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International audience; Block copolymers synthesized via Atom Transfer Radical Polymerization from alkyl acrylate and t-butyl acrylate and the subsequent hydrolysis of the t-butyl acrylate to acrylic acid were systematically varied with respect to their hydrophobic part by the variation in the alkyl chain length and the degree of polymerisation in this block. Depending on the architecture of the hydrophobic part, they had a more or less pronounced tendency to form copolymer micelles in an aqueous solution. They were employed for the preparation of IPECs by mixing the copolymer aggregates with the polycations polydiallyldimethylammonium chloride (PDADMAC) or q-chit. The IPEC structure as a function of the composition was investigated by Static Light and Small Angle Neutron Scattering. For weakly-associated block copolymers (short alkyl chain), complexation with polycation led to the formation of globular complexes, while already existing micelles (long alkyl chain) grew further in mass. In general, aggregates became larger upon the addition of further polycation, but this growth was much more pronounced for PDADMAC compared to q-chit, thereby leading to the formation of clusters of aggregates. Accordingly, the structure of such IPECs with a hydrophobic block depended largely on the type of complexing polyelectrolyte, which allowed for controlling the structural organisation via the molecular architecture of the two oppositely charged polyelectrolytes.

Over the past decade, the polymerization-induced self-assembly (PISA) has become an efficient tool for the preparation of block-copolymer nanoparticles at high solid contents, in both organic solvents and water. Nonetheless, most of the studied systems are currently based on simple AB diblock copolymers (where A = solvophilic, stabilizer block and B = solvophobic block). Another interesting class of block copolymers are associative BAB triblocks. To the best of our knowledge, very few studies report their synthesis by PISA and the polymerizations are performed in mixtures of alcohol and water. In this work, for the first time, a straightforward strategy to synthesize, in pure water, BAB triblock copolymers through the use of reversible deactivation radical polymerization is developed and studied in details. To this end, an hydrophilic, bifunctional macroRAFT agent of poly(N,N-dimethylacrylamide) with a central benzoic acid group was used in the aqueous dispersion polymerization of diacetone acrylamide. Various morphologies (spheres, fibers and vesicles) could be obtained with good polymerization controls. Moreover, we showed that the particle morphology and colloidal stability strongly depend on the degree of ionization of the central charge in the stabilizer loop. Then, the mechanism of formation of these triblock copolymers during PISA was investigated. Finally, we showed the possibility to form dynamic networks of BAB copolymers – using a one-pot process entirely in water – leading to the formation of thermoresponsive copolymer networks with tunable viscosity.; Depuis une dizaine d’années, l’auto-assemblage induit par polymérisation (PISA) s’est révélé être un outil efficace pour la préparation de nanoparticules à base de copolymères amphiphiles à des taux de solide élevés, aussi bien dans des solvants organiques que dans l’eau. Jusqu’à présent, la plupart des systèmes étudiés concernaient les copolymères diblocs AB (dans lesquels A = bloc solvophile stabilisant, et B = bloc solvophobe). Un autre type de copolymères à blocs intéressant est le tribloc associatif BAB. Peu d’études décrivent leur synthèse par PISA et les polymérisations sont réalisées dans des mélanges alcool/eau. Dans ce travail de thèse, et pour la première fois, la synthèse par voie radicalaire contrôlée de copolymères triblocs BAB par PISA a été réalisée dans l’eau pure et une étude approfondie du système a été menée. Un macro-agent RAFT hydrophile symétrique à base de poly(acrylamide de N,N-diméthyle) possédant une unité acide benzoïque au centre, et le diacétone acrylamide (blocs B) ont été sélectionnés pour étudier ce système. Des particules de différentes morphologies (sphères, fibres et vésicules) ont pu être obtenues avec de bons contrôles des polymérisations. Nous avons montré que le degré d’ionisation de l’unité centrale acide benzoïque du bloc stabilisant jouait un rôle crucial dans la stabilité du système et la morphologie obtenue. Le mécanisme de formation de ces copolymères triblocs au cours de la PISA a également été étudié. Enfin, nous avons montré qu’il était possible de former des réseaux dynamiques de copolymères BAB – via un procédé one-pot entièrement dans l’eau – menant à la formation de systèmes thermosensibles avec une viscosité modulable.

International audience; It is reported that low concentration of amphiphilic triblock copolymers of pMeOx‐b‐pTHF‐b‐pMeOx structure (TBCPs) improves gene expression in skeletal muscle upon intramuscular co‐injection with plasmid DNA. Physicochemical studies carried out to understand the involved mechanism show that a phase transition of TBCPs under their unimer state is induced when the temperature is elevated from 25 to 37 °C, the body temperature. Several lines of evidences suggest that TBCP insertion in a lipid bilayer causes enough lipid bilayer destabilization and even pore formation, a phenomenon heightened during the phase transition of TBCPs. Interestingly, this property allows DNA translocation across the lipid bilayer model. Overall, the results indicate that TBCPs exhibiting a phase transition at the body temperature is promising to favor in vivo pDNA translocation in skeletal muscle cells for gene therapy applications.

Amphiphilic copolymers based on renewable resources were involved as emulsifiers to prepare transparent terpene-in-water nanoemulsions. The amphiphilic copolymers are composed of hydrophobically modified poly(acrylic acid) (HMPAA) grafted with different fractions of hydrophobic bio-based tetrahydrogeraniol (THG) side chains. The well-defined PAA were synthesized by reversible addition fragmentation transfer (RAFT) polymerization in order to tune the number-average molar mass of the initial PAA. The self-assembly in aqueous solution of the HMPAA copolymers was investigated through the measurement of their critical aggregation concentration by viscometry, tensiometry, dynamic light scattering and the determination of their aggregation number by static light scattering. Series of oil-in-water nanoemulsions using dihydromyrcenol (DHM) terpene as dispersed phase and PAA-THG as emulsifier were prepared with different PAA-THG/DHM weight ratios and DHM/water weight ratios. The level of transparency of the emulsions was monitored though the transmittance value measured at 600 nm and the measurements of the hydrodynamic diameter of droplets by dynamic light scattering. This study highlights that the structure of the PAAx-THGy is a key parameter to prepare terpene-in-water nanoemulsions with the required high level of transparency. The optimised structure of the emulsifier consists in a moderate degree of polymerization of PAA backbone ( DP ‾ n ,PAA ≤ 180 ) along with an intermediate average degree of substitution in hydrophobic THG side chains (13 ≤ DS ‾ ≤ 32).

The aim of this work was to control the rheological properties of aqueous solutions of amphiphilic copolymers. In water, these copolymers self-assemble and part of their properties can be controlled by their dynamic of exchange. As previously reported, the exchange dynamics can be controlled by the pH and the acrylic acid (AA) content for BAB triblock copolymers (THx) consisting of a poly(acrylic acid) (PAA) A block and two statistical B blocks (MHx) of n-butyl acryle (nBA) and AA.First, the study of the self-association of B blocks (MHx) alone showed a strong relationship between their aggregation and the one of BA diblocks (DHx). This aggregation was mainly controlled by the amount of charges within the B blocks.Then, mixtures of BAB triblocks (THx) with different contents of AA units, x, formed hybrid networks the rheological properties of which were controlled by formulation rather than chemistry.Similar rheological properties were obtained using graft copolymers consisting of a PAA hydrophilic backbone and B grafts. Their rheological properties were mainly controlled by the chemical structure of the B grafts and by the grafting density. Such graft copolymers should be easier to produce at an industrial scale than triblock copolymers.To finish, the strategy consisting of incorporating hydrophilic units inside the hydrophobic blocks of amphiphilic copolymers to control their exchange dynamics was successfully applied to copolymers made of dimethylaminoethyl methacraylate and n-butyl methacrylate. Their rheological properties were controlled by the pH on a different pH-range than the AA based polymers, and, to some extent, by the temperature., L’objectif de ce travail était de contrôler les propriétés rhéologiques de solutions aqueuses de copolymères amphiphiles. Dans l’eau, ces copolymères s’auto-associent et leurs propriétés peuvent être contrôlées en partie par leur dynamique d’échange. Il avait précédemment était montré que cette dynamique pouvait être contrôlée par le pH et la quantité d’unités acide acrylique dans des triblocs BAB (THx) où le bloc A est du poly(acide acrylique) (PAA) et les blocs B sont des copolymères statistiques (MHx) d’acrylate de n-butyle (nBA) et d’acide acrylique (AA). Tout d’abord, l’étude de l’auto-association en solution des blocs B seuls (MHx) a montré un lien fort entre leur agrégation et celle des diblocs de type BA (DHx). Cette agrégation est contrôlée par la quantité de charge des blocs B. Par la suite, des mélanges de triblocs (BAB) THx contenant différentes proportions (x) d’unités AA ont permis la formation de réseaux hybrides dont les propriétés rhéologiques sont maîtrisées par formulation plutôt que via la chimie. Des propriétés rhéologiques similaires aux triblocs BAB (THx) ont été obtenues avec des copolymères greffés possédant un squelette hydrophile PAA et des greffons B. Leurs propriétés rhéologiques sont principalement contrôlées par la structure chimique des blocs B, mais aussi par le taux de greffage. Ces copolymères greffés devraient être plus simples à obtenir à l’échelle industrielle que des triblocs. Pour finir, l’approche consistant à incorporer des unités hydrophiles dans les blocs hydrophobes de copolymères amphiphiles pour en contrôler la dynamique d’échange a été appliquée avec succès à des copolymères à base de méthacrylate de diméthylaminoéthyle et de méthacrylate de n-butyle. Leurs propriétés rhéologiques peuvent être contrôlées à nouveau par le pH, mais dans une gamme différente des polymères à base d’acide acrylique, et aussi dans une certaine mesure par la température.

International Conference on Bio-Based Materials and Composites (ICBMC 14), Montreal, CANADA, MAY 13-16, 2014; International audience; Atom Transfer Radical Polymerization (ATRP) and Ring-Opening Polymerization (ROP) were combined to synthesize diblock environmental friendly poly(E-caprolactone)-block-poly(methyl ether diethylene glycol methacrylate) (PCL-b-PMEO(2)MA) through a sequential two-step strategy. These PCL-b-PMEO2MA copolymers were produced using 2-hydroxyethyl-2-bromoisobutyrate as bifunctional initiator. In the first step, E-caprolactone was initiated by the hydroxyl group of this particular initiator. Tin octoate, zinc triflate and bismuth triflate were tested as non-toxic catalysts to obtain alpha-bromide-omega-hydroxy bifunctional PCL macroinitiator. Secondly, the controlled ATRP of MEO(2)MA was tuned from the same bifunctional initiator. Finally, PCL-b-PMEO(2)MA were produced by carrying out ATRP of MEO(2)MA from PCL macroinitiator. Preliminary data on self-assembly of such thermo-sensitive PCL-b-PMEO(2)MA in aqueous phase are given.

Polyethylene-b-Polyethylene amphiphilic diblock copolymers are composed of one hydrophilic and one hydrophobic block, both able to crystallize. The aim of this thesis is to better understand the behaviour of PE-b-PEG copolymers at solid and liquid interfaces, via the study of the structure and the organization of adsorbed layers. The crystallinity of bulk PE-b-PEG copolymers with different composition was characterized, revealing that the ratio PEG/PE and the blocks length impact the crystallinity degree, the morphology and the growth of crystalline structures. Thin films characterization by PM-IRRAS spectrocopy and AFM allowed to determine quantitatively the macromolecular chains orientation on hydrophobic and hydrophilic substrates. PE-b-PEG copolymers adsorption at the water/air and water/hexane interfaces was studied thanks to the pendant drop and the oscillating drop techniques. These results, supported by particle size analysis, revealed that copolymers can organize as nanometric spherical structures. The influence of the copolymer composition and the type of interfaces on the organization then lead to the elaboration of adsorption models of PE and PEG blocks at solid and liquid interfaces.; Les copolymères à blocs amphiphiles Polyéthylène-b-Polyéthylène glycol comportent un bloc hydrophile et un bloc hydrophobe, tous deux cristallisables. L’intérêt de cette thèse est de mieux comprendre le comportement de ces copolymères aux interfaces solides et liquides, via l’étude de la structure et de l’organisation des couches adsorbées. Des copolymères PE-b-PEG de différentes compositions ont été étudiés à l’état massique, mettant en évidence que le ratio PEG/PE ainsi que la longueur des blocs jouent un rôle significatif sur le taux de cristallinité, la morphologie et la croissance des structures cristallines. La caractérisation en films minces par spectroscopie PM-IRRAS et AFM a permis de déterminer quantitativement l’orientation des chaînes macromoléculaires de chaque bloc sur des substrats modèles hydrophiles et hydrophobes. L’adsorption des copolymères PE-b-PEG a par ailleurs été étudiée aux interfaces eau/air et eau/hexane par les méthodes de la goutte pendante et de la goutte oscillante. Les résultats, appuyés par des mesures de tailles de particules, ont montré que les copolymères sont capables de former des structures sphériques organisées à l’échelle nanométrique. L’influence de la composition du copolymère et de la nature des interfaces sur l’organisation des copolymères a ainsi permis d’élaborer des modèles d’adsorption des blocs aux interfaces.

The development of new biodegradable diblock copolymers poly([epsilon]-caprolactone)-b-poly[oligo(ethylene glycol)methyl ether methacrylate], which could be used in environmental friendly applications such as treatment of contaminated water has been the main goal of this work. For the preparation these copolymers, the ring-opening polymerization (ROP) and the Atom Transfer Radical Polymerization (ATRP) were combined by using a bifunctional initiator. The two-step route for the synthesis of these copolymers was using either ATRP or ROP as first step and the other polymerization secondly. Each polymerization was studied carefully in order to control the macromolecular parameters of the copolymers. On the one hand, the ATRP of methacrylates bearing oligo(ethylene glycol) was carried out by using poly([epsilon]-caprolactone) with bromide end-group as macroinitiator. On the other hand, the ring opening polymerization of [epsilon]-caprolactone was initiated by the hydroxyl end-group of the poly[oligo(ethylene glycol)methyl ether methacrylate], using tin octoate, tin tetrakis(phenylethynyl) or bismuth triflate as catalysts. The Low Critical Solution Temperature (LCST) of these amphiphilic diblock copolymers in aqueous medium have been determined by UV-visible spectroscopy. Their micellar behaviors were also studied by measuring size by HPPS, Les travaux présentés dans ce manuscrit ont porté sur l'élaboration de nouveaux copolymères dibloc amphiphiles (poly([epsilon]-caprolactone)-b-poly(méthacrylate d'oligo(éthylène glycol) méthyl éther) biodégradables, thermostimulables et susceptibles d'être employés dans des applications respectueuses de l'environnement comme le traitement des eaux contaminées. La particularité de ces copolymères provient d'une part de la différence de solubilité des deux blocs et d'autre part de l'association d'un bloc hydrophobe biodégradable à un bloc thermostimulable hydrophile. Les propriétés de ces copolymères en milieu aqueux ont ainsi été évaluées en fonction de la température. Ces composés ont été obtenus par la combinaison de deux techniques de polymérisation contrôlée en utilisant un amorceur difonctionnel. Pour cela, deux stratégies ont été testées : i) la polymérisation par ouverture de cycle (POC) de l'[epsilon]-caprolactone à partir d'un macro-amorceur de poly(méthacrylate d'oligo(éthylène glycol) méthyl éther) à terminaison OH après avoir mis au point les conditions expérimentales de la POC en comparant plusieurs catalyseurs. ii) par polymérisation radicalaire par transfert d'atome (ATRP) du méthacrylate d'oligo(éthylène glycol) amorcée à partir d'une poly([epsilon]-caprolactone) à extrémité bromée. Les températures critiques inférieures de solubilité (LCST) de ces copolymères ont été déterminées par UV visible. Leurs comportements micellaires ont été étudiés par mesures HPPS

The development of new biodegradable diblock copolymers poly([epsilon]-caprolactone)-b-poly[oligo(ethylene glycol)methyl ether methacrylate], which could be used in environmental friendly applications such as treatment of contaminated water has been the main goal of this work. For the preparation these copolymers, the ring-opening polymerization (ROP) and the Atom Transfer Radical Polymerization (ATRP) were combined by using a bifunctional initiator. The two-step route for the synthesis of these copolymers was using either ATRP or ROP as first step and the other polymerization secondly. Each polymerization was studied carefully in order to control the macromolecular parameters of the copolymers. On the one hand, the ATRP of methacrylates bearing oligo(ethylene glycol) was carried out by using poly([epsilon]-caprolactone) with bromide end-group as macroinitiator. On the other hand, the ring opening polymerization of [epsilon]-caprolactone was initiated by the hydroxyl end-group of the poly[oligo(ethylene glycol)methyl ether methacrylate], using tin octoate, tin tetrakis(phenylethynyl) or bismuth triflate as catalysts. The Low Critical Solution Temperature (LCST) of these amphiphilic diblock copolymers in aqueous medium have been determined by UV-visible spectroscopy. Their micellar behaviors were also studied by measuring size by HPPS; Les travaux présentés dans ce manuscrit ont porté sur l'élaboration de nouveaux copolymères dibloc amphiphiles (poly([epsilon]-caprolactone)-b-poly(méthacrylate d'oligo(éthylène glycol) méthyl éther) biodégradables, thermostimulables et susceptibles d'être employés dans des applications respectueuses de l'environnement comme le traitement des eaux contaminées. La particularité de ces copolymères provient d'une part de la différence de solubilité des deux blocs et d'autre part de l'association d'un bloc hydrophobe biodégradable à un bloc thermostimulable hydrophile. Les propriétés de ces copolymères en milieu aqueux ont ainsi été évaluées en fonction de la température. Ces composés ont été obtenus par la combinaison de deux techniques de polymérisation contrôlée en utilisant un amorceur difonctionnel. Pour cela, deux stratégies ont été testées : i) la polymérisation par ouverture de cycle (POC) de l'[epsilon]-caprolactone à partir d'un macro-amorceur de poly(méthacrylate d'oligo(éthylène glycol) méthyl éther) à terminaison OH après avoir mis au point les conditions expérimentales de la POC en comparant plusieurs catalyseurs. ii) par polymérisation radicalaire par transfert d'atome (ATRP) du méthacrylate d'oligo(éthylène glycol) amorcée à partir d'une poly([epsilon]-caprolactone) à extrémité bromée. Les températures critiques inférieures de solubilité (LCST) de ces copolymères ont été déterminées par UV visible. Leurs comportements micellaires ont été étudiés par mesures HPPS

International audience; Drugs used for chemotherapy normally carry out adverse, undesired effects. Nanotechnology brings about new horizons to tackle cancer disease with a different strategy. One of the most promising approaches is the use of nanocarriers to transport active drugs. These nanocarriers need to have special properties to avoid immune responses and toxicity, and it is critical to study these effects. Nanocarriers may have different nature, but polypeptide-based copolymers have attracted considerable attention for their biocompatibility, controlled and slow biodegradability as well as low toxicity. Little has been done regarding specific nanocarriers toxicity. In this study, we performed a thorough toxicological study of two different block copolymer nanoparticles (NPs); poly(trimethylene carbonate)-block-poly(L-glutamic acid) (PTMC-b-PGA) and poly(ethylene glycol)-block-poly(gamma-benzyl-L-glutamate) (PEG-b-PBLG) with sizes between 113 and 131 nm. Low blood-serum-protein interaction was observed. Moreover, general toxicity assays and other endpoints (apoptosis or necrosis) showed good biocompatibility for both NPs. Reactive oxygen species increased in only two cell lines (HepG2 and TK6) in the presence of PTMC-b-PGA. Cytokine production study showed cytokine induction only in one cell line (A549). We also performed the same assays on human skin organ culture before and after UVB light treatment, with a moderate toxicity after treatment independent of NPs presence or absence. Interleukin 1 induction was also observed due to the combined effect of PEG-b-PBLG and UVB light irradiation. Future in vivo studies for biocompatibility and toxicity will provide more valuable information, but, so far, the findings presented here suggest the possibility of using these two NPs as nanocarriers for nanomedical applications, always taking into account the application procedure and the way in which they are implemented.

We herein report the synthesis of original vinylidene fluoride (VDF)-based amphiphilic block copolymers by RAFT/MADIX polymerization. The controlled polymerization of VDF could be successfully mediated by a xanthate chain transfer agent as evidenced by size exclusion chromatography (SEC), 19F NMR, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis. Copolymers of VDF and perfluoro(methyl vinyl ether) (PMVE) of varying controlled chain lengths were also obtained. Finally, the direct synthesis of main-chain fluorinated amphiphilic block copolymers was performed from hydrophilic poly(N,N-dimethylacrylamide) macro-RAFT agents. It is expected that this finding will open interesting perspectives for the development of new class of polymeric surfactants for the stabilization of emulsions based on water and supercritical carbon dioxide media.

The aim of this study is to synthesize new auto-associative copolymers in order to encapsulate a protein in water. These copolymers have to be biocompatible and bioassimilable for a possible biomedical application. Further more, they have to be amphiphilic. This document aims at describing the synthesis of amphiphilic bloc copolymers. The association of the hydrophobic blocs of the copolymer in water should entail to core-shell particle formation in aqueous emulsion. The hydrophobic part of the copolymers is a polylactide synthesized by ring opening polymerization of the L-lactide. The hydrophilic bloc is a poly(glutamic acid) peptide synthesized in two steps. We first synthesized a poly(benzyl glutamate) bloc by ring opening polymerization of a Leuch's anhydride, the N-carboxyanhydride of benzyl L-glutamate. Then we unprotect the acidic functions of this poly(benzyl glutamate), still hydrophobic polymer to yield the hydrophilic poly(glutamic acid). The architecture of this bloc copolymer is obtained thanks to a difunctionnal initiator that initiates the polymerization of the L-lactide in a first step. This polylactide first bloc has an end-group that can initiate the polymerization of the N-carboxyanhydride of benzyl L-glutamate. So we synthesize in a second step the hydrophobic bloc copolymer and we unprotect the acidic functions of the second bloc to yield the amphiphilic bloc copolymer.; Le sujet de cette étude consiste en la synthèse de nouveaux copolymères, associatifs en milieux aqueux, susceptibles d'encapsuler une protéine. Ces copolymères doivent être biocompatibles et biorésorbables pour une application biomédicale éventuelle et doivent de plus être amphiphiles. Le but de ce manuscrit est ainsi de décrire la synthèse de copolymères à blocs amphiphiles. L'association des blocs hydrophobes du copolymère doit en effet permettre la formation de particules en émulsion aqueuse. La partie hydrophobe des copolymères à blocs est constituée de polylactide synthétisé par polymérisation par ouverture de cycle du L-lactide. Le bloc hydrophile est constitué de poly(acide glutamique), peptide obtenu en deux étapes. On synthétise le poly(glutamate de benzyle) lors de la première étape par polymérisation par ouverture de cycle d'un anhydride de Leuchs, le N-carboxyanhydride de L-glutamate de benzyle. On déprotège ensuite les fonctions acide de ce polymère encore hydrophobe, le poly(glutamate de benzyle), pour obtenir le poly(acide glutamique), hydrophile. L'architecture du copolymère à blocs est obtenue à l'aide d'un amorceur difonctionnel qui amorce dans un premier temps la polymérisation du L-lactide. Le premier bloc de polylactide ainsi synthétisé possède en bout de chaîne un groupement susceptible d'amorcer la polymérisation du N-carboxyanhydride de L-glutamate de benzyle. On synthétise donc dans un deuxième temps le copolymère à blocs hydrophobes et on déprotège les fonctions acide du deuxième bloc pour obtenir le copolymère à blocs amphiphiles.