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Functionalized Bispidines and Ultrasmall Silicon Nanoparticles for Cancer Imaging

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Functionalized Bispidines and Ultrasmall Silicon Nanoparticles for Cancer Imaging Functionalized Bispidines and Ultrasmall Silicon Nanoparticles for Cancer Imaging DISSERTATION Zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr.rer.nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von Master of Science Garima Singh geboren am 23. Dezember 1988 in Lucknow Indien eingereicht am 20.03.2019 Die Dissertation wurde in der Zeit von Juli 2015 bis Dezember 2018 am Helmholtz-Zentrum Dresden – Rossendorf im Institut für Radiopharmazeutische Krebsforschung angefertigt. Functionalized Bispidines and Ultrasmall Silicon Nanoparticles for Cancer Imaging DISSERTATION To get the academic degree Doctor rerum naturalium (Dr.rer.nat.) Submitted to The Faculty of Mathematics and Natural Sciences Technical University Dresden Submitted by Master of Science Garima Singh Born on 23. December 1988 in Lucknow India Submitted on 20.03.2019 Defended on 17.05.2019 The dissertation was performed from July 2015 till December 2018 in the Institute of Radiopharmaceutical Cancer Research at the Helmholtz-Zentrum – Dresden Rossendorf. Gutachter: Prof. Dr. rer. nat. habil. Jörg Steinbach (Technical University Dresden and Helmholtz-Zentrum Dresden - Rossendorf) Prof. Luisa De Cola (University of Strasbourg and Karlsruhe Institute of Technology) Eingereicht am: 20.03.2019 Datum der Verteidigung: To my family for always believing in me. Table of Contents Chapter 1 Introduction............................................................................................... 1 1.1 General introduction ....................................................................................... 1 1.2 Aims and objectives of the thesis ................................................................... 6 Chapter 2 Literature review and theoretical part ..................................................... 7 2.1 Molecular imaging of cancer........................................................................... 7 2.1.1 Positron Emission Tomography ............................................................... 8 2.1.2 Optical imaging ......................................................................................19 2.2 Multimodal molecular imaging .......................................................................21 2.2.1 Silicon nanoparticles as multimodal imaging agents ...............................23 2.2.2 Factors affecting the biodistribution and pharmacokinetics of NPs .........27 2.2.3 Tumor targeting strategies for molecular imaging agents .......................30 2.2.4 Targeted functionalization of NPs and BFCAs for imaging purposes ......32 Chapter 3 Results and Discussion ..........................................................................35 3.1 Synthesis, characterization and radiolabeling studies of hexadentate bispidine-based bifunctional chelating agents ..........................................................37 3.1.1 Synthesis of hexadentate bispidine-based ligands .................................39 3.1.2 Radiochemistry of modified bispidine derivatives ...................................59 3.1.3 Conclusions ...........................................................................................61 3.2 Design and synthesis of Bispidine-based TATE and sd antibody bioconjugates 63 3.2.1 Bispidine-based bioconjugates of somatostatin agonist TATE................63 3.2.2 Bispidine-based EGFR targeting sdAb conjugates B5-sdAb ..................71 3.2.3 Conclusions ...........................................................................................80 3.3 Synthesis and characterization of amine-terminated ultrasmall Si NPs .........81 3.3.1 Synthesis of amine-terminated Si NPs ...................................................81 3.3.2 Characterization of Si NPs .....................................................................82 3.3.3 Surface characterization of Si NPs .........................................................84 3.3.4 Conclusions ...........................................................................................85 3.4 Synthesis, characterization, and biodistribution studies of Si NP-based mono- labeled PET and optical imaging agents ..................................................................86 3.4.1 Si NP-NOTA derived PET imaging agent ...............................................88 3.4.2 Synthesis and characterization of Si NP-Bispidine (Si NP-B4) ...............93 3.4.3 Synthesis, characterization, in vitro and in vivo evaluation of Si NP-IR800 as an optical imaging probe ..................................................................................95 3.4.5 Conclusions ......................................................................................... 104 3.5 Development of dual-labeled Si NPs an its in vitro and in vivo evaluation ... 106 3.5.1 Synthesis and characterization of Si NP-IR800-NOTA conjugate ......... 107 3.5.2 Photophysical characterization of Si NP-IR800-NOTA and comparison with mono-labeled imaging agents ..................................................................... 109 3.5.3 Radiolabeling studies of dual-labeled Si NP-IR800-NOTA ................... 110 3.5.4 Quantitative estimation of the amount of fluorophore and the radiolabel on the Si NP conjugate............................................................................................ 111 3.5.5 Cell Cytotoxicity Studies of the Si NP-IR800-NOTA ............................. 114 3.5.6 In vivo PET analysis and biodistribution studies, urine analysis and ex vivo examination of [64Cu]Cu-Si NP-IR800-NOTA .............................................. 115 3.5.7 Comparative analysis of [68Ga]Ga-Si NP-IR800-NOTA and [64Cu]Cu-Si NP-IR800-NOTA in A431 tumor bearing mice .................................................... 121 3.5.8 Conclusions ......................................................................................... 127 3.6 Investigation of mono-labeled and dual-labeled Si NPs as targeted imaging agents .................................................................................................................... 128 3.6.1 Synthesis of Si NP-PEG-5B9 peptide conjugates ................................. 128 3.6.2 Characterization of the targeted Si NP conjugates ............................... 129 3.6.3 Conclusions ......................................................................................... 134 Chapter 4 Conclusions and Outlook ..................................................................... 135 4.1 Conclusions ................................................................................................ 135 4.2 Outlook ....................................................................................................... 140 Chapter 5 Experimental Section ............................................................................ 141 5.1 Chemicals and Materials ............................................................................. 141 5.2 Analysis, characterization and purification techniques and methods ........... 143 5.3 Radionuclide production (68Ga and 64Cu) .................................................... 146 5.4 Syntheses ................................................................................................... 148 5.4.1 Synthesis of bispidines derivatives (B1-B11), intermediates (B1’, B3’, B8’, B9’, B11’) and bifunctional linkers (L1, L2) ......................................................... 148 5.4.2 Synthesis of bispidines-based bioconjugates B4-PEG-TATE and B5- sdAb-7C12 ......................................................................................................... 160 5.4.3 Synthesis and modification of Si NPs by hydrothermal method ............ 161 5.5 Radiolabeling experiments .......................................................................... 166 5.6 In vitro cell experiments ............................................................................... 167 5.7 Cell binding studies .......................................................................................... 169 5.8 Animal experiments ..................................................................................... 170 Chapter 6 References ............................................................................................. 172 Chapter 7 Annex ..................................................................................................... 192 7.1 Acronyms .................................................................................................... 192 7.2 Supplementary Data ................................................................................... 195 Chapter 8 Publications, Conferences and Awards ............................................... 203 Chapter 9 Acknowledgements ............................................................................... 206 Chapter 10 Statement of declaration / Erklärungen .............................................. 208 Table of Figures Figure 1.1.1: Representation of an idealized multimodal nanoparticle for cancer diagnostic and therapeutic applications. ....................................................................... 4 Figure 2.1.1: Electromagnetic spectrum and operating ranges of the different imaging modalities: from radiowaves (MRI) via near-infrared (NIR) to gamma radiation (PET/SPECT). .............................................................................................................. 8 Figure 2.1.2: Illustration of the mechanism and utility of PET imaging. ........................
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