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1. MODULATION OF BRAIN CONNECTIVITY, STRUCTURE, NEURON AND GLIA, AND MOTOR FUNCTION BY SAFINAMIDE MULTIMODAL ACTIONS IN A PRE-CLINICAL MODEL OF PARKINSON’S DISEASE

Author

Bruna Araújo, Jonas Campos, Rita Caridade-Silva, Bárbara Mendes-Pinheiro, Raquel Marques, Sandra Barata, Rui Lima, Joana Martins-Macedo, Eduardo Gomes, Benoit Larrat, António Salgado, Sébastien Mériaux, Sofia Domingues, and Fábio Teixeira

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published
2023
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3. Structural basis of envelope and phase intrinsic coupling modes in the cerebral cortex

Author

Arnaud Messé, Karl J. Hollensteiner, Céline Delettre, Leigh-Anne Dell-Brown, Florian Pieper, Lena J. Nentwig, Edgar E. Galindo-Leon, Benoît Larrat, Sébastien Mériaux, Jean-François Mangin, Isabel Reillo, Camino de Juan Romero, Víctor Borrell, Gerhard Engler, Roberto Toro, Andreas K. Engel, and Claus C. Hilgetag

Subjects
Ferret brain, Intrinsic coupling modes, Structure–function relationship, Time delay, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Intrinsic coupling modes (ICMs) can be observed in ongoing brain activity at multiple spatial and temporal scales. Two families of ICMs can be distinguished: phase and envelope ICMs. The principles that shape these ICMs remain partly elusive, in particular their relation to the underlying brain structure. Here we explored structure-function relationships in the ferret brain between ICMs quantified from ongoing brain activity recorded with chronically implanted micro-ECoG arrays and structural connectivity (SC) obtained from high-resolution diffusion MRI tractography. Large-scale computational models were used to explore the ability to predict both types of ICMs. Importantly, all investigations were conducted with ICM measures that are sensitive or insensitive to volume conduction effects. The results show that both types of ICMs are significantly related to SC, except for phase ICMs when using measures removing zero-lag coupling. The correlation between SC and ICMs increases with increasing frequency which is accompanied by reduced delays. Computational models produced results that were highly dependent on the specific parameter settings. The most consistent predictions were derived from measures solely based on SC. Overall, the results demonstrate that patterns of cortical functional coupling as reflected in both phase and envelope ICMs are both related, albeit to different degrees, to the underlying structural connectivity in the cerebral cortex.

Published
2023
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4. Breaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application

Author

Alban Guesdon-Vennerie, Patrick Couvreur, Fatoumia Ali, Frédéric Pouzoulet, Christophe Roulin, Immaculada Martínez-Rovira, Guillaume Bernadat, François-Xavier Legrand, Claudie Bourgaux, Cyril Lucien Mazars, Sergio Marco, Sylvain Trépout, Simona Mura, Sébastien Mériaux, and Guillaume Bort

Subjects
Science
Abstract

Triggered therapeutics are of interest but currently suffer from limited penetration depth of light sources. Here, the authors report on the development of a system, called radioswitch, that uses ionising irradiation to switch an azobenzene modified drug to an active form for deep tissue triggered therapeutic application.

Published
2022
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5. Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study

Author

Allegra Conti, Francoise Geffroy, Hermes A. S. Kamimura, Anthony Novell, Nicolas Tournier, Sébastien Mériaux, and Benoit Larrat

Subjects
focused ultrasound, BBB-opening, efflux transporter, MRgFUS, drug delivery, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs. However, very little is known about the effect of FUS on the expression of efflux transporters. We investigated the in vivo effects of moderate acoustic pressures on both P-gp and BCRP expression for up to two weeks after sonication. Magnetic resonance-guided FUS was applied in the striatum of 12 rats. P-gp and BCRP expression were determined by immunohistochemistry at 1, 3, 7, and 14 days postFUS. Our results indicate that FUS-induced BBB opening is capable of (i) decreasing P-gp expression up to 3 days after sonication in both the treated and in the contralateral brain regions and is capable of (ii) overexpressing BCRP up to 7 days after FUS in the sonicated regions only. Our findings may help improve FUS-aided drug delivery strategies by considering both the mechanical effect on the TJs and the regulation of P-gp and BCRP.

Published
2022
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6. Generation of Synthetic Rat Brain MRI Scans with a 3D Enhanced Alpha Generative Adversarial Network

Author

André Ferreira, Ricardo Magalhães, Sébastien Mériaux, and Victor Alves

Subjects
alpha generative adversarial network, data augmentation, synthetic data, MRI rat brain, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

Translational brain research using Magnetic Resonance Imaging (MRI) is becoming increasingly popular as animal models are an essential part of scientific studies and more ultra-high-field scanners are becoming available. Some disadvantages of MRI are the availability of MRI scanners and the time required for a full scanning session. Privacy laws and the 3Rs ethics rule also make it difficult to create large datasets for training deep learning models. To overcome these challenges, an adaptation of the alpha Generative Adversarial Networks (GANs) architecture was used to test its ability to generate realistic 3D MRI scans of the rat brain in silico. As far as the authors are aware, this was the first time a GAN-based approach was used to generate synthetic MRI data of the rat brain. The generated scans were evaluated using various quantitative metrics, a Turing test, and a segmentation test. The last two tests proved the realism and applicability of the generated scans to real problems. Therefore, by using the proposed new normalisation layer and loss functions, it was possible to improve the realism of the generated rat MRI scans, and it was shown that using the generated data improved the segmentation model more than using the conventional data augmentation.

Published
2022
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7. Assessing Diffusion in the Extra-Cellular Space of Brain Tissue by Dynamic MRI Mapping of Contrast Agent Concentrations

Author

Sébastien Mériaux, Allegra Conti, and Benoît Larrat

Subjects
brain tissue tortuosity, extracellular diffusion, MRI contrast agents, in vivo concentration quantification, dynamic T1 mapping, ultrasound-induced BBB permeabilization, Physics, QC1-999
Abstract

The characterization of extracellular space (ECS) architecture represents valuable information for the understanding of transport mechanisms occurring in brain parenchyma. ECS tortuosity reflects the hindrance imposed by cell membranes to molecular diffusion. Numerous strategies have been proposed to measure the diffusion through ECS and to estimate its tortuosity. The first method implies the perfusion for several hours of a radiotracer which effective diffusion coefficient D* is determined after post mortem processing. The most well-established techniques are real-time iontophoresis that measures the concentration of a specific ion at known distance from its release point, and integrative optical imaging that relies on acquiring microscopy images of macromolecules labeled with fluorophore. After presenting these methods, we focus on a recent Magnetic Resonance Imaging (MRI)-based technique that consists in acquiring concentration maps of a contrast agent diffusing within ECS. Thanks to MRI properties, molecular diffusion and tortuosity can be estimated in 3D for deep brain regions. To further discuss the reliability of this technique, we point out the influence of the delivery method on the estimation of D*. We compare the value of D* for a contrast agent intracerebrally injected, with its value when the agent is delivered to the brain after an ultrasound-induced blood-brain barrier (BBB) permeabilization. Several studies have already shown that tortuosity may be modified in pathological conditions. Therefore, we believe that MRI-based techniques could be useful in a clinical context for characterizing the diffusion properties of pathological ECS and thus predicting the drug biodistribution into the targeted area.

Published
2018
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17. Structural and functional alterations in the retrosplenial cortex following neuropathic pain

Author

Ricardo Magalhães, Jérôme Busserolles, Julie Barbier, Jean-Marie Bonny, David André Barrière, Sébastien Mériaux, Fabien Marchand, Al Mahdy Hamieh, Amidou Traore, Denis Ardid, Qualité des Produits Animaux (QuaPA), Institut National de la Recherche Agronomique (INRA), UMR 1197 NOPA, Pharmacologie fondamentale et clinique de la douleur, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Life and Health Sciences Research Institute [Braga] (ICVS), University of Minho [Braga], ICVS/3B's—PT Government Associate Laboratory [Braga, Portugal], ANR-13-BSV1-0006,Antares,Vers de nouveaux antalgiques ciblant les récepteurs métabotropiques du glutamate(2013), and Universidade do Minho

Subjects
Male, Imaging biomarker, [SDV]Life Sciences [q-bio], Neuropathic pain, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Retrosplenial cortex, 030202 anesthesiology, Animals, Medicine, ComputingMilieux_MISCELLANEOUS, Functional MRI, Cerebral Cortex, Science & Technology, business.industry, Subiculum, Chronic pain, Brain, Voxel-based morphometry, Nerve injury, medicine.disease, Rats, Anesthesiology and Pain Medicine, Neurology, Hyperalgesia, Neuralgia, Neurology (clinical), Nerve Net, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions. In this article, we conducted a longitudinal and multimodal study to assess how chronic pain affects the brain. Using the spared nerve injury model which promotes both long-lasting mechanical and thermal allodynia/hyperalgesia but also pain-associated comorbidities, we showed that neuropathic pain deeply modified the intrinsic organization of the brain functional network 1 and 2 months after injury. We found that both functional metrics and connectivity of the part A of the retrosplenial granular cortex (RSgA) were significantly correlated with the development of neuropathic pain behaviours. In addition, we found that the functional RSgA connectivity to the subiculum and the prelimbic system are significantly increased in spared nerve injury animals and correlated with peripheral pain thresholds. These brain regions were previously linked to the development of comorbidities associated with neuropathic pain. Using a voxel-based morphometry approach, we showed that neuropathic pain induced a significant increase of the gray matter concentration within the RSgA, associated with a significant activation of both astrocytes and microglial cells. Together, functional and morphological imaging metrics of the RSgA could be used as a predictive biomarker of neuropathic pain., This work was supported by Inserm, Clermont Auvergne University, grants from Agence Nationale de la Recherche (ANR13-BSV1-0006-03), the Société Française d’Étude et de Traitement de la Douleur.

Published
2019

18. Tumor-targeted superfluorinated micellar probe for sensitive in vivo 19 F-MRI

Author

Wai Li Ling, Anaëlle Doerflinger, Edmond Gravel, Erwan Selingue, Eric Doris, Marie Vandamme, Guillaume Pinna, Solenne Vaillant, Lucie Jamgotchian, Agathe Belime, Sébastien Mériaux, Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité d'imagerie par résonance magnétique à très haut champ et de spectroscopie (UNIRS), Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields (BAOBAB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Service de Chimie Bio-Organique et de Marquage (SCBM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Microscopie électronique, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and Unité Baobab (BAOBAB)

Subjects
Carrier system, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, technology, industry, and agriculture, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, 0104 chemical sciences, Encapsulation (networking), Tumor targeted, In vivo, General Materials Science, 0210 nano-technology, ComputingMilieux_MISCELLANEOUS, Biomedical engineering
Abstract

International audience; We describe herein the assembly and in vivo evaluation of a tailor-made micellar carrier system designed for the optimized encapsulation of a superfluorinated MRI probe and further targeting of solid tumors. The in vivo validation was carried out on MC38 tumor-bearing mice which allowed the confirmation of the efficient targeting properties of the nano-carrier, as monitored by 19F-MRI.

Published
2021

19. Tumor-targeted superfluorinated micellar probe for sensitive

Author

Lucie, Jamgotchian, Solenne, Vaillant, Erwan, Selingue, Anaelle, Doerflinger, Agathe, Belime, Marie, Vandamme, Guillaume, Pinna, Wai Li, Ling, Edmond, Gravel, Sébastien, Mériaux, and Eric, Doris

Subjects
Fluorine-19 Magnetic Resonance Imaging, Mice, Neoplasms, Animals, Magnetic Resonance Imaging, Micelles
Abstract

We describe herein the assembly and in vivo evaluation of a tailor-made micellar carrier system designed for the optimized encapsulation of a superfluorinated MRI probe and further targeting of solid tumors. The in vivo validation was carried out on MC38 tumor-bearing mice which allowed the confirmation of the efficient targeting properties of the nano-carrier, as monitored by 19F-MRI.

Published
2021

20. Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Author

Romain Dalmann, Jérémy Pinguet, Laurence Daulhac, Fawzi Boumezbeur, Philippe Sarret, Roberto Cadeddu, Damien Richard, Alain Eschalier, Kevin Whittingstall, Christophe Mallet, Sébastien Mériaux, David André Barrière, Matthieu Keller, Marchoux, Eric, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Faculté de Médecine - Clermont-Auvergne (FM - UCA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Department of Physiology and Biophysics, Université de Sherbrooke (UdeS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Microdialysis, Cannabinoid receptor, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, paracetamol, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Analgesic, AM404, TRPV1, [SDV.SA.ZOO]Life Sciences [q-bio]/Agricultural sciences/Zootechny, periaqueductal grey, Pharmacology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fatty acid amide hydrolase, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, medicine, Animals, Periaqueductal Gray, FAAH, pain, Acetaminophen, Analgesics, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, digestive, oral, and skin physiology, Glutamate receptor, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Research Papers, CB1, 3. Good health, Rats, 030104 developmental biology, Mechanism of action, chemistry, nervous system, [SDV.SA.SPA]Life Sciences [q-bio]/Agricultural sciences/Animal production studies, medicine.symptom, Analgesia, 030217 neurology & neurosurgery, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract

International audience; Background and Purpose We previously demonstrated that paracetamol has to be metabolised in the brain by fatty acid amide hydrolase enzyme into AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) to activate CB1 receptors and TRPV1 channels, which mediate its analgesic effect. However, the brain mechanisms supporting paracetamol-induced analgesia remain unknown. Experimental Approach The effects of paracetamol on brain function in Sprague-Dawley rats were determined by functional MRI. Levels of neurotransmitters in the periaqueductal grey (PAG) were measured using in vivo H-1-NMR and microdialysis. Analgesic effects of paracetamol were assessed by behavioural tests and challenged with different inhibitors, administered systemically or microinjected in the PAG. Key Results Paracetamol decreased the connectivity of major brain structures involved in pain processing (insula, somatosensory cortex, amygdala, hypothalamus, and the PAG). This effect was particularly prominent in the PAG, where paracetamol, after conversion to AM404, (a) modulated neuronal activity and functional connectivity, (b) promoted GABA and glutamate release, and (c) activated a TRPV1 channel-mGlu(5) receptor-PLC-DAGL-CB1 receptor signalling cascade to exert its analgesic effects. Conclusions and Implications The elucidation of the mechanism of action of paracetamol as an analgesic paves the way for pharmacological innovations to improve the pharmacopoeia of analgesic agents.

Published
2021

23. Targeting brain metastases with ultrasmall theranostic nanoparticles, a first-in-human trial from an MRI perspective

Author

Olivier Tillement, Emmanuel L. Barbier, François Lux, Camille Verry, Jacques Balosso, Yannick Crémillieux, Sandrine Dufort, Irène Troprès, Sylvie Grand, Géraldine Le Duc, J. Pietras, Benoit Larrat, Sébastien Mériaux, Benjamin Lemasson, Centre Hospitalier Universitaire [Grenoble] (CHU), NH TherAguix SA [Meylan], NeuroImagerie Fonctionnelle et Perfusion Cérébrale, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), IRMaGe (IRMaGe), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Formation, élaboration de nanomatériaux et cristaux (FENNEC), Institut Lumière Matière [Villeurbanne] (ILM), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), This work was performed on the IRMaGe platform member of France Life Imaging network (grant ANR-11-INBS-0006), ANR-11-INBS-0006,FLI,France Life Imaging(2011), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), VIDAL, Armelle, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
medicine.medical_specialty, [SPI] Engineering Sciences [physics], Theranostic nanoparticles, medicine.medical_treatment, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Phases of clinical research, 02 engineering and technology, [PHYS] Physics [physics], 03 medical and health sciences, [SPI]Engineering Sciences [physics], 0302 clinical medicine, [CHIM] Chemical Sciences, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [CHIM]Chemical Sciences, Health and Medicine, Research Articles, ComputingMilieux_MISCELLANEOUS, [PHYS]Physics [physics], Multidisciplinary, business.industry, Melanoma, SciAdv r-articles, First in human, 021001 nanoscience & nanotechnology, medicine.disease, Image contrast, 3. Good health, Radiation therapy, 030220 oncology & carcinogenesis, Radiology, 0210 nano-technology, business, Mri findings, Research Article
Abstract

Intravenously injected theranostic Gd-based nanoparticles enable targeting and MRI detection of brain metastases in patients., The use of radiosensitizing nanoparticles with both imaging and therapeutic properties on the same nano-object is regarded as a major and promising approach to improve the effectiveness of radiotherapy. Here, we report the MRI findings of a phase 1 clinical trial with a single intravenous administration of Gd-based AGuIX nanoparticles, conducted in 15 patients with four types of brain metastases (melanoma, lung, colon, and breast). The nanoparticles were found to accumulate and to increase image contrast in all types of brain metastases with MRI enhancements equivalent to that of a clinically used contrast agent. The presence of nanoparticles in metastases was monitored and quantified with MRI and was noticed up to 1 week after their administration. To take advantage of the radiosensitizing property of the nanoparticles, patients underwent radiotherapy sessions following their administration. This protocol has been extended to a multicentric phase 2 clinical trial including 100 patients.

Published
2020

24. Optimization of pegylated iron oxide nanoplatforms for antibody coupling and bio-targeting

Author

Ana Šarić, Didier Boquet, Sébastien Mériaux, Patrice X. Petit, Laurence Motte, Marianne Boucher, Yoann Lalatonne, Amaury Herbet, and Sophie Richard

Subjects
Fluorophore, Materials science, medicine.diagnostic_test, Biomedical Engineering, Nanoparticle, 02 engineering and technology, General Chemistry, General Medicine, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, Fluorescence, In vitro, 0104 chemical sciences, Flow cytometry, chemistry.chemical_compound, chemistry, Biochemistry, PEG ratio, PEGylation, medicine, General Materials Science, 0210 nano-technology, Receptor
Abstract

PEGylation has been established as a valuable strategy to minimize nanoparticle clearance by the reticulo-endothelial system due to hydrophilicity and steric repulsion of PEG chains. In this study we functionalized superparamagnetic iron oxide nanoparticle surface with two PEG differing in their length (n = 23 and 44) and terminal functionality, COOH and CH3. By varying the ratio of the two different PEG, we optimized the molecular architecture of the nanoplatform to obtain maximum stability and low toxicity under physiological conditions. The best nanoplatform was evaluated as MRI contrast for mouse brain vascularization imaging at 7 T. The carboxylic acid functions of the nanoplatform were used to covalently bind an antibody, Ab. This antibody, labeled with a fluorophore, targets the ETA receptor, a G-protein-coupled receptor involved in the endothelin axis and overexpressed in various solid tumours, including ovarian, prostate, colon, breast, bladder and lung cancers. In vitro studies, performed by flow cytometry and magnetic quantification, showed the targeting efficiency of the Ab-nanoplatforms. Clearly, an imaging tracer for cancer diagnosis from a bimodal contrast agent (fluorescence and MRI) was thus obtained.

Published
2020

25. Endothelin B receptors targeted by iron oxide nanoparticles functionalized with a specific antibody: toward immunoimaging of brain tumors

Author

Sébastien Mériaux, Marianne Boucher, Sophie Richard, Laurence Motte, Yoann Lalatonne, Didier Boquet, Amaury Herbet, Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), and Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Fluorescence-lifetime imaging microscopy, Pathology, medicine.medical_specialty, Materials science, medicine.drug_class, Biomedical Engineering, Nanoparticle, General Chemistry, General Medicine, Monoclonal antibody, In vitro, 3. Good health, chemistry.chemical_compound, chemistry, In vivo, medicine, Biophysics, [CHIM]Chemical Sciences, General Materials Science, Endothelin receptor, Receptor, Iron oxide nanoparticles, ComputingMilieux_MISCELLANEOUS
Abstract

In this study, we developed a new bimodal imaging tracer directed against endothelin B receptors to detect brain cancer cells using MRI and to assist tumor surgery with fluorescence imaging. This was achieved by coating the surface of iron oxide nanoparticles with a monoclonal antibody, rendomab-B1, labeled with a fluorescent dye. Two nanoplatforms were elaborated differing by the average number of antibodies grafted onto the nanoparticle surface. The targeting efficiency of these nanoplatforms was validated in vitro. Contrasting MRI properties were highlighted in vivo, demonstrating nanoparticle circulation in the brain through the vasculature.

Published
2020

26. Contributors

Author

Elisabeth B. Binder, Tracy L. Bale, Tallie Z. Baram, David André Barrière, Jessica L. Bolton, Mallory E. Bowers, Dennis S. Charney, Alon Chen, Matthew Cranshaw, John F. Cryan, E. Ron de Kloet, Jan M. Deussing, Olivia Engmann, C. Neill Epperson, Edward Ganz, Jakob Hartmann, Marloes J.A.G. Henckens, James P. Herman, Matthew N. Hill, S.B. Hill, Brian M. Iacoviello, Orna Issler, Thérèse M. Jay, Marian Joëls, C.D. King, Stafford L. Lightman, Ekaterina Likhtik, Zachary S. Lorsch, David M. Lyons, Ricardo Magalhães, Isabelle M. Mansuy, Bruce S. McEwen, Sébastien Mériaux, Laia Morató, Kathleen E. Morrison, Iris Müller, Charles B. Nemeroff, Eric J. Nestler, Olivia F. O'Leary, Lilia Papst, Sachin Patel, Rony Paz, K.J. Ressler, Gal Richter-Levin, Mariana Rodrigues, Carmen Sandi, R. Angela Sarabdjitsingh, Alan F. Schatzberg, Mathias V. Schmidt, A.V. Seligowski, Annabel K. Short, Nuno Sousa, Francesca Spiga, Oliver Stork, Shariful A. Syed, Kuldeep Tripathi, Christiaan H. Vinkers, A.P. Wingo, and Rachel Yehuda

Published
2020

27. Biomarkers of resilience and susceptibility in rodent models of stress

Author

Ricardo Magalhães, Edward Ganz, Sébastien Mériaux, Thérèse M. Jay, Nuno Sousa, David André Barrière, and Mariana Rodrigues

Subjects
Fight-or-flight response, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Stressor, Stress resilience, Psychology, 030217 neurology & neurosurgery, 030304 developmental biology, Cognitive psychology, Predictive biomarker
Abstract

A major current trend in stress research is to consider both the spectrum of responses by different individuals to the same stressful stimulus or environment and the dynamics of the stress response within the individual. The motivation for such an approach is the desire for, and need of, developing methods, which are able to identify individuals susceptible/vulnerable to overall stress or to specific stressors and, in that way, to identify those at risk of developing stress-related disorders. Herein, we briefly review and discuss a number of approaches used in this field of research and describe how they led to our current state of knowledge. We also provide a perspective for the future development of the field to produce relevant findings, while simultaneously generating sensitive and specific predictive biomarkers of stress resilience.

Published
2020

28. Iron oxide nanoparticle surface decorated with cRGD peptides for magnetic resonance imaging of brain tumors

Author

Sophie Richard, Yoann Lalatonne, Laurence Motte, Sébastien Mériaux, and Marianne Boucher

Subjects
Male, 0301 basic medicine, Surface Properties, MRI contrast agent, Biophysics, Iron oxide, Contrast Media, Mice, Nude, Nanoparticle, 02 engineering and technology, Ferric Compounds, Biochemistry, Mice, 03 medical and health sciences, chemistry.chemical_compound, Nuclear magnetic resonance, Predictive Value of Tests, Cell Line, Tumor, medicine, Animals, Humans, Magnetite Nanoparticles, Molecular Biology, Tumor xenograft, medicine.diagnostic_test, Brain Neoplasms, Magnetic resonance imaging, 021001 nanoscience & nanotechnology, medicine.disease, Magnetic Resonance Imaging, Nanomedicine, 030104 developmental biology, chemistry, Heterografts, Glioblastoma, 0210 nano-technology, Oligopeptides
Abstract

In this article, a specific targeting Magnetic Resonance Imaging (MRI) nanoplatform, composed by iron oxide nanoparticle (NP) with cRGD peptides as targeting agent onto NP surface, is explored for the diagnosis of brain tumors by MRI using intracranial U87MG mice xenograft tumor. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editor: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.

Published
2017

29. About the Marty model of blood-brain barrier closure after its disruption using focused ultrasound

Author

Allegra Conti, Benoit Larrat, and Sébastien Mériaux

Subjects
Closure (topology), Contrast Media, Context (language use), Blood–brain barrier, Standard deviation, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Sonication, 0302 clinical medicine, Nuclear magnetic resonance, Drug Delivery Systems, Models, medicine, Humans, Radiology, Nuclear Medicine and imaging, Hyperthermia, BBB disruption, Ultrasonography, Physics, brain drug delivery, Microbubbles, Models, Statistical, Radiological and Ultrasound Technology, business.industry, ultrasound, Ultrasound, Induced, Settore FIS/07, Brain, Function (mathematics), Blood flow, Hyperthermia, Induced, Statistical, Magnetic Resonance Imaging, medicine.anatomical_structure, Ultrasonic Waves, Blood-Brain Barrier, 030220 oncology & carcinogenesis, business
Abstract

Many studies have demonstrated that pulsed ultrasound combined with circulating microbubbles can permeate the blood-brain barrier in a reversible manner. In 2012, our group demonstrated that the BBB remains permeable to small MRI contrast agents up to 24 h after ultrasound application and also that this duration was dependent on nanoparticle size. We derived a simple theoretical model explaining these observations (Marty et al 2012 J. Cereb. Blood Flow Metab. 32 1948–58). However, in this original paper the expression of the BBB closure time (t 1/2) as a function of the size of delivered contrast agents (d H) could not be mathematically derived from the model but rather from a guessed function that is fit to the numerical solution of the model. In this context, the two numeric parameters of this fitting function could not be related to the other physical parameters of the model. Here, we present a formal solution, finding the same expression of t 1/2 already published and linking t 1/2 to relevant physical variables such as the molecular hydrodynamic diameter d H, the BBB closure rate k and the standard deviation of the initial BBB gap sizes distribution σ 0.

Published
2019

30. A resting-state functional MR imaging and spectroscopy study of the dorsal hippocampus in the chronic unpredictable stress rat model

Author

Sébastien Mériaux, João Carlos Sousa, Ricardo Magalhães, Fawzi Boumezbeur, Arnaud Cachia, Ashley Cruz Novais, Michel Bottlaender, Nuno Sousa, Thérèse M. Jay, David André Barrière, Fernanda Marques, Paulo Marques, João José Cerqueira, and Universidade do Minho

Subjects
0301 basic medicine, Male, MRS, Magnetic Resonance Spectroscopy, hippocampus, Rest, Medicina Básica [Ciências Médicas], Hippocampus, Hippocampal formation, Amygdala, 03 medical and health sciences, Random Allocation, stress, 0302 clinical medicine, resistance and susceptibility, Piriform cortex, Medicine, Animals, Neurochemistry, Chronic stress, Rats, Wistar, Research Articles, Science & Technology, medicine.diagnostic_test, Resting state fMRI, business.industry, General Neuroscience, fMRI, functional connectivity, Magnetic resonance imaging, Magnetic Resonance Imaging, 3. Good health, Rats, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Ciências Médicas::Medicina Básica, Chronic Disease, business, Neuroscience, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity., This work is part of the Sigma project (FCT-ANR/NEU-OSD/0258/2012) cofinanced by the French ANR (Agence National pour la Recherche, APP Blanc International II 2012), the Portuguese FCT (Fundacao para a Ciencia e Tecnologia) and by the project NORTE-01-0124-FEDER-000021, supported by the Portuguese North Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework (QREN) through the European Regional Development Fund (FEDER), by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement through the FEDER as well as the Competitiveness Factors Operational Programme (COMPETE), and the Foundation for Science and Technology (FCT) under the scope of the project POCI-01-0145-FEDER-007038, and performed on a platform of the France Life Imaging network partly funded by Grant ANR-11-INBS-0006; R.M. was supported by Grant PDE/BDE/113604/2015 from the PhD-iHES program of the School of Medicine of Universidade do Minho. We thank Douglas L. Rothman, Grame F. Mason, and Osborne Almeida for their feedback.

Published
2019

31. AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

Author

Camille Verry, Awatef Allouch, Carolyn J. Anderson, Olivier Tillement, Cyrus Chargari, Nathalie Mignet, Benoit Larrat, Marc Janier, Jacqueline Sidi-Boumedine, Kevin M. Prise, Peter Fries, Bich-Thuy Doan, Erika Porcel, Fabien Rossetti, Jacques Balosso, Marie-Caline Abadjian, Dominique Ardail, Frédéric Boschetti, Yannick Crémillieux, Alexandre Detappe, Claire Rodriguez-Lafrasse, Ross Berbeco, Marie-Thérèse Aloy, Sébastien Mériaux, Vu Long Tran, Emmanuel L. Barbier, Sandrine Lacombe, Sandrine Dufort, Matteo Martini, Andreas Müller, Eric Deutsch, Karl T. Butterworth, Emmanuelle Canet-Soulas, Géraldine Le Duc, Franck Denat, Goran Angelovski, Guillaume Bort, Céline Frochot, Jean-Luc Perfettini, Eloise Thomas, Stéphane Roux, Tristan Doussineau, Muriel Barberi-Heyob, Michael J. Evans, François Lux, Charles Truillet, Stephen J. McMahon, Penelope Bouziotis, Thomas, Noémie, Formation, élaboration de nanomatériaux et cristaux (FENNEC), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), NH TherAguix SA [Meylan], Nano-H SAS, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CheMatech - Macrocycle Design Technologies, Max Planck Institute for Biological Cybernetics, Max-Planck-Gesellschaft, Dana-Farber Cancer Institute [Boston], Centre de résonance magnétique des systèmes biologiques (CRMSB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Université Paris sciences et lettres (PSL), Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Clinic for Diagnostic and Interventional Radiology, Saarland University Medical Center, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Center for Scientific Research 'Demokritos' (NCSR), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Réactions et Génie des Procédés (LRGP), Rayonnement synchrotron et Recherche Médicale, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), University of California [San Francisco] (UC San Francisco), University of California (UC), Université de Lyon, Centre for Cancer Research and Cell Biology, Queen's University [Belfast] (QUB), PRISME (PRISME), Institut de Physique des 2 Infinis de Lyon (IP2I Lyon), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de Physique Nucléaire de Lyon (IPNL), Institut des Sciences Moléculaires d'Orsay (ISMO), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Curiethérapie, Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Institut de Recherche Biomédicale des Armées (IRBA), French Military Health Service Academy, École du Val de Grâce (EVDG), Service de Santé des Armées-Service de Santé des Armées, Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), University of California [San Francisco] (UCSF), University of California, Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), NH Theraguix, Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Service Hospitalier Frédéric Joliot (SHFJ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Résonance magnétique des systèmes biologiques (RMSB), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Paris Sciences et Lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Equipe 6 : Rayonnement synchrotron et Recherche Médicale, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-[GIN] Grenoble Institut des Neurosciences, Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Ecole du Val-de-Grâce, UM Biochimie des Cancers et Biothérapies, CHU Grenoble-Institut de Biologie et Pathologie, Institut Européen des membranes (IEM), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS), Institut Galien Paris-Sud (IGPS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie et de Spectroscopie (LRMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Mécanique et Technologie (LMT), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Institute of Computer Science VI, Université Henri Poincaré - Nancy 1 (UHP)-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Rhône-Alpes Research Program on Hadrontherapy, National French Hadrontherapy Centre - Etoile, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurorestoration Group, King‘s College London-Wolfson Centre for Age-related Diseases, Ciblage thérapeutique en Oncologie (EA3738), Unité Médicale d'Oncologie Moléculaire et Transfert (UMOMT), Hospices Civils de Lyon (HCL), Laboratoire des collisions atomiques et moléculaires (LCAM), Service d'oncologie-radiothérapie, Hôpital d'Instruction des Armées du Val de Grâce, Service de Santé des Armées, and European Synchrotron Radiation Facility (ESRF)

Subjects
Radiation-Sensitizing Agents, Gadolinium, medicine.medical_treatment, 02 engineering and technology, Review Article, Pharmacology, Theranostic Nanomedicine, Mice, 0302 clinical medicine, Melanoma, Brain Neoplasms, General Medicine, [CHIM.MATE]Chemical Sciences/Material chemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Nuclear Medicine & Medical Imaging, Radiology Nuclear Medicine and imaging, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Toxicity, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, Clinical Sciences, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, Enhanced permeability and retention effect, 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Cancer, medicine.disease, Radiation therapy, Clinical trial, chemistry, Nanoparticles, business, Forecasting
Abstract

International audience; AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

Published
2019

32. Structural basis of envelope and phase intrinsic coupling modes of the cerebral cortex

Author

Florian Pieper, Sébastien Mériaux, Camino de Juan Romero, Isabel Reillo, Víctor Borrell, Céline Delettre, Claus C. Hilgetag, Arnaud Messé, Andreas K. Engel, Edgar Galindo-Leon, Roberto Toro, Leigh-Anne Dell, Jean-François Mangin, Lena J Nentwig, Gerhard Engler, Benoit Larrat, and Karl J. Hollensteiner

Subjects
Coupling (electronics), Physics, Computational model, medicine.anatomical_structure, Brain activity and meditation, Cerebral cortex, medicine, Phase (waves), Neuroscience, Diffusion MRI, Envelope (waves), Tractography
Abstract

Intrinsic coupling modes (ICMs) provide a framework for describing the interactions of ongoing brain activity at multiple spatial and temporal scales. Two families of ICMs can be distinguished: phase and envelope ICMs. The principles that shape these ICMs remain partly elusive, in particular their relation to the underlying brain structure. Here we explored structure-function relationships in the ferret brain between ICMs quantified from ongoing brain activity recorded with chronically implanted ECoG arrays and structural connectivity (SC) obtained from high-resolution diffusion MRI tractography. Large-scale computational models as well as simple topological ingredients of SC were used to explore the ability to predict both types of ICMs. Importantly, all investigations were conducted with ICM measures that are sensitive or insensitive to volume conduction effects. The results show that both types of ICMs are strongly related to SC, except when using ICM measures removing zero-lag synchronizations. Computational models are challenged to predict these ICM patterns consistently, and simple predictions from SC topological features can sometimes outperform them. Overall, the results demonstrate that patterns of cortical functional coupling as reflected in both phase and envelope ICMs bear a substantial relation to the underlying structural connectivity of the cerebral cortex.

Published
2018

33. Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib

Author

Sébastien Goutal, Sébastien Mériaux, Nicolas Tournier, Fabien Caillé, Benoit Larrat, Irène Buvat, Sylvain Auvity, Matthieu Gerstenmayer, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB)

Subjects
Male, 0301 basic medicine, Breast Cancer Resistance Protein, ATP Binding Cassette Transporter, Subfamily B, Abcg2, Focused ultrasound, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Pharmaceutical Science, Antineoplastic Agents, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Pharmacology, P-glycoprotein, Blood–brain barrier, Erlotinib Hydrochloride, 03 medical and health sciences, 0302 clinical medicine, In vivo, Tetrahydroisoquinolines, medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Rats, Wistar, Protein Kinase Inhibitors, Blood-brain barrier, Tyrosine kinase inhibitors, Membrane transporter, biology, Chemistry, Biological Transport, Extravasation, Brain tumor, 030104 developmental biology, medicine.anatomical_structure, Ultrasonic Waves, Positron-Emission Tomography, 030220 oncology & carcinogenesis, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Acridines, Erlotinib, Efflux, Tyrosine kinase, Positron Emission Tomography, medicine.drug
Abstract

International audience; Overcoming the efflux mediated by ATP–binding cassette (ABC) transporters at the blood-brain barrier (BBB)remains a challenge for the delivery of small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib to thebrain. Inhibition of ABCB1 and ABCG2 at the mouse BBB improved the BBB permeation of erlotinib but could notbe achieved in humans. BBB disruption induced by focused ultrasound (FUS) was investigated as a strategy toovercome the efflux transport of erlotinib $in\ vivo$.In rats, FUS combined with microbubbles allowed for a large and spatially controlled disruption of the BBB inthe left hemisphere. ABCB1/ABCG2 inhibition was performed using elacridar (10 mg/kg i.v). The brain kineticsof erlotinib was studied using $^{11}$C-erlotinib Positron Emission Tomography (PET) imaging in 5 groups (n = 4–5rats per group) including a baseline group, immediately after sonication (FUS), 48 h after FUS (FUS + 48 h),elacridar (ELA) and their combination (FUS + ELA). BBB integrity was assessed using the Evan's Blue (EB)extravasation test. Brain exposure to $^{11}$C-erlotinib was measured as the area under the curve (AUC) of the brainkinetics (% injected dose (%ID) versus time (min)) in volumes corresponding to the disrupted (left) and the intact(right) hemispheres, respectively.EB extravasation highlighted BBB disruption in the left hemisphere of animals of the FUS and FUS + ELAgroups but not in the control and ELA groups. EB extravasation was not observed 48 h after FUS suggestingrecovery of BBB integrity. Compared with the control group (AUC$_{Baseline}$ = 1.4 $\pm$ 0.5%ID.min), physical BBBdisruption did not impact the brain kinetics of $^{11}$C-erlotinib in the left hemisphere (p > .05) either immediately(AUC$_{FUS}$ = 1.2 $\pm$ 0.1%ID.min) or 48 h after FUS (AUC$_{FUS}$+48h = 1.1 $\pm$ 0.3%ID.min). Elacridar similarly increased $^{11}$C-erlotinib brain exposure to the left hemisphere in the absence (AUC$_{ELA}$ = 2.2 $\pm$ 0.5%ID.min,$p$ < .001) and in the presence of BBB disruption (AUC$_{FUS+ELA}$ = 2.1 $\pm$ 0.5%ID.min, p < .001). AUC$_{left}$ wasnever significantly different from AUC$_{right}$ ($p$ > .05), in any of the tested conditions.BBB integrity is not the rate limiting step for erlotinib delivery to the brain which is mainly governed by ABCmediated efflux. Efflux transport of erlotinib persisted despite BBB disruption.

Published
2018

34. Antioxidative Theranostic Iron Oxide Nanoparticles toward Brain Tumors Imaging and ROS Production

Author

Sophie Richard, Patrice X. Petit, Françoise Geffroy, Marianne Boucher, Sébastien Mériaux, Laurence Motte, Christian Slomianny, Ana Šarić, and Yoann Lalatonne

Subjects
Brain tumor, Metal Nanoparticles, Context (language use), Nanotechnology, 02 engineering and technology, 010402 general chemistry, Ferric Compounds, 01 natural sciences, Biochemistry, Antioxidants, Theranostic Nanomedicine, chemistry.chemical_compound, Microscopy, Electron, Transmission, Cell Line, Tumor, medicine, Caffeic acid, Humans, medicine.diagnostic_test, Brain Neoplasms, food and beverages, Magnetic resonance imaging, acid phenethyl ester, caffeic acid, cancer-cells, in-vitro, toxicity, mechanism, apoptosis, autophagy, lung, genotoxicity, General Medicine, 021001 nanoscience & nanotechnology, medicine.disease, Magnetic Resonance Imaging, 0104 chemical sciences, chemistry, Drug delivery, Cancer research, Molecular Medicine, Magnetic nanoparticles, Nanomedicine, Reactive Oxygen Species, 0210 nano-technology, Iron oxide nanoparticles
Abstract

Gliomas are the most common primary brain tumor in humans. To date, the only treatment of care consists of surgical removal of the tumor bulk, irradiation, and chemotherapy, finally resulting in a very poor prognosis due to the lack of efficiency in diagnostics. In this context, nanomedicine combining both diagnostic and magnetic resonance imaging (MRI) and therapeutic applications is a relevant strategy referred to theranostic. Magnetic nanoparticles (NP) are excellent MRI contrast agents because of their large magnetic moment, which induces high transverse relaxivity (r2) characteristic and increased susceptibility effect (T2*). NP can be also used for drug delivery by coating their surface with therapeutic molecules. Preliminary in vitro studies show the high potential of caffeic acid (CA), a natural polyphenol, as a promising anticancer drug due to its antioxidant, anti-inflammatory, and antimetastatic properties. In this study, the antioxidative properties of iron oxide NP functionalized with caffeic acid (gamma Fe2O3@CA NP) are investigated in vitro on U87-MG brain cancer cell lines. After intravenous injection of these NP in mice bearing a U87 glioblastoma, a negative contrast enhancement was specifically observed on 11.7 T MRI images in cancerous tissue, demonstrating a passive targeting of the tumor with these nanoplatforms

Published
2016

35. Magnetic Nanoparticles Applications for Amyloidosis Study and Detection: A Review

Author

Sébastien Mériaux, François Lux, Jonathan Pansieri, C. Marquette, Matthieu Gerstenmayer, Benoit Larrat, Olivier Tillement, Vincent Forge, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
magnetic nanoparticles, Amyloid, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, General Chemical Engineering, medical imaging, Nanoparticle, Nanotechnology, 02 engineering and technology, Review, Paramagnetic nanoparticles, lcsh:Chemistry, 03 medical and health sciences, Amyloid disease, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer’s diseases, medicine, General Materials Science, amyloidosis, Amyloidosis, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, chemistry, lcsh:QD1-999, Surface modification, Magnetic nanoparticles, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, Pittsburgh compound B, targeted nanoparticles, 030217 neurology & neurosurgery
Abstract

International audience; Magnetic nanoparticles (MNPs) have great potential in biomedical and clinical applications because of their many unique properties. This contribution provides an overview of the MNPs mainly used in the field of amyloid diseases. The first part discusses their use in understanding the amyloid mechanisms of fibrillation, with emphasis on their ability to control aggregation of amyloidogenic proteins. The second part deals with the functionalization by various moieties of numerous MNPs' surfaces (molecules, peptides, antibody fragments, or whole antibodies of MNPs) for the detection and the quantification of amyloid aggregates. The last part of this review focuses on the use of MNPs for magnetic-resonance-based amyloid imaging in biomedical fields, with particular attention to the application of gadolinium-based paramagnetic nanoparticles (AGuIX), which have been recently developed. Biocompatible AGuIX nanoparticles show favorable characteristics for in vivo use, such as nanometric and straightforward functionalization. Their properties have enabled their application in MRI. Here, we report that AGuIX nanoparticles grafted with the Pittsburgh compound B can actively target amyloid aggregates in the brain, beyond the blood⁻brain barrier, and remain the first step in observing amyloid plaques in a mouse model of Alzheimer's disease.

Published
2018

37. Notice of Removal: Weekly ultrasound induced blood-brain barrier openings seem to restore memory in APP/PS1dE9 amyloid mice model

Author

Benoit Larrat, Françoise Geffroy, Sébastien Mériaux, Erwan Selingue, and Matthieu Gerstenmayer

Subjects
Genetically modified mouse, medicine.medical_specialty, Amyloid, business.industry, Ultrasound, Wild type, Blood–brain barrier, Ultrasonic imaging, Endocrinology, medicine.anatomical_structure, Internal medicine, medicine, business, Focus ultrasound
Abstract

Blood-Brain Barrier opening (BBBO) with Focus Ultrasound (FUS) seems to give significant results in clearing amyloid plaques and restoring memory in Alzheimer's disease (AD-Tg) transgenic mice models. So far, only few teams have produced results [Burgess, 2014 — Leinenga, 2015] which motivates more investigations. To do so we set up two protocols: one on wild type (WT) mice and one AD-Tg mice.

Published
2017

38. Notice of Removal: Comparison of single spot and volume ultrasound sonications for efficient nanoparticle delivery to glioblastoma model in rats

Author

Olivier Tillement, Allegra Conti, Benoit Larrat, Françoise Geffroy, Sébastien Mériaux, François Lux, and Matthieu Gerstenmayer

Subjects
business.industry, Chemistry, Ultrasound, Nanoparticle, medicine.disease, 01 natural sciences, Focused ultrasound, Ultrasonic imaging, 0103 physical sciences, Microbubbles, medicine, 010306 general physics, business, Biomedical engineering, Glioblastoma
Abstract

Brain tumors therapy is limited by the Blood-Tumor Barrier (BTB) and Blood-Brain Barrier (BBB), still intact in the infiltrative areas. Low intensity Focused Ultrasound (FUS) in conjunction with microbubbles is the only method allowing the local disruption of the BTB/BBB [Hynynen et al. 2001, Zhao et al. 2015]. Proper study of the influence of acoustic scanning parameters (duty cycle, number of focal spots) on the amount of delivered nanoparticles is not available so far. Here, we compared two acoustic strategies to enhance the molecular concentration within brain tumors. The efficacy of the two methods is evaluated on the basis of absolute concentrations of delivered MR-contrast agents (CA) and on their rates of uptake/clearance by the tumors.

Published
2017

39. Numerical model fully depicting nanoparticle uptake within brain after ultrasound induced Blood-Brain Barrier opening

Author

Allegra Conti, Sébastien Mériaux, Rémi Magnin, and Benoit Larrat

Subjects
Materials science, business.industry, Settore FIS/07, Ultrasound, Nanoparticle, Nanotechnology, Vascular permeability, Blood–brain barrier, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Diffusion process, 030220 oncology & carcinogenesis, medicine, Microbubbles, Particle size, Diffusion (business), business, Biomedical engineering
Abstract

Low intensity Focused Ultrasound (FUS) combined with microbubbles open locally and not invasively the Blood-Brain Barrier (BBB) allowing passage of nanoparticles into the brain [Hynynen et al. 2001]. However, since the quantity of particles that can be delivered with this technique depends on tissue properties, on particle properties as well as on acoustic parameters, so far a model fully predicting the result of a FUS induced BBB opening experiment is missing. Here, we introduce a mathematical model depicting both the vascular permeability as a function of time and the diffusion process occurring in brain tissue. This model takes into account acoustic pressure, particle size, blood pharmacokinetics and diffusion rates.

Published
2017

40. The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome

Author

Ashley Cruz Novais, David André Barrière, Fawzi Boumezbeur, Fernanda Marques, Nuno Sousa, Ricardo Magalhães, Thérèse M. Jay, Paulo Marques, Sébastien Mériaux, Michel Bottlaender, Arnaud Cachia, João Carlos Sousa, João José Cerqueira, and Universidade do Minho

Subjects
0301 basic medicine, Male, Thalamus, Hippocampus, Nucleus accumbens, Biology, Somatosensory system, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neuroimaging, Neural Pathways, medicine, Connectome, Animals, Longitudinal Studies, Rats, Wistar, Molecular Biology, Science & Technology, Ventral Tegmental Area, Brain, Magnetic Resonance Imaging, 3. Good health, Rats, Ventral tegmental area, Psychiatry and Mental health, Stria terminalis, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Disease Susceptibility, Neuroscience, 030217 neurology & neurosurgery, Biomarkers, Stress, Psychological
Abstract

Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei. These structural changes are associated with increasing functional connectivity within a network composed by these regions. Moreover, using a clustering based on endocrine and behavioural outcomes, animals were classified as high and low responders to stress. We reveal that susceptible animals (high responders) develop local atrophy of the ventral tegmental area and an increase in functional connectivity between this area and the thalamus, further spreading to other areas that link the cognitive system with the fight-or-flight system. Through a longitudinal approach we were able to establish two distinct patterns, with functional changes occurring during the exposure to stress, but with an inflection point after the first week of stress when more prominent changes were seen. Finally, our study revealed differences in functional connectivity in a brainstem-limbic network that distinguishes resistant and susceptible responders before any exposure to stress, providing the first potential imaging-based predictive biomarkers of an individual's resilience/vulnerability to stressful conditions., This work is part of the Sigma project with the reference FCT-ANR/NEU-OSD/ 0258/2012 co-financed by the French public funding agency ANR (Agence National pour la Recherche, APP Blanc International II 2012), the Portuguese FCT (Fundação para a Ciência e Tecnologia) and by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Projecto Estratégico co-funded by FCT (PEst-C/SAU/LA0026-/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298). DAB and AN were funded by grants from FCT-ANR/NEU-OSD/0258/2012. RM is supported by the FCT fellowship grant with the reference PDE/BDE/113604/2015 from the PhDiHES program; AC was supported by a grant from the foundation NRJ. PM was funded by Fundação Calouste Gulbenkian (Portugal; ‘Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)’), Grant Number P-139977. We thank Drs Patrício Costa and Pedro Moreira for support on the various statistical analyses., info:eu-repo/semantics/publishedVersion

Published
2017

41. International Society for Therapeutic Ultrasound Conference 2016

Author

Brian Fowlkes, Pejman Ghanouni, Narendra Sanghvi, Constantin Coussios, Paul C. Lyon, Michael Gray, Christophoros Mannaris, Marie de Saint Victor, Eleanor Stride, Robin Cleveland, Robert Carlisle, Feng Wu, Mark Middleton, Fergus Gleeson, Jean-Franҫois Aubry, Kim Butts Pauly, Chrit Moonen, Jacob Vortman, Shirley Sharabi, Dianne Daniels, David Last, David Guez, Yoav Levy, Alexander Volovick, Javier Grinfeld, Itay Rachmilevich, Talia Amar, Zion Zibly, Yael Mardor, Sagi Harnof, Michael Plaksin, Yoni Weissler, Shy Shoham, Eitan Kimmel, Omer Naor, Nairouz Farah, Dong-Guk Paeng, Zhiyuan Xu, John Snell, Anders H. Quigg, Matthew Eames, Changzhu Jin, Ashli C. Everstine, Jason P. Sheehan, Beatriz S. Lopes, Neal Kassell, Thomas Looi, Vera Khokhlova, Charles Mougenot, Kullervo Hynynen, James Drake, Michael Slayton, Richard C. Amodei, Keegan Compton, Ashley McNelly, Daniel Latt, John Kearney, David Melodelima, Aurelien Dupre, Yao Chen, David Perol, Jeremy Vincenot, Jean-Yves Chapelon, Michel Rivoire, Wei Guo, Guoxin Ren, Guofeng Shen, Michael Neidrauer, Leonid Zubkov, Michael S. Weingarten, David J. Margolis, Peter A. Lewin, Nathan McDannold, Jonathan Sutton, Natalia Vykhodtseva, Margaret Livingstone, Thiele Kobus, Yong-Zhi Zhang, Michael Schwartz, Yuexi Huang, Nir Lipsman, Jennifer Jain, Martin Chapman, Tejas Sankar, Andres Lozano, Robert Yeung, Christakis Damianou, Nikolaos Papadopoulos, Omer Brokman, Eyal Zadicario, Ori Brenner, David Castel, Shih-Ying Wu, Julien Grondin, Wenlan Zheng, Marc Heidmann, Maria Eleni Karakatsani, Carlos J. Sierra Sánchez, Vincent Ferrera, Elisa E. Konofagou, Marinos Yiannakou, HongSeok Cho, Hwayoun Lee, Mun Han, Jong-Ryul Choi, Taekwan Lee, Sanghyun Ahn, Yongmin Chang, Juyoung Park, Nicholas Ellens, Ari Partanen, Keyvan Farahani, Raag Airan, Alexandre Carpentier, Michael Canney, Alexandre Vignot, Cyril Lafon, Jean-yves Delattre, Ahmed Idbaih, Henrik Odéen, Bradley Bolster, Eun Kee Jeong, Dennis L. Parker, Pooja Gaur, Xue Feng, Samuel Fielden, Craig Meyer, Beat Werner, William Grissom, Michael Marx, Hans Weber, Valentina Taviani, Brian Hargreaves, Jun Tanaka, Kentaro Kikuchi, Ayumu Ishijima, Takashi Azuma, Kosuke Minamihata, Satoshi Yamaguchi, Teruyuki Nagamune, Ichiro Sakuma, Shu Takagi, Mathieu D. Santin, Laurent Marsac, Guillaume Maimbourg, Morgane Monfort, Benoit Larrat, Chantal François, Stéphane Lehéricy, Mickael Tanter, Gesthimani Samiotaki, Shutao Wang, Camilo Acosta, Eliza R. Feinberg, Zsofia I. Kovacs, Tsang-Wei Tu, Georgios Z. Papadakis, William C. Reid, Dima A. Hammoud, Joseph A. Frank, Zsofia i. Kovacs, Saejeong Kim, Neekita Jikaria, Michele Bresler, Farhan Qureshi, Jingjing Xia, Po-Shiang Tsui, Hao-Li Liu, Juan C. Plata, Bragi Sveinsson, Vasant A. Salgaonkar, Matthew Adams, Chris Diederich, Eugene Ozhinsky, Matthew D. Bucknor, Viola Rieke, Andrew Mikhail, Lauren Severance, Ayele H. Negussie, Bradford Wood, Martijn de Greef, Gerald Schubert, Mario Ries, Megan E. Poorman, Mary Dockery, Vandiver Chaplin, Stephanie O. Dudzinski, Ryan Spears, Charles Caskey, Todd Giorgio, Marcia M. Costa, Efthymia Papaevangelou, Anant Shah, Ian Rivens, Carol Box, Jeff Bamber, Gail ter Haar, Scott R. Burks, Matthew Nagle, Ben Nguyen, Blerta Milo, Nhan M. Le, Shaozhen Song, Kanheng Zhou, Ghulam Nabi, Zhihong Huang, Shmuel Ben-Ezra, Shani Rosen, Senay Mihcin, Jan Strehlow, Ioannis Karakitsios, Nhan Le, Michael Schwenke, Daniel Demedts, Paul Prentice, Sabrina Haase, Tobias Preusser, Andreas Melzer, Jean-Louis Mestas, Kamel Chettab, Gustavo Stadthagen Gomez, Charles Dumontet, Bettina Werle, Fabrice Marquet, Pierre Bour, Fanny Vaillant, Sana Amraoui, Rémi Dubois, Philippe Ritter, Michel Haïssaguerre, Mélèze Hocini, Olivier Bernus, Bruno Quesson, Amit Livneh, Dan Adam, Justine Robin, Bastien Arnal, Mathias Fink, Mathieu Pernot, Tatiana D. Khokhlova, George R. Schade, Yak-Nam Wang, Wayne Kreider, Julianna Simon, Frank Starr, Maria Karzova, Adam Maxwell, Michael R. Bailey, Jonathan E. Lundt, Steven P. Allen, Jonathan R. Sukovich, Timothy Hall, Zhen Xu, Philip May, Daniel W. Lin, Charlotte Constans, Thomas Deffieux, Jean-Francois Aubry, Eun-Joo Park, Yun Deok Ahn, Soo Yeon Kang, Dong-Hyuk Park, Jae Young Lee, J. Vidal-Jove, E. Perich, A. Ruiz, A. Jaen, N. Eres, M. Alvarez del Castillo, Rachel Myers, James Kwan, Christian Coviello, Cliff Rowe, Calum Crake, Sean Finn, Edward Jackson, Antonios Pouliopoulos, Caiqin Li, Marc Tinguely, Meng-Xing Tang, Valeria Garbin, James J. Choi, Lisa Folkes, Michael Stratford, Sandra Nwokeoha, Tong Li, Navid Farr, Samantha D’Andrea, Kayla Gravelle, Hong Chen, Donghoon Lee, Joo Ha Hwang, Sophie Tardoski, Jacqueline Ngo, Evelyne Gineyts, Jean-Pau Roux, Philippe Clézardin, Allegra Conti, Rémi Magnin, Matthieu Gerstenmayer, François Lux, Olivier Tillement, Sébastien Mériaux, Stefania Della Penna, Gian Luca Romani, Erik Dumont, Tao Sun, Chanikarn Power, Eric Miller, Oleg Sapozhnikov, Sergey Tsysar, Petr V. Yuldashev, Victor Svet, Dongli Li, Antonio Pellegrino, Nik Petrinic, Clive Siviour, Antoine Jerusalem, Peter V. Yuldashev, Bryan W. Cunitz, Barbrina Dunmire, Claude Inserra, Matthieu Guedra, Cyril Mauger, Bruno Gilles, Maxim Solovchuk, Tony W. H. Sheu, Marc Thiriet, Yufeng Zhou, Esra Neufeld, Christian Baumgartner, Davnah Payne, Adamos Kyriakou, Niels Kuster, Xu Xiao, Helen McLeod, Christopher Dillon, Allison Payne, Vera A. Khokhova, Ilya Sinilshchikov, Yulia Andriyakhina, Andrey Rybyanets, Natalia Shvetsova, Alex Berkovich, Igor Shvetsov, Caroline J. Shaw, John Civale, Dino Giussani, Christoph Lees, Valery Ozenne, Solenn Toupin, Vasant Salgaonkar, Elena Kaye, Sebastien Monette, Majid Maybody, Govindarajan Srimathveeravalli, Stephen Solomon, Amitabh Gulati, Mario Bezzi, Jürgen W. Jenne, Thomas Lango, Michael Müller, Giora Sat, Christine Tanner, Stephan Zangos, Matthias Günther, Au Hoang Dinh, Emilie Niaf, Flavie Bratan, Nicolas Guillen, Rémi Souchon, Carole Lartizien, Sebastien Crouzet, Olivier Rouviere, Yang Han, Thomas Payen, Carmine Palermo, Steve Sastra, Kenneth Olive, Johanna M. van Breugel, Maurice A. van den Bosch, Benjamin Fellah, Denis Le Bihan, Luis Hernandez-Garcia, Charles A. Cain, Erasmia Lyka, Delphine Elbes, Chunhui Li, Satoshi Tamano, Hayato Jimbo, Shin Yoshizawa, Keisuke Fujiwara, Kazunori Itani, Shin-ichiro Umemura, Dan Stoianovici, Zulfadhli Zaini, Ryo Takagi, Shenyan Zong, Ron Watkins, Aurea Pascal-Tenorio, Peter Jones, Kim Butts-Pauly, Donna Bouley, Yazhu Chen, Chung-Yin Lin, Han-Yi Hsieh, Kuo-Chen Wei, Camille Garnier, Gilles Renault, Reza Seifabadi, Emmanuel Wilson, Avinash Eranki, Peter Kim, Dennis Lübke, Peter Huber, Joachim Georgii, Caroline V. Dresky, Julian Haller, Pavel Yarmolenko, Karun Sharma, Haydar Celik, Guofeng Li, Weibao Qiu, Hairong Zheng, Meng-Yen Tsai, Po-Chun Chu, Taylor Webb, Urvi Vyas, Matthew Walker, Jidan Zhong, Adam C. Waspe, Mojgan Hodaie, Feng-Yi Yang, Sin-Luo Huang, Yuval Zur, Benny Assif, Christian Aurup, Hermes Kamimura, Antonio A. Carneiro, Sven Rothlübbers, Julia Schwaab, Graeme Houston, Haim Azhari, Noam Weiss, Jacob Sosna, S. Nahum Goldberg, Victor Barrere, Kee W. Jang, Bobbi Lewis, Xiaotong Wang, Visa Suomi, David Edwards, Zahary Larrabee, Arik Hananel, Boaz Rafaely, Rasha Elaimy Debbiny, Carmel Zeltser Dekel, Michael Assa, George Menikou, Petros Mouratidis, José A. Pineda-Pardo, Marta Del Álamo de Pedro, Raul Martinez, Frida Hernandez, Silvia Casas, Carlos Oliver, Patricia Pastor, Lidia Vela, Jose Obeso, Paul Greillier, Ali Zorgani, Stefan Catheline, Vyacheslav Solovov, Michael O. Vozdvizhenskiy, Andrew E. Orlov, Chueh-Hung Wu, Ming-Kuan Sun, Tiffany T. Shih, Wen-Shiang Chen, Fabrice Prieur, Arnaud Pillon, Valerie Cartron, Patrick Cebe, Nathalie Chansard, Maxime Lafond, Pauline Muleki Seya, Jean-Christophe Bera, Tanguy Boissenot, Elias Fattal, Alexandre Bordat, Helene Chacun, Claire Guetin, Nicolas Tsapis, Kazuo Maruyama, Johan Unga, Ryo Suzuki, Cécile Fant, Bernadette Rogez, Mercy Afadzi, Ola Finneng Myhre, Siri Vea, Astrid Bjørkøy, Petros Tesfamichael Yemane, Annemieke van Wamel, Sigrid Berg, Rune Hansen, Bjørn Angelsen, and Catharina Davies

Subjects
0301 basic medicine, medicine.medical_specialty, Therapeutic ultrasound, business.industry, Tel aviv, medicine.medical_treatment, 02 engineering and technology, 021001 nanoscience & nanotechnology, 03 medical and health sciences, 030104 developmental biology, Ophthalmology, medicine, Radiology, Nuclear Medicine and imaging, Medical physics, 0210 nano-technology, business
Published
2017

42. Genetically tailored magnetosomes used as MRI probe for molecular imaging of brain tumor

Author

Sandra Prévéral, Erwan Selingue, Sébastien Mériaux, Marianne Boucher, David Pignol, Christopher T. Lefèvre, Michel Pean, Géraldine Adryanczyk-Perrier, Françoise Geffroy, Nicolas Ginet, L. Bellanger, HYBIS, Laboratoire d'étude des transferts en hydrologie et environnement (LTHE), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Grenoble (INPG)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Grenoble (INPG)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Department of Applied Geophysics, Technische Universität Berlin (TUB)-Technische Universität Berlin (TUB), Unité d'imagerie par résonance magnétique à très haut champ et de spectroscopie (UNIRS), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Microbiologie Environnementale et Moléculaire (MEM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Observatoire des Sciences de l'Univers de Grenoble (OSUG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Materials science, media_common.quotation_subject, Magnetosome, Biophysics, Brain tumor, Contrast Media, Molecular Probe Techniques, Bioengineering, Single step, Nanoconjugates, 02 engineering and technology, Article, Biomaterials, Mice, 03 medical and health sciences, Nuclear magnetic resonance, Cell Line, Tumor, Biomarkers, Tumor, medicine, Animals, Tissue Distribution, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internalization, media_common, medicine.diagnostic_test, Brain Neoplasms, RGD peptide, Magnetic resonance imaging, 021001 nanoscience & nanotechnology, medicine.disease, Magnetic Resonance Imaging, Molecular Imaging, Genetic Enhancement, 030104 developmental biology, Mechanics of Materials, Molecular Probes, Ceramics and Composites, Magnetosomes, Lipid vesicle, Molecular imaging, 0210 nano-technology, Oligopeptides
Abstract

International audience; We investigate here the potential of single step production of genetically engineeredmagnetosomes, bacterial biogenic iron-oxide nanoparticles embedded in a lipid vesicle, as a new tailorable magnetic resonance molecular imaging probe. We demonstrate in vitro the specific binding and the significant internalization into U87 cells of magnetosomes decorated with RGD peptide. After injection at the tail vein of glioblastoma-bearing mice, we evidence in the first 2 h the rapid accumulation of both unlabeled and functionalized magnetosomes inside the tumor by Enhanced Permeability and Retention effects. 24 h after the injection, a specific enhancement of the tumor contrast is observed on MR images only for RGD-labeled magnetosomes. Post mortem acquisition of histological data confirms MRI results with more magnetosomes found into the tumor treated with functionalized magnetosomes. This work establishes the first proof-of-concept of a successful bio-integrated production of molecular imaging probe for MRI.

Published
2017

43. A new motorized MR-guided ultrasound system for the delivery of large molecules to the rodent brain

Author

Rémi Magnin, Erik Dumont, D. Le Bihan, Benoit Larrat, and Sébastien Mériaux

Subjects
Transducer, medicine.anatomical_structure, Materials science, business.industry, Duty cycle, Ultrasound, medicine, Microbubbles, Blood–brain barrier, business, Focused ultrasound, Mri guided, Biomedical engineering
Abstract

Focused ultrasound combined with microbubbles injection has shown its potential to transiently disrupt the Blood Brain Barrier (BBB), allowing the delivery of large molecules to the Central Nervous System (CNS). However, the phenomenon has still to be investigated as the optimal parameters remain unknown up to date. To do so, we developed a new MR-guided motorized system, allowing the displacement of the transducer within preclinical magnets in order to choose the location of the opening. We demonstrated the capabilities of our system by opening the BBB along arbitrary trajectories. We also show the existence of an acoustic pressure threshold for BBB disruption estimated at about 0.3 MPa at 1.5 MHz by testing different acoustic conditions on the same animal. Finally, we investigated the BBB opening efficiency with the duty cycle. We proved that the disruption was greater with higher duty cycle.

Published
2017

44. RGD decoration of PEGylated polyester nanocapsules of perfluorooctyl bromide for tumor imaging: Influence of pre or post-functionalization on capsule morphology

Author

Julien Nicolas, Odile Diou, Nicolas Mackiewicz, Elias Fattal, Caroline Robic, Vianney Delplace, Sébastien Mériaux, Julien Valette, and Nicolas Tsapis

Subjects
Surface Properties, Contrast Media, Mice, Nude, Pharmaceutical Science, Nanocapsules, Polyethylene Glycols, Fluorine-19 Magnetic Resonance Imaging, chemistry.chemical_compound, Microscopy, Electron, Transmission, Bromide, Cell Line, Tumor, Neoplasms, Polymer chemistry, Copolymer, Animals, Moiety, Particle Size, chemistry.chemical_classification, Fluorocarbons, Cryoelectron Microscopy, Capsule, General Medicine, Polymer, Hydrocarbons, Brominated, Polyester, chemistry, Biophysics, Surface modification, Female, Oligopeptides, Biotechnology
Abstract

PEGylated polyester nanocapsules of perfluorooctyl bromide (PFOB) were surface-decorated with a RGD (arginine-glycine-aspartic acid) peptide by either pre-functionalization or post-functionalization strategies using carbodiimide-assisted chemistry. Both strategies allowed successful linkage of RGD at the surface of nanocapsules with up to 600-950 peptide units per nanocapsule without modifying the encapsulation efficacy of PFOB used as the (19)F MRI imaging moiety. Cryo-Transmission Electron Microscopy images evidence that slight changes of the polymer used to form the capsule shell strongly influence nanocapsule morphology. While, the use of copolymer blends induces the formation of acorn morphologies, PLA-b-PEG-COOH leads to elongated and "tears of wine"-like nanoconstructs. In vivo evaluation in mice bearing CT26 tumors by (19)F MRI reveals no significant difference of accumulation between PEGylated and RGD-decorated nanocapsules obtained by the post-functionalization approach (highest RGD density/capsule).

Published
2014

45. Characterization of the diffusion process of different Gadolinium-based nanoparticles within the brain tissue after ultrasound induced Blood-Brain Barrier permeabilization

Author

Rémi Magnin, Denis Le Bihan, Olivier Tillement, Erik Dumont, Sébastien Mériaux, Stefania Della Penna, Benoit Larrat, Matthieu Gerstenmayer, Gian Luca Romani, François Lux, Allegra Conti, Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Clinic Sciences and Bioimaging, University G. d'Annunzio Chieti-Pescara, Image Guided Therapy (IGT), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Focused ultrasound, Gadolinium, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Blood–brain barrier, Brain tissue tortuosity, 01 natural sciences, Tortuosity, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, In vivo, 0103 physical sciences, medicine, Extracellular, Diffusion (business), 010306 general physics, Blood-brain barrier, [SPI.ACOU]Engineering Sciences [physics]/Acoustics [physics.class-ph], medicine.diagnostic_test, Chemistry, business.industry, Settore FIS/07, Ultrasound, Magnetic resonance imaging, medicine.anatomical_structure, Drug delivery, business, 030217 neurology & neurosurgery
Abstract

International audience; We present here a new method to study the diffusion process of Gadolinium-based MRI Contrast Agents within the brain extracellular space after ultrasound-induced Blood-Brain Barrier permeabilization. Four compounds were tested (MultiHance, Gadovist, Dotarem and AGuIX). By estimating the Free Diffusion Coefficients from in vitro studies, and the Apparent Diffusion Coefficients from in vivo experiments, an evaluation of the tortuosity (λ) in the right striatum of 11 Sprague-Dawley rats has been performed. The values of λ are in agreement with literature and demonstrate that the chosen permeabilization protocol maintains the integrity of brain tissue.

Published
2016

46. HG-55DEVELOPMENT OF IN VIVO MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) FROM STEREOTACTIC BIOPSIES PERFORMED AT DIAGNOSIS

Author

Ludivine Le Dret, Alexandre Plessier, David Castel, Sébastien Mériaux, Laurence Fiette, Jacques Grill, Pascale Varlet, Marie-Anne Debily, Kevin Beccaria, and Stéphanie Puget

Subjects
Cancer Research, medicine.medical_specialty, Pathology, medicine.diagnostic_test, business.industry, medicine.disease, Pons, Abstracts, Text mining, Oncology, In vivo, Glioma, Biopsy, medicine, Neurology (clinical), Radiology, business
Published
2016

47. In vivo CEST MR imaging of U87 mice brain tumor angiogenesis using targeted LipoCEST contrast agent at 7 T

Author

Fawzi Boumezbeur, Françoise Geffroy, Julien Flament, Marc Port, Sébastien Mériaux, Christelle Medina, Caroline Robic, Jean-François Mayer, Julien Valette, Franck Lethimonnier, Philippe Robert, and Denis Le Bihan

Subjects
Tumor angiogenesis, Pathology, medicine.medical_specialty, biology, Chemistry, Integrin, Colocalization, 02 engineering and technology, 021001 nanoscience & nanotechnology, Mr imaging, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, biology.protein, Immunohistochemistry, Radiology, Nuclear Medicine and imaging, U87, 0210 nano-technology, Receptor
Abstract

LipoCEST are liposome-encapsulating paramagnetic contrast agents (CA) based on chemical exchange saturation transfer with applications in biomolecular MRI. Their attractive features include biocompatibility, subnanomolar sensitivity, and amenability to functionalization for targeting biomarkers. We demonstrate MR imaging using a targeted lipoCEST, injected intravenously. A lipoCEST carrying Tm(III)-complexes was conjugated to RGD tripeptide (RGD-lipoCEST), to target integrin ανβ3 receptors involved in tumor angiogenesis and was compared with an unconjugated lipoCEST. Brain tumors were induced in athymic nude mice by intracerebral injection of U87MG cells and were imaged at 7 T after intravenous injection of either of the two contrast agents (n = 12 for each group). Chemical exchange saturation transfer-MSME sequence was applied over 2 h with an average acquisition time interval of 13.5 min. The chemical exchange saturation transfer signal was ∼1% in the tumor and controlateral regions, and decreased to ∼0.3% after 2 h; while RGD-lipoCEST signal was ∼1.4% in the tumor region and persisted for up to 2 h. Immunohistochemical staining revealed a persistent colocalization of RGD-lipoCEST with ανβ3 receptors in the tumor region. These results constitute an encouraging step toward in vivo MRI imaging of tumor angiogenesis using intravenously injected lipoCEST. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Published
2012

48. Magnetic resonance-guided motorized transcranial ultrasound system for blood-brain barrier permeabilization along arbitrary trajectories in rodents

Author

Benoit Larrat, Fabien Rabusseau, Erik Dumont, Jean-François Aubry, Rémi Magnin, Denis Le Bihan, Frédéric Salabartan, Sébastien Mériaux, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Image Guided Therapy (IGT), Institut Langevin - Ondes et Images (UMR7587) (IL), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Langevin - Ondes et Images, Université Paris Diderot - Paris 7 (UPD7)-ESPCI ParisTech-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Focused ultrasound, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Ultrasound, Mr contrast agent, Magnetic resonance imaging, Blood–brain barrier, Transcranial Doppler, High-field magnetic resonance imaging, [PHYS.MECA.ACOU]Physics [physics]/Mechanics [physics]/Acoustics [physics.class-ph], Transducer, medicine.anatomical_structure, Blood-brain barrier permeabilization, Drug delivery to rodent brains, Region of interest, medicine, Radiology, Nuclear Medicine and imaging, business, Biomedical engineering
Abstract

Background Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols. Methods In this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB. Results The compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session. Conclusions Our system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.

Published
2015

49. High sensitivity 19F MRI of a perfluorooctyl bromide emulsion: application to a dynamic biodistribution study and oxygen tension mapping in the mouse liver and spleen

Author

Fawzi Boumezbeur, Denis Le Bihan, Julien Valette, Marc Port, Céline Giraudeau, Caroline Robic, Philippe Robert, Mohamed Ahmed Ghaly, Franck Lethimonnier, Boucif Djemai, and Sébastien Mériaux

Subjects
Biodistribution, Pathology, medicine.medical_specialty, Chemistry, Spleen, Oxygenation, Polyethylene glycol, Oxygen tension, chemistry.chemical_compound, medicine.anatomical_structure, In vivo, PEG ratio, Emulsion, medicine, Molecular Medicine, Radiology, Nuclear Medicine and imaging, Spectroscopy, Biomedical engineering
Abstract

We have recently developed an optimized multi-spin echo (MSE) sequence dedicated to perfluorooctyl bromide (PFOB) imaging yielding an excellent sensitivity in vitro. The aim of the present study was to apply this sequence to quantitative measurements in the mouse liver and spleen after intravenous (i.v.) injection of PFOB emulsions. We first performed oxygenation maps 25.5 min after a single infusion of emulsion and, contrary to previous studies, shortly after injection. The signal-to-noise ratio (SNR) in the liver and spleen was as high as 45 and 120, respectively, for 3-min images with 11.7-μL pixels. Values of oxygen tension tended to be slightly higher in the spleen than in the liver. Dynamic biodistribution experiments were then performed immediately after intravenous (i.v.) injection of PFOB emulsions grafted with different quantities of polyethylene glycol (PEG) for stealth. Images were acquired every 7 min for 84 min and the SNR measured in the liver and spleen was at least four from the first time point. Uptake rates could be assessed for each PEG amount and, in spite of high standard deviations (SDs) owing to interanimal variability, our data confirmed that increasing quantities of PEG allow more gradual uptake of the emulsion particles by the liver and spleen. In conclusion, our method seems to be a powerful tool to non-invasively perform accurate in vivo quantitative measurements in the liver and spleen using 19 F MRI. Copyright © 2011 John Wiley & Sons, Ltd.

Published
2011

50. Magnetosomes, Biogenic Magnetic Nanomaterials for Brain Molecular Imaging with 17.2 T MRI Scanner

Author

Laurence Motte, Benjamin Marty, Franck Lethimonnier, Sandra Prévéral, Christopher T. Lefèvre, Nicolas Ginet, Yoann Lalatonne, Géraldine Adryanczyk-Perrier, Françoise Geffroy, David Pignol, Michel Pean, Marianne Boucher, Sébastien Mériaux, Daniel Garcia, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biologie végétale et microbiologie environnementale - UMR7265 (BVME), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Materials science, Brain vasculature, Magnetotactic bacteria, Magnetosome, Biomedical Engineering, Pharmaceutical Science, Contrast Media, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Nanomaterials, Biomaterials, chemistry.chemical_compound, Magnetics, Mice, Nuclear magnetic resonance, In vivo, medicine, Animals, [CHIM]Chemical Sciences, Magnetospirillum, Magnetite Nanoparticles, ComputingMilieux_MISCELLANEOUS, Magnetite, medicine.diagnostic_test, Brain, Magnetic resonance imaging, Dextrans, 021001 nanoscience & nanotechnology, Magnetic Resonance Imaging, Ferrosoferric Oxide, 0104 chemical sciences, 3. Good health, Molecular Imaging, Nanostructures, chemistry, Nanoparticles, Magnetosomes, Molecular imaging, 0210 nano-technology, Biomedical engineering
Abstract

The fast development of sensitive molecular diagnostic tools is currently paving the way for a personalized medicine. A new class of ultrasensitive magnetic resonance imaging (MRI) T₂-contrast agents based on magnetosomes, magnetite nanocrystals biomineralized by magnetotactic bacteria, is proposed here. The contrast agents can be injected into the blood circulation and detected in the picomolar range. Purified magnetosomes are water-dispersible and stable within physiological conditions and exhibit at 17.2 T a transverse relaxivity r₂ four times higher than commercial ferumoxide. The subsequent gain in sensitivity by T₂(*) -weighted imaging at 17.2 T of the mouse brain vasculature is evidenced in vivo after tail vein injection of magnetosomes representing a low dose of iron (20 μmoliron kg(-1)), whereas no such phenomenon with the same dose of ferumoxide is observed. Preclinical studies of human pathologies in animal models will benefit from the combination of high magnetic field MRI with sensitive, low dose, easy-to-produce biocompatible contrast agents derived from bacterial magnetosomes.

Published
2015

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