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Synthèse et caractérisation de sondes lipidiques macromoléculaires fluorescentes émettant dans le rouge lointain pour l'imagerie membranaire

Abstract : The aim of this study is to synthesize new far-red emitting fluorescent Lipid-Polymer conjugates, consisting of a polymer chain bearing both multiple fluorophores in lateral position and a lipid at one chain-end. These conjugates are based on an hydrophilic, reactive, flexible and controlled poly(N-acryloylmorpholine-co-N-acryloxysuccinimide) copolymer synthesized by the RAFT process. Multiple far-red emitting fluorophores were bound on the reactive copolymer in lateral position. The strategy used in this study consists of three different steps: Chain Transfer Agents (CTA) functionalized with a lipid were synthesized following a protocol already described in our team, the purity of these CTA was improved (90% molar purity); the use of these CTA for the synthesis of α functional polymers, and finally, the very efficient covalent binding of fluorophores in lateral position. We showed that the lipid-CTA enable a very good control of the NAM/NAS copolymerization. The azeotropic composition enables the synthesis of polymer chains with a controlled composition and with Mn values varying from 5 900 to 33 200 g.mol-1. The optical properties of the bio-conjugates were determined, and we showed that these properties (the fluorescence quantum yield especially) are structure sensitive. All of them show an improved brightness (13 000 M-1.cm-1 in water and 50 000 M-1.cm-1 in CHCl3) compared to the brightness of the free fluorophore. The ability of the bio-conjugates to interact with lipid bilayers was proved using model systems (SUVs, LUVs and GUVs). Finally, biological evaluations showed both an absence of cytotoxicity and an ability of the conjugates to be quickly internalized in leaving cells (< 10 min).
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Salim Adjili. Synthèse et caractérisation de sondes lipidiques macromoléculaires fluorescentes émettant dans le rouge lointain pour l'imagerie membranaire. Autre. INSA de Lyon, 2012. Français. ⟨NNT : 2012ISAL0122⟩. ⟨tel-00876655⟩

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