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Abstract(s)
Introdução: Hipóxia em tecidos ocorre em condições patológicas, tais como cancro, isquemia cardiaca (quando uma artéria é obstruida) e acidente vascular cerebral, caracterizando-se quando a exigência de oxigénio é superior ao oxigénio fornecido (Sinusas, 1999). Atualmente, a maioria das aproximações não-invasivas para deteção de hipóxia no miocárdio baseiam-se ou na medição dos níveis de oxigénio no miocárdio ou na medição dos efeitos associados a esta patologia, entre eles a alteração da função mecânica ou instabilidade elétrica, existindo poucos estudos que reportem o miocárdio hipóxico diretamente. Assim, o objectivo deste trabalho foi planear e sintetizar um agente de contraste extremamente sensível, capaz de selecionar tecidos ou células hipóxicos, com o auxílio de nanopartículas de óxido de ferro, para produzir um contraste visível em Ressonância Magnética.
Métodos: Sabe-se que o composto 2-nitroimidazol acumula nos tecidos hipóxicos. Com a acupulação de nanopartículas magnéticas, este composto irá distorcer o campo magnético, provocando um contraste escuro. Estas nanopartículas foram sintetizadas e, de seguida, funcionalizadas com revestimentos bioactivos para, assim, ser possível a interação com grupos orgânicos, presentes no tracer de hipóxia. O ligante 2-imido-2-metoxi-etil, previamente testado em reações semelhantes(van Kasteren et al, 2009; Pearce et al, 2005), foi o preferido para uma ligação segura e estável entre os dois integrantes do agente de contraste final.
Resultados: Esta modificação das partículas foi desenvolvida com sucesso, com uma taxa de modificação entre 10-30%, suficiente para a obtenção de um contraste percetível no exame de ressonância magnética, em fibroblastos de rato. A possibilidade de deteção e quantificação de áreas de tecidos hipóxicos é de extrema relevância e poderá ter um papel relevante em inúmeras aplicações, entre elas o desenvolvimento de novos agentes cardio-protetores. Poderá ser também um método de deteção precoce de algumas patologias, tais como acidentes vasculares cerebrais, ataques cardíacos ou até mesmo de doenças oncológicas.
Background: Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease (when an artery is occluded) and stroke when oxygen demand is greater than oxygen supply (Sinusas, 1999). Currently, most non-invasive approaches to detect myocardial hypoxia measure either the level of myocardial oxygen supply or the downstream effects of myocardial hypoxia such as altered mechanical function or electric instability, and few studies have reported on imaging of hypoxic myocardium directly. Therefore, the aim of this project was to design and synthesize a highly sensitive Contrast Agent capable of selectively bind to hypoxic cells/tissues, relying on the magnetic properties of iron oxide nanoparticles (IONPs) to deliver a high and sensitive contrast in Magnetic Resonance Imaging (MRI). Methods: 2-nitroimidazole has been shown to accumulate on hypoxic tissues, being the organic complement of the IONPs, responsible for the magnetic distortion of the field, hence, the contrast. These iron oxide particles were firstly synthetized and then functionalized with bioactive coatings, so they could interact, organically, with the hypoxia tracer. The chemical group 2-imido-2-methoxy-ethyl (IME) linker, previously used and tested in similar reactions (van Kasteren et al, 2009; Pearce et al, 2005) was chosen for a stable and safe linkage between the two complements of the final Contrast Agent. Results: Hypoxia tracer modified particles were successfully developed, with a 10-30 % modification level, which was proven to be enough to deliver a detectable contrast, in the cell tests. The ability to detect and to quantify the area of hypoxic tissue is of extreme relevance and it may open the field for numerous applications, e.g. the assessment of novel cardio-protective agents. It may also serve as a pre-asymptomatic diagnosis of several pathologies such as strokes, heart attacks or even cancer.
Background: Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease (when an artery is occluded) and stroke when oxygen demand is greater than oxygen supply (Sinusas, 1999). Currently, most non-invasive approaches to detect myocardial hypoxia measure either the level of myocardial oxygen supply or the downstream effects of myocardial hypoxia such as altered mechanical function or electric instability, and few studies have reported on imaging of hypoxic myocardium directly. Therefore, the aim of this project was to design and synthesize a highly sensitive Contrast Agent capable of selectively bind to hypoxic cells/tissues, relying on the magnetic properties of iron oxide nanoparticles (IONPs) to deliver a high and sensitive contrast in Magnetic Resonance Imaging (MRI). Methods: 2-nitroimidazole has been shown to accumulate on hypoxic tissues, being the organic complement of the IONPs, responsible for the magnetic distortion of the field, hence, the contrast. These iron oxide particles were firstly synthetized and then functionalized with bioactive coatings, so they could interact, organically, with the hypoxia tracer. The chemical group 2-imido-2-methoxy-ethyl (IME) linker, previously used and tested in similar reactions (van Kasteren et al, 2009; Pearce et al, 2005) was chosen for a stable and safe linkage between the two complements of the final Contrast Agent. Results: Hypoxia tracer modified particles were successfully developed, with a 10-30 % modification level, which was proven to be enough to deliver a detectable contrast, in the cell tests. The ability to detect and to quantify the area of hypoxic tissue is of extreme relevance and it may open the field for numerous applications, e.g. the assessment of novel cardio-protective agents. It may also serve as a pre-asymptomatic diagnosis of several pathologies such as strokes, heart attacks or even cancer.
Description
Keywords
Hipóxia Ressonância magnética Agentes de contraste 2-nitroimidazol Nanopartículas de óxido de ferro Hypoxia Magnetic resonance imaging Contrast agents 2-nitroimidazole iron oxide nanoparticles