Thesis (Ph. D.)--University OF MICHIGAN.

Abstract: Drug dosage forms contain many components in addition to the active pharmaceutical ingredient(s) to assist in the manufacturing process as well as to optimise drug delivery. Due to advances in drug delivery technology, excipients are currently included in novel dosage forms to fulfil specific functions and in some cases they directly or indirectly influence the extent and/or rate of drug release and absorption. Since plant polysaccharides comply with many requirements expected of pharmaceutical excipients such as non-toxicity, stability, availability and renewability they are extensively investigated for use in the development of solid oral dosage forms. Furthermore, polysaccharides with varying physicochemical properties can be extracted from plants at relatively low cost and can be chemically modified to suit specific needs. As an example, many polysaccharide-rich plant materials are successfully used as matrix formers in modified release dosage forms. Some natural polysaccharides have even shown environmental-responsive gelation characteristics with the potential to control drug release according to specific therapeutic needs. This review discusses some of the most important plant-derived polymeric compounds that are used or investigated as excipients in drug delivery systems.

Functionalized nano materials have an expansive range of potential uses in bio medical applications. Functionalized synthetic (biocompatible and/or biodegradable) polymers that control or monitor cell signaling can be effective antagonists and promising drug candidates. We have developed a series of biodegradable functional polymer systems (with dimensions in the nanoscale) for creating allergy-effective drugs, using RBL mast cells and anti-2,4 dinitrophenyl (DNP) IgE antibodies that sensitize these cells by binding to high affinity IgE receptors(FceRI); creating polymers which are effective inhibitors of degranulation of mast cells stimulated by a potent allergen. The inhibition is possible because of the specific interaction of the functional polymers with the proteins (IgE) on the mast cell surfaces to control cell-signaling i.e. intelligent design of functional materials to manipulate cellular functions. The functional polymer system is based on biodegradable poly(lactides) carrying two, three or four 2,4-dinitrophenyl (DNP) groups. Although these DNP-functionalized ligands do not stimulate the granule exocytosis response, they have the potential to inhibit the robust response stimulated by other multivalent DNP ligands. These polymeric ligands are effective inhibitors of degranulation of mast cells stimulated by a potent allergen and thus are a potential model drug system. Additionally these lactide based polymers bind and achieve steady state binding with solution IgE within a few seconds at low concentrations; achieving about 75% of the binding below 0.2 uM. The preparation, characterization, processing and effectiveness of the functional polymers to control material-cell interactions will be discussed

The post-polymerization functionalization, characterization and application of block copolymers, hydrogels and cross-linked polymeric micro-beads to particular pharmaceutical and environmental applications are the focus of this thesis. The synthesis of a new amphiphilic and cationic block copolymer, polystyrene- b-poly(N,N,N-trimethylammoniumethylene acrylamide chloride) (PS- b-PTMEACl), from polystyrene-b-poly(tert-butylacrylate) (PS-b-P(tBuA)) is presented. The morphology of the self-assembled copolymers in water is assessed, and finally, we evaluate the potential of this nanoscale system as a bile acid sequestrant. Bile salts represent the major elimination route for cholesterol from the body and bile salt sequestrants have an established reputation as highly effective agents in the facilitation of this elimination. / We also present the functionalization of a series of carbomers and their favorable bile salt binding properties. The synthetic methods were adapted from the post-polymerization functionalization of PS-b-PtBuA. / The peculiar insolubility of ammonium tetraphenylborate in water was the fundamental property exploited in the research described in the final Chapter, where rather than ammonium-ion bearing polymers, ammonium-ion binding polymers are presented. Cross-linked PS resins were functionalized to contain pendent tetraphenylborate moieties and the ammonium-ion sequestering properties of this novel material were investigated. (Organo)ammonium ions from chemical and agro-industrial sources represent a major environmental hazard and our efforts contribute to the elimination of these toxins from effluent.

Polystyrene (PS), functionalized with various ionic groups, was blended with polyamides (PA) in order to investigate the effect of ion-dipole interactions on the miscibility of PS/PA blends. Sulfonic acid groups interact strongly with amides, but catalyze the hydrolysis of the amide bonds of the PA. The neutralization of the sulfonic acid groups eliminates this reaction in the blends, and when the counterion is lithium, strong miscibility enhancement is seen between the lithium sulfonated polystyrene (LiSPS) and polyamides-6 (PA-6), $-$66, $-$610 and $-$11. This miscibility enhancement increases with the lithium sulfonate content of the LiSPS and the amide content of the PA, and is also dependent on the blend composition. An equilibrium thermodynamic approach is used to describe the miscibility behavior of the LiSPS blends with PA-6. When the ionic group is sodium sulfonate, lithium carboxylate or sodium carboxylate, the miscibility enhancement is negligible. As a possibly better alternative to the PS ionomers as a blend component with PAs, novel sulfonated poly(styrene-ethylene-butylene)random ionomers were synthesised and characterized.

We have used the living ring-opening metathesis polymerization (ROMP) reaction with C12(PCy3)2Ru=CHPh to generate a new class of conjugated polymer precursors containing the reactive group 1,2-dichlorocarbonate in their backbone. These polymers possess narrow molecular weight distributions and are easily processable. We have incorporated the 1,2-dichlorocarbonate monomers into block copolymers and have shown that these systems can self-assemble in selective solvents to generate spherical micellar aggregates, as observed by transmission electron microscopy (TEM). Mild hydrolytic treatment of these precursor polymers converts them into novel low band-gap conjugated polymers and block copolymers containing 1,2-diol groups in their backbone. We then report the first synthesis of a ROMP monomer containing the luminescent Ru(phen)32+ moiety. We describe the synthesis, X-Ray structure, electrochemical and photophysical characterization of this novel monomer. Preliminary ROMP studies showed that an oligomeric product is obtained. This oligomer has photophysical and luminescent properties similar to those of the monomer, indicating that the Ru(phen)32+ moiety remained intact during the polymerization. This can potentially lead to the generation of a new class of Ru(phen)32+—containing conjugated polymers. We then used this highly efficient polymerization technique to generate DNAmimetic polymers and copolymers. Polymers with narrow molecular weight distributions and controlled architectures were generated by living ROMP of exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide. The dicarboximide units have been previously shown to exhibit biological activity, can selectively bind to the nucleic acid base adenine by hydrogen-bonding, and are readily functionalizable. Block copolymers containing these moieties were generated, and underwent self-assembly into nanoscale spherical aggregates, with surface localized molecular recognition motifs. In chapter five, we report the f

Research in the self-assembly properties of block copolymers in solution is an established field. Micellar block copolymer aggregates have transcended the fascination of those who study these materials into a broad range of advanced applications. The general goals in materials research revolve around gaining access to new structures, or simplifying pathways of producing known structures, and understanding their behavior in various environments. The morphological dynamics of block copolymer micelles, in response to external changes, have been exploited for a variety of purposes. The present thesis describes crystallinity-driven dynamic behavior that is intrinsic to block copolymer micelles bearing a polycaprolactone core. The first part is concerned with the morphological dynamics of spherical poly(ethylene oxide)-block-polycaprolactone micelles and their relevance to potential pharmaceutical applications. Following nucleation within the micelle core, which transforms micelles into metastable structures, spheres change into elongated rods or ribbons in a reproducible and predictable manner, which is also reversible at temperatures above the melting point. In the next part, homopolymer additives are employed to enhance this crystallinity-induced self-assembly behavior, yielding large lamellar aggregates akin to single crystals of the block copolymer. The uptake of homopolymer chains during micellization has no effect on morphology at first; however, following core crystallization, spherical micelles associate to form rods, which then form lamellae by alignment and coalescence. The self-assembly of supramolecular rods in two dimensions, which was given the name "raft" formation, to yield a discrete lamellar object has not been encountered before. The morphogenic effects of homopolymers are investigated in greater detail in the following part of this thesis, where the phenomenon is attributed to fractional crystallization within the micelle core: surface-exposed homopolymers bridge micellar species together in either one or two dimensions. This materials design principle is applied successfully to polyelectrolyte-stabilized micelles bearing chains of poly(acrylic acid) in the corona. In the final part of this thesis, chain-end modified copolymers are prepared and their self-assembly properties investigated. Spherical micelle formation is unaffected by the functional groups that are introduced, and these spheres also resist morphological change. Surprisingly, some derivatives show signs of phase separation within the micelle core, forming electron-dense nanodomains. Overall, this thesis illustrates how morphology in core-crystalline micelle systems is a dynamic parameter, and that control over these dynamics offers the opportunity to design novel and functional materials. / Les copolymères à blocs contenant des chaines macromoléculaires chimiquement incompatibles peuvent, dans les conditions appropriées, former des agrégats micellaires. Les principaux objectifs de la recherche sur ces matériaux auto-assemblés sont la production de nouvelles structures et le développement de méthodes synthétiques; dans un contexte technologique, il est essentiel de pouvoir prédire les propriétés des matériaux en fonction de leur environnement. Cette thèse porte sur la morphologie des micelles de copolymères à blocs contenant un segment de polycaprolactone et, en particulier, sur les paramètres qui affectent l'évolution de la cristallisation de ce segment. L'aspect des micelles de poly(oxyethylène)-bloc-polycaprolactone est présenté dans la première partie de cette thèse, ces micelles biodégradables ayant déjà démontré un grand potentiel dans le domaine pharmaceutique. Telles que produites, ces micelles ont une morphologie sphérique; par contre, suite à la cristallisation dans le centre de la structure, les micelles se transforment, d'une manière bien définie, en cylindres ou en lamelles élongées. Notamment, on observe le processus inverse à des températures supérieures au point de fusion du polycaprolactone. La seconde partie de cette thèse présente l'utilisation de chaines homopolymères de polycaprolactone, grâce auxquelles il est devenu possible d'obtenir des agrégats lamellaires, semblables à des monocristaux de poly(oxyethylène)-bloc-polycaprolactone, par un processus d'auto-assemblage qui n'a jamais été observé auparavant. En bref, des micelles sphériques contenant ces chaines homopolymères forment, en premier lieu, des cylindres, et l'association latérale de ces cylindres produit des lamelles. L'impact des chaines homopolymères sur la morphologie est décrit en plus de détails dans la section suivante. Un lien est établi entre ces effets et la cristallisation fractionnée dans le centre des micelles: rejetées par la majeure partie du volume cristallin contenu dans la micelle, les chaines homopolymères, par un simple manque d'espace dans une structure aux dimensions nanométriques, s'accumulent près de la surface. Ainsi, les chaines homopolymères facilitent l'adhésion entre les micelles pour en produire soit des cylindres ou des lamelles ayant un taux de cristallinité accru, ce phénomène se produisant même pour des micelles portant en surface des chaines de poly-électrolytes. L'ultime partie de cette thèse se concentre sur l'auto-assemblage de copolymères modifiés au terminus du segment de polycaprolactone. La modification des copolymères n'a aucun effet sur la formation de micelles, ces dernières étant même stabilisées pour ce qui est des changements morphologiques. Cependant, l'observation de la structure interne des micelles a révélé l'organisation spontanée des groupes qui y ont été introduits, pour en former des domaines nanométriques d'une composition chimique différente du reste de la micelle. Dans l'ensemble, le but de cette thèse est de démontrer comment la cristallinité de micelles macromoléculaires peut faire de la morphologie un paramètre dynamique, une relation qui pourrait donner accès à de nouveaux matériaux fonctionnels.

The remarkable molecular recognition specificity of DNA, combined with its structural and biological properties, makes it useful as a programmable and addressable building block for materials science. The materials constructed from nucleic acids have expanded the role of DNA and RNA beyond biology, into a useful component of advanced synthetic materials. The study of DNA self-assembly is rapidly evolving and will most likely find new and unforeseen applications ranging from medicine and biology to nanoelectronics and nano-optics. The error-free and predictable self-assembly of DNA over many length scales is necessary for their use as components of nanodevices and in nanomedicine. The work within this thesis describes an investigation of the self-assembly properties of DNA-macromolecule conjugates with a goal towards predictable long-range order. Conceptually, the work presented in this thesis can be divided into three parts. (1) The first part describes methods to introduce the long-range order achieved by block copolymer assemblies into DNA strands. We present the synthesis of DNA amphiphiles and their hierarchical assembly into nanofibers and ordered networks. (2) In the second part, we use a monodisperse 3D DNA nanoconstruct to direct alkyl chain aggregation below their critical micelle concentration (CMC) through DNA's base pairing ability. (3) The last part describes the hierarchical placement of DNA amphiphiles and of their assemblies along DNA nanotubes. The work described herein offers insight into the synthesis and self-assembly properties of DNA-macromolecule conjugates, and into their hierarchical self-assembly with DNA nanostructures. / En vertu de la fidélité de ses interactions supramoléculaires, ainsi que ses caractéristiques structurales et biologiques, l'ADN est un ajout programmable, contrôlable et, donc, extrêmement utile dans la science des matériaux. Face aux progrès établis dans ce domaine, le rôle de l'ADN et de l'ARN n'est plus restreint qu'à la biologie; en effet, les atouts des acides nucléiques en tant que composants de matériaux synthétiques avancés en sont plusieurs. L'étude de l'auto-assemblage de l'ADN est en évolution vive, axée plutôt vers des réalisations futures au niveau médical, biologique, nano-électronique et nano-optique. Pour que l'ADN adopte un rôle central au sein de la nanotechnologie et la nanomédecine, le contrôle de l'auto-assemblage sur plusieurs échelles de longueur est un prérequis absolu. Le travail réalisé dans cette thèse concerne l'auto-assemblage d'hybrides macromoléculaires d'ADN dans le but de pouvoir organiser ces derniers sur des longueurs au delà du nanométrique. Les concepts seront divisés parmi trois sous-thèmes: (1) La première partie propose des méthodes afin de pourvoir les assemblages de brins d'ADN d'un niveau d'ordre à longue échelle tel que connu chez les copolymères en bloc. Nous présentons la synthèse d'hybrides d'ADN à caractéristiques amphiphiles ainsi que leur assemblage hiérarchique en nano-fibres et en réseaux organisés. (2) Dans la deuxième partie, nous utilisons des assemblages uniformes d'ADN en 3D afin de diriger l'agrégation de chaines alkyles hydrophobiques en dessous de leur concentration micellaire critique (CMC) grâce à la complémentarité de l'ADN. (3) La dernière partie présente le placement hiérarchique de brins d'ADN amphiphiles, ainsi que de leurs assemblages, sur des nanotubes d'ADN. Les principes qui sont sortis de ces travaux démontrent la possibilité de maitriser la synthèse et l'auto-assemblage d'hybrides macromoléculaires d'ADN, ainsi que l'organisation hiérarchique de ceux-ci avec d'autres structures nanométriques à base d'ADN.

Candidate materials for low-loss optical waveguides based on poly(glycidyl methacrylate-ran-pentafluostyrene) (P(GMA-ran-PFS)) copolymers were synthesized by nitroxide mediated polymerization (NMP) initiated with BlocBuilder® (N-(2-methylpropyl)-N-(1-diethlphosphono-2,2-dimethylpropyl)-O-(2-carboxylprop-2-yl) hydroxylamine) bearing a succinimidyl ester group (NHS-BlocBuilder) at 90 oC in 1,4 dioxane. The copolymerizations yielded copolymers with low dispersity between 1.2-1.4. The core structure of single-mode channel waveguides was fabricated by direct UV lithographic patterning. The copolymers with low resulted in line width roughness (LWR) of about 0.16 μm, whereas LWR of copolymers with ~ 3.5 but similar compositions was about 0.5 μm. The improvement in microstructural control allotted by NMP permitted finer pattern replication for copolymers desired for optical waveguides, as suggested for photoresist polymers. / Les matériaux candidats pour des guides d'ondes optiques à faible perte à base de copolymères poly(méthacrylate de glycidyle-ran-pentafluostyrene) (poly(GMA-ran-SSP)) ont été synthétisés par la polymérisation médiée par nitroxyde (NMP) initiée avec BlocBuilder® (N-(2-méthylpropyl)-N-(1-diethlphosphono-2,2-diméthylpropyl)-O-(2-carboxylprop-2-yl) hydroxylamine) portant un groupe d'ester de succinimidyle (NHS-BlocBuilder) à 90 ° C dans du 1,4-dioxane. Les copolymérisations ont donné des copolymères à faible dispersité ( ) entre 1,2-1,4. La structure de base des guides d'ondes canaux monomodes a été fabriqué à l'aide de motifs lithographique par UV directe. Les copolymères de faible ont donné une rugosité à la largeur de ligne (LWR) d'environ 0,16 μm tandis que la LWR des copolymères avec ~3.5 mais de compositions similaires était d'environ 0,5 μm. L'amélioration du contrôle de microstructure attribué par NMP a permis la réplication des motifs plus fins pour les copolymères dont l'utilisation est souhaitée dans les guides d'ondes optiques, tel que suggéré pour les polymères photosensibles.

The in situ, equimolar, trimethylaluminum/H$ sb2$O catalyst was used for the ring opening polymerization of racemic $ beta$-butyrolactone, $ beta$-heptanolactone and $ beta$-nonanolactone to form synthetic analogues of the naturally occurring family of biodegradable poly((R) -$ beta$-hydroxyalkanoate) polymers. This catalyst was found to produce both a better yield and a higher molecular weight of a high isotactic, primarily crystalline fraction of poly($ beta$-(R,S) -hydroxybutyrate) than the conventional in situ, equimolar triethylaluminum/H$ sb2$O catalyst. A mechanically tougher, less isotactic and less crystalline fraction of lower molecular weight and a largely amorphous fraction of even lower molecular weight were also isolated and characterized. / Biodegradation of solid films of synthetic poly($ beta$-(R,S) -hydroxybutyrate) in the presence of an "extracellular" poly($ beta$-(R) -hydroxybutyrate) depolymerase was found to be dependent on accessibility of the enzyme to the (R) linkages along the polymer chain. The semicrystalline fraction was the most susceptible to degradation whereas the high crystallinity fraction showed little degradation and the low crystallinity fraction only showed limited degradation early in the incubation period. / Synthetic poly($ beta$-(R,S) -hydroxyheptanoate) and poly($ beta$-(R,S) -hydroxynonanoate) polyesters were prepared for the first time and the whole product was predominantly isotactic. It was found to have comparable physical properties as the biosynthetic materials, which are only available as terpolymers. Evidence for paracrystalline ordering relating to the organization of the side chains and formation of liquid crystalline-like phases was observed.