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ABSTRACT Effective drug delivery to ocular tissues is an unmet challenge that has significant potential to improve the treatment of ocular diseases. Whether the intended drug delivery target is the anterior or posterior segment, the eye’s efficient natural protection mechanisms prevent effective and sustained drug delivery. Anatomical and physiological barriers including the rapid tear turnover that effectively washes away topically applied drugs, the impermeable characteristics of the cornea, conjunctiva, and sclera, and the tight junctions in the blood-ocular barriers make conventional drug delivery methods ineffective. New materials that are able to overcome these barriers are essential to improving the sustained delivery of ophthalmic therapeutics to the intended targets within the eye. This thesis will explore two polymeric drug delivery systems that have the potential to improve therapeutic delivery to ocular tissues. Chapter 1 will discuss the anatomical and physiological barriers to ophthalmic drug delivery and overview current research in this area. Chapter 2 will discuss the synthesis of N-isopropylacrylamide-based copolymers with adjustable gelation temperatures based on composition and molecular weight. Chapter 3 will discuss further development of these copolymers into an injectable, thermoresponsive, and resorbable polymeric drug delivery system intended for the treatment of diseases in the posterior segment. Chapter 4 will discuss the development of mucoadhesive polymeric micelle nanoparticles based on phenylboronic acid intended for topical administration of ophthalmic therapeutics. Finally, Chapter 5 will provide an overview of potential future work on these materials that could further develop and broaden their therapeutic use. / Thesis / Master of Science in Biomedical Engineering

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Yes / The synthesis of cyclic amphiphilic graft copolymers with a hydrophobic polycarbonate backbone and hydrophilic poly(N-acryloylmorpholine) (PNAM) side arms via a combination of ring-opening polymerization (ROP), cyclization via copper-catalyzed azide–alkyne cycloaddition (CuAAC), and reversible addition–fragmentation chain transfer (RAFT) polymerization is reported. The ability of these cyclic graft copolymers to form unimolecular micelles in water is explored using a combination of light scattering, small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryoTEM) analyses, where particle size was found to increase with increasing PNAM arm length. Further analysis revealed differences in the solution conformations, loading capabilities, and morphologies of the cyclic graft copolymers in comparison to equivalent linear graft copolymer unimolecular micelle analogues. Furthermore, the cyclic and linear graft copolymers were found to exhibit significantly different cloud point temperatures. This study highlights how subtle changes in polymer architecture (linear graft copolymer versus cyclic graft copolymer) can dramatically influence a polymer’s nanostructure and its properties. / Royal Society (Great Britain), Engineering and Physical Sciences Research Council (EPSRC), European Research Council (ERC)

Thesis (DSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Examples of the use of NMR spectroscopy in the study of radical polymerization processes have been described. The studies presented have made a significant contribution to the understanding of the fundamental mechanistic processes in these polymerization systems. It is pointed out that NMR in conventional radical polymerization is of limited use due to the concurrent occurrence of all elementary reactions (initiation, propagation and termination). Conversely, for living radical polymerization, NMR has great value. In that case, the elementary reactions are somewhat more restricted to specific times of the polymerization process. This allows for example the detailed study of the early stages of chain growth in Reversible Addition-­‐Fragmentation Chain Transfer (RAFT) mediated polymerization. Two different studies are described. The first is related to the early stages of RAFT-­‐mediated polymerization. A process for which we coined the name initialization was studied via in situ 1H NMR spectroscopy. It is shown that in many cases, there is a selective reaction that converts the original RAFT agent into its single monomer adduct. A few different examples and their mechanistic interpretation are discussed. It is also shown that NMR spectroscopy can be a valuable tool for the assessment of a RAFT agent in conjunction with a specific monomer and polymerization conditions. In the second study, 15N NMR, 31P NMR and 1H NMR are used for two different types of experiments. The first is a conventional radical copolymerization in which the growing chains are trapped by a 15N labeled nitroxide to yield a stable product. In the second experiment, a similar copolymerization is conducted under nitroxide-­‐mediated conditions. The nitroxide of choice contains phosphorous, which enables the quantification of the terminal monomer in the dormant chains. Each of the experiments individually provides interesting information on conventional radical copolymerization and nitroxide-­‐mediated copolymerization, respectively. Combination of the experimental data reveals an interesting discrepancy in the ratio of terminal monomer units in active chains and dormant chains. Although not unexpected, this result is interesting and useful from a mechanistic as well as a synthetic point of view. In terms of future perspectives, it is expected that the advanced analytical techniques as described here will remain crucial in polymer science. Present developments in radical polymerization, such as investigations into monomer sequence control, rely on accurate knowledge of kinetic and mechanistic details of elementary reactions. It is expected that such detailed studies will be a main challenge for the next decade of polymer research. / AFRIKAANSE OPSOMMING: Voorbeelde van die gebruik van KMR-­‐spektroskopie in die studie van radikaalpolimerisasies word beskryf. Hierdie studies het ʼn beduidende bydrae gelewer tot die verstaan van die fundamentele meganistiese prosesse in hierdie polimerisasiesisteme. Dit het daarop gewys dat KMR beperkte gebruike het in konvensionele radikaalpolimerisasies as gevolg van die gelyktydige voorkoms van alle basiese reaksies (afsetting, voortsetting en beëindiging). Aan die anderkant het KMR groot waarde vir lewende radikaalpolimerisasie. In hierdie geval is die elementêre reaksies ietwat meer beperk tot spesifieke tye van die polimerisasieproses. Gedetailleerde studies kan byvoorbeeld van die vroeë stadiums van die kettinggroei in Omkeerbare Addisie-­‐Fragmentasie-­‐ KettingOordrag (OAFO)-­‐bemiddelde polimerisasie gedoen word. Twee verskillende studies is beskryf. Die eerste het betrekking op die vroeë stadiums van die OAFO-­‐bemiddelde polimerisasie. 'n Proses wat “inisialisering” genoem is, is bestudeer deur middel van in situ 1H KMR-­‐spektroskopie. Dit is bewys dat daar in baie gevalle 'n selektiewe reaksie is wat die oorspronklike OAFO-­‐agent in sy enkelmonomeeradduk verander voor polimerisasie. 'n Paar ander voorbeelde en hul meganistiese interpretasie is bespreek. Dit is ook bewys dat KMR-­‐spektroskopie 'n waardevolle hulpmiddel kan wees vir die assessering van 'n OAFO-­‐agent in samewerking met 'n spesifieke monomeer en polimerisasie toestande. In die tweede studie is 15N KMR, 31P KMR en 1H KMR gebruik vir twee verskillende tipes van die eksperiment. Die eerste is 'n konvensionele radikaalkopolimerisasie waarin die groeiende kettings vasgevang word deur 'n 15N-­‐gemerkte nitroksied om 'n stabiele produk te lewer. In die tweede eksperiment is 'n soortgelyke kopolimerisasie gedoen onder nitroksied-­‐ bemiddelde toestande. Die gekose nitroksied bevat fosfor wat die kwantifisering van die terminale monomeer in die dormante kettings moontlik maak. Elkeen van die individuele eksperimente lewer interessante inligting oor konvensionele radikale kopolimerisasie en nitroksied-­‐bemiddelde kopolimerisasie, onderskeidelik. ʼn Kombinasie van die eksperimentele data toon 'n interessante verskil aan in die verhouding van die terminale monomeereenhede in die aktiewe en sluimerende kettings. Alhoewel dit nie onverwags is nie, is die resultate interessant en van waarde vanuit 'n meganistiese-­‐ sowel as 'n sintetiese oogpunt. In terme van toekomstige perspektiewe word daar verwag dat gevorderde analitiese tegnieke soos hier beskryf, belangrik sal bly in polimeerwetenskap. Huidige ontwikkelinge in radikaalpolimerisasie, soos ondersoeke na die beheer van monomeervolgorde, maak staat op akkurate kennis van kinetiese en meganistiese besonderhede van die basiese reaksies. Daar word verwag dat sulke gedetailleerde studies ʼn uitdaging sal bied vir die volgende dekade van polimeernavorsing.

La recherche actuelle sur le cancer se tourne vers des « stratégies ciblées » afin de développer de nouvelles méthodes diagnostiques plus sensibles et performantes, ainsi que de nouvelles thérapies plus efficaces mais aussi mieux tolérées. Dans ce contexte, nos travaux sont consacrés à la conception de vecteurs synthétiques ciblant un récepteur cellulaire surexprimé par les tumeurs, l'intégrine alphaVbeta3. Ce ciblage permet de concentrer les drogues ou les éléments de détection au niveau tumoral. L'outil utilisé pour la construction chimique de nos vecteurs est un châssis décapeptidique cyclique RAFT (Regioselectively Addressable Functionalized Template) présentant deux domaines indépendants permettant de séparer les deux fonctions du vecteur. Sur un domaine, la fonction de ciblage est assurée par la présentation multivalente de ligands -RGD- spécifiques du récepteur. L'autre domaine du vecteur supporte les molécules d'intérêt à vectoriser : agents thérapeutiques pour limiter la prolifération du foyer malin ou agents de détection pour l'imagerie médicale.

Le NGF est reconnu, et le signal qu’il véhicule est donc médié, par deux récepteurs membranaires : p75NTR et TrkA. Il a été démontré qu’au niveau de la membrane, p75NTR et TrkA sont localisées dans les radeaux membranaires, des microdomaines caractérisés par la présence de protéines cavéolines (Cav-1 et/ou Cav-2). Dans le présent travail, nous avons constaté que la surexpression de Cav-1 dans les neurones des ganglions de la racine dorsale diminue l’extension des neurites. De la même manière, la surexpression de Cav-1 dans les cellules PC12 inhibe les réponses cellulaires déclenchées par l’exposition au NGF. L’activation des effecteurs situés en aval de TrkA n’est pas inhibée. L’expression de Cav-1 provoque une inhibition de la sortie du récepteur des radeaux accompagné par la rétention au niveau de la surface cellulaire, des effecteurs situés en aval incluant Rsk2 phosphorylé. Dans le même temps, la présence de formes phosphorylées de CREB n’est plus détectable. En revanche, la surexpression de Cav-2 potentialise la différenciation des cellules induite par le NGF, ce qui est associé à une activation prolongée des effecteurs situés en aval et à une internalisation des récepteurs. Ces différents effets pourraient être dû à la localisation des cavéolines, qui résulte en une perturbation du microenvironnement des cellules et donc de la signalisation du NGF. En outre, l’expression d’une Cav-1 mutée sur la sérine 80 (S80V) dans des cellules PC12, ne gêne ni le trafic ni la signalisation de TrkA. Au contraire elles se comportent de façon semblable à des cellules Cav-2. Ces études soulignent également le rôle potentiel de Cav-1 et ses mutations dans des cancers NGF-dépendantes. / At the plasma membrane, both NGF receptors have been shown to localized to lipid rafts, specific subdomains that are enriched in cholesterol, sphingolipids and the presence of caveolin proteins (Cav1 and/or Cav2). The focus of this work is on this membrane microenvironment mediated modulation of NGF signaling which via two receptors: p75NTR and TrkA. In the present work we found that overexpression of Cav-1 in mouse dorsal root ganglia neurons significantly impacted neurite extension. Similarly, overexpression of Cav-1 in PC12 cells strongly inhibits their ability to grow neurites in response to NGF. It inhibits NGF signaling without, impairing transient MAPK pathway activation. Rather, it does so by sequestering NGF receptors in lipid rafts, which correlates with the cell surface localization of downstream effectors, and phosphorylated-Rsk2, resulting in the prevention of the phosphorylation of CREB. By contrast, overexpression of Cav-2 potentiates NGF induced differentiation, which is accompanied by sustained activation of downstream effectors, and standard internalization of the receptors. This differential effect could be due to the different localization of Caveolins, that modifies the microenvironment, thereby affecting NGF signaling. Furthermore, PC12 cells expressing the non-phosphorylatable Cav-1 mutant (S80V), neither TrkA trafficking or CREB phosphorylation are inhibited and the response resembles that observed in Cav-2 expressing PC12 cells. These studies underline the interplay between caveolins and NGF signalling, offering insight into the potential impact of Caveolin-1 and mutations thereof in certain cancers where NGF signaling is involved.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2016-03-02T20:36:42Z No. of bitstreams: 1 Dissertação - Sofia Leão Carvalho - 2015.pdf: 4334945 bytes, checksum: 4ec90e6600b19acf8087cafcbd7f821f (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-03-03T12:10:10Z (GMT) No. of bitstreams: 1 Dissertação - Sofia Leão Carvalho - 2015.pdf: 4334945 bytes, checksum: 4ec90e6600b19acf8087cafcbd7f821f (MD5) / Made available in DSpace on 2016-03-03T12:10:10Z (GMT). No. of bitstreams: 1 Dissertação - Sofia Leão Carvalho - 2015.pdf: 4334945 bytes, checksum: 4ec90e6600b19acf8087cafcbd7f821f (MD5) Previous issue date: 2015-09-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The combination of two different types of foundation has become increasingly popular among engineers in the past few decades as a good alternative for large loads due to the trending expansion of taller skyscrapers. This new concept in foundation engineering, called piled raft, combines the raft capacity of withstanding large loads to the reduced settlement provided by a group of piles strategically placed. This new concept of foundation design has stimulated the use of new methodologies that look for understanding the interaction between its elements (raft, piles and soil), the settlement and the distribution of load between them. Over the past decades, the development of faster and more powerful computers has allowed engineers to use numerical methods in the analysis of this type of problem assisted by new software tools. Among all possible numerical methods, the Finite Element Method (FEM) has stood up for being precise and very adaptable to many situations. Despite its extensive applicability, the FEM method has its limitations regarding the processing time and capacity of computers mainly when the third dimension of the foundation is considered. For the fore mentioned reason, hybrid tools have been developed combining FEM to other methods aiming faster analysis and better quality results. In this context, this thesis presents a new tool, called Soil-Foundation Interaction Analysis, SoFIA. The code was developed in object-oriented programming with Approximate Computer Methods. The raft in SoFIA is modelled as two-dimensional finite plate elements, and the group soil/piles ins modelled as an elastic base. Each stage of the tool development and a set of application models are described on this report based on literature review. This work aimed creating a self-sufficient tool capable of analyzing a piled raft model with all the interaction analysis. Furthermore, the program SoFIA was modelled using object-oriented programming, anticipating future expansions, such as different finite elements, non-linear response and other types of foundation. Example results showed good agreement when compared to literature regarding settlement, share of load between raft and piles and moments in x and y directions. Moreover, the axisymmetric interaction analysis between elements of piles and soil indicated similar settlement when compared to complete tridimensional analysis and Boundary Element Method. / A união de dois tipos de fundações tornou-se, nas últimas décadas, uma boa alternativa para carregamentos de fundações maiores, necessárias diante da expansão de edificações cada vez mais altas. Esse novo conceito de fundação, chamada de radier estaqueado, uniu o radier com sua boa capacidade portante às estacas que, quando posicionadas estrategicamente, são boas redutoras de recalques, abrindo um novo campo de estudos na engenharia de fundações. A união de dois tipos de fundações tão diferentes entre si estimulou o uso de novas metodologias que buscassem compreender melhor a interação entre os elementos do radier, das estacas e do solo quanto aos recalques e principalmente, distribuição de carregamento. Com a evolução das máquinas computacionais, alguns métodos numéricos passaram a ser utilizados para analisar esse tipo de fundação e novas ferramentas computacionais surgiram nos últimos anos, dentre elas destacando-se principalmente as baseadas em Método dos Elementos Finitos. Esse método, muito eficaz, tem sido cada vez mais utilizado em todos os campos da engenharia, mas ainda possui limitações principalmente relacionadas a capacidade de processamento das máquinas, quando analisada toda a fundação em suas 3 dimensões. Por esse motivo, algumas ferramentas de metodologia híbrida, utilizando mais de um tipo de método, foram implementadas afim de simplificar a análise, sem perder em qualidade de resultados. Dentro deste contexto, esta dissertação descreve a criação do programa Soil-Foundation Interaction Analysis, SoFIA, uma ferramenta híbrida criada em linguagem orientada a objetos, que analisa o radier em elementos finitos de placas de Kirchhoff e o meio solo/estaca através da superposição das interações de seus elementos dentro do próprio programa, obtidas através de elementos finitos axissimétricos. Nesse trabalho foram mostrada as etapas de construção da ferramenta, comparando resultados a trabalhos existentes na literatura e mostrando todas as aplicações da ferramenta. O objetivo principal desse trabalho foi criar uma ferramenta autossuficiente em linguagem orientada a objetos capaz de analisar o radier estaqueado integrando a análise de interação entre estacas e solo. A escolha da linguagem objetivou a expansão a ferramenta, com novos elementos, análises não lineares e outras tipos fundações. Os exemplos analisados mostraram bons resultados comparados à literatura quanto recalque, divisão do carregamento entre radier e estacas e momentos. Além disso a utilização das interações entre elementos de estacas e solo em uma análise axissimétrica é totalmente aceitável quando comparada a uma análise completa tridimensional e a uma análise em Método dos Elementos de Contorno.