Lung cancer is one of the leading causes of cancer deaths in the United States. Radiation and chemotherapy are conventional treatments, but they result in serious side effects and the probability of tumor recurrence remains high. Therefore, there is an increasing need to enhance the efficacy of conventional treatments. Magnetic nanoparticles have been previously studied for a variety of applications such as magnetic resonance imaging contrast agents, anemia treatment, magnetic cell sorting and magnetically mediated hyperthermia (MMH). In this work, dextran coated iron oxide nanoparticles were developed and functionalized with peptides to target the nanoparticles to either the extracellular matrix (ECM) of tumor tissue or to localize the nanoparticles in subcellular regions after cell uptake. The magnetic nanoparticles were utilized for a variety of applications. First, heating properties of the nanoparticles were utilized to administer hyperthermia treatments combined with chemotherapy. The nanoparticles were functionalized with peptides to target fibrinogen in the ECM and extensively characterized for their physicochemical properties, and MMH combined with chemotherapy was able to enhance the toxicity of chemotherapy. The second application of the nanoparticles was magnetically mediated energy delivery. This treatment does not result in a bulk temperature rise upon actuation of the nanoparticles by an alternating magnetic field (AMF) but rather results in intracellular damage via friction from Brownian rotation or nanoscale heating effects from Neél relaxations. The nanoparticles were functionalized with a cell penetrating peptide to facilitate cell uptake and lysosomal escape. The intracellular effects of the internalized nanoparticles alone and with activation by an AMF were evaluated. Iron concentrations in vivo are highly regulated as excess iron can catalyze the formation of the hydroxyl radical through Fenton chemistry. Although often a concern of using iron oxide nanoparticles for therapeutic applications, these inherent toxicities were harnessed and utilized to enhance radiation therapy. Therefore, the third application of magnetic nanoparticles was their ability to catalyze reactive oxygen species formation and increase efficacy of radiation. Overall, iron oxide nanoparticles have a variety of cancer therapy applications and are a promising class of materials for increasing efficacy and reducing the side effects of conventional cancer treatments.

Sistemas ultrassônicos tiveram uma evolução tecnológica nos últimos anos e isso permitiu que seus recursos de hardware e software pudessem ser explorados para extrair informações, auxiliando em diagnósticos e tratamentos mais eficazes. Através da análise do comportamento mecânico de tecidos moles, técnicas como elastografia estática, vibroacustografia, elastografia transiente e elastografia remota tiveram seu papel reconhecido na complementação do diagnóstico clínico. Contudo, a propagação destas técnicas na medicina tem sido restringida pela acessibilidade às tecnologias utilizadas, ausências de parâmetros quantitativos, dificuldade da excitação em estruturas profundas e acesso a informações em níveis moleculares. Este estudo aborda o desenvolvimento de um protocolo para efetuar medidas quantitativas de viscoelasticidade em tecidos moles marcados com nanopartículas de óxido de ferro usando excitação magnética e medição ultrassônica. Ao aplicar uma força magnética pulsada em um meio fluido marcado com nanopartículas magnéticas, um movimento é induzido, gerando uma onda de cisalhamento que se propaga pelo tecido. A propagação dessa onda é mapeada usando a técnica de ultrassom pulso-eco e processamento de dados usando métricas de similaridades entre ecos (mapa de rf) consecutivos. Nos estudos realizados em mimetizadores de tecidos moles (phantom) com características mecânicas equivalentes ao tecido biológico, a amplitude de deslocamento dessas ondas é da ordem de micrometro. Através da medida da velocidade deslocamento dessa onda avaliou-se o melhor modelo reológico para quantificar os parâmetros mecânicos de viscosidade e elasticidade. Os resultados mostraram a eficiência desta técnica ao quantificar os valores viscoelásticos condizentes com a literatura e a comprovação da análise de tecidos moles marcado com nanopartículas excitadas com campo magnético de baixa intensidade, possibilitando uma avaliação em âmbito molecular em tecidos moles. / Ultrasonic systems had a technological development in recent years and allowed their hardware and software resources could be exploited to extract information, assisting in more effective diagnosis and treatment. Through the mechanical behavior analysis of soft tissue techniques such as static elastography, vibroacoustography, transient elastography and remote elastography had recognized role in complementing clinical diagnosis. However, the spread of these techniques in medicine has been restricted by accessibility to the technologies used, quantitative parameters absences, difficulty of deep structures access and information on molecular levels. This study addresses the development of a protocol to make quantitative measurements of viscoelastic soft tissue labeled with iron oxide nanoparticles using magnetic excitation and ultrasonic measurement. By applying a pulsed magnetic force in a fluid medium labeled with magnetic nanoparticles, a motion is induced, generating a shear wave that propagates through the tissue. The propagation of this wave is mapped using the pulse-echo ultrasound technique and data processing using similarities measurements between echoes (rf map) consecutive. In studies of soft tissue-mimicking phantom with mechanical properties equivalent to the biological tissue, the displacement amplitude of these waves is of micrometer order. By measuring the shear wave velocity, it was evaluated the best rheological model for quantifying mechanical parameters of viscosity and elasticity. The results showed the efficiency of this technique to quantify the viscoelastic values consistent with the literature and the evidence of soft tissue analysis labeled excited nanoparticles with low intensity magnetic field, providing an assessment on the molecular level in soft tissues.

In der vorliegenden Arbeit wird das Prinzip der chemischen Oberflächenmodifikation als allgemeine Synthesestrategie beschrieben. Davon ausgehend werden verschiedene Ansätze der chemischen Funktionalisierung dargestellt, mit denen die Eigenschaften der erhaltenen Materialien eingestellt werden können. Im Fokus der Arbeit stehen Eisenoxid-Nanopartikel, die über die „Benzylalkohol-Route“ dargestellt werden. Es wird auf Basis dieser einfachen und vielseitig anwendbaren Funktionalisierung die Herstellung von neuartigen Hybridmaterialien gezeigt. Zur Funktionalisierung zweier magnetischer molekularer Rezeptoren wurde eine Synthesestrategie entwickelt, bei der organische Gruppen kovalent angebunden wurden. Der erste Rezeptor kann zur Erkennung von Biomarkern und den Metaboliten von Pharmazeutika eingesetzt werden. Die Beschichtung der Oberflächen der Eisenoxid-Nanopartikel gelang dabei durch die Verwendung von Organosilan-basierten Kopplungsreagenzien. Der zweite Rezeptor konnte zur Auftrennung eines racemischen Gemisches eines chiralen cavitand eingesetzt werden. Die Darstellung von Graphenoxid-Eisenoxid-Kompositen gelang erfolgreich durch ein ex-situ Verfahren. Es wurde der Einfluss der Oberflächenfunktionalitäten auf die Beladung und Verteilung der Eisenoxid-Nanopartikel untersucht. Dazu wurden via Diazoniumchemie verschiedene Funktionalitäten auf der Graphenoxid-Oberfläche eingeführt. Die Entwicklung einer wasserfreien one-pot Synthese von Gold-Eisenoxid-hetero-Nanostrukturen beschrieben wurde. Insbesondere wurden die Auswirkungen kleiner organischer Moleküle auf die Bildung der Heterostrukturen untersucht. / This thesis describes diverse approaches of chemical functionalization as a general strategy to tailor material properties depending on the target application. Particular attention was dedicated to the surface chemistry of iron oxide nanoparticles. Crystalline 10 nm-sized magnetite nanoparticles synthesized through the “benzyl alcohol route” exhibit superparamagnetic behaviour. For this reason they are regarded as suitable solid supports for the fabrication of recoverable devices, which is a fundamental requirement for several of the reported studies. Here it is demonstrated, via the fabrication of novel hybrid materials, that the ease of functionalization of iron oxide nanoparticles renders this material a versatile platform for the development of diverse surface chemistries. A covalent organic functionalization strategy was developed for the synthesis of two recoverable magnetic molecular receptors. The first targeted the recognition of drugs metabolites and biomarkers. It is based on the use of organosilanes coupling agents. A second approach aimed to the heterogeneous resolution of a racemic mixture of an inherently chiral cavitand. Graphene oxide-iron oxide composites were successfully fabricated through an ex-situ approach based on non-covalent interactions between the component phases. The effects of surface functionalities on the loading and distribution of iron oxide nanoparticles were studied by introducing selected functionalities at the graphene oxide surface through diazonium chemistry. Finally, the development of a non-aqueous one-pot synthesis route to gold-iron oxide hetero-nanostructures was described. Particular emphasis was dedicated to study the influence of small organic molecules in promoting the formation of the heterostructures.

<p>This work reports the chemical synthesis, characterisation and electrochemical application of titanium dioxide (TiO2) and iron oxide (Fe2O3) nanoparticles in the determination of phthalates. The other part of this work involved electrochemical polymerization of aniline doped with titanium and iron oxide nanoparticles for the sensor platform in the electrolytic determination of phthalates. The TiO2 and Fe2O3 nanoparticles were prepared by sol gel and hydrothermal methods respectively. Particle sizes of 20 nm (TiO2) and 50 nm (Fe2O3) were estimated from transmission electron microscopy (TEM) The other technical methods used in this study for the characterization of the TiO2 and iron oxide Fe2O3 NPs were SEM, XRD and UV- visible spectroscopy. Cyclic voltammetry, square wave voltammetry and electrochemical impedance spectroscopy (EIS) were used to study the electrochemical properties of the nanoparticles. These electrochemical studies of the nanoparticles were performed with a Fe2O3 or TiO2/nafion/glassy carbon membrane electrode in 0.1 M phosphate buffer (pH 7.0) and 0.1 M lithium perchlorate (pH 6.8) under an aerobic condition.</p>

<p>This work reports the chemical synthesis, characterisation and electrochemical application of titanium dioxide (TiO2) and iron oxide (Fe2O3) nanoparticles in the determination of phthalates. The other part of this work involved electrochemical polymerization of aniline doped with titanium and iron oxide nanoparticles for the sensor platform in the electrolytic determination of phthalates. The TiO2 and Fe2O3 nanoparticles were prepared by sol gel and hydrothermal methods respectively. Particle sizes of 20 nm (TiO2) and 50 nm (Fe2O3) were estimated from transmission electron microscopy (TEM) The other technical methods used in this study for the characterization of the TiO2 and iron oxide Fe2O3 NPs were SEM, XRD and UV- visible spectroscopy. Cyclic voltammetry, square wave voltammetry and electrochemical impedance spectroscopy (EIS) were used to study the electrochemical properties of the nanoparticles. These electrochemical studies of the nanoparticles were performed with a Fe2O3 or TiO2/nafion/glassy carbon membrane electrode in 0.1 M phosphate buffer (pH 7.0) and 0.1 M lithium perchlorate (pH 6.8) under an aerobic condition.</p>

Bien que de nombreux progrès aient 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 des patients. Aujourd’hui de nombreux espoirs reposent sur l’utilisation de nanoparticules (NPs) d’oxyde de fer fonctionnalisées permettant de combiner, en un seul nano-objet, le diagnostic (agent de contraste en IRM) et la thérapie par hyperthermie magnétique (i.e. « theranostic »). Dans ce contexte, la stratégie développée est la synthèse de NPs à propriétés magnétiques optimisées par le contrôle de leurs taille, forme et composition, leur biofonctionnalisation et la validation de leurs propriétés théranostiques. Une démarche d’ingénierie des NPs a été mise en place allant de la synthèse du précurseur de fer et de l’étude fine de sa décomposition en passant par l’étude in situ de la formation des NPs jusqu'à leur fonctionnalisation et la détermination de leurs propriétés theranostiques. / Despite numerous advances in cancer treatment, new approaches are necessary in order to minimize the deleterious side effects and to increase patient’s survivals rate. Nowadays, many hopes rely on functionalized iron oxide nanoparticles (NPs) that combine, in a single nano-objects, diagnosis (MRI contrast agent) and magnetic hyperthermia therapy (i.e. “theranostic”). In this context, the strategy is to develop the synthesis of optimized magnetic properties NPs through the control of their size, shape, composition, biofunctionalization and the validation of their theranostic properties. A process of NPs engineering has been developed starting at the iron precursor synthesis and the fine study of its decomposition passing through the in situ formation of the NPs to their functionalization and the determination of their theranostic properties.

Magister Scientiae - MSc / This work reports the chemical synthesis, characterisation and electrochemical application of titanium dioxide (TiO2) and iron oxide (Fe2O3) nanoparticles in the determination of phthalates. The other part of this work involved electrochemical polymerization of aniline doped with titanium and iron oxide nanoparticles for the sensor platform in the electrolytic determination of phthalates. The TiO2 and Fe2O3 nanoparticles were prepared by sol gel and hydrothermal methods respectively. Particle sizes of 20 nm (TiO2) and 50 nm (Fe2O3) were estimated from transmission electron microscopy (TEM) The other technical methods used in this study for the characterization of the TiO2 and iron oxide Fe2O3 NPs were SEM, XRD and UV- visible spectroscopy. Cyclic voltammetry, square wave voltammetry and electrochemical impedance spectroscopy (EIS) were used to study the electrochemical properties of the nanoparticles. These electrochemical studies of the nanoparticles were performed with a Fe2O3 or TiO2/nafion/glassy carbon membrane electrode in 0.1 M phosphate buffer (pH 7.0) and 0.1 M lithium perchlorate (pH 6.8) under an aerobic condition. / South Africa

Sistemas ultrassônicos tiveram uma evolução tecnológica nos últimos anos e isso permitiu que seus recursos de hardware e software pudessem ser explorados para extrair informações, auxiliando em diagnósticos e tratamentos mais eficazes. Através da análise do comportamento mecânico de tecidos moles, técnicas como elastografia estática, vibroacustografia, elastografia transiente e elastografia remota tiveram seu papel reconhecido na complementação do diagnóstico clínico. Contudo, a propagação destas técnicas na medicina tem sido restringida pela acessibilidade às tecnologias utilizadas, ausências de parâmetros quantitativos, dificuldade da excitação em estruturas profundas e acesso a informações em níveis moleculares. Este estudo aborda o desenvolvimento de um protocolo para efetuar medidas quantitativas de viscoelasticidade em tecidos moles marcados com nanopartículas de óxido de ferro usando excitação magnética e medição ultrassônica. Ao aplicar uma força magnética pulsada em um meio fluido marcado com nanopartículas magnéticas, um movimento é induzido, gerando uma onda de cisalhamento que se propaga pelo tecido. A propagação dessa onda é mapeada usando a técnica de ultrassom pulso-eco e processamento de dados usando métricas de similaridades entre ecos (mapa de rf) consecutivos. Nos estudos realizados em mimetizadores de tecidos moles (phantom) com características mecânicas equivalentes ao tecido biológico, a amplitude de deslocamento dessas ondas é da ordem de micrometro. Através da medida da velocidade deslocamento dessa onda avaliou-se o melhor modelo reológico para quantificar os parâmetros mecânicos de viscosidade e elasticidade. Os resultados mostraram a eficiência desta técnica ao quantificar os valores viscoelásticos condizentes com a literatura e a comprovação da análise de tecidos moles marcado com nanopartículas excitadas com campo magnético de baixa intensidade, possibilitando uma avaliação em âmbito molecular em tecidos moles. / Ultrasonic systems had a technological development in recent years and allowed their hardware and software resources could be exploited to extract information, assisting in more effective diagnosis and treatment. Through the mechanical behavior analysis of soft tissue techniques such as static elastography, vibroacoustography, transient elastography and remote elastography had recognized role in complementing clinical diagnosis. However, the spread of these techniques in medicine has been restricted by accessibility to the technologies used, quantitative parameters absences, difficulty of deep structures access and information on molecular levels. This study addresses the development of a protocol to make quantitative measurements of viscoelastic soft tissue labeled with iron oxide nanoparticles using magnetic excitation and ultrasonic measurement. By applying a pulsed magnetic force in a fluid medium labeled with magnetic nanoparticles, a motion is induced, generating a shear wave that propagates through the tissue. The propagation of this wave is mapped using the pulse-echo ultrasound technique and data processing using similarities measurements between echoes (rf map) consecutive. In studies of soft tissue-mimicking phantom with mechanical properties equivalent to the biological tissue, the displacement amplitude of these waves is of micrometer order. By measuring the shear wave velocity, it was evaluated the best rheological model for quantifying mechanical parameters of viscosity and elasticity. The results showed the efficiency of this technique to quantify the viscoelastic values consistent with the literature and the evidence of soft tissue analysis labeled excited nanoparticles with low intensity magnetic field, providing an assessment on the molecular level in soft tissues.

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.

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