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Download Thesis This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Potential of Gallium-67 as a therapeutic radionuclide Bin Othman, Faiz Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 28. Sep. 2021 Potential of Gallium-67 as a Therapeutic Radionuclide Muhamad Faiz Othman A thesis submitted to the University of London for the degree of Doctor of Philosophy in Imaging Sciences and Biomedical Engineering Division of Imaging Sciences and Biomedical Engineering King's College London 2020 1 DECLARATION I, Muhamad Faiz Othman, declare that the PhD thesis entitled "Potential of Gallium-67 as a Therapeutic Radionuclide" is no more than 100, 000 words in length including quotes and exclusive of tables figures, appendices, bibliography, references and footnotes. The thesis contains no material that has been submitted previously, in whole or in part, for the award of any other academic degree or diploma. Except where otherwise indicated, this thesis is my own work. 2 ACKNOWLEDGEMENT First and foremost, to both of my supervisors, Professor Philip Blower and Dr. Samantha Terry, I am honoured to be your student. Thank you for the guidance and continuous support you provide throughout my study. Your patience, motivations and your immense knowledge in the field are to be admired. Your actions are exemplary, and I will surely try to adopt that in my life. To David Thakor, Barry Crook, Dr. Karen Shaw and Dr. Kavitha Sunassee, all of you have been instrumental for me. Ensuring smooth running of the laboratory is not a small task yet all of you managed to do that. The support and advice given were helpful and I am grateful for that. To lab mates, postdoctoral researchers and staff including Dr. Krisanat Chuamsaamarkee, Dr. Putthiporn Charoenphun, Dr. Zaitulhusna Md Safee, Dr. Florian Kampmeier, Dr. Margaret Cooper, Jennifer Young, Dr. Levente Meszaros, Dr. Cinzia Imberti and Dr. Michele Ma, your contributions, help and advice throughout my study were really supportive, thank you. To my wife, Nazhatul Nadiah, you have been a pillar for me. You were there all the time and always been a source of motivation for me. To my two kids, Balqis Hana and Muadz, both of you always cheer me up and my success in life will always for both of you. To my parents, thank you for the understanding and support throughout difficult period. 3 To my sponsor, Malaysian Ministry of Education, thank you for the opportunity and trust that was given to me. 4 ABSTRACT Gallium-67 (67Ga) produces Auger electrons with energy range between 0.95 keV and 9.46 keV [1]. Its therapeutic potential has been reported previously [2-4] but due to a lack of knowledge on gallium radiochemistry, its use has been neglected. The advent of 68Ga-PET has improved molecular targeting with radiogallium, inviting re-evaluation of therapy with 67Ga. Auger electrons have short travelling distance (up to 2 µm) and as a consequence, produce high linear energy transfer (LET) with ionisation rate superior to beta emitters [5]. Because of the limited range, damage only occurs in cells that are specifically targeted with nearby healthy cells remain unaffected. Compared to other Auger emitters, 67Ga produces electrons that able to travel somewhat further and thus may eliminate the need for nuclear localization to exert damage. This study comprises four parts. Firstly, 67Ga ionisation capability was assessed in a cell-free system with plasmid DNA. Absence of correctional mechanisms and the ability to control DNA repair will enable better understanding of the ionising capacity of 67Ga and its electrons. Damage induced with 67Ga was compared to 111In in various conditions including in presence of DMSO and chelators. 67Ga was able to induce plasmid strand breaks better than 111In in all conditions. Toxicity of 67Ga was further tested in various cell lines using a non-targeted approach. The toxicity study was performed in three cell lines (HCC1954, DU145 and MDA-MB-231) in vitro to assess the activity of 67Ga required per cell to kill it. In order to 5 localize 67Ga in these various cell lines, it was trapped within lipophilic complexes that entered the cells passively. Toxicity of 67Ga was compared to 111In delivered similarly in all cell lines. Results showed 67Ga and 111In have similar toxicity in all cell lines tested. The third part of the study assessed 67Ga as a therapeutic radionuclide when specifically targeted to breast cancer cells by trastuzumab, a human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab was labelled with 67Ga. Both HER2 positive and HER2 negative cell lines were used. As in the previous chapter, 67Ga toxicity was compared to 111In. Both 67Ga and 111In demonstrated considerable toxicity on HER2 positive cells without affecting the HER2 negative cells. Finally, the project looked at the potential therapeutic application for 67Ga for prostate cancer. In this chapter, 67Ga was attached to prostate specific membrane antigen (PSMA) and tested for toxicity and specificity of cell killing in PSMA positive and PSMA negative prostate cancer cell lines in vitro. The result showed that 67Ga-PSMA is capable of inducing damage to the PSMA positive cells without affecting the PSMA negative cells. As a conclusion, 67Ga showed therapeutic potential in vitro and warrants further investigations for better understanding of its therapeutic capacity. 6 CONTENTS List of Figures .................................................................................................... 11 List of Tables ...................................................................................................... 13 List of Equations ................................................................................................ 14 LIST of Abbreviations......................................................................................... 15 Chapter 1 Literature Review .......................................................................... 18 1.1 Introduction ......................................................................................... 18 1.2 Radioactive materials in targeted therapy .......................................... 19 1.2.1 Selection of radionuclides for therapy 20 1.3 Particulate radiation in therapy .......................................................... 23 1.3.1 Alpha particles 24 1.3.2 Beta particles 26 1.3.3 Low-energy particles 27 1.4 Auger Electron Emitters For Therapy .................................................. 29 1.4.1 Physical aspects of Auger emitters 30 1.4.2 Radiation biology and damaging effect of Auger electron 37 1.4.3 Clinical experiences with Auger therapy 45 1.4.4 Gallium-67 (67Ga) as a candidate for Auger therapy 48 1.4.5 Translation from 68Ga to 67Ga 54 1.4.6 Summary and Aims 55 Chapter 2 Assessment of 67Ga damage to plasmid DNA................................ 58 2.1 Introuction ........................................................................................... 58 2.2 Aim ....................................................................................................... 60 2.3 Materials and methods ....................................................................... 60 2.3.1 Radionuclide preparation 60 2.3.2 Plasmid damage assessment 61 2.3.3 Agarose gel electrophoresis 63 2.3.4 Image acquisition and analysis 63 7 2.3.5 Theoretical exposure of plasmid to Auger electrons 64 2.4 Results ................................................................................................. 66 2.4.1 Determination of incubated activity 66 2.4.2 Comparison of 67Ga and 111In plasmid damage 68 2.4.3 67Ga and 111In plasmid damage: Effect of chelation 73 2.4.4 Theoretical exposure of plasmid to Auger electrons 77 2.5 Discussion ............................................................................................ 78 2.5.1 Determination of incubated activity 78 2.5.2 67Ga and 111In plasmid damage: mechanism of damage 80 2.5.3 67Ga and 111In plasmid damage: Effect of chelation 83 2.5.4 Theoretical exposure of plasmid to Auger electrons 86 2.6 Conclusion ........................................................................................... 88 Chapter 3 Assessment of 67Ga cellular toxicity in vitro .................................. 90 3.1 Introduction ........................................................................................
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