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Multimodal Imaging Gd-Nanoparticles Functionalized with Pittsburgh Compound B Or a Nanobody for Amyloid Plaques Targeting

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Multimodal Imaging Gd-Nanoparticles Functionalized with Pittsburgh Compound B Or a Nanobody for Amyloid Plaques Targeting Multimodal imaging Gd-nanoparticles functionalized with Pittsburgh compound B or a nanobody for amyloid plaques targeting. Jonathan Pansieri, Marie Plissonneau, Nathalie Stransky-Heilkron, Mireille Dumoulin, Laurence Heinrich-Balard, Pascaline Rivory, Jean-François Morfin, Éva Tóth, Saraiva Maria Joao, Eric Allémann, et al. To cite this version: Jonathan Pansieri, Marie Plissonneau, Nathalie Stransky-Heilkron, Mireille Dumoulin, Laurence Heinrich-Balard, et al.. Multimodal imaging Gd-nanoparticles functionalized with Pittsburgh com- pound B or a nanobody for amyloid plaques targeting.. Nanomedicine, Future Medicine, 2017, 12 (14), pp.1675-1687. 10.2217/nnm-2017-0079. hal-01561318 HAL Id: hal-01561318 https://hal.archives-ouvertes.fr/hal-01561318 Submitted on 5 Feb 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Research Article For reprint orders, please contact: [email protected] 12 Research Article 2017/06/30 Multimodal imaging Gd-nanoparticles functionalized with Pittsburgh compound B or a nanobody for amyloid plaques targeting Jonathan Pansieri‡,1, Marie Nanomedicine (Lond.) Plissonneau‡,2,3, Nathalie Aim: Gadolinium-based nanoparticles were functionalized with either the Pittsburgh Stransky-Heilkron4, Mireille compound B or a nanobody (B10AP) in order to create multimodal tools for an early Dumoulin5, Laurence diagnosis of amyloidoses. Materials & methods: The ability of the functionalized Heinrich-Balard6, Pascaline nanoparticles to target amyloid fibrils made of β-amyloid peptide, amylin or Val30Met- Rivory6, Jean-François mutated transthyretin formed in vitro or from pathological tissues was investigated by Morfin7, Eva Toth7, Maria a range of spectroscopic and biophysics techniques including fluorescence microscopy. Joao Saraiva8, Eric Allémann4, Results: Nanoparticles functionalized by both probes efficiently interacted with the Olivier Tillement3, Vincent 1 ‡,3 three types of amyloid fibrils, with K values in 10 micromolar and 10 nanomolar Forge , François Lux & D ,‡,1 range for, respectively, Pittsburgh compound B and B10AP nanoparticles. Moreover, Christel Marquette* 1Laboratoire de Chimie et Biologie des they allowed the detection of amyloid deposits on pathological tissues. Conclusion: Métaux, Université Grenoble Alpes, CEA Such functionalized nanoparticles could represent promising flexible and multimodal Life Sciences Division, CNRS, 17 rue des imaging tools for the early diagnostic of amyloid diseases, in other words, Alzheimer’s Martyrs, 38054 Grenoble Cedex 9, France disease, Type 2 diabetes mellitus and the familial amyloidotic polyneuropathy. 2Nano-H S.A.S, 38070 Saint Quentin Fallavier, France 3Institut Lumière Matière, University First draft submitted: 10 March 2017; Accepted for publication: 24 May 2017; Published of Lyon, University of Claude Bernard online: 21 June 2017 Lyon 1, CNRS, F-69622, Lyon, France 4School of Pharmaceutical Sciences, Keywords: amyloid imaging • amyloidoses • gadolinium-based nanoparticles • nanobody University of Geneva, University of • PIB Lausanne Pharmaceutical technology, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland Amyloidoses are a set of human diseases in and especially the early diagnosis, remains 5Laboratory of Enzymology & Protein which a normally soluble peptide or protein therefore a great challenge and often requires Folding, Centre for Protein Engineering, InBioS, University of Liege Sart Tilman, aggregates into insoluble and highly orga- several invasive examinations [6,7]. 4000 Liege, Belgium nized aggregates referred to as amyloid fibres. Therefore, there is a need to develop sen- 6 14 University of Lyon, University of These aggregates are rich in cross-β-sheet sitive and minimally invasive tools to detect Claude Bernard Lyon 1, ISPB Faculté de structures [1,2]. So far, 36 proteins are associ- amyloid deposits, in order not only to estab- Pharmacie, MATEIS UMR CNRS 5510, 69373 Lyon, France. ated with either local (e.g., Type 2 diabetes lish the diagnosis of amyloidosis [8] but also 7 mellitus [T2DM] and Alzheimer’s disease allow to follow-up the efficiency of treatment Centre de Biophysique Moléculaire, 2017 CNRS, UPR 4301, Université d’Orléans, Rue [AD]) or systemic (e.g., familial polyneurop- by monitoring the evolution of the amyloid Charles Sadron, 45071 Orléans, France athy and myeloma) amyloid depositions [3]. load [9]. Nowadays, a number of imaging 8Instituto de Inovação e Investigação em These diseases inflict enormous psycho- techniques can be used for these purposes; Saúde (I3S), University of Porto, Portugal; sociological and economic burdens. For they include PET and MRI to detect the Molecular Neurobiology Group, IBMC example, AD and T2DM affect, respectively, deposition of Aβ amyloid in the brain of AD – Institute for Molecular & Cell Biology, University of Porto, 4150–180 Porto, approximately 44 and 415 million people patients [10,11], scintigraphy to detect V30M- Portugal worldwide [4,5]. TTR fibrils involved in cardiac amyloido- *Author for correspondence: Symptoms of amyloidoses, especially in sis [12], autoradiography to target islet amyloid [email protected] ‡Authors contributed equally the cases of systemic amyloidoses, can be polypeptide (IAPP) fibrils in T2DM [13], etc. very subtle and vary widely from person to However, each of these techniques presents person and also depend on which organs some limitations. For example, while MRI are affected. The diagnosis of amyloidosis allows obtaining an outstanding spatial reso- part of 10.2217/nnm-2017-0079 © 2017 Future Medicine Ltd Nanomedicine (Lond.) (Epub ahead of print) ISSN 1743-5889 Research Article Pansieri, Plissonneau, Stransky-Heilkron et al. lution it strongly lacks sensitivity (1–0.01 millimolar fragments displaying a high specificity and affinity range) [14] . On the other hand, PET offers an excellent for the targeted fibrils [29]. For example, an enhanced sensitivity (10–1 pM range) but has a low spatial reso- amyloid-β plaques detection by MRI was observed lution [15] . In order to overcome these limitations, the within AD transgenic mouse using SuperParamagnetic development of probes allowing multimodal imaging Iron Oxide Nanoparticles functionalized with an anti- approaches (i.e., combination of PET and MRI) will AβPP antibody [30]. In this work, we have chosen to represent a breakthrough in the diagnosis of amyloido- functionalize AGuIX with the B10AP which is a chi- ses [16,17]. In this context, nanoparticles have emerged meric protein made of B10, a nanobody (i.e., the vari- in the past decades as a very promising tool to enhance able domain of heavy-chain antibodies) and Escherichia the contrast and the sensitivity of these different imag- coli alkaline phosphatase (AP). B10 has been selected ing techniques. by phage display from a synthetic library of nanobod- In this work, we have functionalized gadolinium ies using Aβ(1–40) fibrils as bait [31] . It also recognizes (Gd) based multimodal nanoparticles (NPs), so called amyloid fibrils of several proteins (madein vitro and on AGuIX with specific probes for the diagnosis of amy- tissues) including insulin, glucagon, β2-microglobulin, loidoses. AGuIX are made of a polysiloxane network serum amyloid A protein and immunoglobulin light 3+ surrounded by several DOTAGA (Gd ) chelates [18,19]. chain (AL) [32]. AP forms homodimers and therefore AGuIX NPs have a diameter smaller than 5 nm and B10AP exhibits two copies of B10 within one molecule have been already efficiently used for MRI and radio- of the chimera; such a bivalent construct exhibits a sensitization [20]. Free ligands are available at the sur- higher overall affinity for Aβ(1–42) amyloid fibrils with face of AGuIX and can be used to chelate radioisotopes a lower dissociation constant (KD: 7 nM and 475 nM 68 3+ 111 3+ (e.g., Ga or In ), in order to perform PET or for B10AP and B10, respectively) [32]. Moreover, the single-photon emission computed tomography imag- phosphatase activity of AP allows an easy and straight- ing [14,21] . Moreover, the covalent grafting of a near forward monitoring of B10AP binding to the amyloid infrared dye, such as cyanine5.5 (Cy5.5), is also achiev- fibrils. able for optical imaging [22]. Finally, we have recently In this work, we have used PIB and B10AP as graft- shown that AGuIX can be functionalized with specific ing ligands on AGuIX NPs, in order to perform active Aβ peptides to selectively target and image Aβ-amyloid targeting on Aβ(1–42) fibrils which deposit in the brain fibrils [23]. However, while the results obtained clearly of AD patients; IAPP fibrils that accumulate in Lang- demonstrate that these functionalized NPs constitute erhans Islet of patients affected with T2DM; and a valuable multimodal imaging tool to selectively tar- V30M-TTR fibrils associated with familial amyloidotic get Aβ fibrils, they displayed a low affinity (100 μM polyneuropathy (FAP). range) for their target. Therefore, the aim of the present work is to functionalize AGuIX with molecules having Methods higher affinity for amyloid
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