Living radical polymerization has proved to be a powerful tool for the synthesis of polymers as it allows for a high degree of control over the polymer microstructure and the synthesis of tailored molecular architectures. Although it has great potential, its use on an industrial scale is limited due to environmental and economical aspects. Nitroxide mediated polymerization is explored to bring this technology closer to adoption in commercial applications. One of the obstacles encountered using nitroxide mediated polymerization in microemulsion systems is the difficulty in controlling both the particle size and target molecular weight. Due to the nature of the formulation, a decrease in the target molecular weight is coupled to an increase in the particle size. For many applications, it is important to be able to design polymer particles with both specifications independently. Strategies to decouple these two properties and processing conditions required for targeting a range of particle sizes and molecular weights for n butyl acrylate latexes are presented. Furthermore, in an attempt to reduce the large amounts of surfactant typically used in microemulsions, these methods were explored at low surfactant to monomer ratios (0.2 to 0.5 by wt.) in order to reduce the costs associated with excess surfactant and post processing steps for surfactant removal (high surfactant levels also give poor water-resistance in coatings). Stable nanolatexes with particle sizes <40 nm have been obtained by other groups using NMP in microemulsions with SG1 but have done so by using much higher surfactant to monomer ratios (~2.5 by wt.) and at much lower solids content (6 10 wt. %). In this work, molecular weights of 20,000 to 80,000 g∙mol-1 were targeted and stable, n-butyl acrylate microemulsions with particle sizes ranging from 20 120 nm were prepared at a solids content of 20 wt. % using much lower surfactant concentrations. Although numerous studies have shown the effects of process parameters on particle sizes and methods to control the molecular weight, the decoupling of the molecular weight and particle size effect in NMP microemulsions under these conditions has not been done to this extent. In copolymer systems, nitroxide mediated polymerization also provides an efficient method to synthesize well defined block copolymers. Random copolymers are widely used as protective colloids, but the use of block copolymers for these applications has not been well studied. It is unclear what effects do the importance of a narrow molecular weight distribution and purity of block copolymers have on their performance as protective colloids. In order to investigate this, a range of block copolymers with different properties would need to be synthesized for systematic analysis. The direct synthesis of polystyrene b poly(acrylic acid) copolymers of varying lengths and compositions was successful by use of nitroxide mediated polymerization in bulk and solution polymerization. The characterization of these amphiphilic block copolymers was explored by titration and nuclear magnetic resonance spectroscopy. / Thesis (Master, Chemical Engineering) -- Queen's University, 2012-09-28 15:43:00.513

Fluoropolymers are a versatile and attractive group of compounds having an interesting mix of properties that make them highly useful for various applications. Because of strong bonding between the carbon and fluorine atom, they exhibit unique physical and chemical properties such as high thermal stability, increased chemical resistance, low refractive index, enhanced inertness towards many solvents and hydro-compounds. These characteristics have led them to be widely used in aerospace, aeronautics, optics, microelectronics, paints and coatings, and engineering structures and as biomaterials. Amphiphilic copolymers possess unique solution and solid-state properties due to their well-defined molecular architecture. These properties arise as the result of covalently combining two thermodynamically different polymer blocks that phase separate on the nanoscale. Amphiphilic copolymers based on a fluoro-monomer will combine the favourable physiochemical properties of the desired fluorine segment in combination with complementary hydrophilic segments. Such fluorinated amphiphilic copolymers are potentially useful for drug delivery vehicles and membrane applications. This project is aimed at making fluorinated amphiphilic block copolymers of hydrophobic 2, 3, 4, 5, 6 –pentafluorostyrene (PFS) and hydrophilic methacrylic acid (MAA). A controlled radical polymerization mechanism, nitroxide mediated polymerization (NMP) using NHS-BlocBuilder as the initiator was employed. The advantage of using NMP is that it facilitates the synthesis of copolymers with well-controlled narrow molecular weight distribution. However, methacrylate homopolymerization by NMP is challenging due to the high dissociation equilibrium constant therefore, the use of PFS as a controlling comonomer was explored. We established that to obtain a controlled copolymerization, a minimum of 70 mol% PFS was required, which is significantly greater than other copolymerization systems such as using as little as 4.5-8 mol% styrene to control the copolymerization of MAA. We surmise that this lack of control is due to the unfavourable reactivity ratios (Appendix I) which favour the addition of MAA rather than PFS (rPFS = 0.012, rMAA = 8.12). However, these unique reactivity ratios suggest that a semi-batch approach can be utilized to synthesize almost pure block copolymers in one pot. Therefore, poly(PFS)–b-(PFS-ran-MAA) block copolymers were synthesized and characterized by a semi batch addition of MAA. While successful, the concentration of irreversibly terminated chains was evident and greater care in reducing these unwanted reactions needs to be addressed.

The basis for this research project is based on the discovery in the previous research that 2,2' ,5-trimethyl-3-( I-phenylethoxy)-4-tert-butyl-3-azahexane, (Styryl- TITNO) is able to control bulk polymerization of styrene at temperature as low as 70°C. The principle objective of this project was to evaluate the feasibility of using Styryl- TITNO to control radical solution and miniemulsion polymerizations at temperatures below 100°C. Styryl- TITNO was shown to effect solution polymerizations of both n-butyl acrylate (BA) and styrene below 100°C. Polymerization temperature was shown to be a crucial parameter for achieving control in Styryl- TITNO -mediated polymerizations. Good control of the number-average molecular weight (Mn) and molecular weight dispersity for the polymerization of BA was observed at 90°C. However, a lower temperature of 70 °C is required for good control of styrene polymerization. Living characteristics of polymer chains were demonstrated by a sequential chain extension of TITNO -terminated PBA with styrene at 90°C to form poly(n-butyl acrylate)- block-poly[(n-butyl acrylate)-co-styrene], [pBA-b-P(BA-co-PS)], block copolymers. An improvement in livingness in these reactions was observed when the second P(BAlstyrene) block was formed at 70°C after the first PBA block was produced at 90°C. Kinetics studies facilitated determination of the activation-deactivation equilibrium constant (K), which for styrene polymerization at 90°C (K = 4.1 x 10.9 mol L-J at 90°C and 3.0 x 10-9 mol L-J at 70 "C) is nearly an order of magnitude higher than that for BA polymerization at the same temperature (K = 8.5 x 10-11 mol L-I). This is the reason why BA polymerization shows better control than styrene polymerization at 90°C. The activation energy (Ea) for thermolysis of Stryl- TITNO is 104.1 kJ mol", which is relatively low compared to the literature values of Ea for various styryl alkoxymines. This explains why Styryl- TITNO is able to effect polymerization at temperatures as low as 70 "C. The studies of Styryl- TITNO-mediated miniemulsion polymerizations at 90 "C indicate that accumulation of free TITNO• in the particles is an issue for use of Styryl- TITNO in miniemulsion polymerizations. The use of L-ascorbic acid (L-AA) and L-ascorbic acid 6-palmitate (L-AAP) as nitroxide scavengers to reduce the level of free TITNO • in the polymerization was investigated. The best result was observed for the polymerization of BA in the presence of 5.35 mol% of L-AAP relative to Styryl- TITNO, which attained 48% conversion after 5 h. The chain extension of isolated TITNO -terminated PBA, TITNO -PBA, was used to examine the livingness of - polymer -chains before the rate of polymerization was severely retarded. The livingness of TITNO-PBA was evidenced by a shift of the staring PBA molecular weight distribution towards higher molecular weight, which provides solid evidence that the majority of polymer chains remained living. Thus, it can be concluded with certainty that the accumulation of free TITNO• was mainly responsible for the suppression of polymerization in miniemulsion polymerizations mediated by Styryl- TITNO.

Non-covalent interactions including nucleobase hydrogen bonding and ionic aggregation were studied in block and end-functional polymers synthesized via living polymerization techniques such as nitroxide mediated polymerization and anionic polymerization. The influence of non-covalent association on the structure/property relationships of these materials were studied in terms of physical properties (tensile, DMA, rheology) as well as morphological studies (AFM, SAXS). Hydrogen bonding, a dynamic interaction with intermediate enthalpies (10-40 kJ/mol) was introduced through complementary heterocyclic DNA nucleobases such as adenine, thymine and uracil. Hydrogen bonding uracil end-functionalized polystyrenes and poly(alkyl acrylate)s were synthesized via nitroxide mediated polymerization from novel uracil-functionalized alkoxyamine unimolecular initiators. Terminal functionalization of poly(alkyl acrylate)s with hydrogen bonding groups increased the melt viscosity, and as expected, the viscosity approached that of nonfunctional analogs as temperature increased. A novel difunctional alkoxyamine, DEPN2, was synthesized and utilized as an efficient initiator in nitroxide-mediated controlled radical polymerization of triblock copolymers. Complementary hydrogen bonding triblock copolymers containing adenine (A) and thymine (T) nucleobase-functionalized outer blocks were synthesized. Hydrogen bonding interactions were observed for blends of the complementary nucleobase-functionalized block copolymers in terms of increased specific viscosity as well as higher scaling exponents for viscosity with solution concentration. Multiple hydrogen bonding interactions were utilized to attach nucleobase-functional quaternary phosphonium ionic guests to complementary adenine-functionalized triblock copolymers. Ionic interactions, which possess stronger interaction energies than hydrogen bonds (~150 kJ/mol) were studied in the context of sulfonated poly(styrene-b-ethylene-co-propylene-b-styrene) block copolymers. Strong ionic interactions resulted in the development of a microphase separated physical network and greater extents for the rubbery plateau in DMA analysis compared to sulfonic acid groups, which exhibit weak hydrogen bonnding interactions. In contrast to the physical networks consisting of sulfonated or hydrogen bonding block copolymers, covalent networks were synthesized using carbon-Michael addition chemistry of acetoacetate functionalized telechelic oligomers to diacrylate Michael acceptors. The thermomechanical properties of the networks based on poly(propylene glycol) oligomers were analyzed with respect to the molecular weight between crosslink points (Mc) and the critical molecular weight for entanglement (Me). / Ph. D.

Use of a mixed triisobutylaluminum/1,1-diphenylhexyllithium intiator enabled the anionic polymerization of methyl methacrylate at room temperature, resulting in narrow molecular weight distributions and syndiorich structures. Polymerizations were controlled above Al:Li = 2, and control significantly decreased at elevated temperatures above 25 °C. A significant increase in Tg with increasing control of syndiotacticity demonstrated the ability to tailor polymer properties using this technique. Analysis with MALDI-TOF/TOF spectroscopy revealed the dominance of a back-biting side reaction at elevated temperatures. Hydroxy-functional random and block copolymers of n-butyl acrylate (nBA) and 2-hydroxyethyl acrylate were synthesized using nitroxide mediated polymerization. Controlled polymerization was demonstrated, resulting in narrow polydispersities and linear molecular weight vs. conversion plots. In situ FTIR spectroscopy monitored the polymerizations and revealed pseudo first order rate kinetics for random copolymerizations. Protection of the hydroxyl using trimethylsilyl chloride alleviated isolation issues of amphiphilic polymer products. For the first time zwitterion-containing copolymers were electrospun to form nanoscale fibers with diameters as low as 100 nm. Free radical copolymerization of nBA and sulfobetaine methacrylamide produced zwitterionic copolymers with 6-13 mol % betaine. Dynamic mechanical analysis revealed a rubbery plateau and biphasic morphology similar to ionomers. Electrospinning from chloroform/ethanol solutions (80/20 v/v) at 2-7 wt % afforded polymeric fibers at viscosities below 0.02 Pa™s, which is the lowest viscosity observed for fiber formation in our laboratories. We hypothesized that intermolecular interactions rather than chain entanglements dominated the electrospinning process. Solution rheology of zwitterionic copolymers containing 6 and 9 mol % sulfobetaine methacrylate functionality revealed two concentration regimes with a boundary at ~1.5 – 2.0 wt %, regardless of molecular weight. This transition occurred at an order of magnitude lower specific viscosity than the entanglement concentration (Ce) for poly(nBA), and correlated to the onset of fiber formation in electrospinning. Comparison to existing models for polymer solution dynamics showed closest agreement to Rubinstein's theory for associating polymers, in support of our hypothesis that zwitterionic interactions dominate solution dynamics. The effect of ionic liquid (IL) uptake on mechanical properties and morphology of zwitterionic copolymers was explored using 1-ethyl-3-methylimidazolium ethylsulfate (EMIm ES). Dynamic mechanical analysis and impedance spectroscopy revealed a significant change in properties above a critical uptake of ~10 wt % IL. X-ray scattering revealed a significant swelling of the ionic domains at 15 wt % IL, with a 0.3 nm-1 shift in the ionomer peak to lower scattering vector. Results indicated the water-miscible IL preferentially swelled ionic domains of zwitterionic copolymers. / Ph. D.

The imidazole ring offers great potential for a variety of applications including gene delivery vectors, ionic liquids, electromechanical actuators, and novel monomers and polymers. The imidazole ring provides a unique building block for these applications due to its thermal stability, aromatic nature, ability to form ionic salts, and ease of functionalization. Free radical polymerization of 1-vinylimidazole (1-VIm) and free radical copolymerizations with methyl methacrylate (MMA) and n-butyl acrylate (nBA) afforded homopolymers and copolymers with tunable solution and thermal properties. Aqueous SEC provided reproducible and reliable molecular weights for poly(1-VIm) in the absence of polymer aggregates. Analysis of the thermal properties revealed ideal random copolymers with MMA and non-ideal copolymers with nBA. Small angle X-ray scattering determined that the spacing between ionic groups remained constant with increased nonionic comonomer incorporation while the spacing between adjacent polymer backbones increased. Functionalization of 1-VIm with varying length alkyl halides and polymerization prepared a series of imidazolium homopolymers. Anion exchange reactions controlled the thermal and solution properties, and the bromide counteranion quantitatively exchanged to tetrafluoroborate (BF4), trifluoromethanesulfonate (TfO), and bis(trifluoromethanesulfonyl)imide (Tf2N). Thermogravimetric analysis revealed that thermal stability increased with decreased alkyl substituent length and larger counteranion size, and differential scanning calorimetry determined that glass transition temperature (Tg) decreased with increased alkyl substituent length and larger counteranion size. Electrochemical impedance spectroscopy determined the ionic conductivities of the imidazolium homopolymers, and analysis using the Vogel-Fulcher-Tammann equation revealed that the activation energy of ion conduction increased as alkyl substituent length increased. Polymer morphology determined using X-ray scattering also influenced the ionic conductivity. As the alkyl substituent length increased, the spacing between adjacent polymer backbones increased, which decreased the ionic conductivity due to the ion-hopping mechanism of ion conduction. Unsuccessful attempts to control the radical polymerization of 1-VIm led to the investigation of 1-(4-vinylbenzyl)imidazole (VBIm), which is a styrenic-based monomer with excellent propagating radical stability. Triblock copolymers incorporating VBIm monomer into a soft random copolymer center block and reinforcing, hard segment outer blocks provided a template for tuning the properties of the ionomer membranes for electroactive devices. Analysis of the morphology and mechanical properties using small angle X-ray scattering and dynamic mechanical analysis determined microphase separation and optimal mechanical properties for electromechanical transducer fabrication. Testing electromechanical transducers revealed superior performance relative to the benchmark Nafion®. Optimization of triblock copolymer design criteria through varying the comonomer ratio of VBIm and nBA in the soft center block, quaternization reactions, and ionic liquid introduction influenced mechanical properties and ionic conductivity. Higher percentages of VBIm and quaternization of VBIm in the random central block increased Tg and ionic conductivity. IL selectively incorporated into the imidazole-containing phases with no leakage observed for ionic systems, reduced the center block Tg, and increased ionic conductivity. Controlling charge density along poly(1-VIm) through well-defined alkylation reactions with 1-bromobutane provided a potential vector for nonviral gene delivery and polyanion binding. Analysis of DNA and heparin binding using gel electrophoresis revealed a decrease in N/P ratio with increased alkylation percentage. Dynamic light scattering indicated an increase in zeta potential with increasing alkylation percentages, and relatively uniform polyplex sizes in aqueous media. The MTT assay developed cytotoxicity profiles with little toxicity prior to 83% alkylation. Finally, the luciferase expression assay revealed inefficient nucleic acid delivery to multiple cell types. Synthesis of poly(1-VIm) vectors with glutathione conjugates provided an avenue for simultaneous therapeutic gene and anti-oxidant delivery in vitro. Cytotoxicity assays of cells pretreated with glutathione-conjugated poly(1-VIm) prior to oxidative stress showed that higher glutathione conjugation levels improved cell viability. / Ph. D.

La nanomédecine, appliquée en particulier au traitement du cancer, suscite depuis une quinzaine d’années un intérêt grandissant, développant des stratégies innovantes pour le ciblage spécifique de tissues malades. De nouveaux progrès en la matière sont encore à venir, mais nécessitent de nouveaux matériaux offrant une grande flexibilité en termes de synthèse, ainsi que la possibilité de fonctionnalités et de propriétés physicochimiques variées ; avantages tous présentés par l’utilisation des techniques de polymérisation radicalaire contrôlée (CRP). Ces techniques de polymérisation ont déjà démontré leur fort potentiel à travers différents systèmes nanoparticulaires à base de prodrogues de polymère, mais aucun d’entre eux ne s’avère dégradable ce qui pourrait empêcher à l’avenir leur utilisation et leur développement.Anticipant les besoins, ce projet a eu pour but la synthèse de polymères PEGylés dégradables par la technique de polymérisation contrôlée par les nitroxydes (NMP), travail très en amont de l’habituel procédé d’élaboration d’un nouveau nanomédicament. Pour ce faire, la NMP du méthacrylate de méthyl éther oligo(éthylène glycol) (MeOEGMA) a été combinée à la polymérisation radicalaire par ouverte de cycle (rROP) des acétals de cétène cyclique (CKAs), connus comme précurseurs de fonctions esters.Parmi trois CKAs étudiés, le 2-méthylène-4-phényl-1,3-dioxolane (MPDL) a montré une capacité unique à copolymériser avec les dérivés de méthacrylates, grâce à sa structure ouverte de type « styrènique » permettant son utilisation en NMP. A travers une étude approfondie des propriétés de contrôle et de caractère vivant de ces copolymères, le MPDL s’est également révélé être le premier comonomère de contrôle des méthacrylates à être dégradable. Un lien direct entre dégradabilité et quantité de MPDL insérée a été démontré, permettant jusqu’à l’hydrolyse complète des matériaux. Ces copolymères n’ont montré aucune cytotoxicité, et ce sur trois types de cellules différents (fibroblastes, cellules endothéliales et macrophages), et une étude similaire sur la toxicité de leurs produits de dégradation a permis d’aboutir à la même conclusion, soulignant la possible biocompatibilité de ces nouveaux matériaux qui, si confirmée, permettrait leur utilisation pour des applications biomédicales.Parallèlement, un second projet portant sur la mise au point d’une nouvelle alcoxyamine à base du nitroxide SG1 et présentant une fonction azlactone, baptisée AzSG1, a été développé pour la synthèse de polymères fonctionnalisables par NMP. Utilisant l’alcoxyamine AzSG1 comme amorceur, les NMPs du styrène, de l’acrylate de n-butyle et du méthacrylate de méthyle ont été réalisées avec succès, ainsi que le couplage quantitatif de la benzylamine comme preuve de concept de la possible fonctionnalisation. Dans un avenir proche, utiliser cet amorceur fonctionnalisable pour la synthèse de copolymères à base de MeOEGMA et de MPDL pourrait ainsi permettre l’élaboration de copolymères PEGylés, dégradables et fonctionnalisables par NMP, pour des applications dans le domaine de la bioconjugaison et du drug delivery. / Nanomedicine, especially for cancer treatment, has attracted much interest over the last fifteen years, developing innovative strategies for targeting diseased tissues. Further improvements of these approaches will require advanced new materials affording versatility, functionalities and specific physico-chemical properties, all advantages offered by the controlled radical polymerization (CRP) techniques. These radical polymerizations already showed their great potential through various efficient anticancer polymer nanocarriers but all lacking of degradability, which may hinder any actual developments.Anticipating the needs, this project focused on the synthesis of degradable PEG-based polymers by nitroxide-mediated polymerization (NMP), as an early stage in the usual process of nanocarrier design. To do so, NMP of oligo(ethylene glycol) methyl ether methacrylate (MeOEGMA) has been for the first time combined to the radical ring-opening polymerization (rROP) of various cyclic ketene acetals (CKAs), known as ester precursors.Among three CKAs tested, 2-methylene-4-phenyl-1,3-dioxolane (MPDL) has shown a unique ability to copolymerize with methacrylate derivatives, likely due to a styrene-like open structure allowing for its use in NMP. Through a careful study of the control and livingness properties of these copolymers, MPDL was also demonstrated to be the first degradable controlling comonomer for polymethacrylate synthesis. The degradability of the resulting PEG-based copolymers was proven to be proportional to the adjustable amount of MPDL inserted, up to complete degradation. These copolymers showed no cytotoxic effect on various cell types (fibroblasts, endothelial cells and macrophages), and an additional study of the innocuousness of their degradation products led to similar results, underlining their potential biocompatibility which, if confirmed, would allow these materials to be used for biomedical applications.A second project about a new azlactone-functionalized SG1-based alkoxyamine (AzSG1) was also set up, as initiator for the synthesis of functionalizable polymers by NMP. Using the AzSG1 alkoxyamine, the NMP of styrene, n-butyl acrylate and methyl methacrylate were successfully performed, as well as a quantitative coupling of benzylamine as proof of concept. In the near future, making use of this functionalizable initiator for copolymerizing MeOEGMA with MPDL may allow the easy synthesis of functionalized degradable copolymers by NMP, for bioconjugation and drug delivery applications.

Self-assembled monolayers and surface-initiated polymer, or polymer brushes, have attracted attention as they form dense layers with much higher structural order than bulk or solution polymers. Another field of research which has emerged over the last two decades is the field of organic and polymer electronics. In this field molecular order and surface modification are of major influence on the device performance, hence that both self-assembled monolayers as polymer brushes have been investigated to find applications in organic electronic devices. After an introduction into the field self-assembled monolayers, polymer brushes and organic electronics, the first part of this thesis focusses on three applications of surface modification techniques for applications in devices. Alignment of the active material is crucial for high mobilities in organic electronics. Chapter 2 discusses the synthesis of a liquid crystalline surface-initiated polymer and its application to induce strong homeotropic alignment. The alignment is homogeneous over large areas and can be patterned by combining the polymerization with soft lithographic techniques. Mobilities of organic electronic materials can also be strongly influenced by dopants in the material. In field-effect transistors the positioning of the dopant is thought to be crucial, as the conductance predominantly takes place in only a small channel near the dielectric interface. In chapter 3 dopant functionalized monolayers and polymer brushes are presented which enable the localized deposition of dopants in the channel of organic transistors. It is shown that the mobility of charges and hence the device performance is affected by the introduction of this dopant layer. Polymer brushes have been suggested for the fabrication of highly ordered semiconducting polymers. In chapter 4 the use of a thiophene functionalized polymer brush is shown, that can be used as a template for the subsequent growth of highly conjugated surface grafted polythiophene layers. Thick polythiophene layers are obtained, that are low in roughness and show photoluminescence and polychromism upon doping. The second part (chapter 5 and 6) of this thesis presents new techniques for surface polymerizations. It is attractive to investigate reduction of reactor volume for polymer brush growth. Chapter 5 discusses a method to achieve volume reduction by back-filling the superfluous volume with beads. It is found that this influences the polymerization kinetics significantly. The combined advantages of less volume and enhanced reaction speeds enable reduction of the total amount of monomer needed by up to 90%. Chapter 6 presents a controlled way to convert initiators for atom transfer radical polymerization into initiators for nitroxide mediated polymerization. In this way mixed polymer brushes and block co-polymer brushes become accessible. This combination makes it an attractive tool to fabricate complex polymer architectures. The technologies used in this thesis show that the synthesis of polymer brushes enable the fabrication of complex architectures without the wastes normally associated with surface-initiated polymers. Combined with several functionalized polymer brushes with properties that enhance order, influence mobility or serve as template for the growth of surface attached conjugated polymers this shows the high potential for the application of surface-initiated polymers in organic electronics.

Une méthodologie générale et efficace pour la synthèse de nanoparticules de prodrogues polymères hétérotéléchéliques à hauts taux de charge a été mise au point en combinant d’une part la méthode dite du “principe actif amorceur” pour obtenir des prodrogues polymères α-fonctionnelles par polymérisation radicalaire contrôlée par les nitroxydes (NMP), et d’autre part la réaction d'échange de nitroxyde à partir d’un nitroxyde fonctionnel pour coupler une seconde molécule d'intérêt en bout de chaîne. Une petite bibliothèque de prodrogues polymères hétérotéléchéliques avec différentes combinaisons pour diverses applications (e.g., libération de principes actifs, imagerie/théranostic, thérapie combinée, ciblage actif) a été synthétisée en utilisant le polyisoprène (PI) comme polymère.En particulier, une alcoxyamine basée sur le nitroxyde SG1 a été fonctionnalisée avec la première molécule d’intérêt et utilisée pour polymériser l'isoprène par NMP et donner la prodrogue polymère désirée. En appliquant ensuite la réaction d'échange de nitroxyde à partir du nitroxyde TEMPO fonctionnalisé avec la seconde molécule d’intérêt, le nitroxyde SG1 en bout de chaîne a été quantitativement remplacé par le TEMPO fonctionnel pour donner la prodrogues hétérobifonctionnelle. Cette approche générale a été appliquée aux combinaisons suivantes : (i) gemcitabine (Gem)/rhodamine (Rho) et Gem/cyanine pour la libération de principes actifs et l’imagerie; (ii) aminoglutethimide (Agm)/doxorubicine (Dox), Gem/Dox and Gem/Lapatinib (Lap) pour la thérapie combinée et (iii) Gem/biotine pour la libération de principes actifs et le ciblage actif in vitro et in vivo. Les propriétés d’imagerie des nanoparticules de prodrogues polymères comportant une molecule fluorescente ont été étudiées in vitro et in vivo, respectivement en termes d’internalisation intracellulaire et de biodistribution. Pour les thérapies combinées, la cytotoxicité in vitro des différentes nanoparticules a été étudiée et comparée à celle émanant d’autres strategies de délivrance de deux principes actifs (e.g., conanoprécipitation, mélange physique de nanoparticules).Enfin, des prodrogues polymères hétérobifonctionnelles comprenant l’adénosine en début de chaîne et un motif maléimide en fin de chaine ont été préparées et fonctionnalisées en surface par des protéines capables de promouvoir le passage des nanoparticules à travers la barrière hémato-encéphalique pour libérer l’adénosine au niveau du cerveau. / A facile and versatile synthetic platform to prepare high drug loading, heterobifunctional polymer prodrug nanoparticles was developed by combining the “drug-initiated” method to obtain α-functional polymer prodrugs by nitroxide-mediated polymerization (NMP), and the nitroxide exchange reaction from a functional nitroxide to attach a second molecule of interest at the ω chain-end. A library of heterotelechelic polymers prodrugs with different combinations for various purposes (e.g., drug delivery, imaging/theranostic, combination therapy, active targeting) was prepared using polyisoprene (PI) as polymer scaffold. More specifically, an alkoxyamine based on the SG1 nitroxide was functionalized with the first drug of interest and used to perform the NMP of isoprene to yield the desired polymer prodrug. Subsequently, by applying the nitroxide exchange reaction using a TEMPO nitroxide functionalized with the second molecule of interest, the SG1 nitroxide at the chain-end was quantitatively replaced by the functional TEMPO and the desired heterobifunctional polymer prodrug was formed. This general methodology was applied to the following combinations: (i) gemcitabine (Gem)/rhodamine (Rho) and Gem/cyanine for drug delivery and imaging; (ii) aminoglutethimide (Agm)/doxorubicin (Dox), Gem/Dox and Gem/Lapatinib (Lap) for combination therapy and (iii) Gem/biotin for drug delivery and active targeting in vitro and in vivo. For polymer prodrug nanoparticles bearing fluorescent dyes, in vitro and in vivo imaging studies were performed to investigate their cellular internalization and their biodistribution, respectively. As for the different combination therapies, the in vitro cytotoxicity of the nanoparticles was determined and compared to that of other strategies to deliver two different drugs (e.g., conanoprecipitation, physical mixture of nanoparticles).Finally, heterobifunctional polymer prodrugs bearing adenosine in alfa position and a maleimide moiety in omega position were synthesized to give nanoparticles that were further surface-functionalized with different proteins able to promote crossing through the blood brain barrier for drug delivery to the brain.

Non-covalent interactions including nucleobase hydrogen bonding and phosphonium/ammonium ionic aggregation were studied in block and random polymers synthesized using controlled radical polymerization techniques such as nitroxide mediated polymerization (NMP) and reversible addition-fragmentation chain transfer polymerization (RAFT). Non-covalent interactions were expected to increase the effective molecular weight of the polymeric precursors through intermolecular associations and to induce microphase separation. The influence of non-covalent association on the structure/property relationships of these materials were studied in terms of physical properties (tensile, DMA, rheology) as well as morphological studies (AFM, SAXS). Ionic interactions, which possess stronger interaction energies than hydrogen bonds (~150 kJ/mol) were studied in the context of phosphonium-containing acrylate triblock (ABA) copolymers and random copolymers. Phosphonium-containing ionic liquid monomers with different alkyl substituent lengths and counterions enabled an investigation of the effects of ionic aggregation of phosphonium cations on the polymer physical properties. The polymerization of styrenic phosphonium-containing ionic liquid monomers using a difunctional alkoxyamine initiator, DEPN2, afforded an ABA triblock copolymer with an n-butyl acrylate soft center block and symmetric phosphonium-containing external reinforcing blocks. Small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) of triblock copolymers revealed pronounced microphase separation at the nanoscale. Phosphonium aggregation governed block copolymer flow activation energies. In random copolymers, the phosphonium cations only weakly aggregated, which strongly depended on the length of alkyl substituents and the type of counterions. Acrylate random copolymers consisting of quaternary ammonium functionalities were synthesized using reversible addition-fragmentation chain transfer polymerization (RAFT). The obtained copolymers possessed controlled compositions and narrow molecular weight distributions with molecular weights ranging from Mn =50,000 to 170,000 g/mol. DMA evidenced the weak aggregation of ammonium cations in the solid state. Additionally, this ionomer was salt-responsive in NaCl aqueous solutions. Hydrogen bonding, a dynamic interaction with intermediate enthalpies (10-40 kJ/mol) was introduced through complementary heterocyclic DNA nucleobases such as adenine, thymine and uracil. Our investigations in this field have focused on the use of DNA nucleobase pair interactions to control polymer self-assembly and rheological behavior. Novel acrylic adenine- and thymine-containing monomers were synthesized from aza-Michael addition reaction. The long alkyl spacers between nucleobase and polymer backbone afforded structural flexibility in self-assembly process. Adenine-containing polyacrylates exhibited unique morphologies due to adenine-adenine π-π interactions. The complementary hydrogen bonding of adenine and thymine resulted in disruption of adenine-adenine π-π interactions, leading to lower plateau modulus and lower softening temperatures. Moreover, hydrogen bonding interactions enabled the compatibilization of complementary hydrogen bonding guest molecules such as uracil phosphonium chloride. / Ph. D.