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In Vitroand in Vivostudies of a Novel Blood Brain Barrier Permeabilizing

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In Vitroand in Vivostudies of a Novel Blood Brain Barrier Permeabilizing In vitro and in vivo studies of a novel blood brain barrier permeabilizing peptide K16ApoE And novel in vivo treatment of melanoma brain metastases Christopher Florian Holte This thesis is submitted in partial fulfilment of the requirements for the degree of Master in Medical Biology – Biomedical Image Sciences Department of Biomedicine University of Bergen 2016 Table of Contents Acknowledgements .................................................................................................................. 4 Abbreviations .......................................................................................................................... 5 Table of figures ....................................................................................................................... 7 Abstract .................................................................................................................................. 9 1 Introduction .........................................................................................................................12 1.1 Skin cancer and melanoma .................................................................................................12 1.2 Incidence and causes of melanoma ......................................................................................13 1.3 Mutations in melanoma development ...................................................................................15 1.4 Grading and staging of melanoma ........................................................................................15 1.5 Treatment of melanoma ......................................................................................................17 1.6 The metastatic process .......................................................................................................18 1.7 Treatment of brain metastases .............................................................................................21 1.8 The Blood Brain Barrier .....................................................................................................22 1.9 Permeabilizing the BBB .....................................................................................................23 1.10 K16ApoE .......................................................................................................................25 1.11 Models to Study Melanoma Progression .............................................................................26 1.11.1 In Vitro Models .............................................................................................................26 1.11.2 In Vivo Models (Xenografts)...........................................................................................26 In Vivo Cancer Metastasis Models ............................................................................................26 Animal brain metastasis models ................................................................................................27 1.12 Imaging ..........................................................................................................................27 1.12.1 Fluorescent microscopy & time-lapse microscopy .............................................................27 1.12.2 Electron Microscopy .....................................................................................................29 Scanning Electron Microscopy (SEM) .......................................................................................29 Transmission Electron Microscopy (TEM) .................................................................................30 1.12.3 Magnetic Resonance Imaging (MRI) ...............................................................................30 The NMR signal .....................................................................................................................30 Magnetic Resonance Imaging (MRI) .........................................................................................32 Contrast enhancement and DCE-MRI ........................................................................................34 1.12.4 Bioluminescence Imaging (BLI) .....................................................................................36 2 Aims of this Study ................................................................................................................37 3 Materials and Methods ..........................................................................................................38 3.1 In Vitro ............................................................................................................................38 Cell lines used: .......................................................................................................................38 Medium and solutions: ............................................................................................................39 3.1.1 General Cell Culture Work ...............................................................................................40 1 3.1.2 Resazurin-resorfin Cell Viability Assay .............................................................................43 3.1.3 Morphological light microscopy .......................................................................................43 3.1.4 Time-lapse fluorescence microscopy .................................................................................44 3.1.5 Electron Microscopy .......................................................................................................44 Scanning Electron Microscopy (SEM) .......................................................................................45 Transmission Electron Microscopy (TEM) .................................................................................45 3.2 In Vivo .............................................................................................................................46 Mice and Housing Conditions ..................................................................................................46 3.2.1 K16ApoE kinetics studies, DCE-MRI ...............................................................................47 3.2.2 Mouse Xenograft Model ..................................................................................................48 3.2.3 Pilot Treatment Experiment..............................................................................................49 3.2.3.1 BLI .............................................................................................................................49 3.2.3.2 MRI (T1, T2, T1-contrast – anatomical sans) ...................................................................50 3.2.3.3 Endpoints ....................................................................................................................50 3.2.3.4 Histology ....................................................................................................................50 3.3 Software ...........................................................................................................................51 4 Results ................................................................................................................................52 4.1 In vitro .............................................................................................................................52 4.1.1 Vemurafenib cell culture experiments................................................................................52 4.1.1.1 Cell Viability assay ......................................................................................................52 4.1.1.2 Light microscopy .........................................................................................................53 4.1.2 K16ApoE cell culture experiments ....................................................................................53 4.1.2.1 Survival assay ..............................................................................................................53 4.1.2.2 Time-lapse Fluorescence Microscopy .............................................................................55 4.1.2.3 Electron Microscopy .....................................................................................................58 Scanning Electron Microscopy .................................................................................................58 Transmission Electron Microscopy ...........................................................................................60 4.2 In Vivo .............................................................................................................................61 4.2.1 K16ApoE Kinetics: DCE-MRI .........................................................................................61 4.2.1.1 K16ApoE effect on BBB 10 minutes post administration ..................................................61 4.2.1.2 Evaluation of duration of BBB opening after injection of K16ApoE ...................................62 4.2.1.3 Half-dose (100 µg K16ApoE) experiments ......................................................................64 4.2.1.4 Intra peritoneal administration of K16ApoE ....................................................................66 4.2.2 Pilot Study: Combinatorial Treatment of xenografted melanoma with vemurafenib and K16ApoE...............................................................................................................................66 4.2.2.1 Animal weight
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