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2014-02-10 - Colloque/Présentation - poster - Anglais - 1 page(s)

Ansciaux Emilie, Burtea Carmen , Laurent Sophie , Vander Elst Luce , Nonclercq Denis , Muller Robert , "A contrast agent vectorized against amyloid plaques and potentially able to cross the blood-­‐brain barrier: toward earlier diagnosis of Alzheimer's disease by molecular imaging" in Belgian Peptide Meeting, Ghent, Belgique, 2014

  • Codes CREF : Sciences biomédicales (DI3200)
Texte intégral :

Abstract(s) :

(Anglais) Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of amyloid-beta peptide (ABP) between nerve cells, where it forms senile plaques several decades before the first symptoms become evident. A non invasive method to detect their presence will contribute to the diagnosis and preventive treatment before occurrence of irreversible neurodegeneration. Molecular imaging aims at the development of new diagnosis technologies using specific reporters for the visualization of molecular processes in vivo, i.e. amyloid plaques (AP) formation. AP are ideal targets for molecular imaging probes, as those proposed by the present work subsequent to the functionalization of an USPIO contrast agent with a peptide (PHO) identified by phage display. Peptide is conjugated covalently to the carboxyl groups exposed by USPIO nanoparticles through their amino-terminal groups. They are also coated with polyethyleneglycol (PEG), which increases their solubility and stealth. USPIO-PHO was characterized in vitro and in vivo, aiming to develop a contrast agent able to early diagnose AD and to assess future therapeutic strategies using magnetic resonance imaging (MRI). In vitro tests were carried out by ELISA and MTT methods to evaluate the affinity for ABP and cytotoxic effects of USPIO-PHO. In vivo studies were performed on NMRI mice to evaluate the biodistribution, the liver and renal functions, and the pharmacokinetic parameters of USPIO-PHO in comparison with a non-vectorized contrast agent, USPIO-PEG. MRI studies were carried out on a Bruker Pharmascan 7T imaging system, using NMRI and transgenic mice (APP/PS1 DE9 and Tg3576) to evaluate the ability to cross the blood-brain barrier (BBB) and to target the AP. In vitro results showed a nanomolar binding affinity and a lack of cytotoxicity on neurons, endothelial cells and hepatocytes, while in vivo data illustrated a faster blood clearance (T1/2 of 184 min) for USPIO-PHO vs. USPIO-PEG (T1/2 of 284 min for), a limited liver capture and the potential ability to cross the BBB ninety minutes post intravenous injection. This last result seems to be confirmed by preliminary MRI studies on transgenic mice, where the texture analysis of post-contrast images revealed at least three-fold higher distribution of dark pixels in the brain of mice injected with USPIO-PHO. According to its nanomolar binding affinity, non-toxic character, optimal biodistribution and pharmacokinetic behavior, and its potential ability to cross the BBB, USPIO-PHO seems to be a promising candidate for an earlier AD diagnosis and therapy monitoring. This work is supported by the SAO-FRMA foundation for Alzheimer Research (grant number 11023), by the UMONS-100 fellowship and by the FNRS.