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RMN d’émulsions fluorées : développements méthodologiques et application à l’évaluation de l’oxymétrie et de la biodistribution dans le foie et la rate, et à la détection de l’angiogenèse tumorale dans le cerveau du rongeur

Abstract : This study aimed at developing a method for detection of brain tumors at 7 teslas thanks to 19F MRI contrast agents. We particularly assessed the potential of this method to highlight tumor angiogenesis with RGD-functionalized contrast agents targeting ανβ3 integrin, a biomarker over-expressed at the surface of new capillary blood vessels. Owing to low local concentrations in contrast agent, the first step consisted in optimizing a multi spin echo sequence dedicated to a well-known biocompatible perfluorocarbon, perfluorooctylbromide (PFOB). We show that careful adjustment of sequence parameters allows cancellation of J-modulation and T2 enhancement, and yields an excellent sensitivity in vitro. Our sequence was then tested for oxygenation measurements in the mouse liver and spleen after injection of a PFOB emulsion. The results demonstrate very good accuracy of the measurements after one single infusion of emulsion. We also perform a dynamic biodistribution study in order to monitor emulsion nanoparticle uptake in the liver and spleen. Moreover, we show that stealth of emulsions grafted with different quantities of polyethylene glycol (PEG) can be assessed by fitting experimental data with a pharmacokinetic empirical model. Our sequence was finally used to visualize ανβ3-targeted nanoparticles in a U87 glioblastoma mouse model. Concentrations found in tumors after injection of an RGD-functionalized emulsion and a control emulsion are compared. Concentrations are found to be significantly higher with the RGD emulsion than with the control emulsion, suggesting specific binding of functionalized nanoparticles with ανβ3 integrin. The last part is dedicated to a new diffusion-weighted 19F NMR spectroscopy sequence. This method aims at suppressing vascular signal coming from circulating PFOB nanoparticles in order to evaluate signal coming from bound nanoparticles only.
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Submitted on : Tuesday, February 14, 2012 - 3:27:30 PM
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Céline Giraudeau. RMN d’émulsions fluorées : développements méthodologiques et application à l’évaluation de l’oxymétrie et de la biodistribution dans le foie et la rate, et à la détection de l’angiogenèse tumorale dans le cerveau du rongeur. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA112004⟩. ⟨tel-00670097⟩

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