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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Engineering dendritic architectures to face nanomedicine issues : biodistribution, toxicity, pharmacokinetics or active targeting / Ingénierie d'architectures dendritiques pour la résolution de problématiques de nanomédecine : biodistribution, toxicité, pharmacocinétique ou ciblage actif

Bordeianu, Catalina 29 September 2016 (has links)
Le cancer est une cause majeure de décès dans le monde, 7,6 millions de décès en 2008. Bien que de nombreux progrès ont été réalisés dans le traitement du cancer, de nouvelles approches sont nécessaires afin de minimiser les effets secondaires délétères et d'augmenter le taux de survie. Par conséquent, l'avenir de la nanomédecine réside dans le développement de nano-plateformes multifonctionnelles. Il ne fait aucun doute que les hybrides organique / inorganique à base de dendrons représentent des outils très avancés, capables de cibler spécifiquement et d'être suivis par imagerie en même temps. Dans ce contexte, les objectifs de cette thèse sont non seulement la conception de nano-objets magnétiques dendronisés biocompatibles permettant à la fois le diagnostic par imagerie à résonance magnétique (IRM) ainsi que par imagerie optique (IO) mais également la validation in vitro et in vivo des propriétés de ces nano-objets et la démonstration de leur efficacité pour le ciblage spécifique de tumeurs. / Cancer is a worldwide leading cause of death, 7.6 million deaths in 2008 with 13% mortality. Although much progress has been made in early cancer diagnosis and treatment, new approaches are needed to minimize the deleterious side effects while increasing survival rate. Therefore, the future of Nanomedicine relies in the development of multifunctional nano-platforms that combine therapeutic components, multimodal imaging and active targeting. Organic/inorganic dendrimer-based hybrids are very advanced tools, especially for targeting a specific cell type or a particular organ and for being followed by imaging techniques at the same time.In this context, the objective of this thesis is not only the design of multifunctional magnetic dendronized nano-objects, but also their in vitro and in vivo validation and assessment of their active targeting effectiveness.
12

Targeted Drug Delivery to Breast Cancer using Polymeric Nanoparticle Micelles

Ho, Karyn 13 December 2012 (has links)
Broad distribution and activity limit the utility of anti-cancer compounds by causing unacceptable systemic toxicity and narrow therapeutic indices. To improve tumour accumulation, drug-loaded macromolecular assemblies have been designed to replace conventional surfactant-based formulations. Their nanoscale size enhances tumour accumulation via hyperpermeable vasculature and reduced lymphatic drainage. Incorporating targeting ligands introduces cell specificity through receptor-specific binding and uptake, enabling drugs to reach intracellular targets. In this work, the targeting properties of polymer nanoparticle micelles of poly(2-methyl-2-carboxytrimethylene carbonate-co-D,L-lactide)-graft-poly(ethylene glycol)-furan (poly(TMCC-co-LA)-g-PEG) were verified using in vitro and in vivo models of breast cancer. To select a relevant mouse model, the vascular and lymphovascular properties of two tumour xenograft models were compared. Greater accumulation of a model nanocarrier was observed in orthotopic mammary fat pad (MFP) tumours than size matched ectopic subcutaneous tumours, suggesting that the organ environment influenced the underlying pathophysiology. Immunostaining revealed greater vascular thickness, density and size, and thinner basement membranes in MFP tumours, likely contributing to greater blood perfusion and vascular permeability. Based on these observations, MFP tumour-bearing mice were used to characterize the pharmacokinetics and biodistribution of a taxol drug, docetaxel, encapsulated in poly(TMCC-co-LA)-g-PEG nanoparticles. The nanoparticle formulation demonstrated longer docetaxel circulation in plasma compared to the conventional surfactant-based formulation. As a result, greater docetaxel retention was uniquely measured in tumour tissue, extending exposure of tumour cells to the active compound and suggesting potential for increased anti-cancer efficacy. Furthermore, active targeting of antibody-modified nanoparticles to live cells was shown to be selective and receptor-specific. Binding isotherms were used to quantify the impact of antibody density on binding strength. The equilibrium binding constant increased linearly with the average number of antibodies per particle, which is consistent with a single antibody-antigen interaction per particle. This mechanistic understanding enables binding behaviour to be adjusted in a predictive manner and guides rational nanoparticle design. These studies validate poly(TMCC-co-LA)-g-PEG nanoparticles as a platform for targeted delivery to cancer on both a tissue and cellular level, forming a compelling justification for further pre-clinical evaluation of this system for safety and efficacy in vivo.
13

Targeted Drug Delivery to Breast Cancer using Polymeric Nanoparticle Micelles

Ho, Karyn 13 December 2012 (has links)
Broad distribution and activity limit the utility of anti-cancer compounds by causing unacceptable systemic toxicity and narrow therapeutic indices. To improve tumour accumulation, drug-loaded macromolecular assemblies have been designed to replace conventional surfactant-based formulations. Their nanoscale size enhances tumour accumulation via hyperpermeable vasculature and reduced lymphatic drainage. Incorporating targeting ligands introduces cell specificity through receptor-specific binding and uptake, enabling drugs to reach intracellular targets. In this work, the targeting properties of polymer nanoparticle micelles of poly(2-methyl-2-carboxytrimethylene carbonate-co-D,L-lactide)-graft-poly(ethylene glycol)-furan (poly(TMCC-co-LA)-g-PEG) were verified using in vitro and in vivo models of breast cancer. To select a relevant mouse model, the vascular and lymphovascular properties of two tumour xenograft models were compared. Greater accumulation of a model nanocarrier was observed in orthotopic mammary fat pad (MFP) tumours than size matched ectopic subcutaneous tumours, suggesting that the organ environment influenced the underlying pathophysiology. Immunostaining revealed greater vascular thickness, density and size, and thinner basement membranes in MFP tumours, likely contributing to greater blood perfusion and vascular permeability. Based on these observations, MFP tumour-bearing mice were used to characterize the pharmacokinetics and biodistribution of a taxol drug, docetaxel, encapsulated in poly(TMCC-co-LA)-g-PEG nanoparticles. The nanoparticle formulation demonstrated longer docetaxel circulation in plasma compared to the conventional surfactant-based formulation. As a result, greater docetaxel retention was uniquely measured in tumour tissue, extending exposure of tumour cells to the active compound and suggesting potential for increased anti-cancer efficacy. Furthermore, active targeting of antibody-modified nanoparticles to live cells was shown to be selective and receptor-specific. Binding isotherms were used to quantify the impact of antibody density on binding strength. The equilibrium binding constant increased linearly with the average number of antibodies per particle, which is consistent with a single antibody-antigen interaction per particle. This mechanistic understanding enables binding behaviour to be adjusted in a predictive manner and guides rational nanoparticle design. These studies validate poly(TMCC-co-LA)-g-PEG nanoparticles as a platform for targeted delivery to cancer on both a tissue and cellular level, forming a compelling justification for further pre-clinical evaluation of this system for safety and efficacy in vivo.
14

Contrast agent based on nano-emulsion for targeted biomedical imaging / Agent de contraste à base de nano-émulsion pour l'imagerie biomédicale ciblée

Attia, Mohamed 03 November 2016 (has links)
Les agents d’imagerie aux rayons X sont essentiels en combinaison avec la tomodensitométrie pour améliorer le contraste de manière à permettre la visualisation complète des vaisseaux sanguins et de fournir l'information structurelle et fonctionnelle de lésions permettant la détection d'une tumeur. Ces outils fondamentaux permettent également de faire la distinction entre les cellules et les agents pathogènes sains. Les agents de contraste aux rayons X commercialisés sont limités dans leur succès dans le cas du Fenestra® VC par le temps court de circulation dans le sang et celui qui est lié à l'élimination rénale rapide du corps comme dans le cas du Xenetix® (Iobitriol). Nous avons développé des agents de contraste à base d’α-tocophérol (vitamine E), de Cholécalciférol (vitamine D3), d'huile de ricin, de Capmul® MCMC8 et d’acide oléique qui sont tous dénués de toxicité, qui contiennent de l’iode sous forme de nano-émulsion et qui sont destinés à l’imagerie préclinique en μ-CT. Ces nano-émulsions formulées ont été préparées par la technique d’émulsification spontanée de basse énergie avec une légère modification pour chaque composé iodé. Ces formulations ont montré de nouvelles caractéristiques spécifiques les rendant prometteuses dans des expérimentations in vivo avec une augmentation du rapport de la toxicité et de celui des interventions thérapeutiques visées. Nous avons étudié l'effet de la taille et de la composition chimique des systèmes nanoparticulaires sur leur biodistribution, leur pharmacocinétique et leur toxicité. Ces études ont permis de mettre en évidence l’importance de la constitution chimique des agents iodés utilisés avec par exemple la vectorisation du foie dans le cas de la vitamine E et une accumulation passive dans la rate pour les formulations à base d'huile de ricin, faisant la preuve-de-concept de l'effet EPR. D'autre part, des formulations identiques ayant deux tailles de gouttelettes différentes et contenant du cholécalciférol indiquent qu’il n’y a pas de réels impacts sur la pharmacocinétique et la biodistribution mais présentaient une augmentation importante de la toxicité. Une autre étude a consisté a étudié l’effet des charges de surface des systèmes nanoparticulaires sur leur biodistribution, c’est pourquoi la nano-émulsion a été sélectionnée pour réaliser cette étude en présence d’un polymère amphiphile tel que le poly (anhydride-alt-1-octadecene maléique) (PMAO). Les résultats in vitro et les évaluations in vivo étaient tout à fait cohérents sachant que les systèmes nanoparticulaires neutres présentent moins de toxicité comparée à celles qui sont chargés négativement qui ont été capturés de manière plus importante dans les cellules causant un stress cellulaire et delà affectent la toxicité. Selon les résultats, elles présentent des biodistributions et des pharmacocinétiques différentes. Dans ce contexte, pour la première fois, nous avons pu fonctionnaliser les nanogouttes des nanoémulsions en fixant des ligands par des liaisons covalentes. Nous avons conçu des nanogouttes enrobées avec un enrobage de silice terminé par des groupements aminés et ainsi réalisé la formation de liaisons amides avec le greffage d’un colorant modèle (colorant bleu coumarine). La quantification des groupements aminés a été réalisée à l'aide de techniques spectroscopiques et microscopiques ainsi que la détermination de l'efficacité du greffage déterminé à 41%. [...] Un de nos objectifs réalisés était de concevoir des systèmes nanoparticulaires polymères multifonctionnels qui peuvent encapsuler des principes actifs hydrophobes modèles et des agents de contraste pour l’imagerie à rayons X, de sorte à construire des dispositifs théranostiques. Pour conclure, de nouveaux agents de contraste et des systèmes de délivrance ont été synthétisés ayant des caractéristiques physico-chimiques exceptionnelles et acceptables pour être utilisées in vivo avec une grande efficacité et une faible toxicité. / X-ray imaging agents are essential in combination with X-ray computed tomography to improve contrast enhancement aiming at providing complete visualization of blood vessels and giving structural and functional information on lesions allowing the detection of a tumor. As well as it is fundamental tool to discriminate between healthy cells and pathogens. We successfully limit the problems presented in commercial Xray contrast agents like poor contrasting in Fenestra® VC associated with short blood circulation time and to avoid rapid renal elimination from the body as found in Xenetix (Iobitriol). We developed nontoxic and blood pool iodine-containing nano-emulsion contrast agents serving in preclinical X-ray μ-CT imaging such as, α- Tocopherol (vitamin E), Cholecalciferol (vitamin D3), Castor oil, Capmul MCMC8 oil and oleic acid. Those formulated nanoemulsions were prepared by low energy spontaneous emulsification technic with slight modification for each platform. They showed new specific features rendering them promising agents in in vivo experiments as improving the balance between the efficacy and the toxicity of targeted therapeutic interventions. We investigate the effect of size and the chemical composition of the nanoparticles on their biodistribution, pharmacokinetics and toxicity. They demonstrated that the chemical structures of the droplet’s cores have significant role in targeting for example vitamin E was mainly accumulated in liver and castor oil formulation was passively accumulated in spleen explaining the proof-of-concept of EPR effect. On the other hand, two different platform sizes of Cholecalciferol molecule revealing that no real impact on the pharmacokinetics and biodistribution but presented remarkable effect on the toxicity. Of particular interest is studying the effect of the surface charge of nanoparticles on their biodistribution, this is why oleic acid nano-emulsion was selected to proceed this study by presence of amphiphilepolymer poly(maleic anhydride-alt-1-octadecene) (PMAO). The in vitro results and in vivo evaluations were completely coherent approving that the neutral charged NPs are less toxic compared to the negatively charged ones that were highly uptaked in the cells causing stress to the cells and thereby affecting the toxicity. As a result they are different in biodistribution and pharmacokinetics. In this context, for the first time, we were able to functionalize the nano-emulsion droplets with ligand molecules by covalent bonds. Likewise we designed nano-droplets and coated by silica shell ended by amino groups and then followed by formation of amide bonds with grafting to dye ligand model (coumarin blue dye). The quantification of amino groups was performed by using spectroscopic and microscopic techniques, with a grafting efficiency as high as 41%. This process improves the targeting properties of such chemotherapeutic agents to the location of interest following active targeting mechanism (ligand receptorstrategy). One of our achieved objectives was to engineer multifunctional polymer-based NPs encapsulating hydrophobic drug model as DDs and iron oxide NPs as a theranostic model. To conclude, novel contrast agents and delivering systems were synthesized with outstanding physicochemical characteristics and suitable for in vivo medium with high efficacy and low toxicity.

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