Actuellement, la mise au point de systèmes de vectorisation d'agents chimio-thérapeutiques performants fait l'objet d'une intense recherche. Les nanoparticules en particulier sont étudiées, car elles permettent de solubiliser des molécules hydrophobes en milieux aqueux tout en diminuant leur toxicité et leur dégradation. Toutefois, le devenir à long terme des nanoparticules est un paramètre important qu'il faut considérer dans la conception de ces nanovecteurs. Pour cette raison, le développement de nanoparticules auto-assemblées constituées de copolymères à bloc entièrement biocompatibles, biodégradables et aux propriétés de libération contrôlée est recommandé. Dans cette perspective, nous avons étudié les propriétés d'auto-organisation de copolymères greffés amphiphiles de type chitooligosaccharide-grafted-polycaprolactone. Le premier chapitre révèle l'utilisation de l'aniline et de son dérivé alcyne comme un outil efficace pour l'amination réductrice de chitooligosaccharides. Dans le second chapitre, différentes familles de polycaprolactone avec des fonctions azide latérales sont décrites. Le troisième chapitre traite du couplage par chimie « click » de chaque bloc ainsi que de la caractérisation physico-chimique des nanoparticules en solution aqueuse. La réticulation de ses particules a permis d'obtenir les nanogels finaux. Pour conclure, des tests d'encapsulation et de libération contrôlée de la Doxorubicine (avec ou sans ajout de glutathion) ont été effectués / Currently, the development of efficient drug delivery systems has a great attention. Nanoparticles are particularly studied for their capacity to solubilise hydrophobic drugs in aqueous media and to decrease their toxicity and degradability. However, long term compatibility has to be considered in the conception of this nanocarrier. For this reasons, the development of self-assembled particles constituted of biocompatible, biodegradable block copolymers is highly recommended. In this perspective, we have studied the self-assembled properties of chitooligosaccharide-grafted-polycaprolactone copolymers. The first chapter reveals aniline catalysis and its alkyne derivative as an efficient way for reductive amination of chitooligosaccharides. The second chapter describes the synthesis of different polycaprolactones with pendant azide groups. The third chapter is dedicated to the grafting of each bloc performed by “click” chemistry as well as the formation and characterisation of nanoparticle conducted in aqueous media. These nanoparticles were cross-linked to form reduction-sensitive final nanogels. At last, entrapment and controlled Doxorubicine release (with or without glutathione) were explored.

Ce travail a consisté en la synthèse de nouveaux copolymères d’acétate de cellulose greffés par du poly(méthyl diéthylène glycol méthacrylate) avec un nombre et une longueur de greffons variables par une méthode de polymérisation radicalaire contrôlée : l’Atom Transfer Radical Polymerization (ATRP). Deux familles de matériaux ont été obtenues ayant mêmes compositions (entre 20 et 50% en masse de greffons) mais des architectures différentes : de nombreux greffons courts ou peu de greffons longs. Ces matériaux ont ensuite été étudiés pour la séparation par pervaporation de mélanges azéotropiques de type aprotique/protique : carbonate de diméthyle/méthanol et éthyl tert-butyl éther/éthanol. Pour la séparation du premier mélange, la réticulation des copolymères s’est avérée nécessaire, conduisant à des matériaux qui restent fragiles sous contrainte et qui présentent des flux élevés au détriment d’une très faible sélectivité. Pour cette séparation, ces matériaux permettent cependant de dépasser la limite thermodynamique imposée par l’azéotrope. Pour le mélange éthyl tert-butyl éther/éthanol, les copolymères montrent d’excellentes performances en extrayant l’éthanol de manière très sélective. L’introduction de greffons permet d’augmenter le flux de pervaporat tout en ne diminuant que faiblement la sélectivité par rapport à l’acétate de cellulose précurseur. L’analyse de la microstructure des copolymères montre que les copolymères avec peu de greffons longs sont beaucoup plus ségrégés que ceux avec de nombreux greffons courts. Les résultats de perméabilité montrent des comportements différents selon l’architecture du copolymère cohérents avec leur microstructure / This work deals with the synthesis of new copolymers of cellulose acetate grafted with poly(methyl diethylene glycol methacrylate) with different numbers and lengths of grafted chains by controlled radical polymerization (Atom Transfer Radical Polymerization ATRP). Two families of materials were obtained with the same compositions (between 20 and 50% in mass of grafted chains) but different architectures : a lot of short chains or a few long chains. These materials were then studied for the pervaporation separation of two aprotic/protic azeotropic mixtures : dimethyl carbonate/methanol and ethyl tert-butyl ether/ethanol. For the separation of the first mixture, copolymers had to be cross-linked but their mechanical withstanding was poor under stress and they showed high fluxes but very low selectivity. Nevertheless, the materials allowed to go over the thermodynamical azeotropic limit. For ethyl tert-butyl ether/ethanol separation, copolymers showed excellent performances with a very selective extraction of ethanol. The presence of grafted chains increased flux along with a slight decrease in selectivity compared with the cellulose acetate precursor. The analysis of the copolymer microstructure showed that copolymers with long grafted chains were more segregated than those with short grafted chains. The results of permeability showed different behaviours according to the copolymer architecture in good agreement with their microstructure

Ce travail a consisté en l’étude par Spectroscopie Diélectrique de la mobilité moléculaire dans trois systèmes nanostructurés et confinés à base de polymère. La dynamique moléculaire des films de copolymères greffés à base d’Acétate de Cellulose (chaîne principale, peu mobile) et de poly(méthyl (diéthylène glycol) méthacrylate) (chaîne greffée, très mobile) a été analysée. Nous avons dans ce cas, observé une augmentation de la mobilité de la chaîne principale et une réduction de la mobilité des greffons. Ensuite nous avons mis en évidence les effets de confinement induits par la phase cristalline sur la phase amorphe des films de Poly(éthylène naphtalène - 2,6 - dicarboxylate) (PEN) cristallisés à différents temps et températures de cristallisation, en fonction de la morphologie des matériaux. Une forte influence de la température de cristallisation sur la dynamique moléculaire du PEN a pu être observée : la mobilité des chaînes dans le cas des échantillons cristallisés aux hautes températures de cristallisation s’est révélée être plus élevée que celle des échantillons cristallisés aux basses températures. Le troisième système choisi consiste en des nanocomposites à base de Polyamide 6 (PA6) et de Montmorillonite (MMT) ont été les derniers matériaux étudiés. Aucune influence significative des feuillets de MMT sur la mobilité des chaînes de PA6 n’a été observée dans ces systèmes. Cependant, les deux relaxations interfaciales observées sont très sensibles au taux de charge. / The aim of this work was to study the molecular dynamics in several polymeric nanostructured and confined systems. Thus, by means of Dielectric Spectroscopy, the molecular mobility of cellulose acetate (rigid chain) grafted poly(methyl (diethylène glycol) methacrylate) (very mobile chains) copolymers were studied. In this case, an increase of the mobility of the main chain and a reduction of the mobility of the grafted moieties have been observed. The confinement effects induced by the presence of the crystalline lamellae on the mobility of the chains belonging to the amorphous region, was also studied as a function of the morphology, in the case of the amorphous films of Poly(ethylene naphtalene - 2,6 - dicarboxylate) (PEN) which were crystallized at different crystallization temperatures during different crystallization times. A strong influence of the crystallization temperature on the molecular dynamics of PEN has been evidenced: in the case of the samples crystallized at high temperatures, the mobility of the chains was higher than in the case of the samples crystallized at low temperatures. Finally, the confinement effects induced by the Montmorillonite (MMT) platelets on the Polyamide 6 (PA6) matrix were studied in the PA6/MMT nanocomposites. No significant influence of the filler on the molecular mobility of the PA6 chains was observed. Nevertheless, as expected, the two interfacial relaxations were very sensitive to the filler content.

Ce travail a consisté en la synthèse et la caractérisation de nouveaux polycondensats poly(urée-imide)s (PUIs) greffés par une réaction de chimie "click" avec des nombres de greffons variables. Deux familles de matériaux ont été obtenues à partir d'un même PUI et de greffons de structures différentes mais de mêmes masses molaires : poly(méthoxy (diéthylène glycol) méthacrylate) (PMDEGMA) synthétisé par polymérisation radicalaire par transfert d’atome (ATRP) ; poly(hydroxyéthyl acrylate) (PHEA) préparé par Single Electron Transfer Living Radical Polymerization (SET-LRP). Ces matériaux ont ensuite été étudiés pour la purification du biocarburant éthyl tert-butyl éther (ETBE) par le procédé membranaire de pervaporation. Pour la séparation correspondante du mélange azéotropique ETBE/éthanol, les polycondensats avec des greffons PMDEGMA ont conduit à d’excellentes performances en extrayant l’éthanol de manière très sélective. La stratégie de greffage a permis d’augmenter fortement le flux tout en maintenant une excellente sélectivité et de pallier ainsi la limitation classique des polycondensats linéaires pour lesquels flux et sélectivité varient fortement de manière opposée. Les propriétés de ces polycondensats greffés ont été corrélées à leur morphologie particulière étudiée par MDSC et Synchrotron SAXS. Les greffons PHEA avec des groupes hydroxyle ont permis d'augmenter encore l'affinité pour l'éthanol. Cette affinité ayant dépassé les espérances avec des membranes trop gonflées par le mélange cible, les propriétés de sorption et de perméation de la seconde famille de copolymères greffés ont finalement étudiées pour le transport de l'eau, autre domaine de la perméabilité à forts enjeux industriels / This work deals with the synthesis and characterization of new graft step-growth copolymers poly(urea-imide)s (PUIs) by ‘click’ chemistry with variable graft amounts. Two families of materials were obtained from the same PUI and polymer grafts with different structures and the same molecular weights : poly(methoxy (diethylene glycol) methacrylate) (PMDEGMA) prepared by Atom Transfer Radical Polymerization (ATRP); poly(hydroxyethyl acrylate) (PHEA) obtained by Single Electron Transfer Living Radical Polymerization (SET-LRP). These materials were then investigated for the purification of the ethyl tert-butyl ether (ETBE) biofuel by the pervaporation membrane process. For the corresponding separation of the azeotropic mixture ETBE/ethanol, the copolymers with the PMDEGMA grafts showed excellent performances with very selective ethanol extraction. The grafting strategy enabled to increase the flux strongly while maintaining an excellent selectivity and thus overcame the classical limitation of linear step-growth copolymers, for which flux and selectivity strongly vary in opposite ways. The properties of the graft copolymers were correlated to their particular morphology characterized by MDSC and Synchrotron SAXS. The PHEA grafts with their hydroxyl groups enabled to further increase affinity for ethanol. This affinity having gone beyond expectation with a too strong membrane swelling in the targeted mixture, the sorption and permeability properties of the second series of graft copolymers were finally investigated for water transport, i.e. another permeability field with strong industrial stakes

Block copolymers can self-assemble into a variety of periodic nanostructures and therefore, are promising candidates for a diverse range of applications. While self-assembly of block copolymers has been widely studied and exploited, graft copolymers have remained far less explored in this context. One of the primary reasons for this is that the most commonly used methods to prepare graft copolymers leads to polymers that do not have precisely defined structures; specifically, controlling the precise location of the grafted segments is a synthetically difficult challenge. In typical chain polymerization processes, statistically random incorporation of monomers takes place and consequently, the periodicity of the grafted segment along the backbone is very difficult to control precisely; therefore, such methods cannot be utilized to prepare periodically grafted copolymers. Some recent efforts towards the preparation of sequence regulated copolymers using controlled radical polymerization in conjunction with periodic dosing of a commoner could provide an alternative to better regulate the periodicity, although this will also not be perfectly periodic. The only approach to control the periodicity perfectly is to utilize condensation polymerization approaches, wherein one of the monomers serve as a spacer whereas the other provides the opportunity to install the graft segment, as depicted in Scheme 1. One of the earliest examples of the utilization of a condensation approach to locate desired units at periodic intervals was reported by Wagener and co-workers using Acrylic Diene Metathesis (ADMET) process.1 ]n periodicity ]n graft segment Scheme 1. Synthetic scheme for the preparation of periodically grafted copolymers using condensation polymerization. From our lab, Roy et al. developed periodically grafted amphiphilic copolymers (PGAC), based on a readily available starting material, diethyl malonate;2 melt trans-esterification between diethyl malonate, containing a pendant hexaethylene glycol monomethyl ether (HEG) segment and 1,22-docosane diol resulted in PGAC wherein the hydrophilic oligo ethylene glycol units were placed on every 27th atom along the backbone (Scheme 2). Such PGAC underwent self-segregation and adopted a folded zigzag conformation, which was driven by the intrinsic immiscibility of the alkylene and HEG segments and was reinforced by the strong tendency for long chain alkylene segments to crystallize in a paraffinic lattice. However, one of the drawbacks of the above approach was that the hydrophilic pendant unit was installed at the monomer stage and consequently, the synthetic approach does not allow easy variation of the hydrophilic grafted segment; this limits the flexibility and any structural variation of the pendant segment would be synthetically tedious. 150 oC DBTDL 5 20 DBTDL = Dibutyltin dilaurate Scheme 2. Synthesis of PGAC, based on diethyl malonate, and immiscibility-driven folding of such PGACs. Mandal et al. developed a more general strategy for the synthesis of such periodically grafted systems; they prepared periodically clickable polyesters carrying propargyl groups at regular intervals, by the solution polycondensation of 2-propargyl-1,3-propanediol or 2,2-dipropargyl-1,3-propanediol and the acid chloride of 1,20-eicosanedioic acid. Such periodically clickable polyesters were shown to react quantitatively with a fluoroalkyl azide3 and PEG 350 azide4, thus allowing them to place different kinds of functionalities precisely along the backbone, as shown in Scheme 3. The immiscibility of the alkylene and fluoroalkyl/PEG segments caused the polymer chains to fold in a zigzag fashion, thereby facilitating the segregation of these segments, as observed earlier in the study by Roy et al.2 The objective of this study was to place various desired functionalities along the polymer backbone and examine their effect on the self-assembly behaviour and morphology of such periodically clicked systems. Scheme 3. Synthetic scheme for the generation of periodically clickable polyesters and their subsequent functionalization via Cu-catalysed click chemistry. In Chapter 2, we describe an alternative general strategy for the scalable synthesis of periodically graftable polyesters and their subsequent functionalization to generate a wide variety of periodically grafted systems. The importance of our approach lies in our choice of the monomer, which is based on itaconic acid, an inexpensive and bio-sourced molecule. We demonstrated that dibutyl itaconate can be melt-condensed with aliphatic diols to generate unsaturated polyesters (Scheme 4); importantly, we showed that the double bonds in the itaconate moiety remain unaffected during the melt polymerization. A particularly useful attribute of these polyesters is that the exo-chain double bonds are conjugated to the ester carbonyl and therefore, can serve as excellent Michael acceptors. A variety of organic thiols, such as alkane thiols, MPEG thiol, thioglycerol, derivative cysteine etc., were shown to quantitatively Michael-add to the exo-chain double bonds and generate interesting functionalized polyesters; similarly, organic amines, such as N-methylbenzylamine, diallyl amine and proline also underwent Michael addition across the double bond (Scheme 4). Thus, such poly(alkylene itaconate)s could be utilized to place diverse functionalities at regular intervals along the polymer backbone. Scheme 4. Preparation of periodically graftable polyesters, based on itaconic acid, and their subsequent modification by Michael addition. In Chapter 3, we examined a series of periodically grafted polyesters carrying long crystallizable alkylene (C-20) segments along the backbone and pendant polyethylene glycol monomethyl ether (MPEG) segments grafted at periodic intervals. Such periodically grafted amphiphilic copolymers (PGAC) having MPEG graft segments of varying lengths were prepared by utilizing the activated exo-chain double bonds in poly(icosyl itaconate) (PII) that carries a 20-carbon alkylene segment; MPEG thiols of varying lengths (TREG, 350, 550 and 750) were quantitatively grafted under standard Michael addition conditions to yield the required graft copolymers, as shown in Scheme 5. Scheme 5. Synthesis of a series of periodically grafted amphiphilic copolymers (PGAC) utilizing post-polymerization modification via Michael addition with MPEG thiols of varying lengths. The immiscibility of the backbone alkylene and pendant MPEG segments, and the strong propensity of the alkylene segments to crystallize in a paraffinic lattice, drive these systems to fold in a zigzag fashion and subsequently organize into a lamellar morphology, as shown in Scheme 6. Interestingly, all the graft copolymers exhibited a clear and invariant melting transition at ~44°C that suggested the crystallization of the backbone C-20 segment; the MPEG segments were, however, amorphous except in the case of polymers carrying MPEG 550/MPEG-750 segments, wherein a second melting transition corresponding to the independent crystallization of the PEG segment was also seen. SAXS studies indicated that all of the samples exhibited lamellar morphologies wherein more importantly, the inter-lamellar spacing was seen to increase linearly with the MPEG length (Scheme 6). This study provides a new design for controlling the dimensions of the microphase-separated nanostructures at significantly smaller length scales (sub-10 nm) than is typically possible using block copolymers. Scheme 6. Schematic representation of formation of lamellar morphology in PGACs and control of interlamellar spacing in such systems. In order to understand the influence of having a mixture of MPEG lengths on the self-assembled morphology, in Chapter 4 we prepared a series of PGACs by co-grafting the parent poly(icosyl itaconate) with a mixture of two different MPEG thiols, namely MPEG-350 and MPEG-750; the mole-ratios of these two PEGs were varied to generate co-grafted PGACs, carrying different amounts of the two MPEG segments randomly distributed along the chain (Scheme 7). Parallely, we also examined the behaviour of physical mixtures of two different PGACs, one bearing MPEG-350 and the other MPEG-750 grafts; keeping the total MPEG content constant, we sought to examine the differences in the behaviour of randomly co-grafted polymers and physical mixtures. Scheme 7. Preparation of co-grafted PGACs and physical mixtures of two different PGACs. The co-grafted PGACs also exhibited a lamellar morphology; interestingly, the inter- lamellar spacing increased linearly with the total volume of PEG domain. This suggested that despite the presence of MPEG segments of two different lengths in the co-grafted samples, there occurred a reorganization of the PEG chains within the amorphous domain ensuring that the condition of incompressibility is not violated, thereby giving rise to a weighted average interlamellar spacing, as shown in Scheme 8. In contrast, the SAXS patterns of the physical mixtures revealed the presence of two distinct lamellar domains in the sample; this indicated that the two homo-grafted samples do not mix and form separate lamellar domains. The self- segregation induced folding and subsequent crystallization of the central alkylene segments clearly appeared to dominate the final morphology. Scheme 8. Schematic depiction of the possible scenarios that could arise when MPEG segments of two different lengths, namely MPEG350 and MPEG750, are present in the PGACs; top panel depicts the co-grafted PGACs, whereas the bottom panel shows the case of mixtures of PGACs with two different MPEG lengths. In Chapter 5, we have dealt with the design and synthesis of chain-end functionalizable polyalkylene itaconates. Changing the monomer from dibutyl itaconate to dipropargyl itaconate and using it in controlled excess allowed us to generate chain-end functionalizable polymers containing propargyl groups at the chain ends, in addition to the exo-chain double bonds along the backbone, thereby providing the opportunity for orthogonal functionalization. In order to obtain three different telechelic polymers with target DPs (degree of polymerization) of 5, 10 and 20 respectively, 3 different mole ratios of the two monomers (dipropargyl itaconate and 1,20-eicosanediol) were used (Scheme 9). Scheme 9. Synthetic scheme for the generation of chain-end functionalizable polyalkylene itaconates. Orthogonal functionalization of the resultant polymers was carried out using thiol-Michael addition and Cu(I)-catalysed alkyne-azide cycloaddition (AAC), without interference between the functional handles present along the polymer backbone and the chain-end, respectively. Michael addition with triethylene glycol thiol and subsequent Cu-catalysed click reaction with MPEG 750 azide led to the generation of ABA type triblock copolymers where the middle block is a periodically grafted amphiphilic block and the two linear end blocks are hydrophilic in nature. Furthermore, such propargyl-terminated polyalkylene itaconates were used as macromonomers to prepare multiblock copolymers. The telechelic polymers were first treated with PEG 600 diazide, resulting in the formation of alternating multiblock copolymers; these multiblock copolymers were further reacted with thioglycerol to generate amphiphilic multiblock copolymers where one of the blocks is a periodically functionalized amphiphilc block, as depicted in Scheme 10. In both these amphiphilic block copolymer systems, a key feature is that the periodically functionalized amphiphilic block folds into a zigzag form, as evident from the presence of a nearly invariant melting peak corresponding to the crystallization of the alkylene segment. Scheme 10. Preparation of multiblock copolymers utilizing propargyl-terminated polyalkylene itaconates as a macromonomer. In summary, the thesis has demonstrated the design and synthesis of a series of novel amphiphilic copolymers using a bio-sourced monomer, wherein the driving theme is the immiscibility driven self-segregation that leads to the folding of the chain; these have been thoroughly examined using DSC, SAXS, WAXS, variable temperature FT-IR and AFM measurements. References (1) Berda, E. B.; Lande, R. E.; Wagener, K. B. Macromolecules 2007, 40, 8547. (2) Roy, R. K.; Gowd, E. B.; Ramakrishnan, S. Macromolecules 2012, 45, 3063. (3) Mandal, J.; Krishna Prasad, S.; Rao, D. S. S.; Ramakrishnan, S. Journal of the American Chemical Society 2014, 136, 2538. (4) Mandal, J.; Ramakrishnan, S. Langmuir 2015, 31, 6035.