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1. Reduction of extended-release tacrolimus dose in low immunological risk kidney transplant recipients increases risk of rejection and appearance of DSA - a randomized study

Author

Gatault, Philippe, Kamar, Nassim, Buchler, Matthias, Colosio, Charlotte, Bertrand, Dominique, Durrbach, Antoine, Albano, Laeticia, Rivalan, Joseph, Le Meur, Yannick, Essig, Marie, Bouvier, Nicolas, Legendre, Christophe, Moulin, Bruno, Heng, Anne-Elisabeth, Weestel, Pierre-François, Sayegh, Johnny, Charpentier, Bernard, Rostaing, Lionel, Thervet, Eric, Lebranchu, Yvon, Service de néphrologie et immunologie clinique [CHRU Tours], Université de Tours (UT)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Multiorgan Transplantation, CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Génie Civil et d'Ingénierie Environnementale (LGCIE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Service de néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Nephrology and Transplantation, University Hospital, Nice, Departement of Nephrology and Transplantation, University Hospital, Nice, Service de néphrologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHRU - Service de néphrologie, dialyse et transplantation rénale, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Department of Nephrology, Intitute for clinical and Experimental Medicine, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Département d'Informatique - Université Laval (IFT), Université Laval [Québec] (ULaval), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Affectations Mineralisantes du Systeme Cardiovasculaire : Calcifications Arterielles et Valvulaires Aortiques, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dyalise et transplantation, Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Department of Kidney Transplantation CHU Angers, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, CHU Toulouse [Toulouse]-Hôpital de Rangueil, Service de Néphrologie et Hémodialyse [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Néphrologie, Immunologie clinique, Hôpital Bretonneau-CHRU Tours, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHRU Tours, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Laboratoire de Génie Civil et d'Ingénierie Environnementale ( LGCIE ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Immunologie et Pathologie ( EA2216 ), Université de Brest ( UBO ) -IFR148, Micro et nanomédecines biomimétiques ( MINT ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université d'Angers ( UA ) -Université Bretagne Loire ( UBL ), Département d'Informatique - Université Laval ( IFT ), Université de Lille, Sciences Humaines et Sociales, Université de Picardie Jules Verne ( UPJV ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Picardie Jules Verne ( UPJV ) -CHU Amiens-Picardie, Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ) -PRES Université Nantes Angers Le Mans ( UNAM ) -Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ) -PRES Université Nantes Angers Le Mans ( UNAM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service de Néphrologie et d’Immunologie Clinique, Hôpital Bretonneau-CHU Tours, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
[ SDV.IMM ] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

2. Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

Author

Sylvie Avril, Catherine Guillet, Claire Legendre, Emmanuel Garcion, Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Université d'Angers ( UA ), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), and Université d'Angers (UA)

Subjects
0301 basic medicine, Cancer Research, Cell cycle checkpoint, [SDV]Life Sciences [q-bio], Pharmacology, Iron Chelating Agents, Benzoates, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Genetics, Cytotoxic T cell, Medicine, Humans, U87, Cytotoxicity, Hypoxia, [ SDV ] Life Sciences [q-bio], business.industry, Deferasirox, Triazoles, Combined Modality Therapy, In vitro, Cell Hypoxia, 3. Good health, Oxygen, 030104 developmental biology, Oncology, Apoptosis, Cell culture, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Resistance to therapy, Iron chelation, business, Glioblastoma, medicine.drug, Research Article
Abstract

Background Overcoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia. Results Under experimental normoxic condition (21 % O2), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3 % O2), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired. Conclusions Taken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2074-y) contains supplementary material, which is available to authorized users.

Published
2016

3. Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

Author

Manh Thông Dao, Nicolas Picard, Patrick Saulnier, Véronique Loustaud-Ratti, Dominique Larrey, Pascal Veillon, Françoise Lunel-Fabiani, Alexandra Ducancelle, Louis d’Alteroche, Nathalie Boyer-Darrigand, Hélène Le Guillou-Guillemette, Isabelle Fouchard-Hubert, Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Laboratoire HIFIH, Université d'Angers ( UA ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Univ Angers, Okina

Subjects
Male, 0301 basic medicine, Simple noninvasive index, Sustained virology response, Gene Expression, Hepacivirus, Pharmacology, medicine.disease_cause, Gastroenterology, Polyethylene Glycols, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pegylated interferon, Significant fibrosis, Pyrophosphatases, Epoetin beta, HCV-Infected Patients, virus diseases, Alanine Transaminase, Anemia, Middle Aged, Viral Load, Recombinant Proteins, 3. Good health, Treatment Outcome, Interferon alpha, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA, Viral, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, ITPA, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Growth factors, Viral load, medicine.drug, Adult, medicine.medical_specialty, Genotype, Hepatitis C virus, Immunology, Alpha interferon, Antiviral Agents, Polymorphism, Single Nucleotide, 03 medical and health sciences, Virology, Internal medicine, Ribavirin, medicine, Humans, Double blind, Aspartate Aminotransferases, Combination therapy, Erythropoietin, [ SDV ] Life Sciences [q-bio], business.industry, Interleukins, Virus genotype-1 patients, Interferon-alpha, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Cell Biology, Hepatitis C, Chronic, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 030104 developmental biology, chemistry, Antiviral treatment, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Interferons, business
Abstract

International audience; To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon alpha-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia.

Published
2016

4. Lauroyl-gemcitabine-loaded lipid nanocapsule hydrogel for the treatment of glioblastoma

Author

Véronique Préat, Frédéric Lagarce, Bernard Ucakar, Kevin Vanvarenberg, Marion Pitorre, Chiara Bastiancich, Guillaume Bastiat, Fabienne Danhier, Université Catholique de Louvain (UCL), Micro et Nanomédecines Biomimétiques, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), LUNAM Université, Lunam Université, Université Catholique de Louvain ( UCL ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Micro et Nanomédecines Biomimétiques (MINT), and LUNAM Université [Nantes Angers Le Mans]

Subjects
[SDV]Life Sciences [q-bio], Pharmaceutical Science, 02 engineering and technology, Pharmacology, Deoxycytidine, Lipid nanocapsules, 0302 clinical medicine, media_common, Chemistry, Brain Neoplasms, Hydrogels, Prodrug, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, Tumor Burden, Nanomedicine, Tolerability, Needles, 030220 oncology & carcinogenesis, Female, medicine.symptom, 0210 nano-technology, Rheology, medicine.drug, Drug, Antimetabolites, Antineoplastic, Cell Survival, media_common.quotation_subject, Mice, Nude, Injections, 03 medical and health sciences, Nanocapsules, Glioma, Cell Line, Tumor, medicine, Animals, Humans, [ SDV ] Life Sciences [q-bio], Gemcitabine, Glioblastoma, Hydrogel, medicine.disease, In vitro, Drug Liberation, Mechanism of action, Delayed-Action Preparations
Abstract

International audience; The local delivery of chemotherapeutic agents is a very promising strategy for the treatment of glioblastoma (GBM). Gemcitabine is a chemotherapeutic agent that has a different mechanism of action compared to alkylating agents and shows excellent radio-sensitizing properties. So, we developed an injectable gel-like nanodelivery system consisting in lipid nanocapsules loaded with anticancer prodrug lauroyl-gemcitabine (GemC12-LNC) in order to obtain a sustained and local delivery of this drug in the brain. In this study, the GemC12-LNC has been formulated and characterized and the viscoelastic properties of the hydrogel were evaluated after extrusion from 30G needles. This system showed a sustained and prolonged in vitro release of the drug over one month. GemC12 and the GemC12-LNC have shown increased in vitro cytotoxic activity on U-87 MG glioma cells compared to the parent hydrophilic drug. The GemC12-LNC hydrogel reduced significantly the size of a subcutaneous human GBM tumor model compared to the drug and short-term tolerability studies showed that this system is suitable for local treatment in the brain. In conclusion, this proof-of-concept study demonstrated the feasibility, safety and efficiency of the injectable GemC12-LNC hydrogel for the local treatment of GBM.

Published
2016

5. Development of prilling process for biodegradable microspheres through experimental designs

Author

Sergent Michelle, Tran Van-Thanh, Violet Fabien, Bastiat Guillaume, Le Minh-Quan, Venier-Julienne Marie-Claire, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Laboratoire d'Instrumentation et Sciences Analytiques (LISA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Laboratoire d'Instrumentation et Sciences Analytiques ( LISA ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Micro et Nanomédecines Biomimétiques, and Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)

Subjects
0301 basic medicine, Materials science, Chemistry, Pharmaceutical, Plga microspheres, Glycofurol, Pharmaceutical Science, Nanotechnology, 02 engineering and technology, Micrococcus, Polyethylene Glycols, Microsphere, 03 medical and health sciences, chemistry.chemical_compound, Polylactic Acid-Polyglycolic Acid Copolymer, Animals, Lactic Acid, Particle Size, Microparticle, Prilling, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, PLGA, 021001 nanoscience & nanotechnology, Microspheres, Experimental design, 030104 developmental biology, chemistry, Drug Design, Scientific method, microsphere, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Muramidase, 0210 nano-technology, Chickens, Polyglycolic Acid, Production quality
Abstract

International audience; The prilling process proposes a microparticle formulation easily transferable to the pharmaceutical production, leading to monodispersed and highly controllable microspheres. PLGA microspheres were used for carrying an encapsulated protein and adhered stem cells on its surface, proposing a tool for regeneration therapy against injured tissue. This work focused on the development of the production of PLGA microspheres by the prilling process without toxic solvent. The required production quality needed a complete optimization of the process. Seventeen parameters were studied through experimental designs and led to an acceptable production. The key parameters and mechanisms of formation were highlighted.

Published
2016

6. NFL-lipid nanocapsules for brain neural stem cell targeting in vitro and in vivo

Author

Dario Carradori, Véronique Préat, Patrick Saulnier, Joël Eyer, Anne des Rieux, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Laboratoire de Neurobiologie et Transgénèse (LNBT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Laboratoire de Neurologie et Transgenèse UPRES EA3143 ( LNBT ), Université d'Angers ( UA ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Subventricular zone, Lipid nanocapsules, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Drug Delivery Systems, Nanocapsules, In vivo, Neurofilament Proteins, Neurosphere, medicine, Animals, Cells, Cultured, Neural stem cells, Drug Carriers, [ SDV ] Life Sciences [q-bio], business.industry, NFL-TBS.40-63, Brain, Anatomy, Spinal cord, Neural stem cell, Peptide Fragments, Cell biology, Rats, Neuroepithelial cell, 030104 developmental biology, medicine.anatomical_structure, Spinal Cord, Brain subventricular zone, Female, Adsorption, business, 030217 neurology & neurosurgery, Cerebral organoid, Adult stem cell
Abstract

International audience; The replacement of injured neurons by the selective stimulation of neural stem cells in situ represents a potential therapeutic strategy for the treatment of neurodegenerative diseases. The peptide NFL-TBS.40-63 showed specific interactions towards neural stem cells of the subventricular zone. The aim of our work was to produce a NFL-based drug delivery system able to target neural stem cells through the selective affinity between the peptide and these cells. NFL-TBS.40-63 (NFL) was adsorbed on lipid nanocapsules (LNC) whom targeting efficiency was evaluated on neural stem cells from the subventricular zone (brain) and from the central canal (spinal cord). NFL-LNC were incubated with primary neural stem cells in vitro or injected in vivo in adult rat brain (right lateral ventricle) or spinal cord (T10). NFL-LNC interactions with neural stem cells were different depending on the origin of the cells. NFL-LNC showed a preferential uptake by neural stem cells from the brain, while they did not interact with neural stem cells from the spinal cord. The results obtained in vivo correlate with the results observed in vitro, demonstrating that NFL-LNC represent a promising therapeutic strategy to selectively deliver bioactive molecules to brain neural stem cells.

Published
2016

7. Long-term results of carmustine wafer implantation for newly diagnosed glioblastomas: a controlled propensity-matched analysis of a French multicenter cohort

Author

Johan, Pallud, Etienne, Audureau, Georges, Noel, Robert, Corns, Emmanuèle, Lechapt-Zalcman, Julien, Duntze, Vladislav, Pavlov, Jacques, Guyotat, Phong Dam, Hieu, Pierre-Jean, Le Reste, Thierry, Faillot, Claude-Fabien, Litre, Nicolas, Desse, Antoine, Petit, Evelyne, Emery, Jimmy, Voirin, Johann, Peltier, François, Caire, Jean-Rodolphe, Vignes, Jean-Luc, Barat, Olivier, Langlois, Edouard, Dezamis, Eduardo, Parraga, Marc, Zanello, Edmond, Nader, Michel, Lefranc, Luc, Bauchet, Bertrand, Devaux, Philippe, Menei, Philippe, Metellus, Anne, Vital, Centre Hospitalier Sainte-Anne, Université Paris Descartes - Paris 5 ( UPD5 ), Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Universitaire de Caen, CHU Caen, Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), CHU Pontchaillou [Rennes], Service de neurochirurgie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Neurochirurgie, CHU Caen-Caen University Hospital, CHU Amiens-Picardie-Hôpital Nord - Amiens, Laboratoire de Neurochirurgie, Centre hospitalier Sainte-Anne (Paris), Imagerie et Modélisation en Neurobiologie et Cancérologie ( IMNC ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), CHU Angers, Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'Investigation Clinique (LIC), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de santé publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Leeds General Infirmary (LGI), Leeds Teaching Hospitals NHS Trust, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Hôpital d'Instruction des Armées Sainte Anne, Service de Santé des Armées, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurochirurgie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital pasteur [Colmar], CHU Strasbourg, CHU Amiens-Picardie, Service de Neurochirurgie [CHU Limoges], CHU Limoges, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Privé Clairval [Marseille], Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Neurochirurgie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Centre Hospitalier Sainte-Anne, Unité d’Epidémiologie et de Biostatistiques [APHP Cochin-Broca-Hôtel Dieu], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Réseau d'Etude des Gliomes, REG, Service de neurochirurgie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Università degli studi di Napoli Federico II, CHU de Bordeaux Pellegrin [Bordeaux], Centre d'Études Préhistoire, Antiquité, Moyen-Age (CEPAM), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de Neurochirurgie [CHU Angers], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Neurochirurgie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques, and Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Survival, [SDV]Life Sciences [q-bio], Clinical Investigations, Kaplan-Meier Estimate, Disease-Free Survival, Cohort Studies, Young Adult, medicine, Humans, Progression-free survival, Young adult, Antineoplastic Agents, Alkylating, Aged, Aged, 80 and over, Carmustine, [ SDV ] Life Sciences [q-bio], Brain Neoplasms, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Hazard ratio, carmustine wafers, Chemoradiotherapy, Middle Aged, 3. Good health, Surgery, Treatment Outcome, Oncology, Chemotherapy, Adjuvant, Cohort, Propensity score matching, Female, Neurology (clinical), business, Glioblastoma, medicine.drug, Cohort study
Abstract

CERVOXY COLL; International audience; BACKGROUND: The standard of care for newly diagnosed glioblastoma is maximal safe surgical resection, followed by chemoradiation therapy. We assessed carmustine wafer implantation efficacy and safety when used in combination with standard care. METHODS: Included were adult patients with (n = 354, implantation group) and without (n = 433, standard group) carmustine wafer implantation during first surgical resection followed by chemoradiation standard protocol. Multivariate and case-matched analyses (controlled propensity-matched cohort, 262 pairs of patients) were conducted. RESULTS: The median progression-free survival was 12.0 months (95% CI: 10.7-12.6) in the implantation group and 10.0 months (9.0-10.0) in the standard group and the median overall survival was 20.4 months (19.0-22.7) and 18.0 months (17.0-19.0), respectively. Carmustine wafer implantation was independently associated with longer progression-free survival in patients with subtotal/total surgical resection in the whole series (adjusted hazard ratio [HR], 0.76 [95% CI: 0.63-0.92], P = .005) and after propensity matching (HR, 0.74 [95% CI: 0.60-0.92], P = .008), whereas no significant difference was found for overall survival (HR, 0.95 [0.80-1.13], P = .574; HR, 1.06 [0.87-1.29], P = .561, respectively). Surgical resection at progression whether alone or combined with carmustine wafer implantation was independently associated with longer overall survival in the whole series (HR, 0.58 [0.44-0.76], P \textless .0001; HR, 0.54 [0.41-0.70], P \textless .0001, respectively) and after propensity matching (HR, 0.56 [95% CI: 0.40-0.78], P \textless .0001; HR, 0.46 [95% CI: 0.33-0.64], P \textless .0001, respectively). The higher postoperative infection rate in the implantation group did not affect survival. CONCLUSIONS: Carmustine wafer implantation during surgical resection followed by the standard chemoradiation protocol for newly diagnosed glioblastoma in adults resulted in a significant progression-free survival benefit

Published
2015

8. Scaffolds for controlled release of cartilage growth factors

Author

Morille , Marie, Venier-Julienne , Marie-Claire, Montero-Menei , Claudia, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Micro et nanomédecines biomimétiques ( MINT ), and Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL )

Subjects
Pharmacologically active microcarriers, [ SDV ] Life Sciences [q-bio], Protein encapsulation, Chondrogenic differentiation, [SDV]Life Sciences [q-bio], Mesenchymal Stem Cells, Transforming growth factor
Abstract

International audience; In recent years, cell-based therapies using adult stem cells have attracted considerable interest in regenerative medicine. A tissue-engineered construct for cartilage repair should provide a support for the cell and allow sustained in situ delivery of bioactive factors capable of inducing cell differentiation into chondrocytes. Pharmacologically active microcarriers (PAMs), made of biodegradable and biocompatible poly (d,l-lactide-co-glycolide acid) (PLGA), are a unique system which combines these properties in an adaptable and simple microdevice. This device relies on nanoprecipitation of proteins encapsulated in polymeric microspheres with a solid in oil in water emulsion-solvent evaporation process, and their subsequent coating with extracellular matrix protein molecules. Here, we describe their preparation process, and some of their characterization methods for an application in cartilage tissue engineering.

Published
2015

9. Targeting and treatment of glioblastomas with human mesenchymal stem cells carrying ferrociphenol lipid nanocapsules

Author

Anne-Laure Lainé, Claudia N. Montero-Menei, Florence Franconi, Philippe Menei, Clément Tétaud, Anne Clavreul, Catherine Passirani, Nolwenn Lautram, Angélique Montagu, Anne Vessières, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CIFAB-PRIMEX, Université d'Angers (UA), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Université d'Angers ( UA ), Plateforme de Radiobiologie et d’Imageries EXpérimentale [SFR ICAT - UA] (PRIMEX), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), and Université d'Angers (UA)-Université d'Angers (UA)

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cell, Pharmaceutical Science, Endogeny, 02 engineering and technology, Mice, International Journal of Nanomedicine, Drug Discovery, Medicine, Cells, Cultured, media_common, Original Research, 0303 health sciences, nanoparticle, General Medicine, Stem-cell therapy, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, medicine.anatomical_structure, Drug delivery, 0210 nano-technology, Drug, Cell Survival, media_common.quotation_subject, Biophysics, Bioengineering, Nanotechnology, Antineoplastic Agents, Mesenchymal Stem Cell Transplantation, Biomaterials, 03 medical and health sciences, Nanocapsules, Cell Line, Tumor, Distribution (pharmacology), Animals, Humans, Viability assay, Ferrous Compounds, targeting, 030304 developmental biology, [ SDV ] Life Sciences [q-bio], business.industry, Organic Chemistry, Mesenchymal stem cell, Mesenchymal Stem Cells, Xenograft Model Antitumor Assays, drug delivery, Cancer research, business, Glioblastoma
Abstract

Anne Clavreul,1 Angélique Montagu,2 Anne-Laure Lainé,2 Clément Tétaud,2 Nolwenn Lautram,2 Florence Franconi,3 Catherine Passirani,2 Anne Vessières,4 Claudia N Montero-Menei,2 Philippe Menei1 1Département de Neurochirurgie, Centre Hospitalier Universitaire, Angers, France; 2INSERM UMR-S 1066, Université d’Angers, LUNAM Université, Angers, France; 3CIFAB-PRIMEX, Université d’Angers, LUNAM Université, Angers, France; 4CNRS-UMR 7223, ENSCP, Paris, France Abstract: Recently developed drug delivery nanosystems, such as lipid nanocapsules (LNCs), hold great promise for the treatment of glioblastomas (GBs). In this study, we used a subpopulation of human mesenchymal stem cells, “marrow-isolated adult multilineage inducible” (MIAMI) cells, which have endogenous tumor-homing activity, to deliver LNCs containing an organometallic complex (ferrociphenol or Fc-diOH), in the orthotopic U87MG GB model. We determined the optimal dose of Fc-diOH-LNCs that can be carried by MIAMI cells and compared the efficacy of Fc-diOH-LNC-loaded MIAMI cells with that of the free-standing Fc-diOH-LNC system. We showed that MIAMI cells entrapped an optimal dose of about 20 pg Fc-diOH per cell, with no effect on cell viability or migration capacity. The survival of U87MG-bearing mice was longer after the intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells than after the injection of Fc-diOH-LNCs alone. The greater effect of the Fc-diOH-LNC-loaded MIAMI cells may be accounted for by their peritumoral distribution and a longer residence time of the drug within the tumor. These results confirm the potential of combinations of stem cell therapy and nanotechnology to improve the local tissue distribution of anticancer drugs in GB.Keywords: glioblastoma, mesenchymal stem cells, nanoparticle, drug delivery, targeting&nbsp

Published
2015

10. Tumour targeting of lipid nanocapsules grafted with cRGD peptides

Author

Jean-Pierre Benoit, François Hindré, Emmanuel Garcion, Samuli Hirsjärvi, Camille Belloche, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), by Ligue Contre le Cancer - Comité Départemental du Maine et Loire (Equipe Labellisée Ligue Nationale Contre le Cancer 2012), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), and Lemaire, Laurent

Subjects
Biodistribution, Mice, Nude, Pharmaceutical Science, Antineoplastic Agents, cRGD peptide, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Peptides, Cyclic, Lipid nanocapsules, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Flow cytometry, law.invention, [ SDV.IB.MN ] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Nanocapsules, In vivo, Confocal microscopy, law, Glioma, Cellular uptake, medicine, Animals, Humans, Tissue Distribution, Molecular Targeted Therapy, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Drug Carriers, Targeting, medicine.diagnostic_test, Chemistry, General Medicine, medicine.disease, [ SDV.IB.BIO ] Life Sciences [q-bio]/Bioengineering/Biomaterials, Lipids, Xenograft Model Antitumor Assays, In vitro, 3. Good health, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, Biochemistry, Cancer cell, Cancer research, Female, Nanocarriers, Biotechnology
Abstract

International audience; Combining targeting to therapy remains a major challenge in cancer treatment. To address this subject, the surface of lipid nanocapsules (LNC) was modified by grafting cRGD peptides, which are known to be recognised by αvβ3 integrins expressed by tumour endothelium and cancer cells. Applicability of this LNC-cRGD in tumour targeting was first assessed in vitro by the use of U87MG glioma cells. Biodistribution and tumour accumulation of radiolabelled LNC-cRGD in vivo were then evaluated in mice bearing the same subcutaneous xenograft. Flow cytometry and confocal microscopy results revealed that the cRGD grafting improved binding and internalisation compared to negative control LNC-cRAD and blank LNC. The peptide-grafted LNC remained in the blood circulation up to 3h with reduced capture by the RES organs. Tumour accumulation of LNC-cRGD with respect to LNC-cRAD was significantly higher at 1-3h. These results show that cRGD grafted to LNC has created a promising tumour-targetable nanocarrier that could be used in cancer treatment.

Published
2014

11. A multicenter blinded study evaluating EGFR and KRAS mutation testing methods in the clinical non-small cell lung cancer setting―IFCT/ERMETIC2 Project Part 1: Comparison of testing methods in 20 French molecular genetic National Cancer Institute platforms

Author

Beau-Faller , Michèle, Blons , Hélène, Domerg , Caroline, Gajda , Dorota, Richard , Nicolas, Escande , Fabienne, Solassol , Jérôme, Denis , Marc G., Cayre , Anne, Nanni-Metellus , Isabelle, Olschwang , Sylviane, Lizard , Sarab, Piard , Fabienne, Pretet , Jean-Luc, Fraipont , Florence, Bièche , Ivan, Cremoux , Patricia, Rouquette , Isabelle, Bringuier , Pierre-Paul, Mosser , Jean, Legrain , Michèle, Voegeli , Anne-Claire, Saulnier , Patrick, Morin , Franck, Pignon , Jean-Pierre, Zalcman , Gérard, Cadranel , Jacques, Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), 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 recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), DAM Île-de-France ( DAM/DIF ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), biology and pathological laboratory, Endocrinologie moléculaire et cellulaire des cancers, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Etude Métabolique des Molécules Marquées, Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Oncogénétique, Hôpital René Huguenin-INSTITUT CURIE, Département de Biologie des Tumeurs, INSTITUT CURIE, Centre national référent cancers rares - mésothéliomes malins pleuraux et tumeurs péritonéales rares ( MESOPATH ), CHU Caen-Hôpital côte de nacre, Equipe 4, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), CIFAB-PRIMEX, Université d'Angers ( UA ), Service d'Etudes des Systèmes Innovants ( SESI ), Service de biostatistique et d'épidémiologie ( SBE ), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de Recherche Clinique, CHU Caen, Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Intergroupe Francophone de Cancérologie Thoracique [Paris] ( IFCT ), Intergroupe Francophone de Cancérologie thoracique, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), 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 recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), DAM Île-de-France (DAM/DIF), Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Curie [Paris]-Hôpital René HUGUENIN (Saint-Cloud), Institut Curie [Paris], Registre Multicentrique à Vocation Nationale des Mésothéliomes Pleuraux (MESONAT), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Université d'Angers (UA), Service d'Etudes des Systèmes Innovants (SESI), Département Etude des Réacteurs (DER), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de recherche clinique [CHU Caen] (CRC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plateforme de Radiobiologie et d’Imageries EXpérimentale [SFR ICAT - UA] (PRIMEX), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Institut Curie-Hôpital René HUGUENIN (Saint-Cloud), Institut Curie, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques, Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CEA-Direction de l'Energie Nucléaire (CEA-DEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), INSTITUT CURIE-Hôpital René HUGUENIN (Saint-Cloud), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Département Etude des Réacteurs ( DER ), CEA-Direction de l'Energie Nucléaire ( CEA-DEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -CEA-Direction de l'Energie Nucléaire ( CEA-DEN ), and Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA )

Subjects
Lung Neoplasms, Genotype, Adenocarcinoma of Lung, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Adenocarcinoma, Cell Line, Proto-Oncogene Proteins p21(ras), Erlotinib Hydrochloride, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Proto-Oncogene Proteins, Humans, False Positive Reactions, Non-Small-Cell Lung, Protein Kinase Inhibitors, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor, Base Sequence, Epidermal Growth Factor, Carcinoma, High-Throughput Nucleotide Sequencing, Gefitinib, Sequence Analysis, DNA, DNA, ErbB Receptors, Molecular Diagnostic Techniques, ras Proteins, Quinazolines, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Sequence Analysis, Nucleic Acid Amplification Techniques, Receptor
Abstract

International audience; Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have limited use as first-line treatment for mutated EGFR metastatic non-small cell lung cancer. The French National Cancer Institute has installed molecular genetics platforms implementing EGFR and KRAS testing. However, there is considerable uncertainty as to which detection methods should be applied for routine diagnosis. This study aimed to compare the EGFR and KRAS genotyping methods developed by the IFCT/ERMETIC2 network platforms in two blind panels: 25 samples of serial dilutions of cell line DNA (20 centers) and 74 FFPE lung tumor samples (10 centers). The best threshold of mutation detection on cell lines was obtained using allele-specific amplification-based technologies. Nonamplifiable tissue samples were significantly less common when using alternative testing versus direct sequencing [15%; 95% confidence interval (CI), 14%-16% versus 40%; 95% CI, 39%-42%; P \textless 0.001]. Mutated cases increased from 42% (95% CI, 31%-54%) to 53% (95% CI, 41%-64%), with three supplementary EGFR mutations (p.G179A at exon 18 and p.L858R and p.L861Q at exon 21) and five supplementary KRAS mutations, when using alternative testing instead of direct sequencing. False-positive results were observed when using a PCR-based sizing assay, high-resolution melting, or pyrosequencing. Concordance analysis returned good kappa test scores for EGFR exon 19 and KRAS analysis when comparing sequencing with alternative methods and revealed no difference between alternative techniques themselves.

Published
2014

12. Effect of particle size on the biodistribution of lipid nanocapsules: Comparison between nuclear and fluorescence imaging and counting

Author

Emmanuel Garcion, François Hindré, Samuli Hirsjärvi, Claire Vanpouille-Box, Sandrine Dufort, Camille Belloche, Lucie Sancey, Jean-Luc Coll, Jean-Pierre Benoit, Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Lumière Matière [Villeurbanne] ( ILM ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Lemaire, Laurent

Subjects
Biodistribution, Fluorescence-lifetime imaging microscopy, Lipid nanocapsules, γ-scintigraphy, Analytical chemistry, Pharmaceutical Science, Nanoparticle, Mice, Nude, 02 engineering and technology, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, [ SDV.IB.MN ] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 03 medical and health sciences, Mice, optical imaging, Optical imaging, Nanocapsules, Animals, Humans, Tissue Distribution, Particle Size, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Radionuclide Imaging, biodistribution, 030304 developmental biology, 0303 health sciences, lipid nanocapsules, Chemistry, Technetium, 021001 nanoscience & nanotechnology, [ SDV.IB.BIO ] Life Sciences [q-bio]/Bioengineering/Biomaterials, Fluorescence, Lipids, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, HEK293 Cells, Permeability (electromagnetism), Biophysics, Scintillation Counting, Female, Particle size, fluorescence, 0210 nano-technology
Abstract

International audience; In vivo biodistribution of nanoparticles depends on several physicochemical parameters such as size. After intravenous injection of 25, 50 and 100nm lipid nanocapsules (LNC) in nude mice bearing HEK293(β3) tumour xenografts, biodistribution was evaluated by γ-scintigraphy and by γ-counting. The small LNC 25nm disappeared faster than the larger LNC 50 and 100nm from the blood circulation due to faster elimination and wider tissue distribution. At 24h, biodistribution profiles of all these LNC were similar. Low LNC quantities were found in this weak EPR (enhanced permeability and retention) tumour regardless the particle size. Co-injected 50nm fluorescent DiD-LNC and (99m)Tc-LNC allowed direct comparison of biodistribution as evaluated by the two methods. Optical imaging underestimated LNC quantity especially in dark-colored organs that were observed to capture extensive quantities of the particles by γ-counting (i.e. liver, spleen, and kidney).

Published
2013

13. Optimisation pharmacologique des dérivés de la créatine pour le traitement du déficit en transporteur de la créatine

Author

Trotier-Faurion, Alexandra, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Pharmacologie et Immunoanalyse (SPI), Université Paris Sud - Paris XI, Aloïse Mabondzo, STAR, ABES, Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Chimie Bio-Organique et de Marquage ( SCBM ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-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 ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, and Service de Pharmacologie et Immunoanalyse ( SPI )

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, Barrière hémato-encéphalique, Maladies métaboliques rares, NanoCapsules Lipidiques, Creatine esters, Esters de créatine, Nanovectorisation, Pharmaceutical formulation, Lipid NanoCapsules, Treatment of creatine transporter deficiency, Traitement du Déficit en transporteur de la créatine, Rare metabolic disease, Nanovectorization, Formulation galénique, [ SDV.SA ] Life Sciences [q-bio]/Agricultural sciences, Blood-brain barrier
Abstract

Creatine transporter deficiency is a rare brain disease associated with the loss of function of the SLC6A8 (creatine transporter) leading to an absence of creatine at the cerebral level and to a dramatic neurodevelopmental retardation in the children. To date, no effective therapy is available.A potential therapeutic option would be the design of a pharmaceutical formulation of lipophilic prodrugs of creatine that will cross the cell membranes passively and target the neurons in order to restore the creatine content inside these cells.One of the main purposes of this dissertation is to propose an original chemistry synthesis process of creatine esters with long aliphatic chain. These compounds show interesting pharmacological properties of structure-activity relationship between the length of the aliphatic chain (i.e. lipophilicity) and the ability for the drug to enter cerebral endothelial, astroglial and neuronal cells. According to our experimental observations, the dodecyl ester creatine seems to be the best drug candidate. Moreover, the dodecyl ester is acted on by cellular esterases inside patients’ fibroblasts with a functional deficit of the SLC6A8 and increases the intracellular creatine content.The pharmaceutical formulation developed in this study consists by incorporation of dodecyl ester inside a nanovector (Lipid NanoCapsules). Two main advantages can be gained by nanovectorization: firstly, the dodecyl ester is protected from the degradation by plasmatic esterases before reaching the brain. Secondly, the nanovectorization strategy is highly valuable to brain targeting bypassing the blood-brain barrier, which remains until now a major impediment in the drug design for the Central Nervous System. Our experimental observations highlight this two-step therapeutic strategy for the treatment of deficiency of the creatine transporter.This work was financially supported by the International PhD Program of the Life Sciences division of the CEA and the Fondation Jérôme Lejeune., Le déficit en transporteur de la créatine est une maladie rare neurologique dans laquelle la perte de fonctionnalité du transporteur de la créatine (SLC6A8) conduit à une absence de créatine au niveau cérébral et à des retards de développement majeurs chez les enfants. A l’heure actuelle, aucune thérapie efficace n’est disponible.Une approche thérapeutique potentielle est le développement de molécules prodrogues de la créatine plus lipophiles qui franchiront les membranes cellulaires de façon passive et la recherche d’une formulation galénique susceptible d’emmener la prodrogue vers les cellules cibles d’intérêt, les neurones. Ainsi, dans cette thèse, nous proposons une nouvelle voie de synthèse originale d’esters de la créatine à longue chaîne aliphatique. Ces composés présentent des propriétés pharmacologiques intéressantes : nous montrons qu’il existe une relation de structure-activité entre la taille de la chaîne aliphatique (et donc la lipophilie) et la capacité de la molécule à être internalisée dans les cellules endothéliales cérébrales, astrocytaires et neuronales, constituant l’unité neurovasculaire. Il ressort de nos observations expérimentales que l’ester dodécylique de créatine est le meilleur candidat médicament. De plus, après avoir été internalisé dans les fibroblastes des patients présentant un déficit fonctionnel du transporteur de la créatine, l’ester dodécylique subit une conversion par les estérases cellulaires, libérant ainsi la créatine dans le compartiment intracellulaire.La formulation galénique permettant de protéger ces esters de créatine jusqu’au cerveau repose, elle, sur la nanovectorisation, par encapsulation de l’ester dodécylique de créatine dans des NanoCapsules Lipidiques. L’avantage de cette formulation est de permettre également un ciblage actif vers la Barrière Hémato-Encéphalique, obstacle majeur dans le développement de thérapies ciblant le Système Nerveux Central. Nos observations expérimentales mettent en exergue cette double stratégie thérapeutique pour le traitement du déficit en transporteur de la créatine.Ce travail a été soutenu financièrement par la Fondation Lejeune.

Published
2013

14. Tuning the noise in magnetic resonance imaging to maximize nonlinear information transmission

Author

François Chapeau-Blondeau, Agnès Delahaies, Florence Franconi, David Rousseau, Laboratoire d'Ingéniérie des Systèmes Automatisés ( LISA ), Université d'Angers ( UA ), 2 - Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), 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 ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Laboratoire d'Ingéniérie des Systèmes Automatisés (LISA), Université d'Angers (UA), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), 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)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)

Subjects
Coupling, Information transmission, medicine.diagnostic_test, General Mathematics, Multiplicative function, Bandwidth (signal processing), General Physics and Astronomy, Magnetic resonance imaging, [ SPI.SIGNAL ] Engineering Sciences [physics]/Signal and Image processing, Topology, 01 natural sciences, 010305 fluids & plasmas, Nonlinear system, Control theory, 0103 physical sciences, medicine, 010306 general physics, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, ComputingMilieux_MISCELLANEOUS, Mathematics
Abstract

We demonstrate a new instance of useful-noise effect or stochastic resonance, occurring in magnetic resonance imaging (MRI). Based on the physics of signal–noise coupling specific to MRI, we establish the possibility of regimes where nonlinear post-processing can benefit from an increase in the level of the noise present in the MRI apparatus. The validation is obtained by both theoretical analysis and experimental observations. We especially show that the beneficial tuning of the noise can be practically achieved by controlling the bandwidth of the sampling receiver of the MRI apparatus. These results constitute a nontrivial extension of stochastic resonance in the domain of images, arising here with a signal–noise coupling in MRI which is distinct from the purely additive or multiplicative couplings previously investigated in the framework of useful-noise effect.

Published
2013

15. DNA nanocarriers for systemic administration: characterization and in vivo bioimaging in healthy mice.: Systemic DNA Administration in Healthy Mice

Author

David , Stéphanie, Passirani , Catherine, Benoit , Jean-Pierre, Carmoy , Nathalie, Morille , Marie, Mevel , Mathieu, Chatin , Benoit, Montier , Tristan, Pitard , Bruno, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), IBISA ' SynNanoVect ' platform, Université de Brest (UBO)-IFR148 ScInBioS, DUMG, In Cell Art, This work was supported by special grants from the 'Association Française contre les Myopathies' (Evry, France), 'Vaincre la Mucoviscidose' (Paris, France), 'Région Pays de la Loire' (CIMATH), 'Biogenouest', 'Région Bretagne', 'Ligue contre le cancer 29', and the 'Canceropole Grand Ouest'., Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078), EFS-Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Brest ( UBO ) -IFR148 ScInBioS, and Université de Brest ( UBO )

Subjects
[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, lipid nanocapsules, [ SDV.MHEP.ME ] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, ABC phenomenon, repeated administration, multimodular systems, targeting
Abstract

International audience; We hereby present different DNA nanocarriers consisting of new multimodular systems (MMS), containing the cationic lipid dioleylaminesuccinylparomomycin (DNA MMS DOSP), or bis (guanidinium)-tren-cholesterol (DNA MMS BGTC), and DNA lipid nanocapsules (DNA LNCs). Active targeting of the asialoglycoprotein receptor (ASGP-R) using galactose as a ligand for DNA MMS (GAL DNA MMS) and passive targeting using a polyethylene glycol coating for DNA LNCs (PEG DNA LNCs) should improve the properties of these DNA nanocarriers. All systems were characterized via physicochemical methods and the DNA payload of DNA LNCs was quantified for the first time. Afterwards, their biodistribution in healthy mice was analyzed after encapsulation of a fluorescent dye via in vivo biofluorescence imaging (BFI), revealing various distribution profiles depending on the cationic lipid used and their surface characteristics. Furthermore, the two vectors with the best prolonged circulation profile were administered twice in healthy mice revealing that the new DNA MMS DOSP vectors showed no toxicity and the same distribution profile for both injections, contrary to PEG DNA LNCs which showed a rapid clearance after the second injection, certainly due to the accelerated blood clearance phenomenon.Molecular Therapy - Nucleic Acids (2013) 2, e64; doi:10.1038/mtna.2012.56; published online 8 January 2013.

Published
2013

16. Self-assembled hyaluronan nanocapsules for the intracellular delivery of anticancer drugs

Author

Dolores Torres, Pradeep K. Dhal, Maria de la Fuente, Marcos Garcia-Fuentes, Ana Cadete, Lídia Gonçalves, Guillaume Bastiat, Magnus Besev, María J. Alonso, Jean-Pierre Benoit, António J. Almeida, Ana Olivera, Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Faculdade de Engenharia da Universidade do Porto, University of Porto, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques, and Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)

Subjects
0301 basic medicine, Lung Neoplasms, lcsh:Medicine, Antineoplastic Agents, Docetaxel, Article, Nanocapsules, Cell delivery, Surface-Active Agents, 03 medical and health sciences, chemistry.chemical_compound, Drug Delivery Systems, 0302 clinical medicine, Hyaluronic acid, Zeta potential, medicine, Humans, Hyaluronic Acid, Cytotoxicity, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Chemistry, lcsh:R, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, In vitro, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, 030104 developmental biology, Chemical engineering, A549 Cells, Drug delivery, Nanoparticles, Nanomedicine, lcsh:Q, 030217 neurology & neurosurgery, Intracellular, Chemical modification, medicine.drug
Abstract

Preparation of sophisticated delivery systems for nanomedicine applications generally involve multi-step procedures using organic solvents. In this study, we have developed a simple self-assembling process to prepare docetaxel-loaded hyaluronic acid (HA) nanocapsules by using a self-emulsification process without the need of organic solvents, heat or high shear forces. These nanocapsules, which comprise an oily core and a shell consisting of an assembly of surfactants and hydrophobically modified HA, have a mean size of 130 nm, a zeta potential of −20 mV, and exhibit high docetaxel encapsulation efficiency. The nanocapsules exhibited an adequate stability in plasma. Furthermore, in vitro studies performed using A549 lung cancer cells, showed effective intracellular delivery of docetaxel. On the other hand, blank nanocapsules showed very low cytotoxicity. Overall, these results highlight the potential of self-emulsifying HA nanocapsules for intracellular drug delivery. The authors acknowledge financial support from Xunta de Galicia (Competitive Reference Groups-FEDER Funds GRC2013-043). A. Cadete acknowledges her doctoral fellowship from the European Commission (EACEA) under the Nanofar program, Erasmus Mundus Joint Doctorate (EMJD). A. Olivera acknowledges her doctoral fellowship from the Spanish Ministry of Science, Innovation and Universities (grant number BES-2015-071236) SI

Published
2019

17. Self-assemblies of azacitidine prodrug: An innovative therapy against myelodysplastic syndromes

Author

Baroud, Milad, Lepeltier, Elise, Thepot, Sylvain, Passirani, Catherine, Duval, Olivier, Micro et Nanomédecines Biomimétiques, Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service des maladies du sang [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratory of Cancer Biology and Molecular Immunology, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract

International audience; 5-azacitidine, a cytidine analogue and a hypomethylating agent, is one of the main drugs being used for the treatment of myelodysplastic syndromes . However after administration, it exhibits several limitations including restricted diffusion and cellular internalization due to its hydrophilicity, and rapid enzymatic degradation. Our objective is to improve the drug diffusion and to protect it from metabolic degradation via the formulation of an amphiphilic prodrug and its self-assembly into a nanoparticle. Following the conjugation of the fatty acid to the azacitidine, the obtained prodrug was solubilized in acetone and mixed with water at different ratios to obtain self-assemblies by nanoprecipitation, thus protecting the active molecule from enzymatic degradation. This prodrug should be cleaved by cathepsin B , an enzyme overexpressed in cancerous cells , thus increasing the specificity of the drug.

Published
2019

18. Nanoprecipitated catestatin released from pharmacologically active microcarriers (PAMs) exerts pro-survival effects on MSC

Author

Claudia Penna, Cédric Paniagua, Marie-Claire Venier-Julienne, Claudia N. Montero-Menei, Carmelina Angotti, Pasquale Pagliaro, Laurence Sindji, Saveria Femminò, Università degli studi di Torino = University of Turin (UNITO), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Michel-Avella, Amandine

Subjects
Catestatin, Drug delivery, Hypoxia, Mesenchymal stem cells, Microcarriers, 0301 basic medicine, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Biocompatible Materials, Nanotechnology, Pharmacology, 03 medical and health sciences, parasitic diseases, Humans, Centrifugation, Drug Carriers, Chemistry, Mesenchymal stem cell, Microcarrier, Cell Differentiation, Controlled release, Peptide Fragments, In vitro, [SDV] Life Sciences [q-bio], Polymeric microspheres, 030104 developmental biology, Chromogranin A, Stress conditions, human activities
Abstract

International audience; Catestatin (CST), a fragment of Chromogranin-A, exerts angiogenic, arteriogenic, vasculogenic and cardioprotective effects. CST is a very promising agent for revascularization purposes, in "NOOPTION" patients. However, peptides have a very short half-life after administration and must be conveniently protected. Fibronectin-coated pharmacologically active microcarriers (FN-PAM), are biodegradable and biocompatible polymeric microspheres that can convey mesenchymal stem cell (MSCs) and therapeutic proteins delivered in a prolonged manner. In this study, we first evaluated whether a small peptide such as CST could be nanoprecipitated and incorporated within FN-PAMs. Subsequently, whether CST may be released in a prolonged manner by functionalized FN-PAMs (FN-PAM-CST). Finally, we assessed the effect of CST released by FN-PAM-CST on the survival of MSCs under stress conditions of hypoxia-reoxygenation. An experimental design, modifying three key parameters (ionic strength, mixing and centrifugation time) of protein nanoprecipitation, was used to define the optimum condition for CST. An optimal nanoprecipitation yield of 76% was obtained allowing encapsulation of solid CST within FN-PAM-CST, which released CST in a prolonged manner. In vitro, MSCs adhered to FN-PAMs, and the controlled release of CST from FN-PAM-CST greatly limited hypoxic MSC-death and enhanced MSC-survival in post-hypoxic environment. These results suggest that FN-PAM-CST are promising tools for cell-therapy.

Published
2017

19. Design, Synthesis, Pharmacological Evaluation and Vascular Effects of Delphinidin Analogues

Author

Yannick Abatuci, Olivier Duval, Claire Lugnier, Sébastien Faure, Jean-Jacques Helesbeux, Hélène Justiniano, Samuel Legeay, Kien Trân, Université d'Angers (UA), Biophotonique et Pharmacologie (CNRS UMR 7213), Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), and Substances d'Origine Naturelle et Analogues Structuraux (SONAS)

Subjects
Vasodilator Agents, Aorta, Thoracic, Pharmacology, Nitric Oxide, Nitric oxide, Anthocyanins, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, In vivo, Drug Discovery, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, Endothelial dysfunction, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Anthocyanidin, 0303 health sciences, Cyclic nucleotide phosphodiesterase, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Estrogen Receptor alpha, Biological activity, medicine.disease, In vitro, chemistry, 030220 oncology & carcinogenesis, Drug Design, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Delphinidin
Abstract

Background: Among polyphenolic compounds suggested to prevent cardiovascular diseases (CVDs) and to explain the “French paradox”, the anthocyanidin delphinidin (Dp) has been reported to support at least partly the vascular beneficial effects of dietary polyphenolic compounds including those from fruits and related products as red wine. It has also been highlighted that Dp interacts directly with the active site of estrogen receptor α (ERα), leading to activation of endothelial NO synthase (eNOS) pathway thus contributing to the prevention of endothelial dysfunction in mice aorta. However, anthocyanidins have very low bioavailability and despite a well described in vitro efficacy, the very high hydrophilicity and physicochemical instability of Dp might explain the lack of in vivo reported effects. Objective: The aim of this study was to identify new Dp analogues with increased lipophilicity and vasorelaxation potential by a chemical modulation of its structure and to characterize the signaling pathway notably in relation with ERα signaling and nitric oxide (NO) production. Method: OCH3-substituted delphinidin analogues were obtained through the coupling of the corresponding acetophenones with substituted benzaldehydes. Prediction of resorption of the flavylium derivatives was performed with the calculated logP and induction of vasorelaxation was performed by myography on WT and ERαKO mice thoracic aorta rings and compared to Dp. NO production was evaluated in vitro on human primary endothelial cells. Results: Eight Dp analogues were synthesized including four new flavylium derivatives. Two compounds (9 and 11) showed a strong increase of vasorelaxation potential and a theoretically increased bioavailability compared to Dp. Interestingly, 9 and 11 induced increased O2 - or NO endothelial production respectively and revealed a novel NO-dependent ERα-independent relaxation compared to Dp. We suggested that this mechanism may be at least in part supported by the inhibition of vascular cyclic nucleotide phosphodiesterase (PDEs). Conclusion: The current study demonstrated that pharmacomodulation of the Dp backbone by replacement of OH groups by OCH3 groups of the A and B rings led to the identification and characterization of two compounds (9 and 11) with enhanced physio-chemical properties that could be associated to higher permeability capability and pharmacological activity for the prevention of CVDs compared to Dp.

Published
2019

20. Understanding the adsorption of salmon calcitonin, antimicrobial peptide AP114 and polymyxin B onto lipid nanocapsules

Author

Patrick Saulnier, Anita Umerska, Anne-Claire Groo, Nada Matougui, Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)

Subjects
Calcitonin, Plectasin, Surface Properties, [SDV]Life Sciences [q-bio], Static Electricity, Pharmaceutical Science, Nanoparticle, Peptide, NZ2114, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Lipid nanocapsules, Surface-Active Agents, symbols.namesake, Adsorption, Anti-Infective Agents, Nanocapsules, Pulmonary surfactant, Dynamic light scattering, Zeta potential, Particle Size, Polymyxin B, chemistry.chemical_classification, Drug Carriers, Chromatography, Chemistry, Langmuir adsorption model, Pulmonary Surfactants, 021001 nanoscience & nanotechnology, Lipids, 0104 chemical sciences, Chemical engineering, Hydrodynamics, symbols, nanoparticles, AP114, Nanocarriers, Peptides, Antimicrobial peptide, 0210 nano-technology
Abstract

International audience; The adsorption of therapeutic molecules, e.g., peptides, onto nanocarriers is influenced by the properties of the carrier, adsorbed molecule and continuous phase. Hence, through changes in the composition of the nanocarrier and the medium, it should be possible to tune the system to make it capable of efficiently adsorbing peptides. The adsorption of calcitonin, antimicrobial peptide AP114 and polymyxin B onto lipid nanocapsules was investigated. The adsorption data were fitted to a Langmuir isotherm. Dynamic light scattering and laser Doppler velocimetry were used to investigate the changes in the hydrodynamic diameter and zeta potential, respectively, of the nanocarrier. The peptide adsorption was primarily governed by electrostatic forces; however, even without the presence of an ionisable surfactant, a significant amount of each tested molecule was adsorbed due to the enormous surface area of the nanocarriers and to peptide-nanocarrier interactions. The addition of an ionisable lipophilic surfactant, lecithin, improved the adsorption yield, which reached values of up to 100%. The adsorption yield and the properties of the nanocarrier, particularly the zeta potential, depended on the carrier and peptide concentrations and their mixing ratio. The adsorption of all tested molecules obeyed the Langmuir model over a limited concentration range.

Published
2016

21. Demonstration of the interactions between aromatic compound-loaded lipid nanocapsules and Acinetobacter baumannii bacterial membrane

Author

Angélique Montagu, Elisabeth Rossines, Marie-Laure Joly-Guillou, Jérôme Bejaud, Patrick Saulnier, Catherine Guillet, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie en Santé (PHB-IRIS) [CHU Angers] (IBS), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service Commun de Cytometrie et d'analyse Nucleotidique - SCCAN [CHU Angers] (Institut de Biologie en Santé), Eydopharma [Romorantin-Lanthenay], and Univ Angers, Okina

Subjects
Acinetobacter baumannii, 0301 basic medicine, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Aromatic compounds, DiO-lipid nanocapsules, [SDV]Life Sciences [q-bio], 030106 microbiology, Pharmaceutical Science, Multi-drug resistant bacteria, Cinnamaldehyde, 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, Nanocapsules, Carvacrol, Acrolein, Pump mechanism, biology, Biological membrane, 04 agricultural and veterinary sciences, Carbocyanines, biology.organism_classification, Lipids, 040401 food science, Hydroxyl functions, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], Membrane, Biochemistry, chemistry, Monoterpenes, Cymenes, Efflux, Antibacterial activity, Bacteria, Acinetobacter Infections
Abstract

International audience; Acinetobacter baumannii is an important nosocomial pathogen that is resistant to many commonly-used antibiotics. One strategy for treatment is the use of aromatic compounds (carvacrol, cinnamaldehyde) against A. baumannii. The aim of this study was to determine the interactions between bacteria and lipid nanocapsules (LNCs) over time based on the fluorescence of 3,3'-Dioctadecyloxacarbocyanine Perchlorate-LNCs (DiO-LNCs) and the properties of trypan blue to analyse the physicochemical mechanisms occurring at the level of the biological membrane. The results demonstrated the capacity of carvacrol-loaded LNCs to interact with and penetrate the bacterial membrane in comparison with cinnamaldehyde-loaded LNCs and unloaded LNCs. Modifications of carvacrol after substitution of hydroxyl functional groups by fatty acids demonstrated the crucial role of hydroxyl functions in antibacterial activity. Finally, after contact with the efflux pump inhibitor, carbonylcyanide-3-chlorophenyl hydrazine (CCCP), the results indicated the total synergistic antibacterial effect with Car-LNCs, showing that CCCP is associated with the action mechanism of carvacrol, especially at the level of the efflux pump mechanism.

Published
2016

22. MRI-visible polymer based on poly(methyl methacrylate) for imaging applications

Author

John El Nakat, Xavier Garric, Cédric Paniagua, Youssef Bakkour, Jean Coudane, Mira Younis, Laurent Lemaire, Benjamin Nottelet, Vincent Darcos, Pauline Ronjat, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), University of Balamand - UOB (LIBAN), Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)

Subjects
chemistry.chemical_classification, Materials science, [SDV]Life Sciences [q-bio], General Chemical Engineering, Radical polymerization, 02 engineering and technology, General Chemistry, Polymer, 021001 nanoscience & nanotechnology, Methacrylate, Poly(methyl methacrylate), 030218 nuclear medicine & medical imaging, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Monomer, chemistry, visual_art, Polymer chemistry, Click chemistry, visual_art.visual_art_medium, Copolymer, Methyl methacrylate, 0210 nano-technology
Abstract

International audience; Macromolecular contrast agents are very attractive to afford efficient magnetic resonance imaging (MRI) visualization of implantable medical devices. In this work, we report on the grafting of a Gd-based DTPA contrast agent onto a poly(methyl methacrylate) derivative backbone by combining free radical polymerization and copper-catalyzed azide-alkyne cycloaddition (CuAAC). Using free radical polymerization, poly(methyl methacrylate-co-propargyl methacrylate) copolymers were prepared with a control of the ratio in propargyl methacrylate monomer units. The synthesis of a new azido monofunctionalized DTPA ligand was also reported and characterized by 1H NMR and mass spectroscopy. After complexation with gadolinium, this ligand has been grafted on the polymer backbone by click chemistry reaction. The obtained macromolecular contrast agent was then coated on a polypropylene mesh using the airbrushing technique and the mesh was assessed for MRI visualization at 7 teslas. The polymeric contrast agent was also tested for cytocompatibility and stability to assess its suitability for biomedical applications.

Published
2016

23. Polyphenols Have No Impact on Endothelial Function in Patients with Obstructive Sleep Apnea: A Randomized Controlled Trial

Author

Maria Carmen Martinez, Khaled Messaoudi, Sylvain Recoquillon, Astrid Darsonval, N. Meslier, Samir Henni, Frédéric Gagnadoux, Ramaroson Andriantsitohaina, Pascaline Priou, Wojciech Trzepizur, Jean-François Hamel, Vanessa Bironneau, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pneumologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de recherche clinique, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacie, Micro et Nanomédecines Biomimétiques, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Mitochondrie : Régulations et Pathologie, Biologie Neurovasculaire Intégrée (BNVI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Micro et Nanomédecines Biomimétiques (MINT)

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Hyperemia, 030204 cardiovascular system & hematology, Placebo, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Heart Rate, Internal medicine, Heart rate, medicine, Humans, Vitis, Continuous positive airway pressure, Endothelial dysfunction, Reactive hyperemia, ComputingMilieux_MISCELLANEOUS, Sleep Apnea, Obstructive, Nutrition and Dietetics, Continuous Positive Airway Pressure, business.industry, Sleep apnea, Polyphenols, Middle Aged, medicine.disease, Atherosclerosis, 3. Good health, Obstructive sleep apnea, Blood pressure, 030228 respiratory system, Fruit, Cardiology, Female, Endothelium, Vascular, business
Abstract

Background Endothelial dysfunction, a pathophysiologic determinant of atherogenesis, has been found to occur in obstructive sleep apnea syndrome (OSA) and is improved by continuous positive airway pressure (CPAP). However, the efficacy of CPAP therapy is limited by variable adherence. Alternative treatment strategies are needed. The impact of polyphenols on endothelial function has never been evaluated in OSA. Objective We evaluated the impact of 1-mo supplementation with grape juice polyphenols (GJPs) on the reactive hyperemia index (RHI), a validated measure of endothelial function in patients with severe OSA. Methods Forty participants [75% men, median (IQR) age: 61 y (34, 64 y), BMI (in kg/m2): 30.6 (20.9, 33.7)] with severe OSA [median apnea-hypopnea index 43/h (33/h, 56/h)] were randomly assigned to receive GJPs (300 mg/d; n = 20) or placebo (n = 20) for 1 mo. The primary outcome was the change in RHI between baseline and after 1 mo of GJPs or placebo. Secondary outcome measures included changes in blood pressure (BP), heart rate (HR), and polysomnographic indexes. Results No significant differences in RHI and BP outcomes were observed between the GJPs and placebo groups. A significant between-group difference was observed for HR changes [-1 bpm (-5, +5 bpm) in the GJPs group compared with +6 bpm (+3, +10 bpm) in the placebo group; P = 0.001]. A significant decrease in total sleep time was observed in the GJPs group compared with the placebo group [-10 min (-33, 6 min) compared with +15 min (-12, 40 min), respectively; P = 0.02], with no between-group differences in the distribution of sleep stages. Conclusions In participants with severe OSA and no overt cardiovascular disease, 1-mo GJP supplementation had no effect on endothelial function. This trial was registered at clinicaltrials.gov as NCT01977924.

Published
2018

24. Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity

Author

Hassan Nehme, Patrick Saulnier, Alyaa A Ramadan, Viviane Cassisa, Catherine Guillet, Matthieu Eveillard, Anita Umerska, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmaceutics [Alexandria, Egypt], Alexandria University [Alexandrie], Laboratoire de Bactériologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service Commun de Cytometrie et d'analyse Nucleotidique - SCCAN [CHU Angers] (Institut de Biologie en Santé), ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Alexandria University, Centre Hospitalier Universitaire d'Angers, Service Commun de Cytometrie et d'analyse Nucleotidique - SCCAN [CHU Angers] ( Institut de Biologie en Santé ), CHU Angers, ATIP AVENIR / ATOMycA ( CRCINA - Département INCIT - Equipe 6 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Cibles thérapeutiques, formulation et expertise pré-clinique du médicament ( CITHEFOR ), Université de Lorraine ( UL ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Escherichia, Chlorpromazine, Staphylococcus, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Microbial Sensitivity Tests, In Vitro Techniques, Gram-Positive Bacteria, Pathology and Laboratory Medicine, Research and Analysis Methods, Microbiology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Model Organisms, Nanocapsules, Enterobacteriaceae, [SDV.CAN] Life Sciences [q-bio]/Cancer, Microbial Control, Gram-Negative Bacteria, Medicine and Health Sciences, Antipsychotics, Staphylococcus Aureus, lcsh:Science, Microbial Pathogens, Pharmacology, Escherichia Coli, Bacteria, Acinetobacter, Antimicrobials, lcsh:R, Gut Bacteria, Organisms, Drugs, Biology and Life Sciences, Lipids, Anti-Bacterial Agents, Bacterial Pathogens, Experimental Organism Systems, Medical Microbiology, Antibiotic Resistance, Antibacterials, Prokaryotic Models, lcsh:Q, Antimicrobial Resistance, Pathogens, Acinetobacter Baumannii, Antipsychotic Agents, Research Article
Abstract

International audience; Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described antipsychotic compounds that present antibacterial activity. Hence, the aims of this study were to evaluate the in vitro antibacterial activity of antipsychotics belonging to different chemical families, to assess the influence of their association with lipid nanocapsules (LNCs) on their antimicro-bial activity as well as drug release and to study the uptake of LNCs by bacterial cells. Anti-bacterial activity was evaluated against Gram-positive Staphylococcus aureus and Gram negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acineto-bacter baumannii by minimum inhibitory concentration (MIC) assay, and the capability of killing tested microorganisms was evaluated by time kill assay. LNCs were prepared by phase inversion method, and the antipsychotic agents were incorporated using pre-loading and post-loading strategies. Only phenothiazines and thioxanthenes showed antibacterial activity , which was independent of antibiotic-resistance patterns. Loading the nanocarriers with the drugs affected the properties of the former, particularly their zeta potential. The release rate depended on the drug and its concentration—a maximum of released drug of less than 40% over 24 hours was observed for promazine. The influence of the drug associations on the antibacterial properties was concentration-dependent since, at low concentrations (high nanocarrier/drug ratio), the activity was lost, probably due to the high affinity of the drug to nanocarriers and slow release rate, whereas at higher concentrations, the activity was well maintained for the majority of the drugs. Chlorpromazine and thioridazine increased the uptake of the LNCs by bacteria compared with blank LNCs, even below the minimum inhibitory concentration.

Published
2018

25. Clinical and biological characterization of MPN patients harboring two driver mutations, a French intergroup of myeloproliferative neoplasms (FIM) study

Author

Jean-François Viallard, Jasmine Chauzeix, Didier Adiko, Valérie Ugo, Jean-Christophe Ianotto, Olivier Fitoussi, Mohamed Touati, Stéphane Giraudier, Olivier Mansier, Françoise Boyer, Yannick Le Bris, Damien Luque Paz, Jérémie Riou, Eric Lippert, Marie C. Béné, Aurélie Chauveau, Carole Conejero, Bernardo, Elizabeth, UFR Sciences de la Vie et de la Santé [Bordeaux], Université de Bordeaux (UB), Laboratoire d'Hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), UFR Santé [Angers], Laboratoire d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Service d'hématologie clinique [CHRU de Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'Hematologie [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), UFR Médecine [Brest], Service des maladies du sang [Angers], Laboratoire d'hématologie [AP-HP Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d’Hémato-oncologie [Polyclinique Bordeaux Nord Aquitaine], Polyclinique Bordeaux Nord Aquitaine, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine-Hématologie [CH Robert Boulin], Centre Hospitalier Libourne, Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, The authors would also like to thank all local tumor biobanks for providing high-quality samples and the French clinical and biological network of myeloproliferative neoplasms (FIMBANK) supported by a grant from the French National Institute of Cancer (INCa BCB 2013). OM was supported by the Ministère de l’Enseignement Superieur et de la Recherche., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux ( UB ), Actions for OnCogenesis understanding and Target Identification in ONcology ( ACTION ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Innate immunity and Immunotherapy ( CRCINA - Département INCIT - Equipe 7 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), CHU Angers, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078), EFS-Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d’Hématologie [CHRU de Brest], Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Université de Bretagne occidentale - UBO, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), CH Robert Boulin [Libourne], Contrôle de la Réponse Immune B et des Lymphoproliférations ( CRIBL ), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST ), and Université de Limoges ( UNILIM ) -Université de Limoges ( UNILIM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Kaplan-Meier Estimate, Statistics, Nonparametric, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Text mining, Age Distribution, Gene Frequency, [SDV.CAN] Life Sciences [q-bio]/Cancer, Article CLINIQUE, Medicine, Humans, Sex Distribution, ComputingMilieux_MISCELLANEOUS, Aged, Proportional Hazards Models, Myeloproliferative Disorders, business.industry, Thrombosis, Hematology, Janus Kinase 2, Middle Aged, Prognosis, Leukemia, Myeloid, Acute, Phenotype, 030220 oncology & carcinogenesis, Mutation, Disease Progression, Female, business, Calreticulin, Receptors, Thrombopoietin, 030215 immunology, Follow-Up Studies
Abstract

International audience; no abstract

Published
2018

26. Combined therapy for critical limb ischaemia: Biomimetic PLGA microcarriers potentiates the pro-angiogenic effect of adipose tissue stromal vascular fraction cells

Author

Laurence Sindji, Franck Festy, Sophie Mirbeau, Cynthia Planesse, Laurence Hoareau, Régis Roche, Florian Fouchet, Emmanuel Delay, Claudia N. Montero-Menei, Stemcis [Sainte Clotilde, La Réunion] (Platform CYROI), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Private Surgery Office [Lyon], French National Research Agency., Bernardo, Elizabeth, Stemcis [Sainte Clotilde, La Réunion] ( Platform CYROI ), Micro et nanomédecines biomimétiques ( MINT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Angers ( UA ) -Université Bretagne Loire ( UBL ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
0301 basic medicine, Male, Necrosis, medicine.medical_treatment, Medicine (miscellaneous), Adipose tissue, 02 engineering and technology, Pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, Polylactic Acid-Polyglycolic Acid Copolymer, limb ischaemia, Biomimetic Materials, Ischemia, Glycolic acid, γ‐irradiation, Mice, Inbred BALB C, PLGA, Stromal vascular fraction, 021001 nanoscience & nanotechnology, Microspheres, Hindlimb, adipose tissue, Perfusion, medicine.symptom, 0210 nano-technology, biomaterials, Adult, Static Electricity, Biomedical Engineering, Mice, Nude, Neovascularization, Physiologic, Arteriotomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, microcarriers, laminin, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Cell Adhesion, Animals, Humans, Particle Size, stromal vascular fraction cells, Microcarrier, Blood flow, Proprioception, Molecular Weight, 030104 developmental biology, chemistry, Regional Blood Flow, Stromal Cells
Abstract

International audience; We propose a regenerative solution in the treatment of critical limb ischaemia (CLI). Poly‐lactic/glycolic acid microcarriers were prepared and coated with laminin to be sterilized through γ‐irradiation of 25 kGy at low temperature. Stromal vascular fraction (SVF) cells were extracted through enzymatic digestion of adipose tissue. Streptozotocin‐induced diabetic mice underwent arteriotomy and received an administration of SVF cells combined or not with biomimetic microcarriers. Functional evaluation of the ischaemic limb was then reported, and tissue reperfusion was evaluated through fluorescence molecular tomography. Microcarriers were stable and functional after γ‐irradiation until at least 12 months of storage. Mice that received an injection of SVF cells in the ischaemic limb have 22% of supplementary blood supply within this limb 7 days after surgery compared with vehicle, whereas no difference was observed at Day 14. With the combined therapy, the improvement of blood flow is significantly higher compared with vehicle, of about 31% at Day 7 and of about 11% at Day 14. Injection of SVF cells induces a significant 27% decrease of necrosis compared with vehicle. This effect is more important when SVF cells were mixed with biomimetic microcarriers: −37% compared with control. Although SVF cells injection leads to a non‐significant 22% proprioception recovery, the combined therapy induces a significant recovery of about 27% compared with vehicle. We show that the combination of SVF cells from adipose tissue with laminin‐coated poly‐lactic/glycolic acid microcarriers is efficient for critical limb ischaemia therapy in a diabetic mouse model.

Published
2018

27. 18F-Flurodeoxyglucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging of Arterial and Cutaneous Alterations in Pseudoxanthoma Elasticum

Author

Pierre-Jean Mention, Georges Leftheriotis, Ludovic Martin, Franck Lacoeuille, Loukman Omarjee, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Dermatologie [CHU Angers] (PXE - le PseudoXanthome Elastique), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), LP2M - Laboratoire de PhysioMédecine Moléculaire [CHU Nice], Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU de Nice), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Biologie Neurovasculaire et Mitochondriale Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Dermatologie [CHU Angers] ( PXE - le PseudoXanthome Elastique ), CHU Angers, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre Hospitalier Universitaire de Nice ( CHU de Nice ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Tunica media, Adult, Male, Pathology, medicine.medical_specialty, Fluorine Radioisotopes, [SDV]Life Sciences [q-bio], ABCC6, 030204 cardiovascular system & hematology, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, sodium fluoride, medicine, Humans, Radiology, Nuclear Medicine and imaging, pseudoxanthoma elasticum, Vascular Calcification, ComputingMilieux_MISCELLANEOUS, Inflammation, medicine.diagnostic_test, biology, [ SDV ] Life Sciences [q-bio], business.industry, Metabolic disorder, medicine.disease, Pseudoxanthoma elasticum, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Positron emission tomography, biology.protein, Radiopharmaceuticals, Cardiology and Cardiovascular Medicine, business, Artery, Calcification
Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder characterized by fragmentation and progressive calcification of elastic fibers in connective tissues, such as the skin, vascular system, and Bruch’s membrane.1 PXE is caused by mutations in the ABCC6 gene, on the short arm of chromosome 16, encoding a transmembrane ATP-binding anion transporter primarily expressed in the liver/kidney.1 Its pathophysiology is unknown, but in several studies, normal tissues exposed to patient with PXE serum/plasma tend to calcify.1 PXE manifestations include yellowish papules on the neck and in large skin folds and cardiovascular complications, such as peripheral artery disease resulting from tunica media calcifications in medium/small-sized arteries.1 Vascular histological studies are limited by poor availability of artery tissue in patients with advanced disease and are unsuitable for longitudinal study of disease progression. Alternative techniques are, therefore, required to investigate the pathogenesis and progression of this condition. In a previous case series, skin and vascular calcification was investigated using 18F-sodium fluoride (18F-NaF) positron emission tomography combined with computed tomographic imaging in 4 patients with PXE.2 18F-flurodeoxyglucose (18F-FDG) has been used in several studies to investigate vascular conditions wherein inflammation is considered essential in the pathogenesis of conditions, such as atherosclerotic plaque.3 Our report hypothesized that in patients with PXE, low-grade chronic inflammation may precede or evolve concomitantly with skin and vascular wall calcification. We report the case of a 42-year-old smoker, …

Published
2018

28. Absence of lung fibrosis after a single pulmonary delivery of lipid nanocapsules in rats

Author

Aurelien Contini, José Hureaux, Frédéric Lagarce, Patrick Saulnier, Thierry Urban, Marie-Christine Rousselet, Jean-Pierre Benoit, Franck Lacoeuille, Service de Pneumologie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service de Médecine Nucléaire [CHU Angers] (Pôle Signal Image Stérilisation), Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Département de Cytologie et d’Histologie Pathologique [CHU Angers] (Pôle de Biologie-Pathologie), Service de la Recherche Clinique et Innovation [CHU Angers], This work was performed with the financial support of the Institut Régional en Santé Respiratoire dans les Pays de la Loire (rue du Landreau, Beaucouzé, France), the Comité départemental du Maine-et-Loire et de Charente, Cancéropôle Grand Ouest and the Bretagne, Centre, Pays de la Loire and Poitou-Charentes Régions., Micro et nanomédecines biomimétiques ( MINT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Angers ( UA ) -Université Bretagne Loire ( UBL ), Service de Pneumologie [CHU Angers] ( Pôle Hippocrate ), Université d'Angers ( UA ) -CHU Angers, Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de Médecine Nucléaire [CHU Angers] ( Pôle Signal Image Stérilisation ), Département de Pharmacie [CHU Angers] ( Pôle Hippocrate ), Département de Cytologie et d’Histologie Pathologique [CHU Angers] ( Pôle de Biologie-Pathologie ), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Pulmonary toxicity, Pharmaceutical Science, 02 engineering and technology, Pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Rats, Sprague-Dawley, 0302 clinical medicine, Drug Delivery Systems, International Journal of Nanomedicine, Drug Discovery, Tissue Distribution, Lung, Phospholipids, Original Research, Drug Carriers, lipid nanocapsules, Chemistry, General Medicine, respiratory system, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, medicine.anatomical_structure, Toxicity, Drug delivery, Female, Pulmonary alveolus, medicine.symptom, pulmonary drug delivery, 0210 nano-technology, Drug carrier, Biodistribution, Paclitaxel, Biophysics, Bioengineering, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, Biomaterials, Lesion, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Nanocapsules, medicine, Animals, Humans, Surface Tension, biodistribution, Aerosols, Biological Products, Organic Chemistry, toxicity, Fibrosis, Pulmonary Alveoli, 030228 respiratory system
Abstract

José Hureaux,1,2 Franck Lacœuille,3,4 Frédéric Lagarce,1,5 Marie-Christine Rousselet,6 Aurélien Contini,3,4 Patrick Saulnier,1,7 Jean-Pierre Benoit,1,5 Thierry Urban1,2 1Unité Micro et Nanomédecines Biomimétiques (MINT), Université d’Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, 2Université d’Angers, CHU, Pôle Hippocrate, Service de Pneumologie, 3Université d’Angers, CHU, Pôle Signal Image Stérilisation, Service de Médecine nucléaire, 4CRCINA, Université Nantes Université Angers, 5Université d’Angers, CHU, Pôle Hippocrate, Pharmacie, 6Université d’Angers, CHU, Pôlede Biologie-Pathologie, Département de Cytologie et d’Histologie Pathologique, 7Université d’Angers, CHU, Service la Recherche Clinique et Innovation, Angers, France Abstract: Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy. Keywords: lipid nanocapsules, pulmonary drug delivery, biodistribution, toxicity, paclitaxel

Published
2017

29. Sustained release of TGF-β1 from biodegradable microparticles prepared by a new green process in CO2 medium

Author

Frank Boury, Pierre Weiss, Alison Dénarnaud, Jérôme Guicheux, Cécile Boyer, Thomas Cordonnier, Amin Swed, Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)

Subjects
Transforming growth factor beta1 (TGF-b1), Protein encapsulation, Cell Survival, Scanning electron microscope, Drug Compounding, [SDV]Life Sciences [q-bio], Glycofurol, Pharmaceutical Science, Nanotechnology, isosorbide dimethyl ether, Isosorbide Dimethyl Ether, Cell Line, Transforming Growth Factor beta1, Injectable solvent, chemistry.chemical_compound, Polylactic Acid-Polyglycolic Acid Copolymer, Zeta potential, Animals, Humans, Lactic Acid, sustained release, Cytotoxicity, Mice, Knockout, chemistry.chemical_classification, Chemistry, Atomic force microscopy, Green Chemistry Technology, Polymer, Carbon Dioxide, Fibroblasts, 3. Good health, Lactic acid, Drug Liberation, Chemical engineering, Delayed-Action Preparations, Polyglycolic Acid, Transforming growth factor
Abstract

International audience; The aim of this work was to encapsulate transforming growth factor b1 (TGF-b1) into PLGA microparticles for regenerative medicine applications. TGF-b1 was firstly precipitated to ensure its stability during subsequent encapsulation within microparticles. A novel emulsification/extraction process in CO2 medium under mild conditions of pressure and temperature was used to encapsulate the protein. Interestingly, non-volatile injectable solvents, isosorbide dimethyl ether (DMI) and glycofurol (GF), were employed to precipitate the protein and to dissolve the polymer. Good encapsulation efficiency was obtained with preserved bioactivity of the protein. The microparticles were characterized in terms of size and zeta potential. In addition, the morphology and surface properties were determined using scanning electron microscopy (SEM) and atomic force microscopy (AFM) respectively. In vitro release study of the protein from microparticles was presented to assess the capacity of these systems to control the protein release. Moreover, cytotoxicity study was performed and showed an excellent cytocompatibility of the obtained microparticles. Thus, we described an effective and original process for TGF-b1 encapsulation into PLGA microparticles. The obtained polymeric carriers could be used in many biomedical applications and were more specifically developed for cartilage regeneration.

Published
2015

30. Synthetic vectors for gene delivery: An overview of their evolution depending on routes of administration

Author

Nawal Belmadi, Catherine Passirani, Pierre Lehn, Tony Le Gall, Tristan Montier, Pascal Loyer, Patrick Midoux, Chantal Pichon, Paul-Alain Jaffrès, 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), Université européenne de Bretagne - European University of Brittany (UEB), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Pôle de recheche et d'enseignement supérieur (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
Drug, Biodistribution, Routes of administration, [SDV]Life Sciences [q-bio], media_common.quotation_subject, Genetic Vectors, Cellular barriers, 02 engineering and technology, Computational biology, Pharmacology, Biology, Gene delivery, Applied Microbiology and Biotechnology, Cell Line, Mice, 03 medical and health sciences, Cations, Sense (molecular biology), Animals, Humans, Tissue Distribution, 030304 developmental biology, media_common, 0303 health sciences, Synthetic vectors, Gene Transfer Techniques, Genetic Therapy, General Medicine, Active protein, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, Nucleic acid, Molecular Medicine, Synthetic Biology, 0210 nano-technology, Function (biology), Potential toxicity
Abstract

International audience; Nucleic acid delivery constitutes an emerging therapeutic strategy to cure various human pathologies. This therapy consists of introducing genetic material into the whole body or isolated cells to correct a cellular abnormality or disfunction. As with any drug, the main objective of nucleic acid delivery is to establish optimal balance between efficacy and tolerance. The methods of administration and the vectors used are selected depending on whether the goal of treatment is the production of an active protein; the replacement of a missing or inactive gene; or the combat of acquired diseases, such as cancer or AIDS. In that sense, synthetic vectors represent a valuable solution because they are well characterized, their structure can be fine tuned, and their potential toxicity can be reduced, since toxicity depends on the composition of the formulations. Here we review various synthetic vectors for gene delivery and address the question of their biodistribution as a function of the route of administration. We highlight the modifications to vectors structure and formulations necessary to overcome the major hurdles limiting the effectiveness of nucleic acid therapies

Published
2015

31. Iron metabolism: a double-edged sword in the resistance of glioblastoma to therapies

Author

Claire Legendre, Emmanuel Garcion, Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)

Subjects
Iron, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Cell, Antineoplastic Agents, Disease, Biology, Resection, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Radioresistance, medicine, Humans, Hypoxia, 030304 developmental biology, 0303 health sciences, medicine.disease, Primary tumor, 3. Good health, radioresistance, medicine.anatomical_structure, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, drug delivery, Drug delivery, Cancer cell, Immunology, Cancer research, brain tumors, nanoparticles, Glioblastoma, iron signaling, Signal Transduction
Abstract

International audience; Glioblastoma (GBM), the deadliest primary tumor of the central nervous system (CNS), is a clear illustration of the resistance of cancer cells to conventional therapies. Application of combinatorial strategies able to overcome pivotal factors of GBM resistance, particularly within the resection margins, represents an essential issue. This review focuses on the role of iron metabolism in GBM progression and resistance to therapy, and the impact of its pharmaceutical modulation on the disease. Iron, through its involvement in many biological processes, is a key factor in the control of cell behavior and cancer biology. Therefore, targeting cellular iron signaling or taking advantage of its dysregulation in cancer cells may lead to new opportunities for improving treatments and drug delivery in GBM.

Published
2015

32. Toward an effective strategy in glioblastoma treatment. Part II: RNA interference as a promising way to sensitize glioblastomas to temozolomide

Author

Anne Clavreul, Frédéric Lagarce, Khaled Messaoudi, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), and Univ Angers, Okina

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor cells, Biology, Bioinformatics, RNAi Therapeutics, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, RNA interference, Drug Discovery, Biomarkers, Tumor, Temozolomide, medicine, Animals, Humans, Antineoplastic Agents, Alkylating, Pharmacology, Regulation of gene expression, Brain Neoplasms, Mechanism (biology), fungi, Gene Transfer Techniques, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, 3. Good health, Dacarbazine, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, medicine.drug, Glioblastoma
Abstract

International audience; RNA interference (RNAi) is a strategy of gene regulation that has opened up many opportunities for the treatment of cancers, especially glioblastoma multiforme (GBM). This strategy reduced the expression of many proteins involved in the resistance of these tumors to anticancer drugs, particularly to temozolomide (TMZ). A significant research effort has gone into RNAi delivery and target selection for clinical application of this new discovery in the treatment of GBMs. However, some limitations must be resolved to enhance the safety of RNAi-based therapeutics and to reduce their immune response. In this review, the mechanism of RNAi will be described. Moreover, the opportunities offered by RNAi strategy to reverse the phenotype of these tumor cells as well as prospects and challenges ahead in the RNAi-based therapy will be discussed.

Published
2015

33. 16α-[18F]-fluoro-17ß-oestradiol ([18F]FES): A biomarker for imaging oestrogen receptor expression with positron emission tomography (PET)

Author

Olivier Couturier, F. Benard, C. Lefebvre-Lacœuille, Caroline Rousseau, F. Lacœuille, F. Courbon, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)

Subjects
Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Biophysics, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Radiology, Nuclear Medicine and imaging, Oestrogen receptor, skin and connective tissue diseases, Receptor, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, Endocrine therapy, Cancer, medicine.disease, 3. Good health, Biomarker (cell), Positron emission tomography, 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, business
Abstract

International audience; Oestrogens play a major role in the development of gynaecological oestrogen-dependent diseases that overexpress oestrogen receptors (ER+). The ER status is assessed using immunohistochemistry analysis of tissues samples. It is believed that a non-invasive method such as positron emission tomography (PET) that would accurately evaluate and quantify in vivo the presence of ER could play an important role in managing such diseases. PET using fluorinated oestrogen analogues may be helpful in selecting patients who will benefit from endocrine therapy or could be used to identify high-grade cancer with poorer prognosis. Among more than 20 fluorinated oestrogens analogues that have been proposed as PET tracer candidates, 16a-[18F]fluoro-17b-oestradiol ([18F]FES) has been the most actively investigated in preclinical and clinical studies.

Published
2015

34. MRI-visible nanoparticles from hydrophobic gadolinium poly(ε-caprolactone) conjugates

Author

Xavier Garric, Benjamin Nottelet, Barbara Porsio, Sarah El Habnouni, Laurent Lemaire, Florence Franconi, Jean Coudane, Vincent Darcos, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Nottelet, Benjamin, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Porsio,B, Lemaire,L, El Habnouni, Darcos, V, Franconi, F, Garric, X, Coudane, J, and Nottelet, B

Subjects
[CHIM.POLY] Chemical Sciences/Polymers, Materials science, Polymers and Plastics, Biocompatibility, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Gadolinium, chemistry.chemical_element, Nanoparticle, 02 engineering and technology, Conjugated system, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Polymer chemistry, Materials Chemistry, polyester, Chelation, Organic Chemistry, 021001 nanoscience & nanotechnology, 0104 chemical sciences, [CHIM.POLY]Chemical Sciences/Polymers, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, chemistry, Propargyl, nanoparticles, Amine gas treating, 0210 nano-technology, Caprolactone, MRI
Abstract

International audience; In this work we report on the synthesis of two hydrophobic and degradable gadolinium poly(ε-caprolactone) conjugates and their use for the preparation of MRI-visible nanoparticles intended for diagnosis applications. Advantage has been taken from functional poly(ε-caprolactone)s (PCL) bearing propargyl (PCL-yne) or amine groups (P(CL-co-NH2VL)) to yield conjugates by following two strategies. In a first approach, an azido-chelate of gadolinium (Gd(III)) has been conjugated by CuAAC to PCL-yne to yield a polymeric chelate containing 2.6 wt% of Gd(III). In a second approach, a dianhydride Gd(III)-ligand was reacted with P(CL-co-NH2VL) to yield, after complexation with Gd(III) salts, a polymeric chelate containing 15.4 wt% of Gd(III). The polymers biocompatibility was assessed against L929 fibroblasts. In a second part, advantage was taken from the PCLs conjugates hydrophobicity to easily prepare by nanoprecipitation nanoparticles with diameters ranging from 120 to 170 nm. The nanoparticles MRI-visibility was then evaluated and confirmed under the spin-echo and the clinically relevant gradient-echo MRI sequences.

Published
2015

35. Novel nanoparticle-based drug delivery system for neural stem cell targeting and differentiation

Author

Carradori, Dario, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Université d'Angers, Université catholique de Louvain (1970-....), Joël Eyer, Patrick Saulnier, Anne Des Rieux, and STAR, ABES

Subjects
Neural stem cells, Acide rétinoïque, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Subventricular zone, Neurodegenerative diseases, Maladies neurodégénératives, Nanoparticules lipidiques, Cellules souches neurales, Zone subventriculaire, Lipid nanocapsules, Membrane plasmique, Nanomedicine, Nanomédecine, Retinoic acid, Nfl-Tbs.40-63, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Plasma membrane
Abstract

Neural stem cells (NSCs) are located in specific regions of the central nervous system called niches. Those cells are able to self-renew and to differentiate into specialized neuronal cells (neurons, astrocytes and oligodendrocytes). Due to this differentiation property, NSCs are studied to replace neuronal cells and restore neurological functions in patients affected by neurodegenerative diseases. Several therapeutic approaches have been developed and endogenous NSC stimulation is one of the most promising. Currently, there is no active molecule or therapeutic system targeting endogenous CSNs and inducing their differentiation at the same time. The aim of the work was to provide a drug delivery system able both to target endogenous CSNs and to induce their differentiation in situ. Here, we developed and characterized lipidic nanoparticles (LNC) targeting endogenous NSCs. A peptide called NFL-TBS.40-63, known for its affinity towards NSCs, was adsorbed at the surface of LNC. We observed that NFL-LNC specifically targeted NSC from the brain and not from the spinal cord in vitro and in vivo. To explain this specificity, we characterized and compared NFL-LNC interactions with the plasmatic membrane of both cell types. Finally, we demonstrated that by loading retinoic acid in NFL-LNC we were able to induce brain NSC differentiation in vitro and in vivo. This work contributes to the development of efficient and safe therapies for the treatment of neurodegenerative disease via the differentiation of endogenous NSCs., Les cellules souches neurales (CSNs) se situent dans des régions spécifiques du système nerveux central qui sont appelées niches. Ces cellules sont capables de se répliquer ou se différentier en cellules neurales spécialisées (neurones, astrocytes et oligodendrocytes). C’est grâce à cette propriété de différentiation que les CSNs sont étudiées comme thérapie chez les patients atteints d’une maladie neurodégénérative. En effet, elles pourraient remplacer les cellules neurales altérées et ainsi restaurer les fonctions neurologiques. De nombreuses approches ont été développées afin de stimuler la différentiation des CSNs, dont la plus prometteuse est la différentiation des cellules endogènes directement au sein de leurs niches. Actuellement, il n’existe pas de molécule active ou de système thérapeutique qui cible les CSNs endogènes et qui induit leur différentiation simultanément. Le but de ce travail est de fournir un système de délivrance de molécules bioactives capable de cibler les CSNs endogènes et d'induire leur différenciation in situ. Nous avons développé et caractérisé des nanoparticules lipidiques (LNC), un système de délivrance très versatile. NFL-TBS.40-63, un peptide ciblant les CSNs, a été adsorbé à la surface des LNC afin de les diriger contre les CSNs endogènes. Nous avons observé que ces NFL-LNC ne ciblaient que les CSNs du cerveau et pas de la moelle. Afin d’étudier les interactions spécifiques entre les nanoparticules et les CSNs, nous avons caractérisé et comparé les propriétés de leur membrane plasmique. Enfin, nous avons encapsulé de l’acide rétinoïque, une molécule connue pour stimuler la différentiation des CSNs, dans les LNC-NFL et étudié leur impact sur la différentiation de CSNs in vitro et in vivo. Ce travail contribue au développement de thérapies efficaces et sures pour le traitement de maladies neurodégénératives à travers la différentiation de CSNs endogènes.

Published
2017

36. Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model

Author

Simona Mura, Patrick Couvreur, Claudia Balducci, Karine Andrieux, Gianluigi Forloni, Julien Nicolas, Orfeu Flores, Benjamin Le Droumaguet, Francesca Re, Alice Gaudin, Massimo Masserini, Francisco Wandosell, Davide Brambilla, Lara Ordóñez-Gutiérrez, Dario Carradori, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Physico-chimie, pharmacotechnie, biopharmacie (PCPB), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie et des Matériaux Paris-Est (ICMPE), Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut Galien Paris-Sud (IGPS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), 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), Micro et Nanomédecines Biomimétiques, Université Bretagne Loire (UBL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CIBER de Enfermedades Neurodegenerativas (CIBERNED), 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), Carradori, D, Balducci, C, Re, F, Brambilla, D, Le Droumaguet, B, Flores, O, Gaudin, A, Mura, S, Forloni, G, Ordoñez-Gutierrez, L, Wandosell, F, Masserini, M, Couvreur, P, Nicolas, J, Andrieux, K, 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
Male, Polymers, Pharmaceutical Science, Medicine (miscellaneous), Peptide, 02 engineering and technology, Oligomer, chemistry.chemical_compound, Mice, 0302 clinical medicine, General Materials Science, ComputingMilieux_MISCELLANEOUS, Blood-brain barrier, chemistry.chemical_classification, biology, Chemistry, nanoparticle, Antibodies, Monoclonal, Alzheimer's disease, 021001 nanoscience & nanotechnology, nanomedicine, Cell biology, medicine.anatomical_structure, Monoclonal, Molecular Medicine, Antibody, Polymer nanoparticle, 0210 nano-technology, Genetically modified mouse, brain, Biomedical Engineering, Bioengineering, Mice, Transgenic, Blood–brain barrier, 03 medical and health sciences, β-Amyloid peptide, Alzheimer Disease, medicine, Animals, Humans, Memory Disorders, Amyloid beta-Peptides, Recovery of Function, medicine.disease, Disease Models, Animal, [CHIM.POLY]Chemical Sciences/Polymers, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, biology.protein, Nanoparticles, Nanocarriers, 030217 neurology & neurosurgery
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-β peptide (Aβ) and especially the Aβ peptide 1-42 (Aβ1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aβ1-42 in the blood and promote its elimination through the “sink effect” and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aβ1-42. Treatment of AD-like transgenic mice with anti-Aβ1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aβ soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aβ levels in plasma. This study represents the first example of Aβ1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.

Published
2017

37. Nouveau système de délivrance de médicament à base de nanoparticules pour le ciblage et la différenciation de cellules souches neurales

Author

Carradori, Dario, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Université d'Angers, Université catholique de Louvain (1970-....), Joël Eyer, Patrick Saulnier, and Anne Des Rieux

Subjects
Neural stem cells, Acide rétinoïque, Subventricular zone, Neurodegenerative diseases, Maladies neurodégénératives, Nanoparticules lipidiques, Cellules souches neurales, Zone subventriculaire, Lipid nanocapsules, Membrane plasmique, Nanomedicine, Nanomédecine, Retinoic acid, Nfl-Tbs.40-63, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Plasma membrane
Abstract

Neural stem cells (NSCs) are located in specific regions of the central nervous system called niches. Those cells are able to self-renew and to differentiate into specialized neuronal cells (neurons, astrocytes and oligodendrocytes). Due to this differentiation property, NSCs are studied to replace neuronal cells and restore neurological functions in patients affected by neurodegenerative diseases. Several therapeutic approaches have been developed and endogenous NSC stimulation is one of the most promising. Currently, there is no active molecule or therapeutic system targeting endogenous CSNs and inducing their differentiation at the same time. The aim of the work was to provide a drug delivery system able both to target endogenous CSNs and to induce their differentiation in situ. Here, we developed and characterized lipidic nanoparticles (LNC) targeting endogenous NSCs. A peptide called NFL-TBS.40-63, known for its affinity towards NSCs, was adsorbed at the surface of LNC. We observed that NFL-LNC specifically targeted NSC from the brain and not from the spinal cord in vitro and in vivo. To explain this specificity, we characterized and compared NFL-LNC interactions with the plasmatic membrane of both cell types. Finally, we demonstrated that by loading retinoic acid in NFL-LNC we were able to induce brain NSC differentiation in vitro and in vivo. This work contributes to the development of efficient and safe therapies for the treatment of neurodegenerative disease via the differentiation of endogenous NSCs.; Les cellules souches neurales (CSNs) se situent dans des régions spécifiques du système nerveux central qui sont appelées niches. Ces cellules sont capables de se répliquer ou se différentier en cellules neurales spécialisées (neurones, astrocytes et oligodendrocytes). C’est grâce à cette propriété de différentiation que les CSNs sont étudiées comme thérapie chez les patients atteints d’une maladie neurodégénérative. En effet, elles pourraient remplacer les cellules neurales altérées et ainsi restaurer les fonctions neurologiques. De nombreuses approches ont été développées afin de stimuler la différentiation des CSNs, dont la plus prometteuse est la différentiation des cellules endogènes directement au sein de leurs niches. Actuellement, il n’existe pas de molécule active ou de système thérapeutique qui cible les CSNs endogènes et qui induit leur différentiation simultanément. Le but de ce travail est de fournir un système de délivrance de molécules bioactives capable de cibler les CSNs endogènes et d'induire leur différenciation in situ. Nous avons développé et caractérisé des nanoparticules lipidiques (LNC), un système de délivrance très versatile. NFL-TBS.40-63, un peptide ciblant les CSNs, a été adsorbé à la surface des LNC afin de les diriger contre les CSNs endogènes. Nous avons observé que ces NFL-LNC ne ciblaient que les CSNs du cerveau et pas de la moelle. Afin d’étudier les interactions spécifiques entre les nanoparticules et les CSNs, nous avons caractérisé et comparé les propriétés de leur membrane plasmique. Enfin, nous avons encapsulé de l’acide rétinoïque, une molécule connue pour stimuler la différentiation des CSNs, dans les LNC-NFL et étudié leur impact sur la différentiation de CSNs in vitro et in vivo. Ce travail contribue au développement de thérapies efficaces et sures pour le traitement de maladies neurodégénératives à travers la différentiation de CSNs endogènes.

Published
2017

38. Stealth nanocarriers based sterosomes using PEG post-insertion process

Author

José Hureaux, Alejandro Nieto Orellana, Jérôme Bejaud, Anna Cieślak, Jean-Pierre Benoit, Claudio J. Salomon, Nathalie Wauthoz, Michel Lafleur, Nolwenn Lautram, Guillaume Bastiat, Micro et Nanomédecines Biomimétiques, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Center for Self-Assembled Chemical Structures (CSACS), Center for Self-Assembled Chemical Structures, Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-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
0301 basic medicine, Biodistribution, Stereochemistry, Kinetics, Palmitic Acid, Pharmaceutical Science, Mice, Nude, macromolecular substances, 02 engineering and technology, Polyethylene glycol, INGENIERÍAS Y TECNOLOGÍAS, Mice, SCID, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, Mice, Drug Delivery Systems, BIODISTRIBUTION, PEG ratio, Zeta potential, [CHIM]Chemical Sciences, Animals, Otras Nanotecnología, ComputingMilieux_MISCELLANEOUS, Nanotecnología, Liposome, Drug Carriers, Formazans, CH50 EXPERIMENT, Chemistry, Macrophages, technology, industry, and agriculture, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, PEG, 030104 developmental biology, STEROSOMES, Cholesterol, Drug delivery, Liposomes, Biophysics, Nanoparticles, Female, Nanocarriers, 0210 nano-technology, MACROPHAGE UPTAKE, Biotechnology
Abstract

Sterosomes (STEs), a new and promising non-phospholipidic liposome platform based on palmitic acid (PA) and cholesterol (Chol) mixtures, need to have polyethylene glycol (PEG) chains grafted to their surface in order to obtain long-circulating nanocarriers in the blood stream. A post-insertion method was chosen to achieve this modification. The post-insertion process of PEG-modified distearoylphosphoethanolamine (DSPE-PEG) was monitored using the zeta potential value of STEs. Various conditions including PEG chain length and the DSPE-PEG/PA-Chol ratio, were explored. Zeta potential of STEs changed from about −40 mV for non-modified STEs to values close to 0 mV by the end of the process, i.e. for PEG-modified STEs. The kinetics of DSPE-PEG insertion and the stability of the resulting PEG-modified STEs were not considerably influenced, within the investigated range, by changes in PEG chain lengths and in DSPE-PEG/PA-Chol proportion. The post-insertion of PEG chains reduced in vitro complement activation as well as in vitro macrophage uptake compared to the non-modified STEs. Moreover, longer blood circulation time in mice was established for PEG-modified STEs intravenously injected compared to non-modified STEs. These results establish that post-insertion process of PEG chains to STEs is a promising strategy for developing long-term circulating drug delivery nanocarriers. Fil: Cieślak, Anna. University Of Angers; Francia Fil: Wauthoz, Nathalie. University Of Angers; Francia. Université Libre de Bruxelles; Bélgica Fil: Nieto Orellana, Alejandro. University Of Angers; Francia Fil: Lautram, Nolwenn. University Of Angers; Francia Fil: Béjaud, Jérôme. University Of Angers; Francia Fil: Hureaux, José. University Of Angers; Francia Fil: Lafleur, Michel. University of Montreal; Canadá Fil: Benoit, Jean-Pierre. University Of Angers; Francia Fil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Bastiat, Guillaume. University Of Angers; Francia

Published
2017

39. Elaboration de matrices microcellulaires de polymère biosourcé par la technologie CO², supercritique

Author

Gay , Swann, Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Institut de Cancérologie de l’Ouest (Nantes), Université d'Angers, Frank Boury, Brice Calvignac, and Alain Gibaud

Subjects
Matrice, Life cycle assessment, Biopolymère, Biopolymer, Matrix, Analyse de cycle de vie (ACV), Tomographie-X synchrotron, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, PolyLactic Acid (PLA), Synchrotron tomography-X, Supercritical CO2, CO2 supercritique
Abstract

In the present context, where the preservation of resources and sustainable development became the main issues of this century, the production of more efficient and environmentally friendly materials is essential. Thus, this work deals with thedevelopment of biobased polymeric porous matrix using SC-CO2. The use of PLA makes it possible to produce 100% biosourced and biodegradable matrices, while the use of CO2-SC reduces the ecological impact of the shaping processes. In a first step, a parametric study of PLA matrix shaping by a thermal induced phase separation (TIPS) method coupled to CO2 drying was performed. Low density microcellular matrices were obtained with tunable structural and mechanical properties. The whole process was analyze by life cycle assessment and the results showed that SC-CO2 replacing freeze drying has reduced the environmental impact between 50 and 90%. Secondly, a phase separation in situ study by tomography-X synchrotron radiation tomography allowed us to better understand the mechanics of our process. Finally, the last part of this work was devoted to the implementation of a solvent free process, using SC-CO2 as a blowing agent. The results obtained were used to carry out a comparative study of the two processes developed.; Dans le contexte actuel, où la préservation des ressources et le développement durable sont devenus des enjeux importants de ce siècle, la production de matériaux tant performants que respectueux de l’environnement est devenue indispensable. Ainsi, ce travail de thèse porte sur l’élaboration de matrices poreuses de biopolymères en utilisant la technologie CO2 supercritique (CO2-SC). L’utilisation du PLA permet de produire des matrices 100% biosourcées et biodégradables, alors que l’utilisation de CO2-SC permet de diminuer l’impact écologique des procédés de mise en forme. Dans un premier temps une étude paramétrique de la mise en forme de matrice de PLA par une méthode de séparation de phase thermique (TIPS) couplée à un séchage par CO2 a été réalisée. Elle a permis de produire des matrices microcellulaires de faible densité (entre 60 et 320 kg/m3) et aux propriétés structurales mécaniques modulables. L’ensemble du procédé a fait l’objet d’une analyse de cycle de vie et il a été démontré que l’utilisation du CO2-SC en remplacement de la lyophilisation a réduit d’entre 50 et 90% l’impact environnemental. Dans un second temps une étude in-situ de la séparation de phase par tomographie-X en rayonnement synchrotron a permis de mieux comprendre la mécanistique de notre procédé. Enfin, la dernière partie de ce travail a été consacré à la mise en forme de matrice de PLA sans solvant, en utilisant le CO2-SC comme agent gonflant. Les résultats obtenus ont servi à réaliser une étude comparative des deux procédés développés.

Published
2017

40. Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia

Author

Briot, Thomas, Roger, Emilie, Lautram, Nolwenn, Verger, Alexis, Clavreul, Anne, Lagarce, Frederic, Micro et nanomédecines biomimétiques ( MINT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Angers ( UA ) -Université Bretagne Loire ( UBL ), Département de Pharmacie [CHU Angers], CHU Angers, Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Département de Neurochirurgie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Antimetabolites, Antineoplastic, Administration, Oral, Biological Availability, Polysorbates, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute myeloid leukemia, Decitabine, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Drug Stability, Nanocapsules, [SDV.CAN] Life Sciences [q-bio]/Cancer, International Journal of Nanomedicine, Cell Line, Tumor, Humans, ComputingMilieux_MISCELLANEOUS, Original Research, Drug Carriers, lipid nanocapsules, Caco2 cells, oral administration, nanomedicine, Lipids, Drug Liberation, Leukemia, Myeloid, Acute, Drug Resistance, Neoplasm, Azacitidine, nanoparticles, Ethylene Glycols, Caco-2 Cells
Abstract

Thomas Briot,1,2 Emilie Roger,1 Nolwenn Lautram,1 Alexis Verger,1 Anne Clavreul,3,4 Frederic Lagarce1,2 1Micro & Nanomédecines Translationelles – MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, MINT IBS-CHU, 2Pharmacy Department, University Hospital of Angers, 3Neurosurgery Department, University Hospital of Angers, 4CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France Abstract: Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML) in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs), originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol® HP (THP-LNCs) and LNCs associated with a mixture of Transcutol® HP and Tween® 80 (THP-T80-LNCs). The second formulation had a diameter of 26.5±0.5nm, high encapsulation efficiency (>85%), and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant) and HL-60 (resistant). The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine. Keywords: lipid nanocapsules, acute myeloid leukemia, decitabine, nanomedicine, nanoparticles, oral administration, Caco2 cells

Published
2017

41. Mucus models to evaluate nanomedicines for diffusion

Author

Frédéric Lagarce, Anne-Claire Groo, Univ Angers, Okina, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Novosibirsk State University, Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)

Subjects
[SDV]Life Sciences [q-bio], Nanotechnology, 02 engineering and technology, Biology, Standard procedure, Diffusion, 03 medical and health sciences, Drug Delivery Systems, fluids and secretions, Drug Discovery, Animals, Humans, Diffusion (business), 030304 developmental biology, Pharmacology, 0303 health sciences, respiratory system, 021001 nanoscience & nanotechnology, Mucus, 3. Good health, [SDV] Life Sciences [q-bio], Nanomedicine, Pharmaceutical Preparations, Drug delivery, Nanoparticles, 0210 nano-technology
Abstract

International audience; In the fast-growing field of nanomedicine, mucus is often the first barrier encountered by drug products in the body, and can be the only barrier if it is not overcome by the drug delivery system. Thus, there is a need to design new nanomedicines that are able to diffuse easily across mucus to reach their pharmacological targets. In this design process, mucus diffusion studies are mandatory and have an important role in the selection of the best drug candidates. However, there is currently no standard procedure for diffusion studies across mucus. In this Foundation Review, we discuss the differences observed within mucus models and experimental protocols in diffusion studies, with an emphasis on nanomedicine diffusion.

Published
2014

42. Characterization of industrial dried whey emulsions at different stages of spray-drying

Author

Patrick Boiron, Jean-Luc Courthaudon, Emilie Donz, Univ Angers, Okina, Grenoble, une chimie bio-motivée - - ARCANE2011 - ANR-11-LABX-0003 - LABX - VALID, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0003,ARCANE,Grenoble, une chimie bio-motivée(2011), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL)

Subjects
Materials science, Dried whey, Free fat, [SDV]Life Sciences [q-bio], Spray-drying, 02 engineering and technology, law.invention, Fine, 0404 agricultural biotechnology, Optical microscope, law, High fat, Food science, Powder size, Coalescence (physics), Dried food, 04 agricultural and veterinary sciences, 021001 nanoscience & nanotechnology, 040401 food science, Laser light scattering, [SDV] Life Sciences [q-bio], Spray drying, Whey emulsion, 0210 nano-technology, Stability, Food Science
Abstract

International audience; Commercial dried food emulsions, with high fat content (50 g fat /100 g), were prepared at plant scale from whey and palm oil. Five powders were analyzed: powder without fines, taken from the bottom of the spray-dryer chamber; fines 1 and fines 2 respectively collected at the bottom of the first and second cyclones, a mix of fines 1 and fines 2 and the final powder, taken during packing. Scanning electronic and optical microscopy showed only spherical particles and also indicated that fines 2 were roughly twice as smaller as other powder particles. Free fat content was significantly higher in fines than in final powder. Reconstituted emulsions (10 g powder/100 g water) were analyzed by laser light scattering. Aggregation and coalescence indexes were very low, except in reconstituted emulsions made with fines 2. This is consistent with their high free fat content and suggests that this results from processing through the cyclones.

Published
2014

43. Osteoblastic differentiation and potent osteogenicity of three-dimensional hBMSC-BCP particle constructs

Author

Cordonnier, Thomas, Langonné, Alain, Corre, Pierre, Renaud, Audrey, Sensebé, Luc, Rosset, Philippe, Layrolle, Pierre, Sohier, Jérôme, Jehan, Frederic, Regenerating Bone defects using New biomedical Engineering approaches - REBORNE - - EC:FP7:HEALTH2010-01-01 - 2015-06-30 - 241879 - VALID, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Laboratoire d'hématopoïèse [Tours], Université Francois Rabelais [Tours], Etablissement Français du Sang Centre-Atlantique (EA3855), EFS, Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Département de Stomatologie et chirurgie maxillo-faciale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement français du sang [Pyrénées-Méditerranée] (EFS Pyrénées-Méditerranée), Départements de chirurgie orthopédique [CHRU Tours], This work was supported by the French National Research Agency (ATOS project) and partially funded by the Directorate-General for Research of the European Commission (Grant No. 241879) through the REBORNE project., European Project: 241879,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,REBORNE(2010), Micro et Nanomédecines Biomimétiques, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Theraptosis Research Laboratory, Theraptosis S.A., Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes] (INSERM U1238), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Equipe de recherche clinique en Odontologie (ERT1051), Université de Nantes (UN), Micro et Nanomédecines Biomimétiques (MINT), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Université Francois Rabelais [Tours], and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université Francois Rabelais [Tours]

Subjects
Male, three dimensional constructs, biphasic calcium phosphate, Mice, Nude, Real-Time Polymerase Chain Reaction, Mice, Implants, Experimental, Osteogenesis, Animals, Humans, RNA, Messenger, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, bone tissue engineering, ComputingMilieux_MISCELLANEOUS, Aged, Cell Proliferation, Aged, 80 and over, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteoblasts, Tissue Scaffolds, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, glass beads, Cell Differentiation, Mesenchymal Stem Cells, Middle Aged, Microspheres, osteogenicity in nude mice, human bone marrow stromal cells, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Female, Hydroxyapatites, osteoblastic differentiation
Abstract

International audience; Bone tissue engineering usually consists of associating osteoprogenitor cells and macroporous scaffolds. This study investigated the in vitro osteoblastic differentiation and resulting in vivo bone formation induced by a different approach that uses particles as substrate for human bone marrow stromal cells (hBMSCs), in order to provide cells with a higher degree of freedom and allow them to synthesize a three-dimensional (3D) environment. Biphasic calcium phosphate (BCP) particles (35 mg, ~175 µm in diameter) were therefore associated with 4 X 10[5] hBMSCs. To discriminate the roles of BCP properties and cell-synthesized 3D environments, inert glass beads (GBs) of similar size were used under the same conditions. In both cases, high cell proliferation and extensive extracellular matrix (ECM) production resulted in the rapid formation of thick cell-synthesized 3D constructs. In vitro, spontaneous osteoblastic differentiation was observed in the 3D constructs at the mRNA and protein levels by monitoring the expression of Runx2, BMP2, ColI, BSP and OCN. The hBMSC–BCP particle constructs implanted in the subcutis of nude mice induced abundant ectopic bone formation after 8 weeks (~35%, n = 5/5). In comparison, only fibrous tissue without bone was observed in the implanted hBMSC–GB constructs (n = 0/5). Furthermore, little bone formation (~3%, n = 5/5) was found in hBMSC–macroporous BCP discs (diameter 8 X 3 mm). This study underlines the lack of correspondence between bone formation and in vitro differentiation assays. Furthermore, these results highlight the importance of using BCP as well as a 3D environment for achieving high bone yield of interest for bone engineering.

Published
2014
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44. Potentiel des dendrimères comme outil d'applications théranostiques

Author

Liko, Flonja, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-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'Angers, François Hindré, and STAR, ABES

Subjects
188Re, Dendrimer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Gatg, Dendrimères, Internal radiotherapy, Radiothérapie interne, Glioblastoma, Gd3+, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Mri, 99mTc
Abstract

A new oncologic strategy, based on the integration of nanovectorized radiotherapy and locoregional delivery, was evaluated for the treatment and imaging of glioblastomas, the most common and lethal type of primary brain tumors. Gallic acidtriethylene glycol (GATG) dendrimers were the nanovectors of choice to deliver the radiotherapeutic 188Re and paramagnetic nuclei Gd3+, with a minimally invasive stereotactic injection, directly depositing the radiotherapeutic dose to the tumor site in a F98 rat glioma model. Intravenous injection was used to further investigate the pharmacokinetics, throughout body distribution and clearance profiles of these dendrimers. Molecular weight and architecture had an important role on the in vivo behavior of the dendrimers. Their use as nanovectors prevented the fast brain clearance of the radionuclide alone, and prolonged the confinement of the internal radiation at the tumor site., Une nouvelle stratégie oncologique, basée sur l’intégration de la radiothérapie nanovectorisée et l’administration loco-régionale, a été évaluée pour le traitement et l’imagerie du glioblastome, le type le plus commun des tumeurs cérébrales primaires. Les dendrimères Gallic Acid-Triethylène Glycol (GATG) sont des nanovecteurs de choix pour délivrer simultanément l’agent thérapeutique (le radioisotope 188Re par son rayonnement béta a été retenu) et l’agent diagnostique (le gadolinium est un agent paramagnétique utilisé en Imagerie par Résonance Magnétique (IRM)). Leur évaluation a été réalisée par administration locorégionale par stéréotaxie sur un modèle de rat F 98. Les données pharmaco-cinétiques ont été également obtenues après injection intraveineuse permettant d’apprécier les propriétés des différents dendrimères synthétisés. Leur apport en terme de confinement au site d’injection représente un avantage majeur de ce nouveau type de radiopharmaceutiques.

Published
2016

45. Développement de nanoparticules contenant microARN-mimétique pour le traitement des tumeurs cérébrales

Author

Anthiya Ramamoorthi, Shubaash, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Université d'Angers, University of Nottingham, Emmanuel Garcion, and Martin Garnett

Subjects
Poly(amidoamine), Thiol crosslinking, Ligand targeting, Réticulation de thiol, MiRNA Delivery, Test de luciférase, Nanomedicine, Vectorisation de microARN, Nanomédecine, Greffage d’un ligand, Glioblastoma, Uciferase assay, Glioblastomes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Glioblastoma are aggressive brain tumours with a median survival of 15 months even with the best currently available treatment options. microRNAs (miRNA) are ~23 nucleotide natural silencing RNAs that have great potentials to improve cancer treatment outcomes. Lack of a safe, stable and efficient delivery system has, however, hindered the use of miRNAs inclinical applications. The aim is therefore to develop amiRNA delivery system adapted to glioblastoma using linear chain cationic polyamidoamine (PAA) polymers.The first part involved the development of luciferase assay that combined the measurement of gene-knockdown efficiency and cytotoxicity of miRNA nanoparticles. The simple two-step procedure was more effective and sensitive compared to the conventional protein-based normalization method. The second part was focused on the development of miRNA nanoparticles. In the initial phase, conditions required for maximum miRNA-polymer binding was achieved, however, the newly developed miRNA-PAA nanoparticlesdid not produce significant functional gene-knockdown after cell treatment. The second stage was focused on the optimization of nanoparticle formulation as a function of stability in physiologicalionic concentration. Stable PAA-nanoparticles displaying moderate cellular uptake and gene-knockdown were obtained. The final stage of development was focused on PAA-nanoparticle tagging with biotin, which improved their cellular uptake. This work developed simple and informative luciferase assay ; the stability of miRNA-PAA-nanoparticles was improved by thiol-crosslinking and the functional performance was strongly enhanced by a simple butsmart method of ligand tagging.; Les glioblastomes sont des tumeurs cérébrales très agressives présentant une médiane de survie de 15 mois malgré l’usage du traitement de référence. Parmi les stratégies innovantes anti-glioblastome, les microARNs (miARN) constituent de nouvelles cibles et des outils thérapeutiques à fort potentiel. En outre, pour atteindre les cellules tumorales notamment au niveau loco-régional, les miARNs nécessitent d’être administrés grâce à des vecteurs sûrs et efficaces. L’objectif de ce travail a été de développer un système nanoparticulaire original de polyamidoamine réticulé (PAA) capable de véhiculer des miARNs au niveau cellulaire et tissulaire. Dans un premier temps, un test basé sur l’expression de la luciférase a été mis au point afin d’étudier la cytotoxicité et l’efficacité de nanoparticules des miARNs. Dans un second temps,des nanoparticules PAA-miARN ont été développées. Différentes conditions de formulation ont été testées afin d’optimiser la complexation entre miARNs et polymères. En l’absence d’efficacité cellulaire significative des premiers objets obtenus, des modifications du procédé de formulation ont été apportées, permettant une plus grande stabilité et une meilleure efficacité. Une fonctionnalisation par greffage de groupements biotine à des complexes PAA thio-réticulés a amélioré l’efficacité des internalisations. En conclusion, ce travail a permis le développement d’une méthode simple et rapide pour l’évaluation de l’efficacité et de la cytotoxicité de nanoparticules de miARN. La stabilité des nanoparticules a été augmentée par réticulation de thiolet leur internalisation a été améliorée par le greffage,adapté et modulable, d’un ligand cellulaire.

Published
2016

46. Multicenter Assessment of Immunohistochemical Methods for Pathological Alpha-Synuclein in Sigmoid Colon of Autopsied Parkinson's Disease and Control Subjects

Author

Anthony Intorcia, Jeffrey H. Kordower, Pascal Derkinderen, Charles H. Adler, Geidy E. Serrano, Jessica E. Walker, Joseph G. Hentz, David G. Munoz, Thomas Kremer, Anne Gaëlle Corbillé, Thomas G. Beach, Franck Letournel, Lucia I. Sue, School of Engineering [Cardiff], Cardiff University, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Rush University [Chicago], Centre de Recherches sur le Stockage Géologique du CO2, Institut de Physique du Globe de Paris (IPG Paris), Institut de Physique du Globe de Paris (IPGP), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), IBM, Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), IPG PARIS, and Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.medical_specialty, Pathology, Parkinson's disease, [SDV]Life Sciences [q-bio], Biopsy, Gastroenterology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, enteric nervous system, 0302 clinical medicine, Colon, Sigmoid, Internal medicine, Submucosa, Diagnosis, medicine, Humans, Pathological, Lewy body, medicine.diagnostic_test, business.industry, Sigmoid colon, Parkinson Disease, medicine.disease, Immunohistochemistry, 3. Good health, Staining, 030104 developmental biology, medicine.anatomical_structure, alpha-Synuclein, gastrointestinal tract, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: Conflicting results from studies of Lewy-type α-synucleinopathy (LTS) in colonic biopsies of subjects with Parkinson's disease (PD) prompted a two-part multicenter assessment. The first assessment, now published (Acta Neuropathol Commun 4 : 35, 2016), examined archived colonic biopsies and found that none of the tested methods was adequately sensitive or specific.OBJECTIVE: As the amount of nervous tissue in typical colonic biopsies may be insufficient, and the clinical diagnosis of PD not completely accurate, the objective of the current study was to use instead full-thickness sections of sigmoid colon from autopsy-proven PD and normal subjects.METHODS: Seven different immunohistochemical (IHC) methods were used, employing five different primary antibodies and four different combinations of epitope exposure and signal development protocols. Specific staining was defined as being restricted to morphological features consistent with neuronal elements. Stained slides from each subject were independently categorized as being positive or negative for LTS, and their density semi-quantitatively graded, by four raters blinded to diagnosis.RESULTS: Agreement and mean diagnostic performance varied markedly between raters. With the two most accurate raters, 5 methods achieved diagnostic accuracies of 70% or greater; one method had 100% accuracy and 100% inter-rater agreement. The submucosa had the highest prevalence of pathological LTS staining, followed by the muscularis and mucosa.CONCLUSIONS: The major conclusion of this study is that, when sufficient submucosa and LTS is present, and when specific staining is defined as being consistent with neuronal morphology, adequately-trained raters may reliably distinguish PD colon from control using suitable IHC methods.

Published
2016

47. Organotypic cultures as tools for optimizing central nervous system cell therapies

Author

Claudia N. Montero-Menei, Miguel A. Perez-Pinzon, Elisa Garbayo, Nicolas Daviaud, Paul C. Schiller, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), and University of Miami Leonard M. Miller School of Medicine (UMMSM)

Subjects
Central Nervous System, Cell type, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Clinical uses of mesenchymal stem cells, Cell therapy, 03 medical and health sciences, Organ Culture Techniques, 0302 clinical medicine, Developmental Neuroscience, medicine, Animals, Humans, Induced pluripotent stem cell, 030304 developmental biology, Neurons, 0303 health sciences, Tissue Engineering, business.industry, Mesenchymal stem cell, Neurodegenerative Diseases, Stem-cell therapy, Neural stem cell, 3. Good health, Neurology, Stem cell, business, Neuroscience, 030217 neurology & neurosurgery, Stem Cell Transplantation
Abstract

International audience; Stem cell therapy is a promising treatment for neurological disorders such as cerebral ischemia, Parkinson's disease and Huntington's disease. In recent years, many clinical trials with various cell types have been performed often showing mixed results. Major problems with cell therapies are the limited cell availability and engraftment and the reduced integration of grafted cells into the host tissue. Stem cell-based therapies can provide a limitless source of cells but survival and differentiation remain a drawback. An improved understanding of the behaviour of stem cells and their interaction with the host tissue, upon implantation, is needed to maximize the therapeutic potential of stem cells in neurological disorders. Organotypic cultures made from brain slices from specific brain regions that can be kept in culture for several weeks after injecting molecules or cells represent a remarkable tool to address these issues. This model allows the researcher to monitor/assess the behaviour and responses of both the endogenous as well as the implanted cells and their interaction with the microenvironment leading to cell engraftment. Moreover, organotypic cultures could be useful to partially model the pathological state of a disease in the brain and to study graft-host interactions prior to testing such grafts for pre-clinical applications. Finally, they can be used to test the therapeutic potential of stem cells when combined with scaffolds, or other therapeutic enhancers, among other aspects, needed to develop novel successful therapeutic strategies or improve on existing ones.

Published
2013

48. The effect of functionalizing lipid nanocapsules with NFL-TBS.40-63 peptide on their uptake by glioblastoma cells

Author

Joël Eyer, Maud Pinier, Raphael Berges, Jean-Pierre Benoit, Patrick Saulnier, Julien Balzeau, Laboratoire de Neurobiologie et Transgénèse (LNBT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), and Univ Angers, Okina

Subjects
Neurofilament, Materials science, Paclitaxel, Cell Survival, [SDV]Life Sciences [q-bio], education, Biophysics, Bioengineering, Peptide, Inbred C57BL, Nanocapsules, Cell Line, Biomaterials, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neurofilament Proteins, In vivo, Cell Line, Tumor, Glioma, medicine, Animals, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Tumor, Cell Death, Brain Neoplasms, Brain, medicine.disease, Lipids, Molecular biology, Peptide Fragments, In vitro, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, chemistry, Mechanics of Materials, Cell culture, Astrocytes, 030220 oncology & carcinogenesis, Ceramics and Composites, Female, Glioblastoma, Protein Binding
Abstract

International audience; We previously described a neurofilament derived cell-penetrating peptide, NFL-TBS.40-63, that specifically enters in glioblastoma cells where it disturbs the microtubule network both in vitro and in vivo. The aim of this study is to test whether this peptide can increase the targeted uptake by glioblastoma cells of lipid nanocapsules filled with Paclitaxel, and thus can increase their anti-proliferation in vitro and in vivo. Here, using the drop tensiometry we show that approximately 60 NFL-TBS.40-63 peptides can bind to one 50 nm lipid nanocapsule. When nanocapsules are filled with a far-red fluorochrome (DiD) and Paclitaxel, the presence of the NFL-TBS.40-63 peptide increases their uptake by glioblastoma cells in culture as evaluated by FACS analysis, and thus reduces their proliferation. Finally, when such nanocapsules were injected in mice bearing a glioma tumour, they are preferentially targeted to the tumour and reduce its progression. These results show that nanocapsules functionalized with the NFL-TBS.40-63 peptide represent a powerful drug-carrier system for glioma targeted treatment.

Published
2013

49. Pharmacologically active microcarriers influence VEGF-A effects on mesenchymal stem cell survival

Author

Claudio Muscari, Claudia N. Montero-Menei, Maria-Giulia Perrelli, Claudia Penna, Jean-Pierre Karam, Carmelina Angotti, Pasquale Pagliaro, Claudia Penna, Maria-Giulia Perrelli, Jean-Pierre Karam, Carmelina Angotti, Claudio Muscari, Claudia N. Montero-Menei, Pasquale Pagliaro, Micro et Nanomédecines Biomimétiques (MINT), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)

Subjects
Vascular Endothelial Growth Factor A, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Wistar, VEGF-A, chemistry.chemical_compound, 0302 clinical medicine, Polylactic Acid-Polyglycolic Acid Copolymer, drug release, mesenchymal stem cell, Mitogen-Activated Protein Kinase 1, Drug Carriers, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Mesenchymal Stromal Cells, Caspase 3, Kinase, apoptosis, growth factor, Cell Hypoxia, Microspheres, 030220 oncology & carcinogenesis, Molecular Medicine, Stem cell, Cell Survival, Drug Compounding, Primary Cell Culture, Biology, Andrology, 03 medical and health sciences, stem cells, Lactate dehydrogenase, medicine, Animals, Pharmacologically active microcarrier, Lactic Acid, Rats, Wistar, 030304 developmental biology, hypoxia, Cell growth, Growth factor, Mesenchymal stem cell, Mesenchymal Stem Cells, Original Articles, Cell Biology, Molecular biology, Rats, Oxygen, Transplantation, Kinetics, chemistry, Apoptosis, Proto-Oncogene Proteins c-akt, Polyglycolic Acid, transplantation
Abstract

International audience; Resistance of transplanted mesenchymal stem cells (MSCs) in post-ischemic heart is limited by their poor vitality. Vascular-endothelial-growth-factor-A (VEGF-A) as such or slowly released by fibronectin-coated pharmacologically-active-microcarriers (FN-PAM-VEGF) could differently affect survival kinases and anti-apoptotic mediator (e.g. Bcl-2). Therefore VEGF-A or FN-PAM-VEGF could differently enhance cell proliferation, and/or resistance to hypoxia/reoxygenation (H/R) of MSCs. To test these hypotheses MSCs were incubated for 6-days with VEGF-A alone or with FN-PAM-VEGF. In addition, MSCs pre-treated for 24-hrs with VEGF-A or FN-PAM-VEGF were subsequently exposed to H/R (72-hrs 3% O(2) and 3-hrs of reoxygenation). Cell-proliferation and post-hypoxic vitality were determined. Kinases were studied at 30-min., 1- and 3-days of treatment. Cell-proliferation increased about twofold (P < 0.01) 6-days after VEGF-A treatment, but by a lesser extent (55% increase) with FN-PAM-VEGF (P < 0.05). While MSC pre-treatment with VEGF-A confirmed cell-proliferation, pre-treatment with FN-PAM-VEGF protected MSCs against H/R. In the early phase of treatments, VEGF-A increased phospho-Akt, phospho-ERK-1/2 and phospho-PKCε compared to the untreated cells or FN-PAM-VEGF. Afterword, kinase phosphorylations were higher with VGEF, except for ERK-1/2, which was similarly increased by both treatments at 3 days. Only FN-PAM-VEGF significantly increased Bcl-2 levels. After H/R, lactate dehydrogenase release and cleaved Caspase-3 levels were mainly reduced by FN-PAM-VEGF. While VEGF-A enhances MSC proliferation in normoxia, FN-PAM-VEGF mainly hampers post-hypoxic MSC death. These different effects underscore the necessity of approaches suited to the various conditions. The use of FN-PAM-VEGF could be considered as a novel approach for enhancing MSC survival and regeneration in hostile environment of post-ischemic tissues.

Published
2013

50. Models for drug absorption from the small intestine: where are we and where are we going?

Author

Emilie Roger, Frédéric Lagarce, Pierre-André Billat, Sébastien Faure, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), and Univ Angers, Okina

Subjects
0301 basic medicine, Pharmacology, [SDV]Life Sciences [q-bio], Biology, 030226 pharmacology & pharmacy, Models, Biological, Small intestine, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Intestinal Absorption, Pharmaceutical Preparations, In vivo, Metabolic enzymes, Drug Discovery, Intestine, Small, medicine, Animals, Humans, Biochemical engineering, Drug transport
Abstract

International audience; The small intestine is a complex organ with movements, flora, mucus and flows. Despite this, the most widely used absorption models consider the organ a cylindrical monoepithelial tube. This review presents the recent evolution of models to take into consideration the complex nature of gut physiology. The most commonly encountered issues are ethical (in vivo models) and differences in drug transport as a result of a modified expression of drug transporters or metabolic enzymes compared with human (in vitro and in vivo models). Finally, this review discusses the way forward to reach an ideal equilibrium between reproducibility, predictability and efficiency for predicting permeability. The features of an ideal model are listed as a guideline for future development.

Published
2016

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