Nanophase-separated hydrophilic-hydrophobic multiblock copolymers are promising proton exchange membrane (PEM) materials due to their ability to form various morphological structures which enhance transport. Four arylene chlorides monomers (2,5-Dichlorobenzophenone and its derivatives) were first successfully synthesized from aluminum chloride-catalyzed, Friedel-Crafts acylation of benzene and various aromatic compounds with 2,5-dichlorobenzoyl chloride. These monomers were then polymerized via Ni (0)-catalyzed coupling reaction to form various high molecular weight substituted poly(2,5-benzophenone)s. Great care must be taken to achieve anhydrous and inert conditions during the reaction. A series of poly(2,5-benzophenone) activated aryl fluoride telechelic oligomers with different block molecular weights were then successfully synthesized by Ni (0)- catalyzed coupling of 2,5-dichloro-benzophenone and the end-capping agent 4-chloro-4'-fluorobenzophenone or 4-chlorophenly-4′-fluorophenyl sulfone. The molecular weights of these oligomers were readily controlled by altering the amount of end-capping agent. These telechelic oligomers (hydrophobic) were then copolymerized with phenoxide terminated disulfonated poly (arylene ether sulfone)s (hydrophilic) by nucleophilic aromatic substitution to form novel hydrophilic-hydrophobic multiblock copolymers. A series of novel multiblock copolymers with number average block lengths ranging from 3,000 to 10,000 g/mol were successfully synthesized. Two separate Tgs were observed via DSC in the transparent multiblock copolymer films when each block length was longer than 6,000 g/mol (6k). Tapping mode atomic force microscopy (AFM) also showed clear nanophase separation between the hydrophilic and hydrophobic domains and the influence of block length, as one increased from 6k to 10k. Transparent and creasable films were solvent-cast and exhibited good proton conductivity and low water uptake. These PAES-PBP multiblock copolymers also showed much less relative humidity (RH) dependence than random sulfonated aromatic copolymers BPSH 35 in proton conductivity, with values that were almost the same as Nafion with decreasing RHs. This phenomenon lies in the fact that this multiblock copolymer possesses a unique co-continuous nanophase separated morphology, as confirmed by AFM and DSC data. Since this unique co-continuous morphology (interconnected channels and networks) dramatically facilitates the proton transport (increase the diffusion coefficient of water), improved proton conductivity under partially hydrated conditions becomes feasible. These multiblock copolymers are therefore considered to be very promising candidates for high temperature proton exchange membranes in fuel cells. / Ph. D.

The isothermal crystallization and melting temperatures of poly(ε-caprolactone) were correlated using fast differential scanning calorimetry. The melting kinetics was found to be independent of isothermal crystallization temperature and time. The conventional Hoffman-Weeks method could not be used to determine the equilibrium melting temperature because the observed melting temperatures were greater than the crystallization temperatures by a constant, so the Gibbs-Thomson method was used instead, yielding an equilibrium melting temperature of 103.4 ± 2.3°C. A modification was proposed to the non-linear Hoffman-Weeks equation that included a non-linear undercooling dependence for the kinetic fold surface free energy upon crystallization and permitted accurate modeling of the observed melting behavior. The isothermal crystallization rates of four narrow molecular weight poly(ethylene oxide) fractions were characterized using fast differential scanning calorimetry for crystallization temperatures spanning 100°C range with the lower limit approaching the glass transition. A transition from homogeneous to heterogeneous primary nucleation was observed at −5°C. The kinetic analysis suggested that the crystal growth geometry depends strongly on temperature, where rod-like structures begin to appear near the glass transition temperature, highly branched solid sheaves grow throughout the homogeneous primary nucleation temperature range, and spherulites grow in the heterogenous primary nucleation range. Poly(δ-valerolactone) was synthesized using microwave-assisted techniques. Narrow molecular weight fractions were obtained using successive precipitation fractionation. Preliminary isothermal crystallization studies suggest that conventional thermal analysis methods are not adequate to measure the melting temperatures accurately due to reorganization during heating. / Doctor of Philosophy / Plastics may be classified into two general categories: those which form ordered domains upon solidification, i.e. undergo crystallization, and those which remain disordered upon solidification, i.e. form glasses. This work is focused on studying the crystallization and melting processes in two linear polymers, poly(ε-caprolactone) and poly(ethylene oxide), using new experimental technology. In the case of poly(ε-caprolactone), the experimental data could not be rationalized by existing theories, and we have proposed modifications to these theories that explained the results. In the case of poly(ethylene oxide), the application of new experimental technology resulted in previously unreported data that indicated novel behavior at very low crystallization temperatures. In the last portion of this work, poly(δ-valerolactone) was made using a novel approach. Conventional experimental approaches to measuring the crystallization and melting behavior were shown to be inadequate.

Poly(arylene ether sulfone)s are high-performance engineering thermoplastics that have been investigated extensively over the past several decades due to their outstanding mechanical properties, high glass transition temperatures (Tg), solvent resistance and exceptional thermal, oxidative and hydrolytic stability. Their thermal and mechanical properties are highly suited to a variety of applications including membrane applications such as reverse osmosis, ultrafiltration, and gas separation. This dissertation covers structure-property-performance relationships of poly(arylene ether sulfone) and poly(ethylene oxide)-containing random and segmented copolymers for reverse osmosis and gas separation membranes. The second chapter of this dissertation describes synthesis of disulfonated poly(arylene ether sulfone) random copolymers with oligomeric molecular weights that contain hydrophilic and hydrophobic segments for thin film composite (TFC) reverse osmosis membranes. These copolymers were synthesized and chemically modified to obtain novel crosslinkable poly(arylene ether sulfone) oligomers with acrylamide groups on both ends. The acrylamide-terminated oligomers were crosslinked with UV radiation in the presence of a multifunctional acrylate and a UV initiator. Transparent, dense films were obtained with high gel fractions. Mechanically robust TFC membranes were prepared from either aqueous or water-methanol solutions cast onto a commercial UDEL® foam support. This was the first example that utilized a water or alcohol solvent system and UV radiation to obtain reverse osmosis TFC membranes. The membranes were characterized with regard to composition, surface properties, and water uptake. Water and salt transport properties were elucidated at the department of chemical engineering at the University of Texas at Austin. The gas separation membranes presented in chapter three were poly(arylene ether sulfone) and poly(ethylene oxide) (PEO)-containing polyurethanes. Poly(arylene ether sulfone) copolymers with controlled molecular weights were synthesized and chemically modified to obtain poly(arylene ether sulfone) polyols with aliphatic hydroxyethyl terminal functionality. The hydroxyethyl-terminated oligomers and α-ω-hydroxy-terminated PEO were chain extended with a diisocyanate to obtain polyurethanes. Compositions with high poly(arylene ether sulfone) content relative to the hydrophilic PEO blocks were of interest due to their mechanical integrity. The membranes were characterized to analyze their compositions, thermal and mechanical properties, water uptake, and molecular weights. These membranes were also evaluated by collaborators at the University of Texas at Austin to explore single gas transport properties. The results showed that both polymer and transport properties closely related to PEO-content. The CO2/CH4 gas selectivities of our membranes were improved from 25 to 34 and the CO2/N2 gas selectivity nearly doubled from 25 to 46 by increasing PEO-content from 0 to 30 wt.% in polyurethanes. Chapter four also focuses on polymers for gas separation membranes. Disulfonated poly(arylene ether sulfone) and poly(ethylene oxide)-containing polyurethanes were synthesized for potential applications as gas separation membranes. Disulfonated polyols containing 20 and 40 mole percent of disulfonated repeat units with controlled molecular weights were synthesized. Poly(arylene ether sulfone) polyols and α,ω-hydroxy-terminated poly(ethylene oxide) were subsequently chain extended with a diisocyanate to obtain polyurethanes. Thermal and mechanical characterization revealed that the polyurethanes had a phase-mixed complex morphology. / Ph. D.

The controllable design of magnetic nanocarriers is essential for advanced in vivo applications such as magnetic resonance image-guided therapeutic delivery and alternating magnetic field-induced remote release of drugs. This work describes the fabrication of polymer-stabilized nanoparticles encapsulating imaging and therapeutic agents and delineates relationships among materials parameters and response. The effect of aggregation of magnetic iron oxide nanoparticles in aqueous suspension was characterized using a well-defined core-corona complex comprised of a superparamagnetic magnetite nanoparticle stabilized by terminally-anchored poly(N-isopropylacrylamide) (PNIPAM) corona. The modified Vagberg density distribution model was employed to verify that the complexes were individually dispersed prior to aggregation and was found to accurately predict the intensity-weighted hydrodynamic diameter in water. Aggregation of the complexes was systematically induced by heating the suspension above the lower critical solution temperature (LCST) of the polymer, and substantial increase in the NMR transverse relaxation rates was noted. Controlled clusters of primary iron oxide nanoparticles stabilized by the biodegradable block copolymer, poly(ethylene oxide-b-D,L-lactide) were fabricated by a scalable, rapid precipitation technique using a multi-inlet vortex mixer. Quantitative control over iron oxide loading, up to 40 wt%, was achieved. Correlations between particle parameters and transverse relaxivities were studied within the framework of the analytical models of transverse relaxivity. The experimental relaxivities typically agreed to within 15% with the values predicted using the analytical models and cluster size distributions derived from cryo-transmission electron microscopy. Hydrophilic-core particles assembled using the poly(ethylene oxide-b-acrylate) copolymer and at similar primary nanoparticle sizes and loadings had considerably higher transverse (r2) and longitudinal (r1) relaxivities, with r2s approaching the theoretical limit for ~ 8 nm magnetite. Block copolymer nanoparticles comprised of poly(D,L-lactide) and poly(butylene oxide) cores were utilized to encapsulate the poorly water-soluble antiretroviral drug, ritonavir, at therapeutically-useful loadings. Controlled size distributions were achieved by incorporation of homopolymer additives, poly(L-lactide) or poly(butylene oxide) during the nanoparticle preparation process. Nanoparticles either co-encapsulating a highly hydrophobic polyester poly(oxy-2,2,4,4-tetramethyl-1,3-cyclobutanediyloxy-1,4-cyclohexanedicarbonyl) within the core or possessing crosslinkable groups around the core were also successfully fabricated for potential sustained release of ritonavir from block copolymer carriers. / Ph. D.

Background: There is a growing understanding that different kinds of interpersonal violence are interrelated. Many victims report experiences of cumulative violence, i.e., being subjected to more than one kind of violent behaviour (sexual, physical, emotional) and/or violence from more than one kind of perpetrator (family members, partners, acquaintances/strangers). To gain a more comprehensive understanding of what violence entails for victims, how victims can be helped and how violence can be prevented, there is a need to learn more about the co-occurrence of violence. Also, despite strong associations repeatedly being found between exposure to violence and the reporting of different kinds of ill-health, only a minority of victims have told health care professionals about their victimization. Less is known about the process of disclosing victimization to health care professionals for men than for women. Main aims: 1) Investigate the prevalence and co-occurrence of self-reported lifetime experiences of different kinds of interpersonal violence among male and female clinical and random population samples in Sweden (Study I-II). 2) Investigate whether cumulative violence is more strongly associated with       self-reported symptoms off psychological ill-health than with any kind of victimization alone (Study III).   3) Develop a theoretical model concerning male victims’ process of disclosing experiences of victimization to health care professionals in Sweden (Study IV).   Method: The self-reported prevalence of interpersonal violence as well as self-reported symptoms of psychological ill-health were estimated by means of secondary analyses of data collected with the NorVold Abuse Questionnaire (NorAQ). Both sexes were represented in clinical (women n=2439 men n=1767) and random population samples (women n=1168 men n=2924). Descriptive statistics as well as binary logistic regression and ordinal regression analyses were used (Study I-III). In study IV, constructivist grounded theory was used, and 12 men were interviewed concerning their experience of disclosing victimization to health care professionals. Results: A large proportion of victims (women: 47-48%, men: 29-31%) reported experiences of more than one kind of violent behaviour. Many also reported being subjected to violence by more than one kind of perpetrator (women: 33-37%, men: 22-23%). Reporting cumulative violence had a stronger association with symptoms of psychological ill-health than reporting only one kind of victimization. In study IV, the interviewed men’s own perceptions and considerations beforehand (e.g., perceived need for help and feelings of shame), as well as the dynamics during the actual health care encounter (e.g., patient-provider relationship and time constraints), were essential for understanding the process of disclosure. Also, the men’s own conformity to hegemonic constructions of masculinity and professionals’ adherence to gender norms had a strong negative influence on the men’s process of disclosure. Discussion: Experiences of cumulative violence were common. Prevalence rates of experiences of different kinds of interpersonal violence were compared to previous studies on interpersonal violence in Sweden. Large discrepancies were found between all studies, which is a symptom of methodological and conceptual difficulties within the research field. Violence is a gendered phenomenon. Differences were seen in the kind of violence men and women reported. In addition to this, the results in study IV indicate that gender affects how violence is perceived and how victims are treated by health care professionals. Conclusion: Integrated approaches in research on interpersonal violence, as well as in clinical work, are needed. If the co-occurrence of violence is ignored, it may hamper our understanding of the experiences and consequences of interpersonal violence for victims. More research is needed into what produces the differences found in prevalence rates between studies to improve the methodology.

Block copolymer (BCP) thin film patterns, generated using directed self-assembly (DSA) of diblock copolymers, have shown excellent promise as templates for semiconductor device manufacturing since they have the potential to produce feature pitches and sizes well below 20 nm and 10 nm, respectively, using current 193 nm optical lithography. The goal of this work is to explore block copolymers with sufficient thermodynamics driving force (as described by the Flory Huggins interaction parameter, χ) for phase separation at these smallest lengths scales. Here, poly(styrene)-b-poly(hydroxystyrene) is investigated since the PHOST domain is known to form extensive hydrogen bond networks resulting in increased χ due to this strong enthalpic interaction. In this work, nitroxide mediated polymerization (NMP) techniques were utilized to produce PS-b-PHOST diblock copolymers with a range of molecular weights (5000-30000) with low PDI approaching 1.2. The phase separation of low molecular weight PS-b-PHOST on neutral underlayer substrates via solvent annealing provided thin film vertical lamellae with 13 nm pitch. These results illustrate the improved resolution of PS-b-PHOST compared with the current industry standard of PS-b-PMMA (with 20 nm pitch). The directed self assembly of lamellar PS-b-PHOST patterns with 18 nm pitch via graphoepitaxy is demonstrated. Also, a highly selective atomic layer deposition (ALD) and etch technique was investigated which provided selective block removal of (PS-b-PHOST) block copolymer patterns which initially exhibited no inherent etch contrast. In this process, the PS domain is removed leaving a high fidelity etch relief pattern of the original block copolymer template. Finally, an alternative system is presented, namely Poly(trimethylsilylstyrene)-block-poly(hydroxystyrene) (PTMSS-b-PHOST), which utilizes silicon containing functionality in one of the blocks, providing high etch contrast. PTMSS-b-PHOST patterns were also exposed to oxygen plasma allowing selective block removal of the PS domain without the need for additional ALD processing steps.

The fields of tissue engineering, regenerative medicine, and stem cell engineering are rapidly growing. However, these fields must overcome several obstacles before they can make a significant impact on treating cellular disorders. Two major hurdles that must be addressed are: determining how to control the pluripotency of stem cells and developing systems for high-throughput culture of stem cells. The prospect of using a cell source capable of differentiating into cells of any tissue in the body (embryonic stem cells) has received enormous interest in recent years. The pluripotent attribute of embryonic stem cells seems ideal but developing methods to drive embryonic stem cells to specific lineages, including the hematopoietic lineage, is a complex process dependent on multiple intrinsic and extrinsic factors including chemical, cellular, and environmental signaling. With regards to environmental signaling, the use of three-dimensional culture systems such as scaffolds and hydrogels, have been utilized in an attempt to drive lineage-specific differentiation in a synthetic, biomimetic microenvironment. To determine specific environmental factors responsible for hematopoietic differentiation a systematic biological and engineering process must be implemented. A biodegradable hydrogel composed of the hyaluronic acid, a polysaccharide abundant in the bone marrow microenvironment, and the synthetic polymer, poly(ethylene glycol) was formulated to culture mouse embryonic stem cells (mESCs). Photoencapsulation of mESCs did not significantly decrease cellular viability or proliferation. The FACS data was inconclusive however, from gene expression studies, it was determined that the hydrogel culture system promoted differentiation of mESCs as evidenced by a down-regulation of the gene encoding for stem cell maintenance transcription factor, Oct-3/4. Furthermore, embryoid bodies, necessary for in vitro differentiation were observed in the hydrogel systems. Although an increase in the gene encoding for the cell surface marker, c-kit was up-regulated, the surface marker, sca-1 was not up-regulated. Up-regulation of both c-kit and sca-1 is necessary for the development of hematopoietic progenitor cells. Results indicate that the differentiation of mESCs into the hematopoietic lineage was unsuccessful but differentiation in these hydrogel systems did occur. Future cell marker and gene expression studies are necessary to determine which cell lineage the encapsulated mESCs are differentiating into before the effects of incorporating other environmental, cellular, and chemical factors can be investigated. / text

Poly is a novel, essential protein in Drosophila melanogaster, loss of function of which results in late larval lethality. Importantly, Poly is evolutionarily conserved with a human homologue. poly mutation was isolated in a P-element mutagenesis screen that aimed to generate a larger collection of single P-element induced mutants. Mutant poly larvae are characterized by extreme larval longevity without pupation, formation of melanotic masses, smaller imaginal discs and brains, and abnormal nuclear morphology in neuroblasts. During the course of my project, I attempted to identify cellular processes and pathways that Poly might be involved in. Interestingly, my data suggest that Poly is a novel interactor and regulator of Insulin receptor/target of rapamycin (InR/TOR) signalling in Drosophila. Linking environmental cues to cell growth and metabolism is an essential process that multicellular organisms need to accomplish successfully for normal development. InR/TOR signalling is a highly conserved pathway that mediates the link between the environment and cellular processes such as growth, metabolism and ageing. My analysis in Drosophila suggests that Poly interacts physically with the InR and mutation of Poly leads to an overall down-regulation of InR/TOR signalling in Drosophila as revealed by decreases in the phosphorylation levels of Akt, S6K and 4E-BP - all downstream effectors of this pathway. In addition, loss of poly results in constitutive activation of autophagy in Drosophila fat body and a decrease in stored triglyceride levels. Furthermore, I show that localisation and levels of Poly protein are dependent on insulin action in both Drosophila and human cells. Together, these data suggest that Poly is a novel mediator of InR signalling that promotes an increase in cell growth and metabolism. Taking into consideration the observed poly mutant phenotype, I also investigated the potential involvement of Poly during cell cycle progression and the Drosophila innate immune response. While my analysis suggests that poly loss of function does not have a direct effect on cell cycle progression, alteration of Poly has consequences on various aspects of the Drosophila innate immune response. Therefore, I conclude that the Drosophila innate immune response is a cellular process in which Poly plays a crucial role.

Master of Science / Department of Chemistry / Santosh Aryal / Nanomedicine-based therapeutics have exhibited clear benefits when compared to unmodified drugs, which include improved pharmacokinetics, drug retention, targeting efficiency, and minimizes toxicity. Every year thousands of bone cancer cases are diagnosed in the United States. Moreover, development of bone metastasis occurs in over 80% to 90% of various cancers that metastasize and signals the entry of the disease into an incurable phase. Cancer in bones can cause pain, fractures, hypercalcemia, and compression of the spinal cord, due to deposits that can erode into the bone using bone-absorbing cells. Bisphosphonates are drugs that reduce the activity of bone-absorbing cells and targets overexpressed calcium. They are characterized pharmacologically to inhibit bone resorption, skeletal distribution, and renal elimination. In addition, they can target bone microenvironment and bind strongly with calcium. The goal of this thesis is to engineer targeted nanomedicine drug with the ability to spatiotemporally control therapeutics delivery to the bone. Herein we synthesized biopolymers with functional end group moieties as alendronate (a molecular member of bisphosphate), which can target overexpressed calcium ions at the vicinity of the bone lesion where bone resorption takes place. In order to achieve our goal, a ring opening polymerization of cyclic L-lactide initiated by ALE in the presence of catalytic amount of stannous octoate was conducted in an inert environment. Thus, formed polymers are characterized for their chemistry and physicochemical properties using various analytical tools. These polymers were characterized by nuclear magnetic resonance (¹H-NMR) and Fourier Transfer Infrared Spectrometer (FT-IR), which shows monomer conversion and the presence of amide and phosphate moiety. Thereafter we engineered bone-homing polymeric nanoparticles of 80nm diameter by nanoprecipitation for controlled delivery of Dox, a first line anticancer drug used in clinics. The in-vitro results show that the nanoparticles have the ability to accumulate and internalized into the bone cancer cells, deliver drugs efficiently, and are least toxic. Therefore, innovative and efficient bisphosphonate functionalized Poly-l-lactide polymers were synthesized to target bone microenvironment.

Les nanotechnologies appliquées aux sciences pharmaceutiques ont pour but d’améliorer l’administration de molécules actives par l’intermédiaire de transporteurs nanométriques. Parmi les différents types de véhicules proposés pour atteindre ce but, on retrouve les nanoparticules polymériques (NP) constituées de copolymères “en bloc”. Ces copolymères permettent à la fois l’encapsulation de molécules actives et confèrent à la particule certaines propriétés de surface (dont l’hydrophilicité) nécessaires à ses interactions avec les milieux biologiques. L’architecture retenue pour ces copolymères est une structure constituée le plus fréquemment de blocs hydrophiles de poly(éthylène glycol) (PEG) associés de façon linéaire à des blocs hydrophobes de type polyesters. Le PEG est le polymère de choix pour conférer une couronne hydrophile aux NPs et son l’efficacité est directement liée à son organisation et sa densité de surface. Néanmoins, malgré les succès limités en clinique de ces copolymères linéaires, peu de travaux se sont attardés à explorer les effets sur la structure des NPs d’architectures alternatives, tels que les copolymères en peigne ou en brosse. Durant ce travail, plusieurs stratégies ont été mises au point pour la synthèse de copolymères en peigne, possédant un squelette polymérique polyesters-co-éther et des chaines de PEG liées sur les groupes pendants disponibles (groupement hydroxyle ou alcyne). Dans la première partie de ce travail, des réactions d’estérification par acylation et de couplage sur des groupes pendants alcool ont permis le greffage de chaîne de PEG. Cette méthode génère des copolymères en peigne (PEG-g-PLA) possédant de 5 à 50% en poids de PEG, en faisant varier le nombre de chaînes branchées sur un squelette de poly(lactique) (PLA). Les propriétés structurales des NPs produites ont été étudiées par DLS, mesure de charge et MET. Une transition critique se situant autour de 15% de PEG (poids/poids) est observée avec un changement de morphologie, d’une particule solide à une particule molle (“nanoagrégat polymére”). La méthode de greffage ainsi que l’addition probable de chaine de PEG en bout de chaîne principale semblent également avoir un rôle dans les changements observés. L’organisation des chaînes de PEG-g-PLA à la surface a été étudiée par RMN et XPS, méthodes permettant de quantifier la densité de surface en chaînes de PEG. Ainsi deux propriétés clés que sont la résistance à l’agrégation en conditions saline ainsi que la résistance à la liaison aux protéines (étudiée par isothermes d’adsorption et microcalorimétrie) ont été reliées à la densité de surface de PEG et à l’architecture des polymères. Dans une seconde partie de ce travail, le greffage des chaînes de PEG a été réalisé de façon directe par cyclo-adition catalysée par le cuivre de mPEG-N3 sur les groupes pendants alcyne. Cette nouvelle stratégie a été pensée dans le but de comprendre la contribution possible des chaines de PEG greffées à l’extrémité de la chaine de PLA. Cette librairie de PEG-g-PLA, en plus d’être composée de PEG-g-PLA avec différentes densités de greffage, comporte des PEG-g-PLA avec des PEG de différent poids moléculaire (750, 2000 et 5000). Les chaines de PEG sont seulement greffées sur les groupes pendants. Les NPs ont été produites par différentes méthodes de nanoprécipitation, incluant la nanoprécipitation « flash » et une méthode en microfluidique. Plusieurs variables de formulation telles que la concentration du polymère et la vitesse de mélange ont été étudiées afin d’observer leur effet sur les caractéristiques structurales et de surface des NPs. Les tailles et les potentiels de charges sont peu affectés par le contenu en PEG (% poids/poids) et la longueur des chaînes de PEG. Les images de MET montrent des objets sphériques solides et l'on n’observe pas d’objets de type agrégat polymériques, malgré des contenus en PEG comparable à la première bibliothèque de polymère. Une explication possible est l’absence sur ces copolymères en peigne de chaine de PEG greffée en bout de la chaîne principale. Comme attendu, les tailles diminuent avec la concentration du polymère dans la phase organique et avec la diminution du temps de mélange des deux phases, pour les différentes méthodes de préparation. Finalement, la densité de surface des chaînes de PEG a été quantifiée par RMN du proton et XPS et ne dépendent pas de la méthode de préparation. Dans la troisième partie de ce travail, nous avons étudié le rôle de l’architecture du polymère sur les propriétés d’encapsulation et de libération de la curcumine. La curcumine a été choisie comme modèle dans le but de développer une plateforme de livraison de molécules actives pour traiter les maladies du système nerveux central impliquant le stress oxydatif. Les NPs chargées en curcumine, montrent la même transition de taille et de morphologie lorsque le contenu en PEG dépasse 15% (poids/poids). Le taux de chargement en molécule active, l’efficacité de changement et les cinétiques de libérations ainsi que les coefficients de diffusion de la curcumine montrent une dépendance à l’architecture des polymères. Les NPs ne présentent pas de toxicité et n’induisent pas de stress oxydatif lorsque testés in vitro sur une lignée cellulaire neuronale. En revanche, les NPs chargées en curcumine préviennent le stress oxydatif induit dans ces cellules neuronales. La magnitude de cet effet est reliée à l’architecture du polymère et à l’organisation de la NP. En résumé, ce travail a permis de mettre en évidence quelques propriétés intéressantes des copolymères en peigne et la relation intime entre l’architecture des polymères et les propriétés physico-chimiques des NPs. De plus les résultats obtenus permettent de proposer de nouvelles approches pour le design des nanotransporteurs polymériques de molécules actives. / The goal set to nanotechnologies applied to pharmaceutical sciences is to improve drug delivery and benefits with the help of nanometer-sized vehicles. At this time different types of drug carriers had been proposed. Amongst them, block copolymer nanoparticles (NP) have been designed to allow, at the same time, efficient drug encapsulation and provide surface properties (hydrophilic layer) to the NP which are necessary for its interactions with biological systems by preventing the opsonisation and the subsequent recognition by the mononuclear macrophage system (MPS) and the rapid elimination of the drug carrier. The most prominent polymer architecture in drug delivery application is the linear di-block copolymer architecture, such as poly(ethylene glycol) blocks (PEG) linked to a polyester hydrophobic chain. PEG is the gold standard to add a hydrophilic corona to drug carrier’s surface, but its efficacy is directly linked to its surface organization and surface densities. In spite of limited success of diblock at the clinical stage, few studies have been devoted to other type of architecture such as comb-like copolymers, either for the exploration of new synthesis routes or for the characterization of particles prepared from alternative architecture polymers. We attempted in preamble of this work to define more closely the conceptual and technical framework allowing quantitative determination of PEG surface densities. This review work has been used in the experimental work to define the characterization methods. Several synthesis strategies have been developed for the preparation of comb copolymers in this work. All strategies are based on random copolymerization of dilactide with small epoxy molecules with a pendant group suitable for subsequent PEG grafting, yielding a polyester-co-ether backbone. In a second step, PEG chains have been grafted on available pendant groups (alcohol groups or alkyne) to produce the final comb copolymers. In the first part of the experimental work, esterification reaction by acylation and coupling (the Steglish reaction) allowed the preparation of a first comb-like copolymer library with PEG content varying from 5 to 50 % (w/w). The number of PEG chains (PEG grafting density) was varying while the lengths of the PEG chains and the hydrophobic PLA backbone were kept constant. The library of comb-like polymers was used to prepare nanocarriers with dense PEG brushes at their surface, stability in suspension, and resistance to protein adsorption. The structural properties of nanoparticles (NPs) produced from these polymers by a surfactant-free method were assessed by DLS, zeta potential, and TEM and were found to be controlled by the amount of PEG present in the polymers. A critical transition from a solid NP structure to a soft particle with either a “micelle-like” or “polymer nano-aggregate” structure was observed when the PEG content was between 15 to 25% w/w. This structural transition was found to have a profound impact on the size of the NPs, their surface charge, their stability in suspension in presence of salts as well as on the binding of proteins to the surface of the NPs. The arrangement of the PEG-g-PLA chains at the surface of the NPs was investigated by 1H NMR and X-ray photoelectron spectroscopy (XPS). NMR results confirmed that the PEG chains were mostly segregated at the NP surface. Moreover, XPS and NMR allowed the quantification of the PEG chain coverage density at the surface of the solid NPs. Concordance of the results between the two methods was found to be remarkable. Physical-chemical properties of the NPs such as resistance to aggregation in saline environment as well as anti-fouling efficacy, assessed by isothermal titration calorimetry (ITC), were related to the PEG surface density and ultimately to polymer architecture. In the second part of this work, grafting of PEG chains on a polyester-co-ether backbone was directly performed using cyclo-addition of PEG azide on pendant alkyne groups. The new strategy was designed to understand the contribution of PEG chains grafted on PLA backbone ends. The new polymer library was composed of PEG-g-PLA with different PEG grafting densities and PEG molecular weights (750, 2000 and 5000 D). PEG chain grafting could only take place on pendant groups with this approach. NPs were produced by different methods of nanoprecipitation, including “flash nanoprecipitation” and microfluidic technology. Some formulation variables such as polymer concentration and speed of mixing were studied in order to observe their effects on NP surface characteristics. Unlike for the first copolymer library, here the NPs size and zeta potential were found to not be much affected by the PEG content (% w/w in polymer). Sizes were also not affected by the PEG chains length. TEM images show round shaped object and as expected sizes were found to decrease with polymer concentration in the organic phase and with a decrease in mixing time of the two phases (for flash nanoprecipitation and microfluidic technology). PEG chain surface densities were assessed by quantitative 1H NMR and XPS. In the third experimental part, we explored the role of polymer architecture on drug encapsulation and release of curcumin from NPs. Curcumin has been chosen as a model with a view to develop a delivery platform to treat diseases involving oxidative stress affecting the CNS. As previously observed with blank NPs, a sharp decrease in curcumin-loaded NP size and morphology change occurred between 15 to 20 % w/w of PEG. Drug loading, Drug loading efficiency and the diffusion coefficients of curcumin in NPs are showing a dependence over the polymer architecture. NPs did not present any significant toxicity when tested in vitro on a neuronal cell line. Moreover, the ability of NPs carrying curcumin to prevent oxidative stress was evidenced and linked to polymer architecture and NPs organization. In a nutshell, our study showed the intimate relationship between the polymer architecture and the biophysical properties of the resulting NPs and sheds light on new approaches to design efficient NP-based drug carriers. The results obtained lead us to propose PEG-g-PLA comb architecture copolymers for nanomedecine development as an alternative to the predominant polyester-PEG diblock polymers.