). Starting with a fixed number of micelles, we conduct each coalescence-redispersion and nucleation events in this population, in the ratio of their relative frequencies. Our simulation code is much more general and realistic than the scheme of Li and Park (Langmuir, 15,1999, 952). Poisson distribution with realistic micellar occupancies of reactants, binomial redispersion of solutes after fission, a nucleation rate with critical number of molecules and Brownian collision-fusion rates were used. These considerations are based on our earlier findings in g-1 precipitation and those known in the literature too. The simulation of Li and Park then becomes a special case of our code. Our simulation code was then used to predict experimental data on two systems. The results of Lianos and Thomas (Chem. Phys. Lett. 125, 1986, 299 and /. Colloid Interface 5c/., 117, 1987, 505), on number of molecules per CdS particle, as a function of micelle size and reactant concentrations have been predicted very well. For the Fe(OH)3 nanoparticles, our simulation provides a better prediction of the experimental particle size range, than that of Li and Park. Finally, 1-1 precipitation on mixing two emulsions, having respectively the two reactants, has been simulated. Here, large reactant amount leads to multiple nucleation in a single drop and renders growth rate to be finite. This requires solving a PBE for particle population in each drop. Moreover, emulsions have a drop size distribution due to independent coalescence and breakage. The IQ technique was used for handling these events. Thus a composite model of PBE and MC for a drop population was developed. Simulation of particle size distribution in MgCO3 precipitation shows that nearly monodisperse nanoparticles can be produced in emulsions. Furthermore, average particle size can be controlled by changing reactant concentration in a drop. The findings of the thesis have provided new issues to be addressed in modelling nanoparticle formation. It points out the importance of finding models for coalescence efficiency and critical nuclear size in micelles. Extension of our model and simulation to precipitation in other organized surfactant assemblies can be done by starting from appropriate time scale analysis.

La dualité hydrophobe/hydrophile des molécules amphiphiles est à l’origine de leur autoassemblage en solution, sous forme de nombreuses structures supramoléculaires, telles que les micelles. Ce travail de thèse présente la formation, la caractérisation et l’étude de nouvelles micelles diacétylèniques photopolymérisables. Une première partie décrit ainsi lasynthèse de nouvelles micelles cationiques et l’étude de leur utilisation en tant qu’agent de transfert de gènes. Dans une seconde partie, nos travaux présentent l’étude de micelles polydiacétylèniques, porteuses de têtes polaires octaéthylèneglycol, comme potentiel système de délivrance de médicament. Les propriétés d’encapsulation de ces micelles ont été évaluées en présence d’un dérivé fullerène fluorescent. Puis, l’incorporation d’une sonde membranaire dans leur couronne lipophile a permis de réaliser une étude de leurs propriétés de délivrance in vitro. Une étude préliminaire de leur biodistribution in vivo a également été réalisée par tomographie à émission monophotonique grâce à la chélation d’un isotoperadioactif sur la surface des micelles. Enfin une dernière partie présente l’analyse de deux nouveaux auto-assemblages tubulaires obtenus au cours de nos travaux. / The hydrophobic/hydrophilic duality of amphiphilic molecules is at the origin of their selfassembly in solution, into many supramolecular structures such as micelles. This thesis presents the formation, characterization and study of new photopolymerizable diacetylenic micelles. The first part describes the synthesis of new cationic micelles and the study of theiruse as gene transfer agent. In the second part, our work presents the study of polydiacetylene micelles, bearing polar heads octaétylèneglycol as potential drug delivery system. The encapsulation properties of these micelles were first evaluated in the presence of a fluorescent fullerene derivative. Then, the incorporation of a membrane probe in their lipophilic shell has allowed a study of their in vitro delivery properties. Finally a study of their in vivo biodistribution was also carried out by single photon emission tomography through the chelation of a radioactive isotope on micelle surface. Finally the last part presents theanalysis of two new tubularself-assemblies, obtained during our work.

Notre équipe a récemment développé une méthode polyvalente permettant de préparer des dérivés complexes de C60 hexa-adduits fonctionnalisés. Cette méthodologie permet d’obtenir des produits aux caractéristiques originales. Le C60 central agit comme un support central peu réactif, autour duquel des fonctionnalités sont réparties dans un espace octaédrique parfaitement défini. La première partie de ce travail de thèse a consisté à exploiter cette méthodologie pour créer des C60 hexa-adduits polycationiques aux propriétés de transfection remarquables. Dans un second temps, les dendrons polyamines synthétisés ont été mis à profit pour créer des structures supramoléculaires de C60 hexa-adduits, sous forme micellaire. Par la suite, l’étude de ces assemblages a orienté nos investigations vers l’élaboration de dérivés de C60 hexa-adduits mannosylés multivalents résultant d’un assemblage supramoléculaire, dont leurs possibles applications biologiques sont actuellement à l’étude. En parallèle une synthèse covalente a permis d’obtenir un «équivalent dendritique» de C60 hexa-adduit multimannosylé. Partant du constat que notre méthodologie est efficace principalement pour des dérivés de C60 hexa-adduits qui ont une régio-sélectivité particulière, la dernière partie a été consacrée au développement de nouvelles voies de synthèses qui pourront permettre de créer des dérivés de C60 avec un contrôle régio-sélectif original. / Our team has recently built a polyvalent method that gives complex functionalized C60 hexa-adducts. This methodology permits to obtain products with original features. C60 acts as an inert scaffold, around which functionnalities are distributed in a well-defined octahedral space. The first part of this thesis describes exploitation of this methodology to create polycationics C60 hexa-adducts, which have shown remarkable gene delivery capabilities. Next, the synthetized polyamine dendrons were used to build supramolecular structure of C60 hexa-adducts, as micellar forms. The study of these self-assembled structures has guided us to design micelles of mannosylated C60 hexa-adducts, which biological applications are under investigation. In parallel a covalent synthesis has furnished a dendrimers-like multimannosylated C60 hexa-adduct. Based on the observation that our methodology to create C60 hexa-adduct is efficient only for a specific regio-selectivity, the last part of this thesis was devoted to the development of new synthetic routes to obtain C60 derivates with an original regio-selective control.

Parmi les méthodes de Récupération Améliorée du Pétrole (RAP) il en existe une, dite chimique, qui fait appel à des fluides complexes (polymères, gels, tensioactifs) qui permet de modifier la viscosité et/ou la tension interfaciale Les solutions de polymères utilisées actuellement présentent l’inconvénient d’être sensibles de manière irréversible aux taux de cisaillement élevés observés au voisinage des puits. Une alternative à ces solutions de polymères pourrait nous être donnée par l’utilisation de micelles géantes. Il s’agit d’auto-assemblages de molécules amphiphiles dont le comportement est similaire à celui des polymères avec l’avantage d’une meilleure stabilité aux cisaillements élevés (capacité des micelles à se reformer après cisaillement).L’objectif de ce travail est d’étudier l’écoulement d’une solution de micelles géantes en milieu poreux, dans le but de déterminer son éventuelle utilité dans le RAP. Il s’agit d’une caractérisation en milieu poreux à l’échelle du laboratoire, utilisant des milieux poreux naturels, de façon à se placer dans un cadre d’étude le plus réaliste possible. Cette étude se divise en trois parties :- Une étude rhéologique de la solution de micelles géantes- Une étude monophasique de l’injection de la solution dans un milieu poreux naturel- Une étude diphasique du déplacement d’huile par la solution de micelles.Les résultats de cette étude seront comparés avec des expériences références utilisant des techniques classiques de récupération telles que l’ASP et l’injection de polymères / Among all the Enhanced Oil Recovery (EOR) methods used to improve oil recovery, chemical methods require the use of complex fluids like polymers or surfactant solutions. Those fluids present particular chemical and mechanical properties allowing to modify viscosity and/or interfacial tension to increase oil recovery. However, polymer solutions show a high sensitivity to shear rates existing close to wells and may lose their mechanical properties when they are injected in a porous media. An alternative method could be to use self arrangement of surfactant molecules (wormlike micelles) to displace oil in porous media. These systems show not only a similar behaviour as polymers but also a low sensibility to temperature and shear rates.The goal of this experimental work is to study the flow of wormlike micelle solutions innatural porous media in order to determine its ability to flow and displace oil in place. Itconsists in a characterization at laboratoty scale. We will use natural porous media in orderto be close to a realistic situation. This study is divided in three parts:- A rheological characterization of the micellar system- A monophasic injection within the porous medium- A diphasic _ow study of oil displacementThe results of this work are compared to standard reference experiments using classicaltechniques such as ASP or polymer injection.

Le développement de nanomédicaments pour l'imagerie et le traitement du cancer a suscité un intérêt croissant à cause de leur grand potentiel. En particulier les vecteurs à base de polymères et de micelles polymères sont très intéressants, car ils peuvent être conçus avec des fonctionnalités adaptées aux besoins.Nous avons utilisé des copolymères amphiphiles triséquencés pour développer de nouveaux nanovecteurs moléculaires (unimères) et supramoléculaires (micelles stabilisées par photo- réticulation). Nous les avons fonctionnalisés avec un marqueur fluorescent ou radioactif pour permettre leur imagerie in vitro et in vivo. Les interactions in vitro et in vivo ont été étudiées pour comprendre l'influence des propriétés des copolymères sur les interactions biologiques.Cette thèse présente le développement complet de nanovecteurs depuis les premières étapes de la caractérisation physico-chimique fondamentale jusqu'à l'évaluation de leur intérêt pour différentes applications cliniques. / The interest in developing new nanocarriers for imaging and therapy of cancer has been growing due to their high potential. Particularly nanocarriers based on polymers and polymeric micelles are very interesting because they can be tailor-made with certain functionalities to meet our needs.We have used amphiphilic triblock copolymers to develop new molecular (unimers) and supramolecular (micelles stabilized by photo cross-linking) nanocarriers. The carriers were then functionalized with fluorescent or radioactive markers to enable their in vitro and in vivo imaging. The in vitro and in vivo interactions were then studied to understand the influence of the copolymers properties on the biological interactions.This thesis presents the complete development of the nanocarriers from the early stages of fundamental physicochemical characterization up to the evaluation of their interest for different clinical applications