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1. Combination of thermal ablation by focused ultrasound, pFAR4-IL-12 transfection and lipidic adjuvant provide a distal immune response

Author

Hai Doan Do, Corinne Marie, Stéphanie Bessoles, Hélène Dhotel, Johanne Seguin, Benoit Larrat, Bich-Thuy Doan, Daniel Scherman, Virginie Escriou, Salima Hacein-Bey-Abina, and Nathalie Mignet

Subjects
gene delivery, cancer, transfection, immunotherapy, toll-like receptor 2-agonists, combined therapy, therapeutic ultrasound, Internal medicine, RC31-1245
Abstract

Aim: Gene-based immunotherapy against cancer is limited by low gene transfer efficiency. In the literature, interleukin-12 (IL-12) encoding plasmid associated with sonoporation has been shown to enhance antitumoral activity. Moreover, non-viral carriers and high-frequency ultrasound have both been shown to promote immune response activation. Here, IL-12 encoding plasmid, non-viral carrier stimulating the immune response and focused ultrasound were combined in order to improve the antitumoral efficiency. Methods: In order to enhance a gene-based antitumoral immune response, home-made lipids Toll-like receptor 2 (TLR2) agonists and plasmid free of antibiotic resistance version 4 (pFAR4), a mini-plasmid, encoding the IL-12 cytokine were combined with high-intensity focused ultrasound (HIFU). The lipid composition and the combination conditions were selected following in vitro and in vivo preliminary studies. The expression of IL-12 from our plasmid construct was measured in vitro and in vivo. The combination strategy was evaluated in mice bearing colon carcinoma cells (CT26) tumors following their weight, tumor volume, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) levels in the serum and produced by splenocytes exposed to CT26 tumor cells. Results: Lipid-mediated cell transfection and intratumoral injection into CT26 tumor mice using pFAR4-IL-12 led to the secretion of the IL-12 cytokine into cell supernatant and mice sera, respectively. Conditions of thermal deposition using HIFU were optimized. The plasmid encoding pFAR4-IL-12 or TLR2 agonist alone had no impact on tumor growth compared with control mice, whereas the complete treatment consisting of pFAR4-IL-12, TLR2 lipid agonist, and HIFU limited tumor growth. Moreover, only the complete treatment increased significantly mice survival and provided an abscopal effect on a metastatic CT26 model. Conclusions: The HIFU condition was highly efficient to stop tumor growth. The combined therapy was the most efficient in terms of IL-12 and IFN-γ production and mice survival. The study showed the feasibility and the limits of this combined therapy which has the potential to be improved.

Published
2022
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2. Synthesis, Characterization and Evaluation of Peptide Nanostructures for Biomedical Applications

Author

Fanny d’Orlyé, Laura Trapiella-Alfonso, Camille Lescot, Marie Pinvidic, Bich-Thuy Doan, and Anne Varenne

Subjects
peptide synthesis, flow chemistry, peptide self-assembly, physicochemical and biological characterization, biomedical applications, nanotheranostics, Organic chemistry, QD241-441
Abstract

There is a challenging need for the development of new alternative nanostructures that can allow the coupling and/or encapsulation of therapeutic/diagnostic molecules while reducing their toxicity and improving their circulation and in-vivo targeting. Among the new materials using natural building blocks, peptides have attracted significant interest because of their simple structure, relative chemical and physical stability, diversity of sequences and forms, their easy functionalization with (bio)molecules and the possibility of synthesizing them in large quantities. A number of them have the ability to self-assemble into nanotubes, -spheres, -vesicles or -rods under mild conditions, which opens up new applications in biology and nanomedicine due to their intrinsic biocompatibility and biodegradability as well as their surface chemical reactivity via amino- and carboxyl groups. In order to obtain nanostructures suitable for biomedical applications, the structure, size, shape and surface chemistry of these nanoplatforms must be optimized. These properties depend directly on the nature and sequence of the amino acids that constitute them. It is therefore essential to control the order in which the amino acids are introduced during the synthesis of short peptide chains and to evaluate their in-vitro and in-vivo physico-chemical properties before testing them for biomedical applications. This review therefore focuses on the synthesis, functionalization and characterization of peptide sequences that can self-assemble to form nanostructures. The synthesis in batch or with new continuous flow and microflow techniques will be described and compared in terms of amino acids sequence, purification processes, functionalization or encapsulation of targeting ligands, imaging probes as well as therapeutic molecules. Their chemical and biological characterization will be presented to evaluate their purity, toxicity, biocompatibility and biodistribution, and some therapeutic properties in vitro and in vivo. Finally, their main applications in the biomedical field will be presented so as to highlight their importance and advantages over classical nanostructures.

Published
2021
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3. Development of Theranostic Cationic Liposomes Designed for Image-Guided Delivery of Nucleic Acid

Author

Hai Doan Do, Christine Ménager, Aude Michel, Johanne Seguin, Tawba Korichi, Hélène Dhotel, Corinne Marie, Bich-Thuy Doan, and Nathalie Mignet

Subjects
magnetic cationic liposome, nucleic acid delivery, magnetofection, MRI, magnetic targeting, Pharmacy and materia medica, RS1-441
Abstract

Cationic liposomes have been considered as potential vectors for gene delivery thanks to their ability to transfect cells with high efficiency. Recently, the combination of diagnostic agent and therapeutic agents in the same particle to form a theranostic system has been reported. Magnetic liposomes are one of these examples. Due to the magnetic nanoparticles encapsulated in the liposomes, they can act as a drug delivery system and, at the same time, a magnetic resonance imaging contrast enhancement agent or hyperthermia. In this work, nucleic acid delivery systems based on magnetic cationic liposomes (MCLs) were developed. Two different techniques, reverse phase evaporation and cosolvent sonication, were employed for liposome preparation. Both strategies produced MCLs of less than 200 nm with highly positive charge. Enhancement of their transverse and longitudinal relaxivities r2 and r1 was obtained with both kinds of magnetic liposomes compared to free magnetic nanoparticles. Moreover, these MCLs showed high capacity to form complexes and transfect CT-26 cells using the antibiotic-free pFAR4-luc plasmid. The transfection enhancement with magnetofection was also carried out in CT26 cells. These results suggested that our MCLs could be a promising candidate for image-guided gene therapy.

Published
2020
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4. Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.

Author

Dieudonnée Togbe, Paulo Loureiro de Sousa, Mathilde Fauconnier, Victorine Boissay, Lizette Fick, Stefanie Scheu, Klaus Pfeffer, Robert Menard, Georges E Grau, Bich-Thuy Doan, Jean Claude Beloeil, Laurent Renia, Anna M Hansen, Helen J Ball, Nicholas H Hunt, Bernhard Ryffel, and Valerie F J Quesniaux

Subjects
Medicine, Science
Abstract

BackgroundTNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.Methodology/principal findingsLTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.Conclusions/significanceLTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.

Published
2008
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5. Doxorubicin (DOX) Gadolinium–Gold-Complex: A New Way to Tune Hybrid Nanorods as Theranostic Agent

Author

Memona Khan, Celia Arib, Nadia Djaker, Amadou Thierno Diallo, Jolanda Spadavecchia, Bich-Thuy Doan, Sarah Boumati, Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Sorbonne Paris Nord

Subjects
Gadolinium, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Nanoparticle, 02 engineering and technology, 01 natural sciences, Theranostic Nanomedicine, Mice, International Journal of Nanomedicine, Neoplasms, Drug Discovery, ComputingMilieux_MISCELLANEOUS, Original Research, Antibiotics, Antineoplastic, Nanotubes, Cell Death, General Medicine, 021001 nanoscience & nanotechnology, hyperthermia, Magnetic Resonance Imaging, Endocytosis, Nanorod, 0210 nano-technology, medicine.drug, MRI, hybrid nanorods, Biocompatibility, Photothermal Therapy, Biophysics, chemistry.chemical_element, Bioengineering, Conjugated system, 010402 general chemistry, doxorubicin, Biomaterials, Inhibitory Concentration 50, Cell Line, Tumor, medicine, [CHIM]Chemical Sciences, Animals, Humans, Chelation, Doxorubicin, Organic Chemistry, Photothermal therapy, Combinatorial chemistry, 0104 chemical sciences, MIAPaCa-2 cells, Drug Liberation, chemistry, Spectrophotometry, Ultraviolet, Gold
Abstract

Memona Khan,1 Sarah Boumati,2 Celia Arib,1 Amadou Thierno Diallo,1 Nadia Djaker,1 Bich-thuy Doan,2 Jolanda Spadavecchia1 1CNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomatériaux et d’Agents Thérapeutiques, Université Sorbonne Paris Nord, Bobigny, 93000, France; 2CNRS UMR 8060, iCLeHS, Synthèse, Electrochimie, Imagerie et Systèmes Analytiques Pour le Diagnostic SEISAD, Chimie ParisTech, Université PSL, Paris, 75231, FranceCorrespondence: Bich-thuy DoanCNRS, UMR 8060, iCLeHS, Synthèse, Electrochimie, Imagerie et Systèmes Analytiques Pour le Diagnostic SEISAD, Chimie ParisTech, PSL University, 11 Rue Pierre et Marie Curie, Paris Cedex 05, Paris, 75231, FranceEmail bich-thuy.doan@chimieparistech.psl.euJolanda SpadavecchiaCNRS, UMR 7244, CSPBAT, Laboratoire de Chimie, Structures et Propriétés de Biomatériaux et d’Agents Thérapeutiques, Sorbonne Paris Nord University, 1 rue chablis, Bobigny, 93000, FranceEmail jolanda.spadavecchia@gmail.comIntroduction: In this paper, we have designed and formulated, a novel synthesis of doxorubicin (DOX) loaded bimetallic gold nanorods in which gold salt (HAuCl4) is chelated with anthracycline (DOX), diacid polyethylene-glycol (PEG-COOH) and gadolinium salt (GdCl3 * 6 H2O) to form DOX IN-Gd-AuNRs compared with DOX ON-Gd-AuNRs in which the drug was grafted onto the bimetallic pegylated nanoparticle surface by electrostatic adsorption.Material and Method: The physical and chemical evaluation was performed by spectroscopic analytical techniques (Raman spectroscopy, UV-Visible and transmission electron microscopy (TEM)). Magnetic features at 7T were also measured. Photothermal abilities were assessed. Cytotoxicity studies on MIA PaCa-2, human pancreatic carcinoma and TIB-75 hepatocytes cell lines were carried out to evaluate their biocompatibility and showed a 320 fold higher efficiency for DOX after encapsulation.Results: Exhaustive physicochemical characterization studies were conducted showing a mid size of 20 to 40 nm diameters obtained with low polydispersity, efficient synthesis using seed mediated synthesis with chelation reaction with high scale-up, long duration stability, specific doxorubicin release with acidic pH, strong photothermal abilities at 808 nm in the NIR transparency window, strong magnetic r1 relaxivities for positive MRI, well adapted for image guided therapy and therapeutical purpose in biological tissues.Conclusion: In this paper, we have developed a novel theranostic nanoparticle composed of gadolinium complexes to gold ions, with a PEG biopolymer matrix conjugated with antitumoral doxorubicin, providing multifunctional therapeutic features. Particularly, these nano conjugates enhanced the cytotoxicity toward tumoral MIAPaCa-2 cells by a factor of 320 compared to doxorubicin alone. Moreover, MRI T1 features at 7T enables interesting positive contrast for bioimaging and their adapted size for potential passive targeting to tumors by Enhanced Permeability Retention. Given these encouraging antitumoral and imaging properties, this bimetallic theranostic nanomaterial system represents a veritable promise as a therapeutic entity in the field of medicinal applications.Keywords: hybrid nanorods, doxorubicin, MRI, MIAPaCa-2 cells, hyperthermia

Published
2021

6. Design and Synthesis of Gold-Gadolinium-Core-Shell Nanoparticles as Contrast Agent: a Smart Way to Future Nanomaterials for Nanomedicine Applications [Retraction]

Author

Fatima Aouidat, Sarah Boumati, Memona Khan, Frederik Tielens, Bich-Thuy Doan, and Jolanda Spadavecchia

Subjects
Biomaterials, International Journal of Nanomedicine, Organic Chemistry, Drug Discovery, Biophysics, Pharmaceutical Science, Bioengineering, General Medicine
Abstract

Aouidat F, Boumati S, Khan M, Tielens F, Doan BT, Spadavecchia J. Int J Nanomedicine. 2019;14:9309–9324. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. The authors raised concerns regarding errors that had been made during the calculation of the size of the nanostructures shown in Figure 2. The sizes reported in the histograms of Figure 2; a1, a2 and a3 were incorrect due to miscalculations that occurred during analysis of the gold core and polymer shells of the spherical nanostructures represented in TEM images of Figure 2A. The authors provided the editor with data from the original study and requested to remove the incorrect histograms and replace them. However, the Editor determined that this part of the article was integral to the study and the admission of these errors, because of the miscalculation, meant the data was unreliable and would not accept the correction proposed by the authors. The Editor requested for the article to be retracted and the authors were notified but do not agree with this decision. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Published
2022

7. Development of Theranostic Cationic Liposomes Designed for Image-Guided Delivery of Nucleic Acid

Author

Johanne Seguin, Bich-Thuy Doan, Tawba Korichi, Corinne Marie, Hai Doan Do, Nathalie Mignet, Aude Michel, Hélène Dhotel, Christine Ménager, and Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Sonication, Pharmaceutical Science, lcsh:RS1-441, 02 engineering and technology, Gene delivery, magnetic cationic liposome, 030226 pharmacology & pharmacy, Article, lcsh:Pharmacy and materia medica, 03 medical and health sciences, 0302 clinical medicine, nucleic acid delivery, [CHIM]Chemical Sciences, Cationic liposome, Liposome, Chemistry, Transfection, 021001 nanoscience & nanotechnology, equipment and supplies, magnetic targeting, Drug delivery, Magnetofection, Biophysics, Magnetic nanoparticles, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, human activities, magnetofection, MRI
Abstract

Cationic liposomes have been considered as potential vectors for gene delivery thanks to their ability to transfect cells with high efficiency. Recently, the combination of diagnostic agent and therapeutic agents in the same particle to form a theranostic system has been reported. Magnetic liposomes are one of these examples. Due to the magnetic nanoparticles encapsulated in the liposomes, they can act as a drug delivery system and, at the same time, a magnetic resonance imaging contrast enhancement agent or hyperthermia. In this work, nucleic acid delivery systems based on magnetic cationic liposomes (MCLs) were developed. Two different techniques, reverse phase evaporation and cosolvent sonication, were employed for liposome preparation. Both strategies produced MCLs of less than 200 nm with highly positive charge. Enhancement of their transverse and longitudinal relaxivities r2and r1 was obtained with both kinds of magnetic liposomes compared to free magnetic nanoparticles. Moreover, these MCLs showed high capacity to form complexes and transfect CT-26 cells using the antibiotic-free pFAR4-luc plasmid. The transfection enhancement with magnetofection was also carried out in CT26 cells. These results suggested that our MCLs could be a promising candidate for image-guided gene therapy.

Published
2020
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8. Mucoadhesive thermosensitive hydrogel for the intra-tumoral delivery of immunomodulatory agents, in vivo evidence of adhesion by means of non-invasive imaging techniques

Author

Cyrille Richard, Claude Capron, Nathalie Mignet, Christelle Lesieur, Johanne Seguin, Chantal Al Sabbagh, Bich-Thuy Doan, Robert Malafosse, Vincent Boudy, Katia Lemdani, Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-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 Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-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 Galien Paris-Sud (IGPS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS), Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), 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), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Agence Générale des Equipements et Produits de Santé [Paris] (AGEPS), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), 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), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, 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), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Pharmaceutical Science, 02 engineering and technology, CD8-Positive T-Lymphocytes, 030226 pharmacology & pharmacy, Mice, Drug Delivery Systems, 0302 clinical medicine, Bone Marrow, Neoplasms, Cytotoxic T cell, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Optical Imaging, Adhesiveness, Hydrogels, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Rheology, 0210 nano-technology, Adjuvant, Agonist, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poloxamer, 03 medical and health sciences, Immune system, In vivo, Cell Line, Tumor, medicine, Animals, Immunologic Factors, [CHIM]Chemical Sciences, Mucins, Granulocyte-Macrophage Colony-Stimulating Factor, Dendritic Cells, Mycobacterium tuberculosis, Colony-stimulating factor, In vitro, [CHIM.POLY]Chemical Sciences/Polymers, NIH 3T3 Cells, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, CD8
Abstract

Intratumoral injection of biocompatible gels is increasingly used for the sustained delivery of drugs and vaccines to enhance the anti-cancer immune response. Granulocyte-macrophage colony stimulating factor (GM-CSF) has become an attractive adjuvant thanks to its ability to boost the antitumor immune response by inducing proliferation, maturation and migration of the dendritic-cells (DCs) and the differentiation of lymphocytes. Killed Mycobacteria, such as Heat-killed Mycobacterium tuberculosis (HKMT) have been used in several studies as TLR-2 agonist to increase maturation of DCs. In this study, we designed a mucoadhesive thermosensitive formulation for the local delivery of GM-CSF and HKMT in order to enhance DCs activation and improve the local antitumor immune response. This formulation was selected based on its elastic and mucoadhesive properties obtained thanks to rheological studies. More importantly, intratumoral residence time of the labelled gel and protein were evidenced by means of MRI and non invasive in vivo optical imaging. Then, the efficacy of the combination of immunomodulators loaded thermogel was demonstated in vitro and in vivo. The selected thermogel exhibits rheological properties which confer a good elasticity and increased residence time of the immunostimulatory agents in the tumor, thus increasing the recruitment of DCs and T cytotoxic CD8+ lymphocytes.

Published
2019

9. Design and Synthesis of Gold-Gadolinium-Core-Shell Nanoparticles as contrast agent: a Smart Way to Future Nanomaterials for Nanomedicine Applications

Author

Memona Khan, Frederik Tielens, Jolanda Spadavecchia, Fatima Aouidat, Sarah Boumati, Bich-Thuy Doan, Chemistry, Centre National de la Recherche Scientifique (CNRS), Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC), and Savarin, Philippe

Subjects
Polymers, Gadolinium, Pharmaceutical Science, Nanoparticle, Contrast Media, Metal Nanoparticles, 02 engineering and technology, 01 natural sciences, Nanomaterials, International Journal of Nanomedicine, Drug Discovery, [CHIM] Chemical Sciences, Tissue Distribution, ComputingMilieux_MISCELLANEOUS, Original Research, Mice, Inbred BALB C, Cell Death, General Medicine, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, theoretical study, Magnetic Resonance Imaging, Nanomedicine, Colloidal gold, relaxivity, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, MRI, Biodistribution, Materials science, Biocompatibility, Cell Survival, Biophysics, chemistry.chemical_element, Bioengineering, Nanotechnology, Gd-gold complex, 010402 general chemistry, Biomaterials, Animals, [CHIM]Chemical Sciences, biodistribution, [CHIM.MATE] Chemical Sciences/Material chemistry, Organic Chemistry, 0104 chemical sciences, Drug Liberation, Kinetics, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Gold, Nanoconjugates
Abstract

Fatima Aouidat,1 Sarah Boumati,2 Memona Khan,1 Frederik Tielens,3 Bich-Thuy Doan,2 Jolanda Spadavecchia1 1CNRS, UMR 7244, CSPBAT, Laboratory of Chemistry, Structures and Properties of Biomaterials And Therapeutic Agents University Paris 13, Sorbonne Paris Cité, Bobigny, France; 2UTCBS – Chimie ParisTech – University Paris Descartes - CNRS UMR 8258 – INSERM U1022 Equipe “Synthesis, Electrochemistry, Imaging and Analytical Systems for Diagnostics” SEISAD, Paris, France; 3General Chemistry (ALGC), Vrije University of Brussel (Free University Brussels-VUB), Brussel, BelgiumCorrespondence: Jolanda Spadavecchia Email jolanda.spadavecchia@univ-paris13.frIntroduction: The development of biopolymers for the synthesis of Gd(III) nanoparticles, as therapeutics, could play a key role in nanomedicine. Biocompatible polymers are not only used for complex monovalent biomolecules, but also for the realization of multivalent active targeting materials as diagnostic and/or therapeutic hybrid nanoparticles. In this article, it was reported for the first time, a novel synthesis of Gd(III)–biopolymer–Au(III) complex, acting as a key ingredient of core-shell gold nanoparticles (Gd(@AuNPs).Material and methods: The physical and chemical evaluation was carried out by spectroscopic analytical techniques (Raman spectroscopy, UV-visible and TEM). The theoretical characterization by DFT (density functional theory) analysis was carried out under specific conditions to investigate the interaction between the Au and the Gd precursors, during the first nucleation step. Magnetic features with relaxivity measurements at 7T were also performed as well as cytotoxicity studies on hepatocyte cell lines for biocompatibility studies. The in vivo detailed dynamic biodistribution studies in mice to characterize the potential applications for biology as MRI contrast agents were then achieved.Results: Physical–chemical evaluation confirms the successful design and reaction supposed. Viabilities of TIB-75 (hepatocytes) cells were evaluated using Alamar blue cytotoxic tests with increasing concentrations of nanoparticles. In vivo biodistribution studies were then accomplished to assess the kinetic behavior of the nanoparticles in mice and characterize their stealthiness property after intravenous injection.Conclusion: We demonstrated that Gd@AuNPs have some advantages to display hepatocytes in the liver. Particularly, these nanoconjugates give a good cellular uptake of several quantities of Gd@NPs into cells, while preserving a T1 contrast inside cells that provide a robust in vivo detection using T1-weighted MR images. These results will strengthen the role of gadolinium as complex to gold in order to tune Gd(@AuNPs) as an innovative diagnostic agent in the field of nanomedicine.Keywords: Gd-gold complex, theoretical study, MRI, relaxivity, biodistribution

Published
2019

10. Advances on non-invasive physically triggered nucleic acid delivery from nanocarriers

Author

Yohann Corvis, Brice Martin Couillaud, Nathalie Mignet, Hai Doan Do, Bich-Thuy Doan, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), CCSD, Accord Elsevier, and 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 Cité (UPCité)

Subjects
Light, Endosome, Magnetic, Exogenous trigger, Pharmaceutical Science, 02 engineering and technology, Gene delivery, 03 medical and health sciences, Nucleic Acids, Nucleic acid delivery, Ultrasound, Animals, Humans, 030304 developmental biology, [SDV.IB] Life Sciences [q-bio]/Bioengineering, 0303 health sciences, [CHIM.MATE] Chemical Sciences/Material chemistry, Chemistry, Non invasive, Gene Transfer Techniques, Transfection, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, Cold Temperature, Magnetic Fields, Ultrasonic Waves, Target site, Biophysics, Nucleic acid, Nanoparticles, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Delivery system, Nanocarriers, 0210 nano-technology, Cold-shock
Abstract

International audience; Nucleic acids (NAs) have been considered as promising therapeutic agents for various types of diseases. However, their clinical applications still face many limitations due to their charge, high molecular weight, instability in biological environment and low levels of transfection. To overcome these drawbacks, therapeutic NAs should be carried in a stable nanocarrier, which can be viral or non-viral vectors, and released at specific target site. Various controllable gene release strategies are currently being evaluated with interesting results. Endogenous stimuli-responsive systems, for example pH-, redox reaction-, enzymatic-triggered approaches have been widely studied based on the physiological differences between pathological and normal tissues. Meanwhile, exogenous triggered release strategies require the use of externally non-invasive physical triggering signals such as light, heat, magnetic field and ultrasound. Compared to internal triggered strategies, external triggered gene release is time and site specifically controllable through active management of outside stimuli. The signal induces changes in the stability of the delivery system or some specific reactions which lead to endosomal escape and/or gene release. In the present review, the mechanisms and examples of exogenous triggered gene release approaches are detailed. Challenges and perspectives of such gene delivery systems are also discussed.

Published
2019
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11. 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

12. In Vivo Evaluation of Magnetic Targeting in Mice Colon Tumors with Ultra-Magnetic Liposomes Monitored by MRI

Author

Bich-Thuy Doan, Caroline J. Thébault, Claire Beauvineau, Johanne Seguin, Christian Girard, Grégory Ramniceanu, Nathalie Mignet, Christine Ménager, Aude Michel, 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), PHysicochimie des Electrolytes et Nanosystèmes InterfaciauX (PHENIX), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL-SU, Gestionnaire, 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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Centre National de la Recherche Scientifique (CNRS)-ESPCI ParisTech-Université Pierre et Marie Curie - Paris 6 (UPMC), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'élaboration de matériaux et d'études structurales (CEMES), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), 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), Liquides Ioniques et Interfaces Chargées (LI2C), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Cell Survival, Magnetic nanoparticle, Image analysis method, [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Magnetics, Mice, Magnetic targeting, 0302 clinical medicine, In vivo, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Medicine, Distribution (pharmacology), Animals, Radiology, Nuclear Medicine and imaging, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Magnetite Nanoparticles, ComputingMilieux_MISCELLANEOUS, Liposome, Mice, Inbred BALB C, Tumor, medicine.diagnostic_test, business.industry, Cancer, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Oncology, Liver, Drug delivery, Colonic Neoplasms, Liposomes, NIH 3T3 Cells, Female, Nanocarriers, business, Ex vivo, Biomedical engineering, MRI
Abstract

International audience; PurposeThe development of theranostic nanocarriers as an innovative therapy against cancer has been improved by targeting properties in order to optimize the drug delivery to safely achieve its desired therapeutic effect. The aim of this paper is to evaluate the magnetic targeting (MT) efficiency of ultra-magnetic liposomes (UML) into CT26 murine colon tumor by magnetic resonance imaging (MRI).ProceduresDynamic susceptibility contrast MRI was applied to assess the bloodstream circulation time. A novel semi-quantitative method called %I0.25, based on the intensity distribution in T2*-weighted MRI images was developed to compare the accumulation of T2 contrast agent in tumors with or without MT. To evaluate the efficiency of magnetic targeting, the percentage of pixels under the intensity value I0.25 (I0.25 = 0.25(Imax − Imin)) was calculated on the intensity distribution histogram.ResultsThis innovative method of processing MRI images showed the MT efficiency by a %I0.25 that was significantly higher in tumors using MT compared to passive accumulation, from 15.3 to 28.6 %. This methodology was validated by ex vivo methods with an iron concentration that is 3-fold higher in tumors using MT.ConclusionsWe have developed a method that allows a semi-quantitative evaluation of targeting efficiency in tumors, which could be applied to different T2 contrast agents.

Published
2018

13. Gadolinium and Platinum in Tandem:Real-time Multi-Modal Monitoring of Drug Delivery by MRI and Fluorescence Imaging

Author

Ga Lai Law, René M. Botnar, Chi-Fai Chan, Sara Lacerda, Cyrille Richard, Grégory Ramniceanu, Ka-Leung Wong, Bich-Thuy Doan, Bethany I. Harriss, Alkystis Phinikaridou, Nicholas J. Long, Ka-Lok Ho, Hongguang Li, Rongfeng Lan, Wai Sum Lo, Hong Kong Baptist University (HKBU), Imperial College London, King‘s College London, 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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), The Hong Kong Polytechnic University [Hong Kong] (POLYU), The Royal Society, LEGOUPIL, Laëtitia, and 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)

Subjects
Fluorescence-lifetime imaging microscopy, MRI contrast agent, Gadolinium, [SDV]Life Sciences [q-bio], Biomedical Engineering, Medicine (miscellaneous), chemistry.chemical_element, cisplatin, multi-modal, 010402 general chemistry, 01 natural sciences, 03 medical and health sciences, Nuclear magnetic resonance, fluorescence imaging, medicine, Therapy efficacy, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), 030304 developmental biology, Cisplatin, 0303 health sciences, Chemistry, Prodrug, 3. Good health, 0104 chemical sciences, Clearance time, [SDV] Life Sciences [q-bio], Drug delivery, drug delivery, prodrug, Biotechnology, medicine.drug, Biomedical engineering, Research Paper, MRI
Abstract

International audience; A novel dual-imaging cisplatin-carrying molecular cargo capable of performing simultaneous optical and MR imaging is reported herein. This long-lasting MRI contrast agent (r1 relaxivity of 23.4 mM-1s-1 at 3T, 25 oC) is a photo-activated cisplatin prodrug (PtGdL) which enables real-time monitoring of anti-cancer efficacy. PtGdL is a model for monitoring the drug delivery and anti-cancer efficacy by MRI with a much longer retention time (24 hours) in several organs such as renal cortex and spleen than GdDOTA and its motif control GdL. Upon complete release of cisplatin, all PtGdL is converted to GdL enabling subsequent MRI analyses of therapy efficacy within its reasonably short clearance time of 4 hours. There is also responsive fluorescence enhancement for monitoring by photon-excitation.

Published
2017

14. Mechanostereoselective One-Pot Synthesis of Functionalized Head-to-Head Cyclodextrin [3]Rotaxanes and Their Application as Magnetic Resonance Imaging Contrast Agents

Author

Célia S. Bonnet, Éva Tóth, Matthieu Sollogoub, Mickaël Ménand, Guillaume Vives, Jérémy Scelle, Jean Wilfried Fredy, Grégory Ramniceanu, Bernold Hasenknopf, Bich-Thuy Doan, Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), 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)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Moléculaire ( IPCM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -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 Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), 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 d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE09-0018,RotaxImage,Imagerie et diagnostic avec des polyrotaxanes(2016)

Subjects
chemistry.chemical_classification, medicine.diagnostic_test, Cyclodextrin, 010405 organic chemistry, Stereochemistry, Chemistry, Head to head, MRI contrast agent, Gadolinium, Organic Chemistry, One-pot synthesis, chemistry.chemical_element, Magnetic resonance imaging, 010402 general chemistry, [ CHIM ] Chemical Sciences, 01 natural sciences, Biochemistry, Combinatorial chemistry, Cycloaddition, 0104 chemical sciences, In vivo, medicine, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry
Abstract

International audience; A versatile, five-component, one-pot synthesis of cyclodextrin (CD) [3]rotaxanes using copper-catalyzed azide–alkyne cycloaddition has been developed. Head-to-head [3]rotaxanes of α-CD selectively functionalized by one or two gadolinium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide complexes were obtained mechanostereoselectively. The magnetic resonance imaging efficiency, expressed by the longitudinal proton relaxivity of the rotaxanes, was significantly improved as compared to the functionalized CD. In vitro and in vivo preclinical studies showed a higher contrast and retention in the kidney than gadolinium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex, demonstrating the potential of these rotaxanes as MRI contrast agent.

Published
2017

15. Delayed hepatic uptake of multi-phosphonic acid poly(ethylene glycol) coated iron oxide measured by real-time Magnetic Resonance Imaging

Author

Grégory Ramniceanu, Jean-François Berret, Bich-Thuy Doan, C. Vezignol, Nathalie Mignet, Cédric Loubat, Alain Graillot, 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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Specific polymers, CNRS UMR 7057 - Laboratoire Matières et Systèmes Complexes (MSC) (MSC), Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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), 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 Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Recherche en Informatique ( LRI ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Matière et Systèmes Complexes ( MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), and Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
T-2 CONTRAST, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, General Chemical Engineering, Iron oxide, Nanoparticle, FOS: Physical sciences, Protein Corona, CELLULAR UPTAKE, 02 engineering and technology, Polyethylene glycol, engineering.material, 010402 general chemistry, 01 natural sciences, [SPI.MAT]Engineering Sciences [physics]/Materials, chemistry.chemical_compound, Coating, POLYETHYLENE-GLYCOL, PEG ratio, BIOMEDICAL APPLICATIONS, NANOPARTICLES, Physics - Biological Physics, IN-VIVO, chemistry.chemical_classification, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Biomolecules (q-bio.BM), General Chemistry, Polymer, 021001 nanoscience & nanotechnology, 0104 chemical sciences, SURFACE-CHARGE, Quantitative Biology - Biomolecules, chemistry, Biological Physics (physics.bio-ph), FOS: Biological sciences, engineering, [ PHYS.COND.CM-SCM ] Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], CONTRAST AGENTS, 0210 nano-technology, Ethylene glycol, [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], PROTEIN CORONA, Nuclear chemistry, MRI
Abstract

We report on the synthesis, characterization, stability and pharmacokinetics of novel iron based contrast agents for magnetic resonance imaging (MRI). Statistical copolymers combining multiple phosphonic acid groups and poly(ethylene glycol) (PEG) were synthesized and used as coating agents for 10 nm iron oxide nanocrystals. In vitro, protein corona and stability assays show that phosphonic acid PEG copolymers outperform all other coating types examined, including low molecular weight anionic ligands and polymers. In vivo, the particle pharmacokinetics is investigated by monitoring the MRI signal intensity from mouse liver, spleen and arteries as a function of the time, between one minute and seven days after injection. Iron oxide particles coated with multi-phosphonic acid PEG polymers are shown to have a blood circulation lifetime of 250 minutes, i.e. 10 to 50 times greater than that of recently published PEGylated probes and benchmarks. The clearance from the liver takes in average 2 to 3 days and is independent of the core size, coating and particle stability. By comparing identical core particles with different coatings, we are able to determine the optimum conditions for stealth MRI probes., Comment: 19 pages 8 figures, RSC Advances, 2016

Published
2016
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16. Single-cell detection by gradient echo 9.4 T MRI: a parametric study

Author

Brigitte Gillet, Claire Wilhelm, P. Smirnov, Florence Gazeau, Jean-Claude Beloeil, Bich-Thuy Doan, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), 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)-Institut de Chimie du CNRS (INC), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO), and Centre National de la Recherche Scientifique (CNRS)

Subjects
Time Factors, Proton, Cell Survival, Cells, Iron, Dephasing, Ferric Compounds, 030218 nuclear medicine & medical imaging, Magnetics, 03 medical and health sciences, chemistry.chemical_compound, Magnetization, 0302 clinical medicine, Nuclear magnetic resonance, In vivo, medicine, Humans, Radiology, Nuclear Medicine and imaging, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Magnetic resonance imaging, equipment and supplies, Magnetic Resonance Imaging, Magnetic field, Spin echo, human activities, Iron oxide nanoparticles, HeLa Cells
Abstract

International audience; Recent studies have shown that cell migration can be monitored in vivo by magnetic resonance imaging after intracellular contrast agent incorporation. This is due to the dephasing effect on proton magnetization of the local magnetic field created by a labelled cell. Anionic iron oxide nanoparticles (AMNP) are among the most efficient and non-toxic contrast agents to be spontaneously taken up by a wide variety of cells. Here we measured the iron load and magnetization of HeLa turnout cells labelled with AMNP, as a function of the external magnetic field. High-resolution gradient echo 9.4T MRI detected individual labelled cells, whereas spin echo sequences were poorly sensitive. We then conducted a systematic study in order to determine the gradient echo sequence parameters (echo time, cell magnetization and resolution) most suitable for in vivo identification of single cells.

Published
2006

17. Impaired voluntary running capacity of creatine kinase-deficient mice

Author

Patrick Lechêne, Renée Ventura-Clapier, Vladimir Veksler, Dominique Fortin, Jacqueline Hoerter, Xavier Bigard, Philippe Mateo, Bich Thuy Doan, Iman Momken, and Nathalie Koulmann

Subjects
Gene isoform, 0303 health sciences, medicine.medical_specialty, biology, Physiology, Stimulation, Anatomy, Peripheral blood mononuclear cell, Isozyme, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Myosin, biology.protein, medicine, Creatine kinase, Dobutamine, medicine.symptom, 030217 neurology & neurosurgery, 030304 developmental biology, Muscle contraction, medicine.drug
Abstract

The creatine kinase system (CK) is important for energy delivery in skeletal and cardiac muscles. The two main isoforms of this enzyme, cytosolic MM-CK and mitochondrial mi-CK, are expressed in a developmental and muscle-type specific manner. Mice deficient in one or both of these isoforms are viable and fertile but exhibit profound functional, metabolic and structural muscle remodelling that primarily affects fast skeletal muscles, which show an increased contribution of oxidative metabolism to contractile function. However, the consequences of these alterations in terms of physical capabilities have not yet been characterized. Consequently, we compared the voluntary exercise capacity of 9-month-old male wild-type (WT), M-CK knockout (M-CK(-/-)), and M-CK and mi-CK double knockout (CK(-/-)) mice, using cages equipped with running wheels. Exercise performance, calculated by total distance covered and by work done during the training period, was more than 10-fold lower in CK(-/-) mice than controls, with M-CK(-/-) mice exhibiting intermediate performance. Similarly, the mean distance run per activation was lower in M-CK(-/-) and even lower in CK(-/-) mice. However, the maximal running speed (V(max)) was lower only for CK(-/-) mice. This was accompanied by severe skeletal muscle mass decrease in CK(-/-) mice, with signs of histological damage that included enlarged interstitial areas, aggregations of mononuclear cells in the interstitium, heterogeneity of myofibre size and the presence of very small fibres. No overt sign of cardiac dysfunction was observed by magnetic resonance imaging during dobutamine stimulation. These results show that metabolic failure induced by CK deficiency profoundly affects the ability of mice to engage in chronic bouts of endurance running exercise and that this decrease in performance is also associated with muscle wasting.

Published
2005

18. Evaluation of Nonradiative Clinical Imaging Techniques for the Longitudinal Assessment of Tumour Growth in Murine CT26 Colon Carcinoma

Author

Guy G. Chabot, Daniel Scherman, Heldmuth Latorre Ossa, Mickael Tanter, Lauriane Jugé, Johanne Seguin, Bich-Thuy Doan, Nathalie Mignet, and Jean-Luc Gennisson

Subjects
Pathology, medicine.medical_specialty, Noninvasive imaging, Article Subject, medicine.diagnostic_test, business.industry, Ultrasound, Magnetic resonance imaging, Histology, Text mining, Colon carcinoma, Cancer cell, Medicine, Radiology, Nuclear Medicine and imaging, Clinical imaging, Nuclear medicine, business, Research Article
Abstract

Background and Objectives. To determine the most appropriate technique for tumour followup in experimental therapeutics, we compared ultrasound (US) and magnetic resonance imaging (MRI) to characterize ectopic and orthotopic colon carcinoma models. Methods. CT26 tumours were implanted subcutaneously (s.c.) in Balb/c mice for the ectopic model or into the caecum for the orthotopic model. Tumours were evaluated by histology, spectrofluorescence, MRI, and US. Results. Histology of CT26 tumour showed homogeneously dispersed cancer cells and blood vessels. The visualization of the vascular network using labelled albumin showed that CT26 tumours were highly vascularized and disorganized. MRI allowed high-resolution and accurate 3D tumour measurements and provided additional anatomical and functional information. Noninvasive US imaging allowed good delineation of tumours despite an hypoechogenic signal. Monitoring of tumour growth with US could be accomplished as early as 5 days after implantation with a shorter acquisition time (Conclusion. MRI and US afforded excellent noninvasive imaging techniques to accurately follow tumour growth of ectopic and orthotopic CT26 tumours. These two techniques can be appropriately used for tumour treatment followup, with a preference for US imaging, due to its short acquisition time and simplicity of use.

Published
2013

19. Colon tumor growth and antivascular treatment in mice: complementary assessment with MR elastography and diffusion-weighted MR imaging

Author

Bernard E. Van Beers, Lauriane Jugé, Daniel Scherman, Johanne Seguin, Nathalie Mignet, Ralph Sinkus, Valérie Vilgrain, Valérie Paradis, Bich-Thuy Doan, Miguel Albuquerque, Benoit Larrat, and Guy G. Chabot

Subjects
medicine.medical_specialty, Microcirculation, Neovascularization, Elasticity Imaging Techniques, Mice, Stilbenes, medicine, Animals, Radiology, Nuclear Medicine and imaging, Tumor growth, skin and connective tissue diseases, Diffusion-Weighted MR Imaging, Mice, Inbred BALB C, medicine.diagnostic_test, Neovascularization, Pathologic, business.industry, Mr imaging, Diffusion Magnetic Resonance Imaging, Tumor vascularity, Colonic Neoplasms, Female, sense organs, Radiology, Elastography, medicine.symptom, business
Abstract

To investigate the potential value of magnetic resonance (MR) elastography and diffusion-weighted (DW) MR imaging in the detection of microstructural changes of murine colon tumors during growth and antivascular treatment.The study was approved by the regional ethics committee for animal care. Sixty Balb-C mice, bearing ectopic and orthotopic colon tumors, were monitored for 3 weeks with high-resolution T2-weighted MR imaging, three-dimensional steady-state MR elastography, and DW MR imaging at 7 T. The same imaging protocol was performed 24 hours after injection of combretastatin A4 phosphate (CA4P) in 12 mice. The absolute value of the complex shear modulus (|G*|) and the apparent diffusion coefficient (ADC) were measured in the viable zones of tumors and compared with microvessel density (MVD), cellularity, and micronecrosis by using the Pearson correlation coefficient.During tumor growth, |G*| increase was correlated with MVD (r = 0.70 [P = .08] and r = 0.78 [P = .002], for both the ectopic and orthotopic models, respectively). Moreover, the ectopic tumors displayed decreased ADC, which correlated with increased cellularity (r = 0.77, P = .04), whereas no changes in ADC and cellularity were observed in orthotopic tumors. After CA4P administration, |G*| decreased in the ectopic model (P.0001), similar to the MVD evolution (P = .03), whereas no significant changes in |G*| (P = .7) and MVD (P = .6) were observed in the orthotopic model. ADC increased in both models (P = .047 and P = .01 for the ectopic and the orthotopic models, respectively) in relation to increased micronecrosis.Imaging of mechanical properties and diffusivity provide complementary information during tumor growth and regression that are respectively linked to vascularity and tumor cell alterations, including cellularity and micronecrosis.

Published
2012

20. Chronic exposure to glufosinate-ammonium induces spatial memory impairments, hippocampal MRI modifications and glutamine synthetase activation in mice

Author

André-Guilhem Calas, William Même, Olivier Richard, Sandra Même, Wim E. Crusio, Bich-Thuy Doan, Jacques Pichon, Thierry Gefflaut, Céline Montécot, Jean-Claude Beloeil, Laboratoire de Neurobiologie, Université d'Orléans (UO), 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)-Institut de Chimie du CNRS (INC), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Neurosciences cognitives (NC), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-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 Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Time Factors, Hippocampus, Spatial learning, Hippocampal formation, Toxicology, Mice, chemistry.chemical_compound, 0302 clinical medicine, Glutamate homeostasis, Neurotransmitter, 0303 health sciences, Behavior, Animal, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Aminobutyrates, General Neuroscience, Glutamate receptor, Magnetic Resonance Imaging, 3. Good health, medicine.anatomical_structure, Biochemistry, MRI, medicine.medical_specialty, Central nervous system, Biology, Glufosinate-ammonium, Glutamine synthetase, Chronic pesticide intoxication, 03 medical and health sciences, Glutamate-Ammonia Ligase, Internal medicine, medicine, Animals, Memory disorder, Maze Learning, 030304 developmental biology, Analysis of Variance, Memory Disorders, Chi-Square Distribution, Dose-Response Relationship, Drug, medicine.disease, Enzyme Activation, Mice, Inbred C57BL, Endocrinology, chemistry, Space Perception, Exploratory Behavior, 030217 neurology & neurosurgery
Abstract

International audience; Glufosinate-ammonium (GLA), the active compound of a worldwide-used herbicide, acts by inhibiting the plant glutamine synthetase (GS) leading to a lethal accumulation of ammonia. GS plays a pivotal role in the mammalian brain where it allows neurotransmitter glutamate recycling within astroglia. Clinical studies report that an acute GLA ingestion induces convulsions and memory impairment in humans. Toxicological studies performed at doses used for herbicidal activity showed that GLA is probably harmless at short or medium range periods. However, effects of low doses of GLA on chronically exposed subjects are not known. In our study, C57BL/6J mice were treated during 10 weeks three times a week with 2.5, 5 and 10 mg/kg of GLA. Effects of this chronic treatment were assessed at behavioral, structural and metabolic levels by using tests of spatial memory, locomotor activity and anxiety, hippocampal magnetic resonance imaging (MRI) texture analysis, and hippocampal GS activity assay, respectively. Chronic GLA treatments have effects neither on anxiety nor on locomotor activity of mice but at 5 and 10 mg/kg induce (1) mild memory impairments, (2) a modification of hippocampal texture and (3) a significant increase in hippocampal GS activity. It is suggested that these modifications may be causally linked one to another. Since glutamate is the main neurotransmitter in hippocampus where it plays a crucial role in spatial memory, hippocampal MRI texture and spatial memory alterations might be the consequences of hippocampal glutamate homeostasis modification revealed by increased GS activity in hippocampus. The present study provides the first data that show cerebral alterations after chronic exposure to GLA.

Published
2008

21. In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applications

Author

William Même, Jean-Claude Beloeil, Paulo Loureiro de Sousa, Carlos F. G. C. Geraldes, M. I. M. Prata, Lothar Helm, Ana C. Santos, Andre E. Merbach, Bich-Thuy Doan, João Bruno Livramento, Éva Tóth, 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)-Institut de Chimie du CNRS (INC), Laboratoire de Chimie Inorganique et Bioinorganique (LCIB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire de Neurobiologie, Université d'Orléans (UO), Laboratoire de Chimie Inorganique et Bioinorganique, laboratoire de Neurobiologie, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centro de Fisica Computacional, University of Coimbra, Université de Coimbra, Instituto de Investigaçao das Pescas e do Mar, and Instituto Nacional de Pesquisas da Amazônia (INPA)

Subjects
Male, gamma imaging, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Gadolinium, Inner sphere electron transfer, Kidney, 01 natural sciences, 030218 nuclear medicine & medical imaging, MESH: Magnetic Resonance Imaging, Mice, 0302 clinical medicine, Nuclear magnetic resonance, magnetic resonance imaging, Tissue Distribution, Whole Body Imaging, MESH: Animals, MESH: Organ Specificity, g imaging, high magnetic field, medicine.diagnostic_test, Chemistry, Relaxation (NMR), Brain, in vivo, Organ Specificity, MESH: Image Enhancement, pharmacokinetics, Biodistribution, Metabolic Clearance Rate, chemistry.chemical_element, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, 03 medical and health sciences, MESH: Brain, Pharmacokinetics, MESH: Whole Body Imaging, In vivo, medicine, Animals, Radiology, Nuclear Medicine and imaging, contrast agents, MESH: Tissue Distribution, biodistribution, MESH: Mice, MESH: Metabolic Clearance Rate, Magnetic resonance imaging, MESH: Kidney, Image Enhancement, In vitro, MESH: Male, 0104 chemical sciences, gadolinium, MESH: Gadolinium
Abstract

International audience; Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.

Published
2008

22. In vivo cellular imaging of lymphocyte trafficking by MRI : a tumor model approach to cell-based anticancer therapy

Author

Béhazine Combadière, Olivier Clément, Christophe Combadière, Alexandre Boissonnas, Elise Lavergne, Bich-Thuy Doan, Brigitte Gillet, Florence Gazeau, P. Smirnov, Maïté Lewin, Laboratoire de Recherche en Imagerie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, medicine.medical_specialty, Lymphoma, Lymphocyte, Contrast Media, Spleen, Biology, Immunotherapy, Adoptive, Cell therapy, Mice, Immune system, In vivo, Cell Line, Tumor, Image Interpretation, Computer-Assisted, medicine, Splenocyte, Animals, Radiology, Nuclear Medicine and imaging, in vivo cellular imaging, Lymphocytes, [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], superparamagnetic iron oxide nanoparticles, [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], Image Enhancement, lymphocyte trafficking, Magnetic Resonance Imaging, Mice, Inbred C57BL, medicine.anatomical_structure, Lymphocyte Transfusion, Feasibility Studies, Female, cell therapy, Ex vivo, Cell based, MRI
Abstract

The aim of this study was to demonstrate the feasibility of in vivo cell tracking to monitor anticancer cell therapy by means of a high-resolution noninvasive MRI method. Ovalbumin-specific splenocytes (OT-1) labeled with anionic -Fe2O3 superparamagnetic iron oxide (SPIO) nanoparticles were adoptively transferred into C57BL/6 mice with growing ovalbumin-expressing tumors. OT-1 cells were tracked in vivo by 7 T MRI 24, 48, and 72 hr after they were injected. The results showed significant negative enhancement of the spleen at 24 hr, and of the tumor at 48 and 72 hr, after labeled cell injection. This suggests that the lymphocytes initially homed toward the spleen and were then recruited by the tumor. The presence of labeled cells was confirmed in ex vivo by 9.4 T microimaging of tumors and magnetic sorting of spleen cells. These results confirm that MR tracking of lymphocytes is feasible in vivo. This high-resolution imaging method could be used to improve the monitoring of immune cell therapy. Magn Reson Med 56:498 –508, 2006.

Published
2006

23. Magnetic resonance imaging of Klebsiella pneumoniae-induced pneumonia in mice

Author

Philippe J. Sansonetti, Bich-Thuy Doan, Régis Tournebize, Marie-Agnès Dillies, Jean-Claude Beloeil, Sabine Maurin, Pathogénie Microbienne Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Puces à ADN (Plate-Forme 2) (PF2), Institut Pasteur [Paris], Histotechnologie et Pathologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
Klebsiella pneumoniae, Immunology, Virulence, Inflammation, Biology, Microbiology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Virology, medicine, Pneumonia, Bacterial, Animals, Pathogen, Lung, 030304 developmental biology, 0303 health sciences, Mice, Inbred BALB C, medicine.diagnostic_test, Magnetic resonance imaging, biology.organism_classification, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Pneumonia, Female, medicine.symptom, Preclinical imaging
Abstract

Summary In vivo imaging of small animals is a rapidly developing field. However, the potential of global imaging of infectious processes in animal models remains poorly explored. We used magnetic resonance imaging (MRI) to follow the development and regression of inflammatory lesions caused by infection by Klebsiella pneumoniae in mouse lungs. A virulent strain caused an intense inflammation within 2 days in the whole lungs, while an avirulent strain did not show significant changes. Mice infected with the virulent strain and subsequently treated with antibiotics presented a severe inflammation localized mainly in the left lung that disappeared after a week. The lesions observed by MRI correlated with the damage seen by histological analysis and a 3D representation of the tissue allowed better visualization of the development and healing of inflammatory lesions. MRI thus represents a powerful technique to study in vivo the interactions between a pathogen and its host in real time.

Published
2005

24. Impaired voluntary running capacity of creatine kinase-deficient mice

Author

Iman Momken, Patrick Lechêne, Nathalie Koulmann, Dominique Fortin, Philippe Mateo, Bich-Thuy DOAN, Jacqueline Hoerter, Xavier Bigard, Vladimir Veksler, Renée Ventura-Clapier, Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches du Service de Santé des Armées (CRSSA), Service de Santé des Armées, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Ventura-Clapier, Renée, and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mice, Knockout, Volition, Myosin Heavy Chains, Myocardium, Body Weight, Physical Exertion, Creatine Kinase, Mitochondrial Form, Creatine Kinase, MM Form, Gene Expression, Myocardial Contraction, Ventricular Function, Left, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Running, Isoenzymes, Mice, Inbred C57BL, Mice, Muscular Atrophy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Integrative Physiology, Animals, Muscle, Skeletal, Creatine Kinase, Muscle Contraction
Abstract

International audience; The creatine kinase system (CK) is important for energy delivery in skeletal and cardiac muscles. The two main isoforms of this enzyme, cytosolic MM-CK and mitochondrial mi-CK, are expressed in a developmental and muscle-type specific manner. Mice deficient in one or both of these isoforms are viable and fertile but exhibit profound functional, metabolic and structural muscle remodelling that primarily affects fast skeletal muscles, which show an increased contribution of oxidative metabolism to contractile function. However, the consequences of these alterations in terms of physical capabilities have not yet been characterized. Consequently, we compared the voluntary exercise capacity of 9-month-old male wild-type (WT), M-CK knockout (M-CK(-/-)), and M-CK and mi-CK double knockout (CK(-/-)) mice, using cages equipped with running wheels. Exercise performance, calculated by total distance covered and by work done during the training period, was more than 10-fold lower in CK(-/-) mice than controls, with M-CK(-/-) mice exhibiting intermediate performance. Similarly, the mean distance run per activation was lower in M-CK(-/-) and even lower in CK(-/-) mice. However, the maximal running speed (V(max)) was lower only for CK(-/-) mice. This was accompanied by severe skeletal muscle mass decrease in CK(-/-) mice, with signs of histological damage that included enlarged interstitial areas, aggregations of mononuclear cells in the interstitium, heterogeneity of myofibre size and the presence of very small fibres. No overt sign of cardiac dysfunction was observed by magnetic resonance imaging during dobutamine stimulation. These results show that metabolic failure induced by CK deficiency profoundly affects the ability of mice to engage in chronic bouts of endurance running exercise and that this decrease in performance is also associated with muscle wasting.

Published
2005

25. Chemical modifications of the vasoconstrictor peptide angiotensin II by nitrogen oxides (NO, HNO2, HOONO)--evaluation by mass spectrometry

Author

Laurent Serani, Claire Ducrocq, Didier Payen, Maryvonne Dendane, Bich-Thuy Doan, Abdelhak Karim, Brigitte Gillet, Alain Carayon, Bhupesh C. Das, Nadia Bouchemal-Chibani, and Olivier Laprévote

Subjects
Magnetic Resonance Spectroscopy, Arginine, Stereochemistry, Biochemistry, Mass Spectrometry, Rats, Sprague-Dawley, Residue (chemistry), chemistry.chemical_compound, Nitration, Animals, Humans, Vasoconstrictor Agents, Tyrosine, Reactive nitrogen species, Nitrates, Molecular Structure, Chemistry, Superoxide, Angiotensin II, Oxidants, Rats, Molecular Weight, Vasoconstriction, Nitrogen Oxides, Peroxynitrite
Abstract

Nitric oxide (NO) and angiotensin II are natural regulators of blood pressure. Under aerobic conditions, NO is transformed into its higher oxides (N2O4, NO2, NO/NO2 or N2O3) and oxoperoxonitrate (currently named peroxynitrite) by coupling with superoxide. Previous studies have shown that these reactive nitrogen species should be involved in vivo in the transformation of cysteine and tyrosine into the corresponding nitrosothiol and 3-nitrotyrosine. In the present study, attention has been focused on the relative reactivities of HNO2, peroxynitrite, and NO in the presence of dioxygen, towards the arginine and tyrosine residues of the peptide angiotensin II. Nitration of the tyrosine residue is clearly the main reaction with peroxynitrite. By contrast, besides 20 % of nitration of the tyrosine residue, NO in the presence of dioxygen leads to nitrosation reactions with the arginine residue similar to those observed with HNO2 at pH 5, possibly through the intermediate N2O3 reactive species. Angiotensin II is converted for the most part to peptides having lost either a terminal amine function or the whole guanido group, leading respectively to citrulline-containing angiotensin II or to a diene derivative. Identification established mainly by tandem mass spectrometry of peptidic by-products allows us to propose a cascade of nitrosations of all the amine functions of the arginine residue. Further in vivo studies show that transformations of the arginine residue in angiotensin II do not alter its vasoconstrictive properties, whereas nitration of the tyrosine residue totally inhibits them.

Published
1998

26. Inside Cover: X-ray Photolysis To Release Ligands from Caged Reagents by an Intramolecular Antenna Sensitive to Magnetic Resonance Imaging (Angew. Chem. Int. Ed. 41/2011)

Author

Guillaume Bort, Peter I. Dalko, Morgane Petit, Bich-Thuy Doan, David Ogden, Cécile Sicard, Daniel Scherman, and Clotilde Ferroud

Subjects
chemistry, Gadolinium, Intramolecular force, Reagent, Photodissociation, Radiolysis, X-ray, chemistry.chemical_element, General Chemistry, Antenna (radio), Photochemistry, Catalysis
Published
2011

27. Both Functional LTβ Receptor and TNF Receptor 2 Are Required for the Development of Experimental Cerebral Malaria

Author

Valérie F. J. Quesniaux, Robert Ménard, Nicholas H. Hunt, Stefanie Scheu, Bernhard Ryffel, Dieudonnée Togbe, Paulo Loureiro de Sousa, Mathilde Fauconnier, Jean-Claude Beloeil, Laurent Rénia, Lizette Fick, Helen J. Ball, Victorine Boissay, Georges E. Grau, Klaus Pfeffer, Anna M. Hansen, Bich-Thuy Doan, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Stromal cell, Plasmodium berghei, T-Lymphocytes, Science, Malaria, Cerebral, Mice, Transgenic, Mice, 03 medical and health sciences, 0302 clinical medicine, Lymphotoxin beta Receptor, Immunology/Immunity to Infections, parasitic diseases, Animals, Receptors, Tumor Necrosis Factor, Type II, Cytotoxic T cell, Receptor, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Infectious Diseases/Protozoal Infections, Radiology and Medical Imaging/Magnetic Resonance Imaging, biology.organism_classification, Magnetic Resonance Imaging, 3. Good health, Lymphotoxin, Perforin, Models, Animal, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Medicine, Stromal Cells, Lymphotoxin beta receptor, CD8, Research Article, Signal Transduction, 030215 immunology
Abstract

BackgroundTNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.Methodology/principal findingsLTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.Conclusions/significanceLTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.

Published
2008

28. KIT is required for hepatic function during mouse post-natal development

Author

Stéphanie Retif, Martin Hrabé de Angelis, Jean-Jacques Panthier, Laetitia Magnol, Yann Herault, Patricia Lopes Pereira, Marie-Clémence Chevallier, Sandra Andrzejewski, Helmut Fuchs, Anne Puech, Jean-Claude Beloeil, Valérie Nalesso, Martina Klempt, Michel Riottot, Bich-Thuy Doan, Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), Research centre, Institute of Experimental Genetics (GSF), Neurobiologie de l'Olfaction et de la Prise Alimentaire (NOPA), Institut National de la Recherche Agronomique (INRA), Neurobiologie de l'apprentissage, de la mémoire et de la communication (NAMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Consortium National de Recherche en Génomique (CNRG), 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)-Institut de Chimie du CNRS (INC), Génétique fonctionnelle et médicale (GFM - ENVA), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Institute for Experimental Genetics, GSF - National Research Center for Environment and Health, Centre National de Ressources Génomiques Végétales (CNRGV), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire d'Alfort (ENVA), Institut de transgénose, GSF research center, Institute of Experimental Genetis, Consortium national de recherche en génomique (CNRG), Consortium national de recherche en génomique, CNRS, EUMORPHIA, EUROCOMP, Guiffan, Sebastien, Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and École nationale vétérinaire - Alfort (ENVA)

Subjects
NEW BORN, MESH: Signal Transduction, MESH: Anemia, Mutant, POLYMERASE CHAIN REACTION, souris, PROTO-ONCOGENE PROTEINS, medicine.disease_cause, MESH: Animals, Newborn, Receptor tyrosine kinase, développement postnatal, Mice, 0302 clinical medicine, gène kit, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Developmental, animal, MESH: Animals, MESH: Fatty Liver, [SDV.BDD]Life Sciences [q-bio]/Development Biology, lcsh:QH301-705.5, MESH: Lipid Metabolism, Regulation of gene expression, REVERSE TRANSCRIPTASE, 0303 health sciences, Mutation, Mice, Inbred C3H, biology, Reverse Transcriptase Polymerase Chain Reaction, Biologie du développement, Gene Expression Regulation, Developmental, Anemia, INBRED C3H, foie, Development Biology, Phenotype, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, Liver, protéine, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Signal transduction, Mouse phenotyping, systemic effects, lipid metabolism, Kit gene, hepatic function, Research Article, Signal Transduction, MESH: Mutation, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Phenotype, ALLELES, ANEMIA, FATTY LIVER, FETAL STEM CELLS, GENE EXPRESSION REGULATION, DEVELOPMENTAL, LIPID METABOLISM, LIVER, INBRED C57BL, PHENOTYPE, C-KIT, SIGNAL TRANSDUCTION, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Fetal Stem Cells, medicine, Animals, MESH: Mice, Inbred C3H, MESH: Mice, Gene, lipide, Alleles, 030304 developmental biology, métabolisme lipidique, Fetal Stem Cells, MESH: Alleles, [SCCO.NEUR]Cognitive science/Neuroscience, fonction hépatique, Lipid Metabolism, Molecular biology, Fatty Liver, Mice, Inbred C57BL, lcsh:Biology (General), Animals, Newborn, biology.protein, MESH: Liver, Developmental Biology
Abstract

Background The Kit gene encodes a receptor tyrosine kinase involved in various biological processes including melanogenesis, hematopoiesis and gametogenesis in mice and human. A large number of Kit mutants has been described so far showing the pleiotropic phenotypes associated with partial loss-of-function of the gene. Hypomorphic mutations can induce a light coat color phenotype while complete lack of KIT function interferes with embryogenesis. Interestingly several intermediate hypomorphic mutations induced in addition growth retardation and post-natal mortality. Results In this report we investigated the post-natal role of Kit by using a panel of chemically-induced hypomorphic mutations recently isolated in the mouse. We found that, in addition to the classical phenotypes, mutations of Kit induced juvenile steatosis, associated with the downregulation of the three genes, VldlR, Lpin1 and Lpl, controlling lipid metabolism in the post-natal liver. Hence, Kit loss-of-functions mimicked the inactivation of genes controlling the hepatic metabolism of triglycerides, the major source of energy from maternal milk, leading to growth and viability defects during neonatal development. Conclusion This is a first report involving KIT in the control of lipid metabolism in neonates and opening new perspectives for understanding juvenile steatosis. Moreover, it reinforces the role of Kit during development of the liver and underscores the caution that should be exerted in using KIT inhibitors during anti-cancer treatment.

Published
2007

29. MRI characterization of structural mouse brain changes in response to chronic exposure to the glufosinate ammonium herbicide

Author

Céline Montécot, Jean-Claude Beloeil, André-Guilhem Calas, William Même, Bich Thuy Doan, Thierry Gefflaut, Oliver Richard, Jacques Pichon, Sandra Même, Hélène Gautier, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurobiologie, Université d'Orléans (UO), laboratoire de Neurobiologie, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Male, [SDV]Life Sciences [q-bio], Central nervous system, Hippocampus, Pharmacology, Biology, Toxicology, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Cortex (anatomy), Glutamine synthetase, Glial Fibrillary Acidic Protein, medicine, Animals, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Glial fibrillary acidic protein, Herbicides, Aminobutyrates, Brain, Immunohistochemistry, Magnetic Resonance Imaging, In vitro, Mice, Inbred C57BL, medicine.anatomical_structure, Biochemistry, Astrocytes, biology.protein, 030217 neurology & neurosurgery, Ex vivo
Abstract

Glufosinate ammonium (GLA) is the active component of herbicides widely used in agriculture, truck farming, or public domains. GLA acts by inhibiting the plant glutamine synthetase (GlnS). It also inhibits mammalian GlnS in vitro and ex vivo. In the central nervous system this enzyme is exclusively localized in glial cells. Whereas acute neurotoxic effects of GLA are well documented, long-term effects during chronic exposure at low doses remain largely undisclosed. In the present work, C57BL/6J mice were treated intraperitoneally with 2.5, 5, and 10 mg/kg of GLA three times a week during 10 weeks. Cerebral magnetic resonance imaging (MRI) experiments were performed at high field (9.4 T) and the images were analyzed with four texture analysis (TA) methods. TA highlighted structural changes in seven brain structures after chronic GLA treatments. Changes are dose dependent and can be seen at a dose as low as 2.5 mg/kg for two areas, namely hippocampus and somatosensorial cortex. Glial fibrillary acidic protein (GFAP) expression in the same seven brain structures and GlnS activity in the hippocampus and cortex areas were also studied. The number of GFAP-positive cells is modified in six out of the seven areas examined. GlnS activity was significantly increased in the hippocampus but not in the cortex. These results indicate some kind of suffering at the cerebral level after chronic GLA treatment. Changes in TA were compared with the modification of the number of GFAP-positive astrocytes in the studied brain areas after GLA treatment. We show that the noninvasive MRI-TA is a sensitive method and we suggest that it would be a very helpful tool that can efficiently contribute to the detection of cerebral alterations in vivo during chronic exposure to xenobiotics.

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