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Dissertation.Pdf UNIVERSITÄTSKLINIKUM HAMBURG-EPPENDORF Zentrum für Experimentelle Medizin, Institut für Experimentelle Pharmakologie und Toxikologie Direktor: Professor T. Eschenhagen Thrombus-Targeted Theranostic Microbubbles for Simultaneous Ultrasound Diagnosis and Therapy of Thrombosis. Title page Dissertation zur Erlangung des Grades eines Doktors der Medizin an der Medizinischen Fakultät der Universität Hamburg. vorgelegt von: Yannik Andreas Gkanatsas aus Bremen Hamburg 2017 Angenommen von der Medizinischen Fakultät der Universität Hamburg am: 13.12.2017 Veröffentlicht mit Genehmigung der Medizinischen Fakultät der Universität Hamburg. Prüfungsausschuss, der Vorsitzende: Prof. Dr. Thomas Eschenhagen Prüfungsausschuss, zweite Gutachterin: Prof. Dr. Renate Bonin-Schnabel Prüfungsausschuss, dritter Gutachter: PD Dr. Florian Langer 2 Table of contents Title page ..................................................................................................................... 1 Table of contents ......................................................................................................... 3 List of Figures: ............................................................................................................. 6 List of Tables: .............................................................................................................. 7 Chapter 1. Introduction ............................................................................................. 8 1.1 Cardiovascular Disease (CVD) .......................................................................................... 8 1.1.1 Epidemiology and Importance of CVD ........................................................................ 8 1.1.2 Atherosclerosis ............................................................................................................ 8 1.1.3 The role of platelets in atherosclerosis and atherothrombosis .................................... 9 1.2 Haemostatic System ........................................................................................................ 10 1.2.1 Platelets ..................................................................................................................... 10 1.2.2 Coagulation cascade ................................................................................................. 13 1.2.3 Fibrinolysis and thrombolytic therapy ........................................................................ 15 1.3 Antibodies ......................................................................................................................... 18 1.3.1 Single chain antibodies .............................................................................................. 18 1.4 Ultrasound ........................................................................................................................ 20 1.4.1 Basic physics ............................................................................................................. 20 1.4.2 Ultrasound contrast agents – Microbubbles (MB) ..................................................... 21 1.4.3 Clinical indications for the use of MBs ....................................................................... 23 1.5 Molecular ultrasound imaging: ......................................................................................... 24 1.5.1 Molecular ultrasound imaging in cancer .................................................................... 25 1.5.2 Molecular ultrasound imaging in inflammation and thrombosis ................................. 25 1.6 Theranostics: .................................................................................................................... 27 Chapter 2. Material and Methods ........................................................................... 29 2.1 Material ............................................................................................................................. 29 2.1.1 List of chemicals ........................................................................................................ 29 2.1.2 List of equipment ....................................................................................................... 30 2.1.3 List of software .......................................................................................................... 32 2.1.4 List of enzymes and reaction kits .............................................................................. 33 2.1.5 Buffers and media ..................................................................................................... 34 2.1.6 Primers and plasmids ................................................................................................ 37 2.1.7 Antibodies .................................................................................................................. 38 2.3 Molecular biology methods ............................................................................................... 39 2.3.1 DNA Isolation ............................................................................................................. 39 2.3.2 Separation of DNA by agarose gel electrophoresis ................................................... 39 2.3.3 Nano Drop® – Concentration and Purity of DNA ...................................................... 40 2.3.4 Preparation of competent cells .................................................................................. 40 2.3.5 Amplification of DNA .................................................................................................. 40 2.3.6 Vectors ...................................................................................................................... 41 2.3.7 Restriction enzyme digest ......................................................................................... 42 2.3.8 Ligation ...................................................................................................................... 42 2.3.9 DNA introduction into cells ........................................................................................ 43 2.3.10 Screening for positive clones after transformation .................................................. 43 2.3.11 DNA sequencing: ..................................................................................................... 44 2.4 Protein chemical methods: ............................................................................................... 44 3 2.4.1 Protein expression and production in E. coli strains .................................................. 44 2.4.2 Production of proteins in mammalian cells: Human embryonic kidney (HEK) cells 293F ................................................................................................................................... 45 2.4.3 Small scale purification (SCP) of proteins ................................................................. 46 2.4.4 Large scale purification of proteins ............................................................................ 46 2.4.5 Dialysis of protein samples ........................................................................................ 47 2.4.6 Bicinchoninic Acid (BCA) Protein assay .................................................................... 47 2.4.7 Analysis of protein samples using sodium dodecyl suplatepolyacrylamide gel electrophoresis (SDS-PAGE) ............................................................................................. 47 2.4.8 Analysis of protein samples with Coomassie brilliant blue G250 staining ................. 49 2.4.9 Analysis of protein using western blotting ................................................................. 49 2.4.10 Immunoreactions ..................................................................................................... 50 2.4.11 Sortase-A reaction ................................................................................................... 50 2.4.12 Negative purification after Sortase A reaction ......................................................... 50 2.5 Blood collection ................................................................................................................ 51 2.5.1 Generation of platelet rich plasma (PRP) .................................................................. 51 2.6 Flow cytometry ................................................................................................................. 51 2.6.1 Parameters for analysis in flow cytometry ................................................................. 51 2.6.2 Gating of cells on flow cytometry ............................................................................... 52 2.6.3 Data analysis with histograms on flow cytometry ...................................................... 52 2.6.4 Flow cytometry of platelets with scFvanti-LIBS ............................................................... 52 2.7 Conjugation of proteins to microbubbles .......................................................................... 53 2.7.1 Conjugation of biotinylated scFv-AviTag and biotinylated scuPa construct to commercial streptavidin coated lipid microbubbles via biotin-streptavidin coupling ........... 53 2.7.2 Calculations of protein need for conjugation ............................................................. 54 2.8 In vitro assays .................................................................................................................. 55 2.8.1 Urokinase activity assay with 2444X
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