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Synthèse de nanocapsules polymères pour la détection de tumeurs solides par échographie et IRM du Fluor : vers un outil théranostique

Abstract : Cancer is a worldwide public health concern and significant health care resources are spent on diagnosis. The sooner the tumor detection, the better the chance of remission without relapse. Furthermore, imaging modalities facilitate the treatment monitoring and feedback, and support decision making to change the strategy when the treatment fails. When used in combination with targeted contrast agents, imaging modalities even enable to probe molecular structures on specific cells opening the doors to personalized cancer therapy [1, 2]. Ultrasonography and Magnetic Resonance Imaging (MRI) are two complementary and non invasive imaging modalities, which allow the detection of a broad range of cancers (breast, colon, brain…). Ultrasonography is cost-effective, portable and provides real-time anatomical information. MRI imparts deep penetration into soft tissues with high contrast and better sensitivity [3]. Nevertheless the use of these techniques in combination with contrast agents is challenging, mostly because the local concentration reached in the tumor is often below the sensitivity detection range [4]. In the last 20 years, multifunctional contrast agents were custom-built to achieve preferential accumulation in the diseased tissue [5]. In this study, passive and active tumor targeting strategies were considered to enhance the local concentration of polymeric nanocapsules, containing a liquid core of perfluorooctyl bromide (PFOB). The passive tumor targeting approach is based on the enhanced permeation and retention (EPR) effect. The related nanocapsules require to be small enough (< 400nm) and have extended plasmatic half life. The active tumor targeting approach is based on the specific receptor-ligand recognition.For passive tumor targeting, the nanocapsules were prepared with PLGA-b-PEG by an emulsion-evaporation process. The core shell morphology was confirmed by cryoTEM and 19F NMR. The surface of nanocapsules was densely covered by PEG chains with brush conformation, as assessed by XPS and Small Angle Neutrons Scattering. The related stealthiness of nanocapsules was evidenced in vitro by complement activation measurements and in vivo by a kinetic study of the mice liver uptake, performed after intravenous administration of nanocapsules. The tumor imaging, by 19F MRI, revealed that only 1% of the injected dose was accumulated in the diseased tissue whereas, by ultrasonography no contrast enhancement was observed. Thus, another targeting approach was required to increase nanocapsule distribution within the tumor. Nanocapsules were functionalized with an Arginine-Glycine-Aspartic acid (RGD) peptide to target the αvβ3 integrins, which are overexpressed proteins on neovessels. Two strategies, called bottom-up and top-down, were designed to achieve satisfying peptide decoration on nanocapsule surface. The coupling efficiency was measured by 1H NMR. The nanocapsule morphology was studied by CryoTEM.
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Odile Diou. Synthèse de nanocapsules polymères pour la détection de tumeurs solides par échographie et IRM du Fluor : vers un outil théranostique. Sciences agricoles. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA114854⟩. ⟨tel-00907145⟩

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