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The delivery of nucleic acids at the tissue and cellular levels remains one of the major hurdles in this scientific area. Since nucleic acids are bulky macromolecules and unstable in the presence of nucleases, vehicles are required to compact them into nanosized particles, offer protection from degradation in vivo, and release the therapeutic cargo at the desired location. Polycationic vehicles are good candidates for these purposes since they can be chemically modified to tune the desired properties in nanoparticle formulations. We designed a family of trehalose-oligoethyleneamine copolymers that showed promising plasmid DNA (pDNA) transfection results in the presence of serum proteins. A diazidotrehalose monomer was copolymerized with linear oligoethyleneamines of varying length and containing alkyne end-groups via step-growth Cu(I)-catalyzed azide-alkyne cycloaddition polymerization resulting in a series of trehalose copolymers with a range of secondary amines (from 4 to 6) within the polymer backbone. Upon electrostatic complexation of the polycations and pDNA in aqueous media, nanosized particles were formed, and their sizes and zeta-potentials were characterized via dynamic light scattering (DLS). The glycopolymers were tested for pDNA binding, toxicity, cellular uptake, and transfection efficiency in vitro. Characterization of these polymers revealed a significant influence of minor structural modifications on bioactivity. In general, all of the polymers efficiently bind pDNA at low nitrogen to phosphate (N/P) ratios forming nanoparticles below 100 nm in size and demonstrated cellular uptake and transfection. Polymers comprised of trehalose moieties and four secondary amines in the repeat unit showed the greatest promise in pDNA delivery in vitro. Because of its large hydration volume, we hypothesize that trehalose contributes to particle stabilization in serum. The trehalose-based polymers with four secondary amines (Tr4) were subsequently modified with PEG (5kDa). This modification lead to the development of well-defined polymeric structures with PEG moieties selectively incorporated at the ends of linear trehalose-oligoethyleneamine polycations. The study of the effect of this modification on bioactivity revealed that there were no significant difference in the toxicity profiles within this series of PEGylated and non-PEGylated materials; however, overall results suggest that both modified and unmodified trehalose-oligoethyleneamine copolymers have a great promise for stem cell-based and regenerative therapies. / Ph. D.

Stimuli responsive polymers (SRP) have attracted a lot of attention, due to their potential and promising applications in many fields, as protein-ligand recognition, on-off switches for modulated drug delivery or artificial organs. Poly(N-isopropylacrylamide) (PNIPAM) is one of the most widely studied polymers due to its lower critical solution temperature (LCST) at ~ 32° C in aqueous solution. Additionally, glycopolymers, where free sugar units are present, have potentially interesting applications especially in bio-recognition where sugars play an important role. In this work, our interest was focused on the synthesis of glycomonomers and its block- and random- copolymers with NIPAM. NIPAM homopolymers with an active chain transfer unit at the chain end could be prepared by RAFT. They were used as macro-chain transfer agents to prepare a variety of sugar containing responsive block copolymers from new glycomonomers by the monomer addition concept. The LCSTs of the aqueous solutions of the copolymers are affected strongly by the comonomer content, spacer chain length of the glycomonomer and the chain architecture of the copolymers. These polymers were coated on a solid substrate by spin coating and crosslinked by plasma immobilization. Characterization of the polymers was performed by nuclear magnetic resonance spectroscopy (NMR), ultraviolet (UV), dynamic light scattering (DLS, detection of aggregation behaviour) and gel permeation chromatography (GPC). Polymer films were investigated by ellipsometry, X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) regarding their surface properties. Afterwards sulfation of sugar – OH groups was performed in order to obtain heparin like structure, as heparin exhibits numerous important biological activities, like good interaction with diverse proteins. Finally, affinity of the polymers (sulfated and non sulfated form) on a solid support to the endothelial cells was investigated.

Stimuli responsive polymers (SRP) have attracted a lot of attention, due to their potential and promising applications in many fields, as protein-ligand recognition, on-off switches for modulated drug delivery or artificial organs. Poly(N-isopropylacrylamide) (PNIPAM) is one of the most widely studied polymers due to its lower critical solution temperature (LCST) at ~ 32° C in aqueous solution. Additionally, glycopolymers, where free sugar units are present, have potentially interesting applications especially in bio-recognition where sugars play an important role. In this work, our interest was focused on the synthesis of glycomonomers and its block- and random- copolymers with NIPAM. NIPAM homopolymers with an active chain transfer unit at the chain end could be prepared by RAFT. They were used as macro-chain transfer agents to prepare a variety of sugar containing responsive block copolymers from new glycomonomers by the monomer addition concept. The LCSTs of the aqueous solutions of the copolymers are affected strongly by the comonomer content, spacer chain length of the glycomonomer and the chain architecture of the copolymers. These polymers were coated on a solid substrate by spin coating and crosslinked by plasma immobilization. Characterization of the polymers was performed by nuclear magnetic resonance spectroscopy (NMR), ultraviolet (UV), dynamic light scattering (DLS, detection of aggregation behaviour) and gel permeation chromatography (GPC). Polymer films were investigated by ellipsometry, X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) regarding their surface properties. Afterwards sulfation of sugar – OH groups was performed in order to obtain heparin like structure, as heparin exhibits numerous important biological activities, like good interaction with diverse proteins. Finally, affinity of the polymers (sulfated and non sulfated form) on a solid support to the endothelial cells was investigated.

Thesis (PhD (Chemistry and Polymer Science))--Stellenbosch University, 2008. / The synthesis of glycopolymers with various comonomers as prepared via the RAFT process is investigated. The macro-RAFT agent poly(3-O-methacryloyl-1,2:5,6-di-O-isopropylidene-D-glucofuranose) (PMAlpGlc) was prepared by polymerization of the glycomonomer with cumyl phenyl dithioacetate as the chain transfer agent. Chain extension with styrene or methyl acrylate or acrylic acid afforded novel diblock copolymers, (PMAlGlc-b-poly[styrene] or PMAGlc-b-poly[methyl acrylate] or PMAlGlc-b-poly[acrylic acid]), with predetermined molecular weights and narrow molecular weight distributions. The poly(acrylic acid) based glycopolymer was used to modify the surface of CaCO3, forming what will be referred to as a ‘sugar-coated CaCO3’ particle. This surface modifying effect was evaluated in depth; a schematic study of the effect of reaction temperature, pH, reaction time and glycopolymer concentration on CaCO3 crystallization was carried out. The analytical techniques Thermal Gravimetric Analysis (TGA) and Scanning Electron Microscopy (SEM) were used to verify that these ‘sugar-coated CaCO3’ particles have an increased adherence to cellulose compared to ‘non sugar-coated’ particles. A series of polymer configurations comprising various ratios of glycomoiety to poly(acrylic acid) was prepared. The effect of this polymer series on CaCO3 crystallization was evaluated and the ideal polymer configuration and its optimum synthesis conditions (i.e. reaction pH, temperature, time and polymer concentration) that gave maximum adherence of the ‘sugar-coated CaCO3’ particle onto cellulose were identified. The ability of these poly(acrylic acid) based glycopolymers to increase the interaction between CaCO3 and cellulose was then evaluated. This was done by simply mixing all three substrates, i.e. glycopolymer, cellulose and CaCO3 together. Analysis by TGA, SEM and Thin Layer Chromatography (TLC) revealed both the ideal polymer configuration that favoured increased adherence of the CaCO3 to cellulose and the optimum reaction conditions required for application and testing. In addition to studying the interaction between cellulose and CaCO3, the amphiphilic nature of the glycopolymers was determined. Transmission Electron Microscopy (TEM) confirmed that coreshell particles were prepared and that these particles are solvent exchangeable (in the case of styrene and methyl acrylate glyco-blocks) or pH exchangeable (in the case of acrylic acid glyco-blocks).

Thesis (PhD (Chemistry and Polymer Science))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Please refer to full text for abstract

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Maîtriser la biocontamination surfacique et les risques susceptibles d’y être associés demeure un challenge majeur. Cette maîtrise passe par la préparation de nouveaux matériaux polymères possédant des propriétés de surface adaptées. Dans cette optique le LCOM développe depuis quelques années une thématique consistant à mettre au point des méthodes de modifications de surfaces de matériaux polymères par greffage de biomolecules. [ ] [ ] [ ] Dans ce contexte, l’objectif de cette étude est de fonctionnaliser des films polymères de type poly (téréphtalate d’éthylène) (PET) avec des dérivés sucrés et/ou polysaccharides dans le but d’étudier le caractère bactériostatique, biocide et pro ou anti-adhésion. [ ] La préparation des matériaux se fait en plusieurs étapes :Etape 1 : Fonctionnalisation de surfaces polymères (films) par traitement plasma N2/H2 et NH3 pour introduire à la surface des fonctions amines. Cette technique modifie la surface sans changer les propriétés intrinsèques des matériaux.Etape 2 : Greffage d’un amorceur de polymérisation radicalaire par transfert d’atome (ATRP)Etape 3 : Polymérisation en surface d’un monomère sucré par ATRP (contrôle de la longueur des chaînes greffées). La mise au point des paramètres de polymérisation ATRP de ces monomères est d’abord menée en solution avant d’étudier la polymérisation en surface.Etape 4 : Etudes microbiologiques des surfaces modifiées.Après chaque étape de modification de surface, les matériaux sont caractérisés par différentes méthodes d’analyses telles que : la spectroscopie de photoélectrons X (XPS), la microscopie à force atomique, la chromatographie d’exclusion stérique. Des glycopolymères protégés et déprotégés issus du galactose et de la glucosamine ont été synthétisés. Ceux issus de la glucosamine ont été synthétisés afin de mimer les propriétés antibactériennes du chitosane. Le glycomonomère issu du galactose est polymérisé par ATRP par voie « grafting from » sur des surfaces de PET. Ces surfaces modifiées présentent des propriétés anti-adhésives intéressantes contre les bactéries du type Bacillus subtilis. En effet, après greffage du glycomonomère déprotégé, il n’ ya plus d’adhésion de bactéries. Des polymères contenant des fonctions ammonium quaternaire et fluor ont aussi été greffés avec succès sur les films de PET par la même méthode. / Control surface contamination by microorganism is of great concern in a variety of areas such as food packaging, medical devices, hospitals and so on. To reduce or prevent microbial adhesion, new polymer surfaces must be developed. In this context, we investigate a new theme which deals with the modification of polymer materials containing carbohydrate molecules. , , The aim of the study is to attach covalently glycopolymers or potential antimicrobial polymers on films of polyethylene terephthalate (PET) in order to study the biocidal or anti-fooling properties. Indeed, grafting glycopolymers on PP fibers have brought anti-fooling properties. The surfaces are prepared in several steps:Step 1: Incorporation of primary amino groups by N2/H2 or NH3 plasma treatment. The pretreatment by plasma exhibits many benefits for the surface modification, which enables to introduce functional groups at the surface without any modification of the chemical and mechanical properties of the material during the process.Step 2: Insertion of Atom Transfer Radical Polymerization (ATRP) initiatorStep 3: Grafting from surface polymerization method of a monomer in order to control the molecular weight distribution on the surfaces. ATRP parameters of glycomonomers are studied in solution before carrying polymerization on surfaces.Step 4: Microbial adhesion tests of modified surfaces with Bacillus Subtilis and Lactoccocus Lactis as bacterial strains. Several analytical techniques such as X-ray photoelectron spectroscopy (XPS), Atomic Force Microscopy, size exclusion chromatography of polymers obtained in solution have been used to characterize the modified surfaces. The first step was to optimize plasma parameters in order to have a high density of primary amino group on the surfaces. Then several monomers have been studied especially glycomonomers from galactose and glucosamine to mimic antimicrobial properties of chitosan. Protected and deprotected glycopolymers from galactose polymerized on PET surfaces exhibit anti-fooling properties toward Bacillus Subtilis. Polymers containing quaternary ammonium salt or fluor have also been successfully polymerized by a grafting from method on PET films.

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