title: In vitro and in vivo characterization of several functionalized ultrasmall particles of iron oxide, vectorized against amyloid plaques and potentially able to cross the blood-brain barrier: toward earlier diagnosis of Alzheimer's disease by molecular imaging.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder most often diagnosed 10 years after its onset and development. It is characterized by the accumulation of amyloid-β peptide (ABP) into amyloid plaques between nerve cells, which produces a massive local neurodegeneration. Molecular magnetic resonance imaging allows diagnosis of AD by showing ABP accumulation in the brain. The ultrasmall particles of iron oxide (USPIO) derivatives proposed in the present work were functionalized with peptides that present an affinity for ABP, independently of its state of aggregation. Their nanomolar Kd * confirms the high affinity of our vectorized contrast agents (VCA) for ABP and therefore their high labeling potential, specificity and sensitivity. Their lack of toxicity has been demonstrated, both by in vitro studies using the MTT method on several cell types, and by in vivo investigations with assessment of renal and hepatic biomarkers and by histopathology evaluation. The results of biodistribution studies corroborated by MRI demonstrate that USPIO-PHO (USPIO coupled to peptide C-IPLPFYN-C) are able to cross the blood-brain barrier without any facilitating strategy, and accumulates in the brain 90 min after its injection in NMRI mice. None of the USPIO derivatives were found in any organs one week after administration. To conclude, USPIO-PHO seems to have a genuine potential for labeling amyloid plaques in the brain; it has a nanomolar binding affinity, no toxic effects, and its elimination half-life is about 3 h. Further tests will be made on transgenic mice, aimed at confirming the potential of early AD diagnosis using our VCA.
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000, Mons, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Ansciaux
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000, Mons, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Burtea
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000, Mons, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Laurent
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000, Mons, Belgium.
authors.forename: Deborah
authors.initials: D
authors.lastname: Crombez
authors.affiliation: Laboratory of Histology, University of Mons, Pentagon - 1B, 6 Avenue du Champ de Mars, B-7000, Mons, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Nonclercq
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000, Mons, Belgium.
authors.forename: Luce
authors.initials: L
authors.lastname: Vander Elst
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000, Mons, Belgium.|Center for Microscopy and Molecular Imaging, 8, rue Adrienne Bolland, 6041, Gosselies, Belgium.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Muller
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis*; D016229:Amyloid beta-Peptides; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000494:pharmacology; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053768:Metal Nanoparticles; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D058225:Plaque, Amyloid / Q000175:diagnosis*; D012680:Sensitivity and Specificity
chemical_list: D016229:Amyloid beta-Peptides; D003287:Contrast Media; D005290:Ferric Compounds; C000499:ferric oxide
keywords: Alzheimer's disease; MRI; amyloid-β peptide; blood-brain barrier; contrast agents; functionalized iron oxide nanoparticles