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Implant chargé en nanoparticules pour la libération contrôlée et le ciblage lymphatique de nucléotides et d’analogues nucléotidiques

Abstract : Natural nucleotides and nucleotide analogs display important pharmacological activities: for example the nucleotide adenosine triphosphate (ATP) could be an interesting molecule for the treatment of ischemia or atherosclerotic plaques. The clinical use of these molecules is however limited due to the presence of a triphosphate group, which is prone to hydrolysis in vivo, and responsible for the high hydrophilicity of the molecules, thereby strongly limiting their uptake by targeted cells and access to their intracellular pharmacological targets. To overcome these limitations and enable the administration of nucleotides and nucleotide analogs, the use of drug delivery systems such as nanoparticles may enable the protection and the targeted delivery of these drugs. Nanoparticles designed for intravenous injections are however not always convenient, e.g. in the case of chronic diseases. Therefore, a subcutaneous implant with sustained release features might represent a valid alternative, which is less invasive and can reach lymphatic tissues (important targets of many therapies). The first chapter of this thesis presents the formulation of nanoparticles to encapsulate ATP as well as zidovudine triphosphate (AZT-TP), thanks to the presence of chitosan (CS). These nanoparticles are formed through ionic interactions between the positive charges of chitosan and the negative charges of the triphosphate groups of ATP or AZT-TP. In this work, nanoparticles are characterized and their cellular delivery of ATP and AZT-TP inside a macrophage cell line is demonstrated. In a second time, the stability of these systems has been improved in order to obtain a better behavior in physiological conditions. This improved stability has been achieved through the complexation of chitosan to iron(III) (CS-Fe). This strategy has been applied to TPP and ATP nanoparticles. These nanoparticles have been tested on two macrophages cell lines showing an improved internalization compared to the previous ones. Finally, CS-Fe/ATP nanoparticles have been dispersed in a PLGA solution in order to develop an in situ forming implant. Once in contact with physiological fluids, the suspension turns into a solid depot. In vitro release studies show the ability of the systems to retain nanoparticles inside the matrix and to gradually release them over 5 days. After subcutaneous administration to mice, PLGA implants containing nanoparticles were able to retain ATP at the injection site for up to 50 hours, as compared to few hours of free ATP or free nanoparticles, showing therefore their relevance as sustained release systems of nucleotides.
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Giovanna Giacalone. Implant chargé en nanoparticules pour la libération contrôlée et le ciblage lymphatique de nucléotides et d’analogues nucléotidiques. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2014. Français. ⟨NNT : 2014PA114845⟩. ⟨tel-02889750⟩

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