Aminoglycosides are a group of broad-spectrum antibiotics that, under neutral pH conditions, carry a positive charge. The net cationic charge arises from the high number of amino groups in the core structure of aminoglycosides. Previous studies performed have shown that negatively charged citrate ligand-capped gold nanoparticles (AuNPs) can interact with various biomolecules such as aminoglycosides. AuNPs bound to biomolecules have been used in conjugation with various assaying techniques to detect and study compounds in vitro and in vivo. AuNPs also have strong light scattering properties that can be used with a wide variety of imaging and assaying techniques. Our laboratory has previously performed experiments on the aminoglycoside antibiotic ribostamycin sulfate. During this experiment, the concentration dependent rod-like assembly of ribostamycin sulfate was characterized. This experiment used three analytical techniques in conjunction with AuNPs: (1) dynamic light scattering (DLS), (2) UV-Vis absorption spectroscopy, and (3) dark field optical microscope imaging (DFM). This suite of techniques was used to analyze mixtures of ribostamycin sulfate at different concentration with different sized AuNPs. The primary objective of this research was to determine if the techniques used to characterize the self-assembly of ribostamycin sulfate could be generalized and applied to other aminoglycoside antibiotics. The secondary objective of this research was to determine if other aminoglycoside antibiotics formed rod-like assemblies. This study demonstrated that AuNPs can be used to detect self-assembled oligomers for different aminoglycoside antibiotics. In addition, this study also revealed that not all aminoglycoside antibiotics will self assemble into rod-like oligomers similar to ribostamycin. It was observed that the aminoglycoside antibiotic amikacin self assembled into rod-like aggregates similar to ribostamycin sulfate but the aminoglycoside antibiotics neomycin sulfate and streptomycin sulfate did not.

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No description available.

Cancer is currently the second most common cause of death in the world. Despite tremendous progress in the treatment of different forms of cancer, the five year survival rates for lung, colorectal, breast, prostate, pancreatic and ovarian cancers remain quite low. New therapies are urgently needed for the better management of these diseases. In this context, both therapeutic gene and drug delivery constitute promising approaches for cancer treatment and are addressed in this thesis. Focusing on gene delivery, we are proposing the use new pyridinium amphiphiles for obtaining gene delivery systems with improved stability and efficiency and low toxicity (Chapters 2 and 3). The main focus was on pyridinium gemini surfactants (GSs), which possess a soft charge, a high charge/mass ratio and a high molecular flexibility - all key parameters that recommend their use in synthetic gene delivery systems with in vitro and in vivo efficiency. In Chapter 2, we optimized a novel DNA delivery systems through interfacial engineering of pyridinium GS at the level of linker, hydrophobic chains and counterions. In Chapter 3, we tested the effects of blending pyridinium cationic GS into pyridinium cationic lipid bilayers and we have evaluated these blends towards plasmid DNA compaction and delivery process. We have also correlated the cationic bilayer composition with the dynamics of the DNA compaction process, and with transfection efficiency, cytotoxicity and internalization mechanism of resulted nucleic acid complexes. Toward improved drug delivery systems, we introduced new amphiphilic block copolymers synthesized from biocompatible and biodegradable segments. Although their capabilites for loading, transport and release of lipophilic substances stored in their hydrophobic cores are widely known, their stability in vivo is limited due to rapid degradation by esterases present in the body. In Chapter 4, we examined the possibility to increase the enzymatic stability of PEG-PCL macromolecular amphiphiles through interfacial engineering, in a process which separates the hydrophilic/hydrophobic interface from the degradable/non-degradable block interface. We evaluated the stability, toxicity, drug loading and release properties of these new polymers using docetaxel as a model chemotherapeutic drug. The results revealed how hydrophilic/ hydrophobic interface tuning can be used to adjust key properties of polymeric drug delivery systems of this type. / Pharmaceutical Sciences

Tratamentos de superfície são técnicas amplamente utilizadas com a finalidade de aumentar a resistência à corrosão de materiais metálicos. No caso específico do alumínio e ligas de alumínio, o tratamento com cromo hexavalente é um dos processos mais utilizados. Isso, em razão da eficiência e da facilidade de aplicação desse processo. Entretanto, em virtude de restrições ambientais e do elevado custo de tratamento de resíduos gerados neste processo, métodos alternativos para sua substituição vêm sendo avaliados. Neste contexto, o presente estudo investigou o processo de formação e proteção à corrosão fornecida por filmes de moléculas autoorganizáveis de compostos à base de fosfonatos sobre a liga de alumínio 1050. Para definir as condições do tratamento foram utilizadas medidas de condutividade e de ângulo de contato, juntamente com ensaios eletroquímicos. Técnicas eletroquímicas, especificamente: medidas de variação do potencial a circuito aberto (PCA), espectroscopia de impedância eletroquímica (EIE) e polarização potenciodinâmica foram utilizadas para avaliar a proteção à corrosão. Os diagramas experimentais de impedância foram interpretados utilizando circuitos elétricos equivalentes que simulam modelos do filme de óxido que se forma na superfície da liga. Os resultados fornecidos com a liga tratada com moléculas auto-organizáveis foram comparados com resultados obtidos em iguais condições com amostras da liga sem qualquer tratamento ou cromatizada com Cr(VI) e mostraram que o tratamento com moléculas auto-organizáveis aumenta significativamente a resistência à corrosão da liga e apresenta, em determinadas condições, desempenho próximo ao fornecido pelo processo de cromatização. / Surface treatments are widely used to increase the corrosion resistance of metallic materials. Specifically for aluminum and aluminum alloys, treatment with hexavalent chromium is one of the most used, due to its efficiency and ease of application. However, because of environmental restrictions and the high cost involved in the treatments of waste generated in this process, alternative methods for its replacement are necessary. In this context, this study investigated the effect of the surface treatment with self-assembling molecules (SAM) based on phosphonate compounds on the corrosion of the 1050 aluminum alloy. The conditions adopted for the SAM treatment were determined by conductivity and contact angle measurements, besides electrochemical experiments. Electrochemical techniques, specifically: measurement of the open circuit potential (OCP) variation with time, electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization curves were used to evaluate the corrosion resistance of the 1050 aluminum alloy exposed to SAM treatment The experimental impedance diagrams were interpreted using equivalent electrical circuit models that simulate film that is formed on the alloy surface. The results of the samples treated with SAM were compared with those of samples either without any treatment or treated with chromatizing conversion coating with Cr(VI) and showed that the first treatment significantly increased the corrosion resistance of the aluminum alloy and approached that of chromatizing with Cr(VI) process.

An ideal drug delivery system should contain an appropriate therapeutic agent and biocompatible carrier. In this study, we investigated the ability of the all-complementary self-assembling peptide AC8 in stabilizing the anticancer compound and determined the in-vitro therapeutic efficacy of the peptide-mediated anticancer drug delivery. The all-complementary peptide AC8 was designed based on the amino acid pairing principle (AAP), which contains hydrogen bonding, electrostatic, and hydrophobic interaction amino acid pairs. AAP interactions make the peptide capable of self-assembling into β-sheet structure in solution in a concentration dependent manner. Peptide solution concentration is a key parameter in controlling the nanoscale assembling of the peptide. The critical assembly concentration (CAC) of the peptide was found ~ 0.01 mg/ml by several techniques. The all-complementary peptide AC8 was found to be able to stabilize neutral state of hydrophobic anticancer compound ellipticine in aqueous solution. The formation of peptide-ellipticine complex was monitored by fluorescence spectroscopy at different mass ratios of peptide-to-ellipticine. The anticancer activity of the complexes with neutral state of ellipticine was found to show great anticancer activity against two cancer cells lines, A-549 and MCF-7. This peptide-mediated anticancer delivery system showed the induction of apoptosis on cancer cells in vitro by flow Cytometry.

An ideal drug delivery system should contain an appropriate therapeutic agent and biocompatible carrier. In this study, we investigated the ability of the all-complementary self-assembling peptide AC8 in stabilizing the anticancer compound and determined the in-vitro therapeutic efficacy of the peptide-mediated anticancer drug delivery. The all-complementary peptide AC8 was designed based on the amino acid pairing principle (AAP), which contains hydrogen bonding, electrostatic, and hydrophobic interaction amino acid pairs. AAP interactions make the peptide capable of self-assembling into β-sheet structure in solution in a concentration dependent manner. Peptide solution concentration is a key parameter in controlling the nanoscale assembling of the peptide. The critical assembly concentration (CAC) of the peptide was found ~ 0.01 mg/ml by several techniques. The all-complementary peptide AC8 was found to be able to stabilize neutral state of hydrophobic anticancer compound ellipticine in aqueous solution. The formation of peptide-ellipticine complex was monitored by fluorescence spectroscopy at different mass ratios of peptide-to-ellipticine. The anticancer activity of the complexes with neutral state of ellipticine was found to show great anticancer activity against two cancer cells lines, A-549 and MCF-7. This peptide-mediated anticancer delivery system showed the induction of apoptosis on cancer cells in vitro by flow Cytometry.

Les matériaux les plus répandus dans le domaine du photovoltaïque (PV) organique à base de polymères sont le poly(3-hexylthiophène) régiorégulier (rr-P3HT) et le [6,6]-phenyl-C61-butyric acide methyl ester (PCBM). La couche active est une hétérojonction en volume (BHJ) de nanodomaines interpénétrés accepteur d’électron (le PCBM) et donneur d’électron (le P3HT). Le contrôle de la morphologie de la couche active et de sa stabilité est un défi majeur pour le développement des cellules organiques et est au centre de ce travail de thèse.Dans un premier temps, nous avons cherché à contrôler la morphologie du mélange P3HT:PCBM via l’utilisation de compatibilisants. Deux familles de copolymères à blocs rigide et souple ont été étudiées. Elles ont en commun leur bloc rigide à base de P3HT et diffèrent par leur bloc souple. Pourla première famille, le bloc souple poly-butylacrylate est greffé de C60, ce qui lui confère une affinité chimique avec les domaines de PCBM, et la seconde famille a un bloc souple poly(4-vinylpiridine) (P4VP) non greffé en C60. De par son affinité chimique avec le C60, le PCBM se localisera préférentiellement au voisinage des domaines P4VP.Dans un deuxième temps, nous avons exploité les propriétés d’auto-assemblages des copolymères à blocs afin de les étudier en tant que matériaux photo-actifs. Nous avons cherché à appréhender l’influence de la nature du bloc flexible let de a taille des blocs souple et rigide sur l’organisation des copolymères ainsi que sur les propriétés de transport de charge et sur les performances PV. / Polymer/fullerene bulk heterojunction (BHJ) solar cells use an interpenetrating network of TT-conjugated electron-donor polymers and electron-acceptor C60 as photo-active layer. Currently, the most investigated blends are constituted of regioregular poly(3-hexylthiophene) (rr-P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). The nanostructured active layer determines to great extend the overall performance of the devices.First of all, we introduced rod-coil block copolymers as compatibilizer into P3HT:PCBM blends and investigate their influence on the blend morphology and the related photovoltaic performance. Two P3HT-based block copolymer families have been studied. The first one has a C60-grafted polybutylacrylate coil block and the second one is based on poly(4-vinylpyridine) (P4VP) coil block. The film morphology and device efficiencies are investigated as a function of copolymer content, P3HT/PCBM mass ratio and coil nature.A second possible route to obtain a stable donor/acceptor nanostructure consists of using semiconductor block copolymers as photoactive layer, since these materials are able to self-assemble into donor/acceptor BHJ by microphase separation. We explored P3HT-P4VP rod-coil block copolymers blended with PCBM in view of their utilization in photovoltaic devices. The copolymer selfassembles into nano-domains rich in either P3HT or P4VP, while the strong chemical affinity of P4VP with PCBM leads to an accumulation of the latter in the P4VP domains, providing them an acceptorcharacter. It is found that organized and thermally stable thin films, that exhibit ambipolar field effect mobilities, can be achieved for a specific rod/coil ratio.

Le cartilage a une capacité de régénération très limitée car il n'est pas vascularisé. Laréparation de ce tissu est un défi et les techniques chirurgicales actuelles sont insatisfaisantes à longterme. Le cartilage est donc un bon candidat pour l'ingénierie tissulaire. La transplantation dechondrocytes autologues (TCA) a été la première thérapie cellulaire développée en rhumatologie maiscette procédure implique une amplification des cellules qui aboutit à une perte du phénotypechondrocytaire (perte de l'expression du collagène de type II, protéine majoritaire du cartilage), auprofit d'un phénotype fibroblastique (caractérisé par l'expression du collagène de type I, retrouvé dansles tissus fibreux). La TCA conduit donc à une greffe de chondrocytes dédifférenciés produisant unfibrocartilage, dont les propriétés mécaniques sont inférieures à celles du cartilage articulaire.Aujourd'hui, les agences de santé au niveau international s'accordent pour dire que cette procédurenécessite d'être améliorée, par un meilleur contrôle du phénotype cellulaire et l'utilisation debiomatériaux pour mieux combler les lésions articulaires. Il s'agit donc de passer de la thérapiecellulaire à l'ingénierie tissulaire du cartilage.L'objectif de nos travaux a été d'évaluer la capacité d'un gel innovant de peptides autoassemblants,l'hydrogel IEIK13, à jouer le rôle de support pour des chondrocytes humains afin qu'ilsproduisent une matrice cartilage sous l'action de facteurs chondrogéniques. L'objectif visé a été lacréation d'un gel cartilage implantable par arthroscopie. Le défi a été de surmonter la dédifférenciationdes chondrocytes inhérente à leur amplification et incontournable pour augmenter le réservoircellulaire. L'amplification de chondrocytes humains a été réalisée en présence de FGF-2 et d'insuline(cocktail FI) puis leur redifférenciation a été induite en gel IEIK13 sous l'action de BMP-2, d'insuline etd'hormone T3 (cocktail BIT). C'est la combinaison sélective des deux cocktails qui permet la séquencedédifférenciation-redifférenciation. Le phénotype des chondrocytes et la nature de la matriceextracellulaire synthétisée en gel ont été évalués dans un premier temps in vitro, par des analyses dePCR en temps réel, Western-blots et d'immunohistochimie. Dans un second temps, nous avonstransplanté le gel cartilage dans des lésions articulaires de genou d'un modèle original de primate nonhumain(singe cynomolgus), un type de gros animal dont la posture et le fonctionnement desarticulations s'apparentent à l'homme. Nos études d'imagerie non invasive (telle qu'elle est pratiquéechez l'homme) et immunohistochimiques trois mois après implantation montrent une réparationsatisfaisante des lésions, en comparaison avec les lésions laissées non comblées. L'ensemble de nosrésultats montre pour la première fois que l'hydrogel IEIK13 est un biomatériau favorable pourreconstruire le cartilage et que le primate non-humain est un modèle préclinique unique pour évaluerl'efficacité de l'ingénierie tissulaire du cartilage / Cartilage is not vascularized and presents poor capacity of self-regeneration. Repairing thistissue is a challenge and current surgical techniques are not satisfactory in the long term. Cartilage isthus a good candidate for tissue engineering. Autologous chondrocyte transplantation (ACT) was thefirst cell therapy developed for cartilage repair. This procedure implies amplification of cells whichresults in chondrocyte dedifferentiation (loss of expression of type II collagen, the major protein ofcartilage and acquisition of expression of type I collagen, the major protein found in fibrous tissues).Thus, ACT results in implantation of fibroblastic cells producing fibrocartilage with biomechanicalproperties inferior to native articular cartilage. The international health agencies agree that ACT needsto be improved with better control of the chondrocyte phenotype and use of biomaterials. Therefore,cell therapy of cartilage needs to move towards tissue engineering of cartilage.The objective of our study was to evaluate the capacity of an innovative self-assemblingpeptide (IEIK13) to support cartilage matrix production by human chondrocytes. Our goal was to createa cartilage gel that can be implanted by arthroscopy. A main challenge was to meet the problem ofchondrocyte dedifferentiation induced by cell amplification necessary to increase the cellularreservoir. Amplification of human chondrocytes was performed in the presence of FGF-2 and insulin(cocktail FI), and redifferentiation was subsequently induced in IEIK13 gel with BMP-2, insulin, andtriiodothyronine T3 (cocktail BIT). The specific combination of these two cocktails alloweddedifferentiation-redifferentiation of chondrocytes. The status of the chondrocyte phenotype and thenature of the extracellular matrix secreted in gel were first assessed in vitro by real-time PCR, Westernblottingand immunhostochemistry analyses. With a view of clinical application, we then transplantedIEIK13-engineered cartilages into defects created in knees of an original model of non-human primate(cynomolgus monkey), a type of large animal whose anatomy and biomechanics mimic human. Ournon-invasive imaging analyses and our inmmunohistochemical studies performed three months afterimplantation show correct reparation of the lesions, in comparison with the defects left untreated.Altogether, our results demonstrate for the first time that IEIK13 is a suitable biomaterial for cartilagerepair and that cynomolgus monkey represents a unique preclinical model to evaluate efficiency ofcartilage tissue engineering.

La dualité hydrophobe/hydrophile des molécules amphiphiles est à l’origine de leur autoassemblage en solution, sous forme de nombreuses structures supramoléculaires, telles que les micelles. Ce travail de thèse présente la formation, la caractérisation et l’étude de nouvelles micelles diacétylèniques photopolymérisables. Une première partie décrit ainsi lasynthèse de nouvelles micelles cationiques et l’étude de leur utilisation en tant qu’agent de transfert de gènes. Dans une seconde partie, nos travaux présentent l’étude de micelles polydiacétylèniques, porteuses de têtes polaires octaéthylèneglycol, comme potentiel système de délivrance de médicament. Les propriétés d’encapsulation de ces micelles ont été évaluées en présence d’un dérivé fullerène fluorescent. Puis, l’incorporation d’une sonde membranaire dans leur couronne lipophile a permis de réaliser une étude de leurs propriétés de délivrance in vitro. Une étude préliminaire de leur biodistribution in vivo a également été réalisée par tomographie à émission monophotonique grâce à la chélation d’un isotoperadioactif sur la surface des micelles. Enfin une dernière partie présente l’analyse de deux nouveaux auto-assemblages tubulaires obtenus au cours de nos travaux. / The hydrophobic/hydrophilic duality of amphiphilic molecules is at the origin of their selfassembly in solution, into many supramolecular structures such as micelles. This thesis presents the formation, characterization and study of new photopolymerizable diacetylenic micelles. The first part describes the synthesis of new cationic micelles and the study of theiruse as gene transfer agent. In the second part, our work presents the study of polydiacetylene micelles, bearing polar heads octaétylèneglycol as potential drug delivery system. The encapsulation properties of these micelles were first evaluated in the presence of a fluorescent fullerene derivative. Then, the incorporation of a membrane probe in their lipophilic shell has allowed a study of their in vitro delivery properties. Finally a study of their in vivo biodistribution was also carried out by single photon emission tomography through the chelation of a radioactive isotope on micelle surface. Finally the last part presents theanalysis of two new tubularself-assemblies, obtained during our work.