DOCSLIB.ORG

Cryogel-Integrated Hepatic Cell Culture Microchips for Liver Tissue Engineering

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cryogel-Integrated Hepatic Cell Culture Microchips for Liver Tissue Engineering Par Lilandra BOULAIS Cryogel-integrated hepatic cell culture microchips for liver tissue engineering Thèse présentée pour l’obtention du grade de Docteur de l’UTC Soutenue le 31 août 2020 Spécialité : Bio-ingénierie : Unité de Recherche Biomécanique et Bio-ingénierie (UMR-7338) D2561 THÈSE DE DOCTORAT Ecole doctorale 71 : Sciences pour l’ingénieur Spécialité de doctorat : Bioingénierie Cryogel-integrated hepatic cell culture microchips for liver tissue engineering Présentée et soutenue publiquement par Lilandra BOULAIS le 31 août 2020 Pour obtenir le grade de docteur de UNIVERSITÉ DE TECHNOLOGIE DE COMPIÈGNE Directeurs de thèse: Dr. Cécile LEGALLAIS, Dr. Sidi BENCHERIF Laboratoire de BioMécanique et BioIngénierie (BMBI) Equipe Cellules Biomatériaux Bioréacteurs (CBB) CNRS UMR 7338 Jury: Sidi Bencherif Assistant Professor, Northeastern University Directeur de thèse Dominique Collard DR CNRS, UMI CNRS 2820, LIMMS Tokyo Rapporteur Bertrand David CR CNRS, UMR CNRS 8579, Centrale Supelec Examinateur Nathalie Maubon CEO/CSO HCS Pharma Examinateur Cécile Legallais DR CNRS, UMR CNRS 7338, UTC Directrice de thèse Nathalie Picollet D’hahan Chercheur HDR, CEA Rapporteur Muriel Vayssade Professeur, UMR CNRS 7338, UTC Examinateur Contents Acknowledgements/Remerciements7 Abstract 9 Resume 11 Abbreviation 21 Introduction 23 1 Liver and drugs, a close relationship 25 1.1 Drug development................................ 25 1.1.1 A long, difficult and costly process................... 25 1.1.2 Drug safety................................ 27 Toxicology................................. 27 Pharmacology............................... 28 1.2 The liver: an essential organ in the metabolism of xenobiotics....... 29 1.2.1 Structure.................................. 29 1.2.2 Cells and organization.......................... 31 1.2.3 Functions................................. 31 Major metabolic activities........................ 32 Xenobiotic activities........................... 33 1.3 From in vivo to in vitro models.......................... 36 1.3.1 In vivo issues............................... 36 1.3.2 Alternative models............................ 37 In silico models.............................. 37 In vitro models.............................. 38 2 Current research on tissue engineered liver models 41 2.1 Cells......................................... 41 2.1.1 Primary cells............................... 41 2.1.2 Cell lines.................................. 42 2.1.3 Stem cells................................. 43 2.1.4 Co-cultures................................ 43 2.2 Engineering strategies.............................. 44 2.2.1 Micropatterning.............................. 45 2.2.2 Sandwich and layer-by-layer...................... 46 3 2.2.3 Spheroids and beads........................... 48 2.2.4 Polymer based scaffolds......................... 49 2.2.5 Bioprinting................................ 51 2.2.6 Perfusion systems............................ 52 2.3 Liver on chip.................................... 53 2.3.1 Liver on chip sandwich and layer-by-layer.............. 53 2.3.2 Liver on chip with 3D spheroids.................... 55 2.3.3 Liver on chip 3D bioprinting...................... 56 2.4 Thesis project: a new generation of liver on chip............... 57 2.4.1 Microchip used.............................. 58 2.4.2 Alginate cryogel as 3D scaffold..................... 59 2.4.3 Objectives................................. 61 3 Materials and methods 65 3.1 Materials...................................... 65 3.2 Alginate cryogels................................. 66 3.2.1 Synthesis.................................. 66 3.2.2 Mechanical properties.......................... 66 3.2.3 Physical properties............................ 66 3.2.4 Microstructure analysis......................... 67 3.2.5 Aminofluorescein functionalization.................. 67 3.2.6 RGD functionalization.......................... 67 3.2.7 Collagen coating............................. 68 3.2.8 Collagen staining............................. 68 3.3 Microchip..................................... 68 3.3.1 Fabrication................................. 68 3.3.2 Hydrodynamic characterization.................... 69 3.4 Cell culture..................................... 69 3.4.1 HepG2/C3A............................... 69 3.4.2 Primary human hepatocytes...................... 69 3.4.3 HUVEC.................................. 70 3.4.4 MDA-MB-231............................... 70 3.5 Cell culture in alginate cryogel-integrated microchip............. 70 3.5.1 Perfusion devices: IDCCM and bubble trap.............. 70 Bubble trap system............................ 70 IDCCM device.............................. 71 3.5.2 HepG2/C3A culture........................... 72 3.5.3 PHH culture................................ 74 3.5.4 HepG2/C3A and HUVEC co-culture................. 74 3.5.5 HepG2/C3A and MDA-MB-231 co-culture.............. 75 3.5.6 Alginate lyase............................... 77 3.6 Cell culture analysis: imaging.......................... 77 4 3.6.1 Cell viability................................ 77 3.6.2 Confocal and epifluorescence microscopy............... 78 3.6.3 Scanning electron microscopy...................... 79 3.7 Cell culture analysis: quantification....................... 79 3.7.1 Albumin.................................. 79 3.7.2 Glucose.................................. 80 3.7.3 Lactate dehydrogenase......................... 80 3.7.4 APAP metabolites............................ 80 3.8 Statistical analyses................................ 81 4 Alginate cryogel integrated microchip for liver tissue engineering: characteri- zation 83 4.1 Alginate cryogel characterization........................ 83 4.1.1 Cryopolymerization: choice of the freezing temperature...... 83 4.1.2 Mechanical properties.......................... 84 4.1.3 Degree of connectivity and swelling ratio............... 87 4.1.4 Morphology................................ 88 4.2 Implementation of alginate cryogel in the microchip............. 90 4.2.1 General characterization......................... 90 4.2.2 Hydrodynamic characterization.................... 91 4.3 Modification of alginate cryogel for cell culture................ 93 4.3.1 RGD functionalization.......................... 93 4.3.2 Collagen coating............................. 94 4.4 Discussion and conclusion............................ 95 5 Feasibility study : human liver cancer cell line HepG2/C3A culture in alginate cryogel integrated microchip 101 5.1 Cell viability and structure............................ 101 5.2 Metabolic activities................................ 102 5.2.1 Glucose consumption.......................... 105 5.2.2 Albumin production........................... 106 5.3 Xenobiotic activity: APAP biotransformation................. 107 5.4 Alginate cryogel removal............................ 108 5.5 Discussion and conclusion............................ 110 6 Towards a complex liver-on-chip: primary human hepatocytes and co-cultures 113 6.1 Primary human hepatocytes culture...................... 113 6.1.1 Context................................... 113 6.1.2 Preliminary results............................ 114 6.1.3 Discussion and conclusion........................ 117 6.2 Co-culture of HepG2/C3A and HUVEC.................... 118 6.2.1 Context................................... 118 6.2.2 Preliminary results............................ 118 5 6.2.3 Discussion and conclusion........................ 120 6.3 HepG2/C3A and MDA-MB-231: an example of study for circulating tu- mor cells...................................... 121 6.3.1 Context................................... 121 6.3.2 Preliminary results............................ 122 6.3.3 Discussion and conclusion........................ 125 Conclusion and perspectives 127 Communications 131 Bibliography 133 6 Acknowledgements/Remerciements Je souhaite d’abord remercier les membres de mon jury qui ont accepté d’évaluer mes travaux de thèse : Dominique Collard et Nathalie Picollet D’hahan pour leurs rapports et leurs questions ainsi que Bertrand David, Nathalie Maubon et Muriel Vayssade pour les échanges sur leurs domaines d’expertise respectif. Je remercie également mes directeurs de thèse, Cécile Legallais et Sidi Bencherif, de m’avoir donné l’opportunité de réaliser cette thèse, tout en poursuivant des activités annexes. Un grand merci à Cécile pour sa disponibilité, l’autonomie et la confiance ac- cordée, ainsi que la relecture de ce manuscrit. Merci à Sidi de m’avoir accueillie dans son laboratoire à l’université Northeastern à Boston et pour ses remarques constructives. Merci à Anne Le Goff et Anne Dubart Kupperschmitt d’avoir fait partie de mon comité de suivi scientifique. J’ai apprécié échanger avec vous et voir votre optimisme qui me motivait chaque année. J’aimerais également remercier toutes les personnes avec qui j’ai pu travailler pen- dant ces 4 années. Frédéric Nadaud pour le temps passé à observer les échantillons au mi- croscope électronique à balayage et Caroline Lefebvre pour sa formation au microscope confocal. Merci également à Margaux, Solène, Anna, Darlène et Lauretta, qui m’ont aidé à différents moments du projet et que j’ai eu le plaisir d’encadrer pendant leur stage. Merci à tout le laboratoire BMBI et en particulier l’équipe CBB qui m’a accompa- gnée pendant ce doctorat. Rachid, Ulysse, Pascale, un grand merci pour vos conseils, votre disponibilité et votre écoute. Vous avez toujours su m’aider et me remonter le moral. Vanessa, Murielle, Christophe, Muriel, Patrick, merci
Load more

Recommended publications
  • Genetically Modified Baculoviruses for Pest
    INSECT CONTROL BIOLOGICAL AND SYNTHETIC AGENTS This page intentionally left blank INSECT CONTROL BIOLOGICAL AND SYNTHETIC AGENTS EDITED BY LAWRENCE I. GILBERT SARJEET S. GILL Amsterdam • Boston • Heidelberg • London • New York • Oxford Paris • San Diego • San Francisco • Singapore • Sydney • Tokyo Academic Press is an imprint of Elsevier Academic Press, 32 Jamestown Road, London, NW1 7BU, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA ª 2010 Elsevier B.V. All rights reserved The chapters first appeared in Comprehensive Molecular Insect Science, edited by Lawrence I. Gilbert, Kostas Iatrou, and Sarjeet S. Gill (Elsevier, B.V. 2005). All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. Permissions may be sought directly from Elsevier’s Rights Department in Oxford, UK: phone (þ44) 1865 843830, fax (þ44) 1865 853333, e-mail [email protected]. Requests may also be completed on-line via the homepage (http://www.elsevier.com/locate/permissions). Library of Congress Cataloging-in-Publication Data Insect control : biological and synthetic agents / editors-in-chief: Lawrence I. Gilbert, Sarjeet S. Gill. – 1st ed. p. cm. Includes bibliographical references and index. ISBN 978-0-12-381449-4 (alk. paper) 1. Insect pests–Control. 2. Insecticides. I. Gilbert, Lawrence I. (Lawrence Irwin), 1929- II. Gill, Sarjeet S. SB931.I42 2010 632’.7–dc22 2010010547 A catalogue record for this book is available from the British Library ISBN 978-0-12-381449-4 Cover Images: (Top Left) Important pest insect targeted by neonicotinoid insecticides: Sweet-potato whitefly, Bemisia tabaci; (Top Right) Control (bottom) and tebufenozide intoxicated by ingestion (top) larvae of the white tussock moth, from Chapter 4; (Bottom) Mode of action of Cry1A toxins, from Addendum A7.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,264,917 B1 Klaveness Et Al
    USOO6264,917B1 (12) United States Patent (10) Patent No.: US 6,264,917 B1 Klaveness et al. (45) Date of Patent: Jul. 24, 2001 (54) TARGETED ULTRASOUND CONTRAST 5,733,572 3/1998 Unger et al.. AGENTS 5,780,010 7/1998 Lanza et al. 5,846,517 12/1998 Unger .................................. 424/9.52 (75) Inventors: Jo Klaveness; Pál Rongved; Dagfinn 5,849,727 12/1998 Porter et al. ......................... 514/156 Lovhaug, all of Oslo (NO) 5,910,300 6/1999 Tournier et al. .................... 424/9.34 FOREIGN PATENT DOCUMENTS (73) Assignee: Nycomed Imaging AS, Oslo (NO) 2 145 SOS 4/1994 (CA). (*) Notice: Subject to any disclaimer, the term of this 19 626 530 1/1998 (DE). patent is extended or adjusted under 35 O 727 225 8/1996 (EP). U.S.C. 154(b) by 0 days. WO91/15244 10/1991 (WO). WO 93/20802 10/1993 (WO). WO 94/07539 4/1994 (WO). (21) Appl. No.: 08/958,993 WO 94/28873 12/1994 (WO). WO 94/28874 12/1994 (WO). (22) Filed: Oct. 28, 1997 WO95/03356 2/1995 (WO). WO95/03357 2/1995 (WO). Related U.S. Application Data WO95/07072 3/1995 (WO). (60) Provisional application No. 60/049.264, filed on Jun. 7, WO95/15118 6/1995 (WO). 1997, provisional application No. 60/049,265, filed on Jun. WO 96/39149 12/1996 (WO). 7, 1997, and provisional application No. 60/049.268, filed WO 96/40277 12/1996 (WO). on Jun. 7, 1997. WO 96/40285 12/1996 (WO). (30) Foreign Application Priority Data WO 96/41647 12/1996 (WO).
    [Show full text]
  • Discovery, Synthesis and Structure-Activity Relationship Study
    Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Fall 12-18-2020 Antiparasitic Peptide from the Ocean: Discovery, Synthesis and Structure-Activity Relationship Study Kh Tanvir Ahmed Follow this and additional works at: https://dsc.duq.edu/etd Part of the Medicinal Chemistry and Pharmaceutics Commons Recommended Citation Ahmed, K. (2020). Antiparasitic Peptide from the Ocean: Discovery, Synthesis and Structure-Activity Relationship Study (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1924 This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. ANTIPARASITIC PEPTIDE FROM THE OCEAN: DISCOVERY, SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP STUDY A Thesis Submitted to the Graduate School of Pharmaceutical Sciences Duquesne University In partial fulfillment of the requirements for the degree of Master of Science By Kh Tanvir Ahmed December 2020 Copyright by Kh Tanvir Ahmed 2020 ANTIPARASITIC PEPTIDE FROM THE OCEAN: DISCOVERY, SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP STUDY By Kh Tanvir Ahmed Approved August 21, 2020 ________________________________ ________________________________ Kevin J. Tidgewell, Ph.D. Aleem Gangjee, Ph.D. Associate Professor of Medicinal Professor of Medicinal Chemistry Chemistry (Committee Member) (Committee Chair) ________________________________ ________________________________
    [Show full text]
  • Downloaded, Instead, and Converted to 3D Using Obabel (O’Boyle Et Al., 2011)
    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.30.225821; this version posted July 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 New tyrosinases with a broad spectrum of action against contaminants of emerging 2 concern: Insights from in silico analyses 3 4 Marcus V. X. Senra† & Ana Lúcia Fonseca 5 6 Instituto de Recursos Naturais, Universidade Federal de Itajubá, 37500-903, Itajubá, Minas 7 Gerais – Brazil 8 †Corresponding author – [email protected]; Orcid - 0000-0002-3866-8837 9 10 Abstract 11 Tyrosinases (EC 1.14.18.1) are type-3 copper metalloenzymes with strong oxidative capacities 12 and low allosteric selectivity to phenolic and non-phenolic aromatic compounds that have been 13 used as biosensors and biocatalysts to mitigate the impacts of environmental contaminants over 14 aquatic ecosystems. However, the widespread use of these polyphenol oxidases is limited by 15 elevated production costs and restricted knowledge on their spectrum of action. Here, six 16 tyrosinase homologs were identified and characterized from the genomes of 4 widespread 17 freshwater ciliates using bioinformatics. Binding energies between 3D models of these 18 homologs and ~1000 contaminants of emerging concern (CECs), including fine chemicals, 19 pharmaceuticals, personal care products, illicit drugs, natural toxins, and pesticides were 20 estimated through virtual screening, suggesting their spectrum of action and potential uses in 21 environmental biotechnology might be considerably broader than previously thought.
    [Show full text]
  • The Organic Chemistry of Drug Synthesis
    The Organic Chemistry of Drug Synthesis VOLUME 2 DANIEL LEDNICER Mead Johnson and Company Evansville, Indiana LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY AND SONS, New York • Chichester • Brisbane • Toronto Copyright © 1980 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging in Publication Data: Lednicer, Daniel, 1929- The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." 1. Chemistry, Medical and pharmaceutical. 2. Drugs. 3. Chemistry, Organic. I. Mitscher, Lester A., joint author. II. Title. RS421 .L423 615M 91 76-28387 ISBN 0-471-04392-3 Printed in the United States of America 10 987654321 It is our pleasure again to dedicate a book to our helpmeets: Beryle and Betty. "Has it ever occurred to you that medicinal chemists are just like compulsive gamblers: the next compound will be the real winner." R. L. Clark at the 16th National Medicinal Chemistry Symposium, June, 1978. vii Preface The reception accorded "Organic Chemistry of Drug Synthesis11 seems to us to indicate widespread interest in the organic chemistry involved in the search for new pharmaceutical agents. We are only too aware of the fact that the book deals with a limited segment of the field; the earlier volume cannot be considered either comprehensive or completely up to date.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7,795,310 B2 Lee Et Al
    US00779531 OB2 (12) United States Patent (10) Patent No.: US 7,795,310 B2 Lee et al. (45) Date of Patent: Sep. 14, 2010 (54) METHODS AND REAGENTS FOR THE WO WO 2005/025673 3, 2005 TREATMENT OF METABOLIC DISORDERS OTHER PUBLICATIONS (75) Inventors: Margaret S. Lee, Middleton, MA (US); Tenenbaum et al., “Peroxisome Proliferator-Activated Receptor Grant R. Zimmermann, Somerville, Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in MA (US); Alyce L. Finelli, Patients With Coronary Artery Disease'. Circulation, 2004, pp. 2197 Framingham, MA (US); Daniel Grau, 22O2.* Shen et al., “Effect of gemfibrozil treatment in sulfonylurea-treated Cambridge, MA (US); Curtis Keith, patients with noninsulin-dependent diabetes mellitus'. The Journal Boston, MA (US); M. James Nichols, of Clinical Endocrinology & Metabolism, vol. 73, pp. 503-510, Boston, MA (US) 1991 (see enclosed abstract).* International Search Report from PCT/US2005/023030, mailed Dec. (73) Assignee: CombinatoRx, Inc., Cambridge, MA 1, 2005. (US) Lin et al., “Effect of Experimental Diabetes on Elimination Kinetics of Diflunisal in Rats.” Drug Metab. Dispos. 17:147-152 (1989). (*) Notice: Subject to any disclaimer, the term of this Abstract only. patent is extended or adjusted under 35 Neogi et al., “Synthesis and Structure-Activity Relationship Studies U.S.C. 154(b) by 0 days. of Cinnamic Acid-Based Novel Thiazolidinedione Antihyperglycemic Agents.” Bioorg. Med. Chem. 11:4059-4067 (21) Appl. No.: 11/171,566 (2003). Vessby et al., “Effects of Bezafibrate on the Serum Lipoprotein Lipid and Apollipoprotein Composition, Lipoprotein Triglyceride Removal (22) Filed: Jun. 30, 2005 Capacity and the Fatty Acid Composition of the Plasma Lipid Esters.” Atherosclerosis 37:257-269 (1980).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2002/0102215 A1 100 Ol
    US 2002O102215A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0102215 A1 Klaveness et al. (43) Pub. Date: Aug. 1, 2002 (54) DIAGNOSTIC/THERAPEUTICAGENTS (60) Provisional application No. 60/049.264, filed on Jun. 6, 1997. Provisional application No. 60/049,265, filed (75) Inventors: Jo Klaveness, Oslo (NO); Pal on Jun. 6, 1997. Provisional application No. 60/049, Rongved, Oslo (NO); Anders Hogset, 268, filed on Jun. 7, 1997. Oslo (NO); Helge Tolleshaug, Oslo (NO); Anne Naevestad, Oslo (NO); (30) Foreign Application Priority Data Halldis Hellebust, Oslo (NO); Lars Hoff, Oslo (NO); Alan Cuthbertson, Oct. 28, 1996 (GB)......................................... 9622.366.4 Oslo (NO); Dagfinn Lovhaug, Oslo Oct. 28, 1996 (GB). ... 96223672 (NO); Magne Solbakken, Oslo (NO) Oct. 28, 1996 (GB). 9622368.0 Jan. 15, 1997 (GB). ... 97OO699.3 Correspondence Address: Apr. 24, 1997 (GB). ... 9708265.5 BACON & THOMAS, PLLC Jun. 6, 1997 (GB). ... 9711842.6 4th Floor Jun. 6, 1997 (GB)......................................... 97.11846.7 625 Slaters Lane Alexandria, VA 22314-1176 (US) Publication Classification (73) Assignee: NYCOMED IMAGING AS (51) Int. Cl." .......................... A61K 49/00; A61K 48/00 (52) U.S. Cl. ............................................. 424/9.52; 514/44 (21) Appl. No.: 09/765,614 (22) Filed: Jan. 22, 2001 (57) ABSTRACT Related U.S. Application Data Targetable diagnostic and/or therapeutically active agents, (63) Continuation of application No. 08/960,054, filed on e.g. ultrasound contrast agents, having reporters comprising Oct. 29, 1997, now patented, which is a continuation gas-filled microbubbles stabilized by monolayers of film in-part of application No. 08/958,993, filed on Oct.
    [Show full text]
  • Dimethylethanolamine (DMAE) [108-01-0] and Selected Salts
    Dimethylethanolamine (DMAE) [108-01-0] and Selected Salts and Esters DMAE Aceglutamate [3342-61-8] DMAE p-Acetamidobenzoate [281131-6] and [3635-74-3] DMAE Bitartrate [5988-51-2] DMAE Dihydrogen Phosphate [6909-62-2] DMAE Hydrochloride [2698-25-1] DMAE Orotate [1446-06-6] DMAE Succinate [10549-59-4] Centrophenoxine [3685-84-5] Centrophenoxine Orotate [27166-15-0] Meclofenoxate [51-68-3] Review of Toxicological Literature (Update) November 2002 Dimethylethanolamine (DMAE) [108-01-0] and Selected Salts and Esters DMAE Aceglutamate [3342-61-8] DMAE p-Acetamidobenzoate [281131-6] and [3635-74-3] DMAE Bitartrate [5988-51-2] DMAE Dihydrogen Phosphate [6909-62-2] DMAE Hydrochloride [2698-25-1] DMAE Orotate [1446-06-6] DMAE Succinate [10549-59-4] Centrophenoxine [3685-84-5] Centrophenoxine Orotate [27166-15-0] Meclofenoxate [51-68-3] Review of Toxicological Literature (Update) Prepared for Scott Masten, Ph.D. National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, North Carolina 27709 Contract No. N01-ES-65402 Submitted by Karen E. Haneke, M.S. Integrated Laboratory Systems, Inc. P.O. Box 13501 Research Triangle Park, North Carolina 27709 November 2002 Toxicological Summary for Dimethylethanolamine and Selected Salts and Esters 11/2002 Executive Summary Nomination Dimethylethanolamine (DMAE) was nominated by the NIEHS for toxicological characterization, including metabolism, reproductive and developmental toxicity, subchronic toxicity, carcinogenicity and mechanistic studies. The nomination is based on the potential for widespread human exposure to DMAE through its use in industrial and consumer products and an inadequate toxicological database. Studies to address potential hazards of consumer (e.g. dietary supplement) exposures, including use by pregnant women and children, and the potential for reproductive effects and carcinogenic effects are limited.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,261,537 B1 Klaveness Et Al
    USOO626.1537B1 (12) United States Patent (10) Patent No.: US 6,261,537 B1 Klaveness et al. (45) Date of Patent: *Jul.17, 2001 (54) DIAGNOSTIC/THERAPEUTICAGENTS 5,632,983 5/1997 Tait et al.. HAVING MICROBUBBLES COUPLED TO 5,643,553 * 7/1997 Schneider et al. .................. 424/9.52 ONE OR MORE VECTORS 5,650,156 7/1997 Grinstaff et al. ..................... 424/400 5,656.211 * 8/1997 Unger et al. .......................... 264/4.1 5,665,383 9/1997 Grinstaff et al. (75) Inventors: Jo Klaveness; Pál Rongved; Anders 5,690,907 11/1997 Lanza et al. .......................... 424/9.5 Høgset; Helge Tolleshaug, Anne 5,716,594 2/1998 Elmaleh et al. Naevestad; Halldis Hellebust; Lars 5,733,572 3/1998 Unger et al.. Hoff, Alan Cuthbertson; Dagfinn 5,780,010 7/1998 Lanza et al. Levhaug, Magne Solbakken, all of 5,846,517 12/1998 Unger. Oslo (NO) 5,849,727 12/1998 Porter et al.. 5,910,300 6/1999 Tournier et al. .................... 424/9.34 (73) Assignee: Nycomed Imaging AS, Oslo (NO) FOREIGN PATENT DOCUMENTS (*) Notice: This patent issued on a continued pros ecution application filed under 37 CFR 2 145 505 4/1994 (CA). 19 626 530 1/1998 (DE). 1.53(d), and is subject to the twenty year 0 727 225 8/1996 (EP). patent term provisions of 35 U.S.C. WO91/15244 10/1991 (WO). 154(a)(2). WO 93/20802 10/1993 (WO). WO 94/07539 4/1994 (WO). Subject to any disclaimer, the term of this WO 94/28873 12/1994 (WO).
    [Show full text]
  • New Synthetic Approaches for the Introduction of Pentafluorosulfanyl Group (SF5) Into Heterocycles Ewelina Falkowska
    New synthetic approaches for the introduction of pentafluorosulfanyl group (SF5) into heterocycles Ewelina Falkowska To cite this version: Ewelina Falkowska. New synthetic approaches for the introduction of pentafluorosulfanyl group (SF5) into heterocycles. Organic chemistry. INSA de Rouen, 2015. English. NNT : 2015ISAM0016. tel- 01309324 HAL Id: tel-01309324 https://tel.archives-ouvertes.fr/tel-01309324 Submitted on 29 Apr 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ÉCOLE DOCTORALE NORMANDE DE CHIMIE THÈSE Présentée à L’Institut National des Sciences Appliquées de Rouen Pour l’obtention du grade de DOCTEUR EN CHIMIE ORGANIQUE Par Ewelina FALKOWSKA New Synthetic Approaches for the Introduction of PentafluoroPentafluorosulfsulfanylanyl Group (SF5) into HeterocHeterocyclesycles le 16 décembre 2015 Devant le jury composé de: Dr. Julien PYTKOWICZ Université de Cergy-Pontoise Rapporteur Dr. Stéphane LEBRUN Université Lille 1 Rapporteur Dr. Petr BEIER Academy of Sciences of the Czech Republic Examinateur Pr. Jean-Philippe BOUILLON Université de Rouen Examinateur Pr. Philippe JUBAULT INSA de Rouen Examinateur Pr. Xavier PANNECOUCKE INSA de Rouen Examinateur Acknowledgement First of all, I would like to thank Dr. Petr Beier (Academy of Sciences of the Czech Republic), Dr.
    [Show full text]
  • Stardrop Refernce Guide
    © 2015 Optibrium Ltd. Optibrium™, StarDrop™, Glowing Molecule™, Nova™, Auto-Modeller™, Card View™ and MPO Explorer™ are trademarks of Optibrium Ltd. BIOSTER™ is a trademark of Digital Chemistry Ltd., Derek Nexus™ is a trademark of Lhasa Ltd., torch3D™ is a trademark of Cresset Biomolecular Research Ltd. and Matsy™ is a trademark of NextMove Software Ltd. 1 INTRODUCTION ....................................................................................................................... 5 1.1 StarDrop overview ............................................................................................................................. 5 1.2 Reference guide summary ............................................................................................................... 8 2 PROBABILISTIC SCORING .................................................................................................. 10 2.1 Defining scoring criteria ................................................................................................................. 10 2.2 Importance of uncertainty ............................................................................................................. 14 2.3 Interpreting scores .......................................................................................................................... 16 3 CHEMICAL SPACE AND COMPOUND SELECTION .......................................................... 18 3.1 Introduction ....................................................................................................................................
    [Show full text]
  • Florencio Zaragoza Dörwald Lead Optimization for Medicinal Chemists
    Florencio Zaragoza Dorwald¨ Lead Optimization for Medicinal Chemists Related Titles Smith, D. A., Allerton, C., Kalgutkar, A. S., Curry, S. H., Whelpton, R. van de Waterbeemd, H., Walker, D. K. Drug Disposition and Pharmacokinetics and Metabolism Pharmacokinetics in Drug Design From Principles to Applications 2012 2011 ISBN: 978-3-527-32954-0 ISBN: 978-0-470-68446-7 Gad, S. C. (ed.) Rankovic, Z., Morphy, R. Development of Therapeutic Lead Generation Approaches Agents Handbook in Drug Discovery 2012 2010 ISBN: 978-0-471-21385-7 ISBN: 978-0-470-25761-6 Tsaioun, K., Kates, S. A. (eds.) Han, C., Davis, C. B., Wang, B. (eds.) ADMET for Medicinal Chemists Evaluation of Drug Candidates A Practical Guide for Preclinical Development 2011 Pharmacokinetics, Metabolism, ISBN: 978-0-470-48407-4 Pharmaceutics, and Toxicology 2010 ISBN: 978-0-470-04491-9 Sotriffer, C. (ed.) Virtual Screening Principles, Challenges, and Practical Faller, B., Urban, L. (eds.) Guidelines Hit and Lead Profiling 2011 Identification and Optimization ISBN: 978-3-527-32636-5 of Drug-like Molecules 2009 ISBN: 978-3-527-32331-9 Florencio Zaragoza Dorwald¨ Lead Optimization for Medicinal Chemists Pharmacokinetic Properties of Functional Groups and Organic Compounds The Author All books published by Wiley-VCH are carefully produced. Nevertheless, authors, Dr. Florencio Zaragoza D¨orwald editors, and publisher do not warrant the Lonza AG information contained in these books, Rottenstrasse 6 including this book, to be free of errors. 3930 Visp Readers are advised to keep in mind that Switzerland statements, data, illustrations, procedural details or other items may inadvertently be Cover illustration: inaccurate.
    [Show full text]