Bacterial infection in burn wounds can jeopardize healing and can even lead to a patient’s death. Recently using a topical wound dressing with antimicrobial ability has been increasing. An ideal dressing for a burn wound is required to be antimicrobial, pain free and able to control the wound moisture to facilitate healing. In this research, a UV-radiation grafting method for depositing polyacrylamide (PAM) layer was used to improve the non-adherence properties of two commercially available silver based wound dressings. The dressing adherence, evaluated via an in vitro gelatine model, dramatically decreases after the deposition of PAM. This deposition did not negatively affect the antibacterial ability and cytotoxicity of the dressings. Furthermore, a poly(amidoamine) dendrimer based biocide was incorporated into PET dressings coated with poly(acrylic acid-co-acrylamide ) hydrogel. The resulting dressing was able to release a therapeutic dose of the antimicrobial agent in a sustained manner. / February 2016

Philosophiae Doctor - PhD / In this thesis, I present the electrochemical studies of three dendrimeric polypropylene imine (PPI) nanomaterials and their applications as a platform in the development of a novel label free DNA nanobiosensor based on electrochemical impedance spectroscopy. Cyclic voltammetry (CV), differentia pulse voltammetry (DPV), square wave voltammetry (SWV) and electrochemical impedance spectroscopy (EIS) techniques were used to study and model the electrochemical reactivities of the nanomaterials on glassy carbon electrode (GCE) as the working electrode. / South Africa

Les dendrimères sont des entités chimiques "arborescentes" multi-ramifiées. Cette famille de polymères non linéaires comporte des applications dans différents domaines. Un dendrimère nommé ABP a montré des propriétés immuno-modulatrices sur le système immunitaire humain in vitro. Ce dendrimère comporte le profil d'un nouvel agent thérapeutique pour être utilisé dans le traitement de maladies inflammatoires chez l'homme. Parmi les cellules mononucléaires du sang humain, le dendrimère ABP cible principalement les monocytes et induit une activation anti-inflammatoire de ces cellules. Cette nouvelle étude a visé à comprendre l'interaction entre le dendrimère ABP et les monocytes humains. De manière intéressante, une interaction spécifique a été observée. En utilisant des expériences de modélisation, de physico-chimie et de biologie moléculaire, nous démontrons que le dendrimère ABP induit une activation anti-inflammatoire des monocytes humains par l'intermédiaire d'un ou de récepteur (s). / Dendrimers are multi-branched "tree-like" chemical entities. This family of non-linear polymers has already been applied in different fields. A dendrimer named ABP has shown some immuno-modulatory properties toward the Human immune system in vitro. This dendrimer is at the dawn to become a new therapeutic agent by itself for the treatment of inflammatory diseases in Human. Among human Peripheral Blood Mononuclear Cells (PBMC), the ABP dendrimer selectively targets human monocytes and induces an anti-inflammatory activation of these cells. This new study aims at understanding the interaction between the ABP dendrimer and human monocytes. Interestingly, a specific interaction was observed. Using, biological, physico-chemical and molecular modelling experiments we demonstrated that the ABP dendrimer triggers monocyte activation through receptor(s) recognition.

Thin film Nanocomposite (TFN) membranes are a relatively new class of high-performance semipermeable membranes for Reverse Osmosis (RO) applications. Large scale applications of TFN membranes have not been achieved yet due to the high production cost of the nanoparticles, agglomeration of the nanoparticles in the thin polyamide matrix of the membrane, and leaching out of typically toxic inorganic nanoparticles into the downstream. In this work, these challenges are addressed by incorporation of two different nanofillers: Cellulose NanoCrystals (CNC), and surface functionalized Halloysite NanoTubes (HNT). Amine groups, carboxylic acid groups, and the first generation of poly(amidoamine) (PAMAM) dendrimers were used for functionalization of the HNT. CNC and HNT are environmentally friendly, low/non-toxic, abundant, and inexpensive nanoparticles with a unique size, and chemical properties. TFN membranes were synthesized via in situ interfacial polymerization of m-phenylenediamine (MPD) with trimesoyl chloride (TMC) and the nanoparticles. The control Thin Film Composite (TFC) membranes, and CNC and HNT based TFN membranes were characterized by Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), X-Ray Diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), Fourier Transform Infrared spectroscopy (FTIR) and contact angle measurements. The antifouling capacity of CNC based membranes was investigated with a solution of Bovine Serum Albumin (BSA) as the fouling agent. Also, the leachability of the HNT from the membranes was examined by shaking the membranes in a batch incubator for 48 h, and then tracing the leached out HNT using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Separation characteristics of the membranes were studied by desalination of synthetic brackish water with a cross flow RO filtration system. It was revealed that incorporation of functionalized HNT enhanced the permeate flux without sacrificing the salt rejection (99.1 % ± 0.1 %). Also, incorporation of 0.1% (w/v) CNC doubled the permeate flux (from 30 to 63 L/m2.h at 20 bar) without compromising the salt rejection (97.8%). At the same time, leaching out of HNT from the TFN membranes was decreased as a result of the HNT functionalization and formation of covalent bonds with the TMC. Also, antifouling properties of the CNC-TFN membranes were 11% improved in comparison with control TFC membrane.

Un nouveau dendron phénol trialcyne a été développé par analogie avec le dendron phénol triallyle déjà connu. En nous appuyant sur les cœurs dendritiques polyiodés du laboratoire, nous avons obtenu une famille de dendrimères polyalcynes comportant 27, 81 et 243 branches. Des ferrocènes ont ensuite été greffés par chimie « click » à la périphérie de ces dendrimères. La série obtenue permet la reconnaissance électrochimique d’oxo-anions d’intérêt biologique, comme l’ATP, et de cations métalliques. Grâce aux propriétés d’adsorption des grand dendrimères, nous avons obtenu des électrodes de platine modifiées, robustes et recyclables, permettant de réaliser cette reconnaissance. Une série de glycodendrimères comportant 27, 81 et 243 xylopyranosides terminaux a également été synthétisée. Les méthodes de caractérisation de nanoobjets ont été investiguées, et en particulier, les techniques permettant d’obtenir la taille des molécules en solution comme la RMN DOSY et la diffusion dynamique de la lumière (DLS). Enfin, une série de dendrimères robustes comportant 4 à 6 branches alcynes très longues a été développée. Le greffage périphérique par chimie « click » de beta-cyclodextrines méthylées aléatoirement est également rapporté. / A new easily accessible trialkyne phenol dendron has been developed mimicking the already known triallyl phenol dendron. A family of polyalkynyl containing dendrimers with 27, 81 and 243 terminal branches was obtained starting from the classical polyiodo dendritic cores of the laboratory. Ferrocenes were then grafted using “click” chemistry. The dendrimers obtained allowed electrochemical sensing of both biologically interesting oxo-anions like ATP and metallic cations. Robust and recyclable modified platinum electrodes were obtained thank to the adsorption properties of large dendrimers. These electrodes are able to recognize the same ions as the dendrimer in solution. A novel series of glycodendrimers with 27, 81 and 243 modified xylopyranosides termini was synthesized too. The characterization methods for such nanoobjects were investigated, and particularly technics that allow to obtain the size of the molecules like dynamic light scattering (DLS) and DOSY NMR. Finally, a family of robust polyalkynyl containing dendrimers with 4 to 6 enlarged branches was developed. The functionalization with randomly methylated beta-cyclodextrins using “click” chemistry is also reported.

Le glycérol est une molécule bio-sourcée, abondamment disponible, issue de la saponification des corps gras et de la transestérification des huiles végétales. Les travaux portent sur l'utilisation du glycérol comme base structurale de cœurs de dendrimère, en particulier par addition d'oxa-Michael sur des dérivés acryliques. La fonctionnalisation en surface de dendrimères par des motifs imidazolium est explorée afin d’obtenir un dendrimère liquide ionique (DLI) aux propriétés thermosensibles. Le chapitre bibliographique est consacré dans une première partie, aux méthodes de synthèse de dendrimère mettant en jeu des dérivés acryliques et à leurs applications et dans une seconde partie, aux travaux consacrés à l'addition oxa-Michael d'alcools sur des dérivés acryliques. Le deuxième chapitre porte sur les synthèses, à partir du glycérol, de la base structurale du cœur de dendrimère. La réaction d’acylation du glycérol par le chlorure d’acryloyle est présentée ainsi que les différentes constructions de dendrimères poly(estersulfure) à partir du triacrylate de glycérol. L’addition nucléophile du glycérol sur l’acroléine, l’acrylamide, des acrylates et l’acrylonitrile a été étudiée. Avec les acrylates, la réaction d'addition nucléophile est en compétition avec la réaction de transestérification, à l’exception de l'acrylate de t-butyle résistant en milieu basique. Avec l’acrylonitrile, la synthèse du 1,2,3-tricyanoéthylglycéryléther a pu être menée sans solvant, en 5 heures à température ambiante, en présence d’un catalyseur peu coûteux (la soude 4 mol %) avec un rendement de 88% et une pureté de 99% sans méthode de purification. Les intermédiaires de réaction mono- et di-cyanoéthylglycéryléther ont été caractérisés et ont permis un suivi cinétique de la réaction. La synthèse de dendrimères poly(amidoamine) à partir du 1,2,3-tricyanoéthylglycéryl éther fait l’objet du troisième chapitre : synthèse des générations G0 à G2,5, caractérisation des dendrimères. Des défauts de structure dus à une cyclisation intramoléculaire ont été mis en évidence par HRMS pour les générations entières et les dendrimères de demi-génération Gn+5 (n entier) sont purifiés par colonne chromatographique. Différentes voies de synthèse pour l’obtention d’un DLI à termini imidazolium sont présentées / Glycerol is a bio-based molecule, abundantly available, from the saponification of triglyceride and the transesterification of vegetable oils. The work described in this PhD thesis concerns the use of glycerol as structural base of dendrimer's core, in particular by oxa-Michael addition on acrylic derivatives. The surface functionalization of dendrimers by imidazolium units is explored in order to obtain an ionic liquid dendrimer (DLI) with thermosensitive properties. In the first part, the bibliographic chapter presents the methods of dendrimers synthesis involving acrylic derivatives and their applications and, in a second part, the work introduces the oxa-Michael addition of alcohols to acrylic derivatives. The second chapter deals with the synthesis of the structural base of the dendrimer core from glycerol. The reaction of acylation of glycerol with acryloyl chloride is presented as well as the various constructions of poly(estersulfide) dendrimers from glycerol triacrylate. The nucleophilic addition of glycerol to acrolein, acrylamide, acrylates and acrylonitrile has been studied. With the acrylates, the nucleophilic addition reaction is in competition with the transesterification reaction, with the exception of t-butyl acrylate, resistant in basic medium. With acrylonitrile, the synthesis of 1,2,3-tricyanoethylglycerylether was carried out without solvent in 5 hours at room temperature in the presence of an inexpensive catalyst (4 mol% sodium hydroxide) in a yield of 88% and purity of 99% without purification method. The mono- and di-cyanoethylglycerylether reaction intermediates were characterized and allowed kinetic monitoring of the reaction. The synthesis of poly(amidoamine) dendrimers from 1,2,3-tricyanoethylglycerylether is the subject of the third chapter: synthesis of generations G0 to G2,5 and characterization of dendrimers. The defects in the structure due to intramolecular cyclization have been demonstrated by HRMS for generations Gn and the half-generation dendrimers Gn+5 (n=0, 1, 2) were purified by chromatographic column. Several routes of synthesis for the synthesis of DLI with imidazolium termini are presented

Rapid and high-sensitivity detections of biological analytes are critically important to ensure timely diagnosis of disease and effective monitoring of public health. Although various new biosensing platforms have been established as alternatives to conventional laboratory methods, most of these biosensing platforms suffer from insufficient sensitivities that severely limit their wide applications. To improve the detection sensitivities of these biosensors, surface modifications based on poly(amidoamine) (PAMAM) dendrimers and rolling circle amplification (RCA) have been proven to be effective methods. In this thesis, surface modification strategies based on PAMAM dendrimers and RCA have been applied on three biosensing platforms, including enzyme-linked immunosorbent assay (ELISA), localized surface plasmon resonance (LSPR) sensor chip, and affinity membrane, to improve their detection sensitivities. For the ELISA platform, glass-bottom and poly(styrene) 96-well plates are surface modified by dendrimer-aptamer conjugates to improve detection performances of human platelet-derived growth factor-BB using ELISA. The results show that the ELISA performed using the modified 96-well plates presents a much broader linear detection range and a significantly lower limit of detection (LOD) than conventional ELISA plates. For the LSPR platform, the dendrimer and aptamer modification strategy is employed to surface modify LSPR sensor chips for sensitive detection of the SARS-CoV-2 virus, and an RCA-AuNPs complex is developed to amplify the detection signals. The results show that the modified chip can sensitively detect the SARS-CoV-2 virus with a LOD of 148 vp/mL, suggesting that the modified LSPR chip and signal amplification method can be used for early diagnosis of Covid-19. For the affinity membrane platform, nylon membranes with dendrimer and dual-RCA surface modifications are developed to detect Escherichia coli O157:H7 in food samples. The surface-modified membranes significantly reduce the detection time of the target bacteria to two hours instead of several days using traditional bacterial detection methods. In addition, the new membranes achieve higher sample throughputs (around 4-5 mL/s) with a lower LOD (10 cells/ 250 mL) in processing real-world food samples compared to other similar detection platforms. The excellent properties of our surface modification approaches may provide further advantages when employed in other platforms, such as target separation and enrichment, antifouling and antibacterial, and drug delivery applications.

This study investigated a CNF/dendrimer hydrogel and how different concentrations of the carboxylated CNF and bis-MPA ammonium dendrimer affected the hydrogels’ rheological properties. A third generation bis-MPA ammonium dendrimer was diffused into a dispersion of carboxylated cellulose nanofibrils. The CNF was carboxylated by TEMPO-oxidation and phosphate buffer deprotonating the carboxylic group. The ammonium dendrimers are cationic and, when added to the dispersion, act as a salt together with the CNF-carboxy anion creating a cationic dendrimer salt bridge. These will serve as physical crosslinks, and a CNF/dendrimer network is formed; the structure and the absorbed water make a hydrogel. Amplitude strain sweeps were performed with a rheometer to determine the gels' elastic capabilities in terms of storage modulus, G’ and loss modulus, G” as the function of the shear stress. The result shows that a higher concentration of both CNF dispersion and dendrimer yielded a higher value of the storage modulus and a lower critical strain, meaning that the hydrogel becomes firmer and less elastic. / I denna studie undersöktes en CNF/dendrimer hydrogel och hur olika koncentrationer av den karboxylerade CNF och bis-MPA ammonium dendrimer påverkar hydrogelens reologiska egenskaper. En tredje generations bis-MPA ammonium dendrimer läts diffusera i en dispersion av karboxylerade cellulosa nanofibriller (CNF). CNF karboxylerades via TEMPO-oxidation, varefter en fosfatbuffer adderades för att skapa en anjon. Dendrimerens ammoniumgrupper är katjoner och då den adderas till dispersionen kommer den agera som ett salt tillsammans med CNF-karboxyanjonen vilket skapar en katjonisk dendrimersaltbrygga. Denna agerar som en fysisk tvärbindning och skapar ett nätverk av CNF och dendrimer. Nätverket skapar tillsammans med det absorberade vattnet en hydrogel.  En amplitude strain sweep utfördes för att bestämma gelernas viskoelastiska förmåga, från mätningarna fås elasticitetsmodulen, G’ och den viskösa modulen, G’’ som funktioner av skjuvningen. Resultatet visar att en högre koncentration av CNF-dispersionen och dendrimeren leder till ett högre värde på elasticitetsmodulen samt ett lägre värde för den kritiska skjuvningen. Detta innebär att hydrogelen blir hårdare och mindre elastisk.

Understanding structure-property relationship of molecules is imperative for designing efficient materials for organic semiconductors. Organic semiconductors are based on π-conjugated molecules, either small molecules or macromolecules such as dendrimers or polymers. Charge transport through organic materials is one of the most important processes that drive organic electronic devices. We have investigated the charge transport properties in various molecular designs based on dendrons, dendron-rod-coil molecular triads, and conjugated oligomers. The charge transport properties were studied using bottom contact field effect transistors, in which the material was deposited by spin coating. In case of dendrons, their generation and density of charge transporting functionalities were found to play a significant role in influencing the charge transport properties. In case of macromolecules such as dendron-rod-coil molecules, the solid state morphology plays a significant role in influencing the charge transport properties. While these molecules exhibit only electron transporting behavior in field-effect transistor measurements, ambipolar charge transport is observed in the diode configuration. Short conjugated oligomers, based on donor-acceptor-donor design, provide model systems for conjugated polymers. Effect of varying the donor functionality on optoelectronic and charge transport properties was studied in short donor-acceptor-donor molecules. While donor-acceptor-donor molecules are well known in the literature, the effect of molecular composition on the charge transport properties is not well understood. We designed molecules with 2,1,3-benzothiadiazole as the acceptor and thiophene based donor functionalities. These molecules exhibit a reduced bandgap, good solution processability and charge mobility making them interesting systems for application in organic photovoltaics. Cyclopentadithiophene (CPD) based materials have been widely utilized as organic semiconductors due to their planar nature which favors intermolecular charge transport. While most CPD based materials are hole transporting, incorporation of electron withdrawing fluorinated substituents imparts n-type behavior to these molecules. This change in charge transport properties has often been attributed to the lowering of the LUMO energy level due to the increased electron affinity in the molecule. We designed CPD based semiconductors in which the bridgehead position was functionalized with electron withdrawing ketone or dicyanomethylene group and the -positions were substituted with phenyl or pentafluorophenyl groups. Both the phenyl substituted molecules are p-type materials, even though the dicyanomethylene group lowers the LUMO by 500 meV as compared to the carbonyl compound. The pentafluorophenyl substituted molecules are n-type materials even as their LUMO energy levels are about 300 meV higher than the corresponding phenyl substituted molecules. This indicates that charge transport behavior is not an exclusive function of the frontier orbital energy levels.

The objective of this research was to develop and validate new macromolecular imaging agents to detect and characterize malignant tumours. Using well-defined, highly branched macromolecules called dendrimers as the structural scaffold, efficient functionalization of the periphery was demonstrated using “click” chemistry in order to prepare multivalent imaging probes. Furthermore, a transmetalation was demonstrated to displace chelated copper with technetium, enabling “click” reactions to be performed in the presence of the dipicolylamine (DPA), a ligand known to chelate many metals. The dendritic scaffold was functionalized with either hydrophobic or hydrophilic targeting vectors. The hydrophobic ligand, an acyloxymethyl ketone targeting the overexpression of cathepsin B exhibited poor in vitro affinity when coupled to either G1 or G2 dendrimers, despite the use of various linkers. A glu-urea-lys dipeptide, representing a hydrophilic prostate specific membrane antigen targeting vector, demonstrated excellent affinity in vitro. The lead compound, a G2 dendrimer bearing four PSMA targeting vectors attached via an alkyl spacer was further investigated in vitro and in vivo. Unfortunately, poor tumor uptake was observed and the compound was hypothesized to hydrolyze readily (<15min), based on the in vitro plasma stability data. To rectify the aforementioned problem, non neo-pentyl esters were replaced with either carbamate or ether linkages. In vitro plasma stability analysis of the analogous compounds demonstrated increased stability. In particular, the ether analogue was found to be most stable, with minimal degradation observed after 4 hours. / Thesis / Doctor of Philosophy (PhD)