title: Gd-nanoparticles functionalization with specific peptides for ß-amyloid plaques targeting.
abstract: BACKGROUND
  Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteinaceous aggregates highly organized into cross-β structure and referred to as amyloid fibrils. Nowadays, the diagnosis of these diseases remains tedious and involves multiple examinations while an early and accurate protein typing is crucial for the patients' treatment. Routinely used neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using Pittsburgh compound B, [(11)C]PIB, provide structural information and allow to assess the amyloid burden, respectively, but cannot discriminate between different amyloid deposits. Therefore, the availability of efficient multimodal imaging nanoparticles targeting specific amyloid fibrils would provide a minimally-invasive imaging tool useful for amyloidoses typing and early diagnosis. In the present study, we have functionalized gadolinium-based MRI nanoparticles (AGuIX) with peptides highly specific for Aβ amyloid fibrils, LPFFD and KLVFF. The capacity of such nanoparticles grafted with peptide to discriminate among different amyloid proteins, was tested with Aβ(1-42) fibrils and with mutated-(V30M) transthyretin (TTR) fibrils.
  
  
  RESULTS
  The results of surface plasmon resonance studies showed that both functionalized nanoparticles interact with Aβ(1-42) fibrils with equilibrium dissociation constant (Kd) values of 403 and 350 µM respectively, whilst they did not interact with V30M-TTR fibrils. Similar experiments, performed with PIB, displayed an interaction both with Aβ(1-42) fibrils and V30M-TTR fibrils, with Kd values of 6 and 10 µM respectively, confirming this agent as a general amyloid fibril marker. Thereafter, the ability of functionalized nanoparticle to target and bind selectively Aβ aggregates was further investigated by immunohistochemistry on AD like-neuropathology brain tissue. Pictures clearly indicated that KLVFF-grafted or LPFFD-grafted to AGuIX nanoparticle recognized and bound the Aβ amyloid plaque localized in the mouse hippocampus.
  
  
  CONCLUSIONS
  These results constitute a first step for considering these functionalized nanoparticles as a valuable multimodal imaging tool to selectively discriminate and diagnose amyloidoses.
authors.affiliation: Nano-H S.A.S, 38070, Saint Quentin Fallavier, France.|Institut Lumière Matière, UMR5306 CNRS Université Claude Bernard Lyon 1, Domaine Scientifique de La Doua, 2 rue Victor Grignard, 69622, Villeurbanne Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Plissonneau
authors.affiliation: Laboratoire de Chimie et Biologie des Métaux, Université Grenoble Alpes, CEA Life Science Division, CNRS, 17 rue des Martyrs, 38054, Grenoble Cedex 9, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pansieri
authors.affiliation: Université de Lyon, Lyon, France.|ISPB Faculté de Pharmacie, 4bis-MATEIS UMR CNRS 5510, 69373, Lyon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Heinrich-Balard
authors.affiliation: Centre de biophysique moléculaire, UPR 4301, Rue Charles Sadron CS 80054, 45071, Orléans Cedex 2, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Morfin
authors.affiliation: School of pharmaceutical Sciences, University of Geneva, University of Lausanne Pharmaceutical technology, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Stransky-Heilkron
authors.affiliation: Université de Lyon, Lyon, France.|ISPB Faculté de Pharmacie, 4bis-MATEIS UMR CNRS 5510, 69373, Lyon, France.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Rivory
authors.affiliation: Laboratoire de Chimie et Biologie des Métaux, Université Grenoble Alpes, CEA Life Science Division, CNRS, 17 rue des Martyrs, 38054, Grenoble Cedex 9, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mowat
authors.affiliation: Centre for Protein Engineering, Laboratory of Enzymology and Protein Folding Institut of Chemistry, B6 University of Liege Sart Tilman, 4000, Liege, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: Dumoulin
authors.affiliation: Université de Lyon, Lyon, France.|ISPB Faculté de Pharmacie, 4bis-MATEIS UMR CNRS 5510, 69373, Lyon, France.|Laboratoire de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Cohen
authors.affiliation: School of pharmaceutical Sciences, University of Geneva, University of Lausanne Pharmaceutical technology, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland.
authors.forename: Éric
authors.initials: É
authors.lastname: Allémann
authors.affiliation: Centre de biophysique moléculaire, UPR 4301, Rue Charles Sadron CS 80054, 45071, Orléans Cedex 2, France.
authors.forename: Éva
authors.initials: É
authors.lastname: Tόth
authors.affiliation: Molecular Neurobiology Group, Institute of Biology, Molecular and Cellular, R. Campo Alegre 823, 4150, Porto, Portugal.
authors.forename: Maria Joao
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: Nano-H S.A.S, 38070, Saint Quentin Fallavier, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Louis
authors.affiliation: Institut Lumière Matière, UMR5306 CNRS Université Claude Bernard Lyon 1, Domaine Scientifique de La Doua, 2 rue Victor Grignard, 69622, Villeurbanne Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Tillement
authors.affiliation: Laboratoire de Chimie et Biologie des Métaux, Université Grenoble Alpes, CEA Life Science Division, CNRS, 17 rue des Martyrs, 38054, Grenoble Cedex 9, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Forge
authors.affiliation: Institut Lumière Matière, UMR5306 CNRS Université Claude Bernard Lyon 1, Domaine Scientifique de La Doua, 2 rue Victor Grignard, 69622, Villeurbanne Cedex, France.
authors.forename: François
authors.initials: F
authors.lastname: Lux
authors.affiliation: Laboratoire de Chimie et Biologie des Métaux, Université Grenoble Alpes, CEA Life Science Division, CNRS, 17 rue des Martyrs, 38054, Grenoble Cedex 9, France. christel.marquette@cea.fr.
authors.forename: Christel
authors.identifier: http://orcid.org/0000-0002-0640-3025
authors.initials: C
authors.lastname: Marquette
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005682:Gadolinium / Q000737:chemistry*; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020349:Surface Plasmon Resonance
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D011228:Prealbumin; C075222:amyloid beta-protein (1-42); D005682:Gadolinium
keywords: Alzheimer’s disease; Amyloid imaging; Beta-amyloid fibrils; Gadolinium based nanoparticles; MRI contrast agent; Peptide-targeting