This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Radionuclide Dosimetry at Microscopic and Macroscopic Level in a Thyroid Model Chuamsaamarkkee, Krisanat 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). 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Sep. 2021 Radionuclide Dosimetry at Microscopic and Macroscopic Level in a Thyroid Model A thesis submitted to King’s College London for the degree of Doctor of Philosophy in Imaging Sciences and Radiation Biology Krisanat Chuamsaamarkkee Division of Imaging Sciences and Biomedical Engineering King’s College London 2016 1 Abstract This study proposes to evaluate dosimetrically the feasibility of using rhenium isotopes (186Re and 188Re) in the form of perrhenate (which is also a substrate of the sodium iodide symporter, NIS) for the treatment of benign nodular thyroid disease and non-thyroidal NIS expressing tumours. While radioiodine (131I-NaI) has practical limitations, there is a window in which rhenium isotopes might offer greater therapeutic advantages. For instance, 186Re and 188Re-perrhenate have shorter half-life, higher energy beta particles, longer range and less abundant gamma photons thus reducing effective dose to the whole body and members of the public and family. Generally, dosimetry in nuclear medicine is considered only at macroscopic level with radionuclide uptake assumed to have a uniform distribution throughout the organ. However, this assumption is not always correct as radionuclides may or may not get incorporated into intracellular structures which, depending on the particular energy transfer mechanisms, may be influential. Therefore, an aim of this thesis was to study the effect of tracer localisation on microscopic and macroscopic dosimetry by using the thyroid as a model. First, a basic performance evaluation of preclinical imaging systems was carried out. The image-based quantification accuracy of SPECT radionuclides (99mTc, 123I and 188Re) and PET (18F) with regard to effect of object size, acquisition time and reconstruction parameters (number of iterations) were examined with a mouse-size micro-hollow sphere phantom. Quantification accuracy in small objects was attempted to be improved using phantom-derived correction factors (Chapter 2). Then, a series of in vivo experiments was carried out aimed at spatio-temporal quantification with the available SPECT NIS-radiotracers (99mTc-pertechnetate, 123I-NaI, 131I-NaI and 188Re-perrhenate) and a forthcoming clinical PET radiotracer (18F-tetrafluoroborate). These data demonstrated distinct differences of uptake patterns between metabolised (123I- and 131I-NaI) and non-metabolised tracers (18F-tetrafluoroborate, 99mTc-pertechnetate and 188Re-perrhenate), and also subtle differences between the non-metabolised tracers. Human-equivalent effective dose calculations for diagnostic use of these radiotracers were reported in this study. Dose estimations were conducted on the same strain sex- and age-matched animals to allow approximate comparison. Dosimetric estimations relevant to treatment of benign nodular thyroid disease indicated that rhenium isotopes were equally effective when excluding the highly variable uptake in the stomach and urinary bladder. The effective dose per unit of administered activity from 186Re and 188Re was lower than conventional radioiodine. Also red marrow absorbed dose 2 was about 1.5 and 3 times (for 186Re and 188Re respectively) lower than that produced by radioiodine. In xenograft bearing non-thyroidal NIS adenocarcinoma tumour (human NIS- engineered model), our data indicated that both rhenium isotopes delivered higher absorbed dose to the tumour (6.33 and 8.68 times higher for 186Re and 188Re) compared to 131I-NaI. Additionally, the therapy indexes (tumour to effective dose and tumour to thyroid ratio) for both rhenium isotopes were greater than 131I-NaI. An investigation of the radionuclide distribution at the microscopic level in thyroid tissue with electron microscopy and micro-autoradiography techniques illustrated that non-metabolised tracers were only located in thyrocytes whereas iodide was detected in the colloid. This information (thyroid geometrical model and tracer distribution) were used as an input for small-scale pilot dosimetry using the MCNPx (Monte Carlo N-particle extended) platform. The simulation results indicated that the mode of absorbed dose when 188Re distributed in thyrocytes was higher and more uniform when compared with 131I being located in the colloid. In conclusion, dose delivered to the thyroid is dependent on cellular distribution of radiotracers. The work presented in this thesis has been an important step for initial dosimetric estimates of the therapeutic potential of these radiotracers to inform future translation with pilot studies in humans. 3 Statement of Authorship I, the undersigned, hereby confirm that: o This submission is my own work and that to the best of my knowledge. o This work was done wholly or mainly while in candidature for a research degree at this university. o I have fully acknowledged and referenced the ideas and work of others, whether published or unpublished, in my thesis. o I have prepared my thesis specifically for the degree of Doctor of Philosophy, while under supervision at this university. o My thesis does not contain work extracted from a thesis, dissertation or research paper previously presented for another degree or diploma at this or any other university. (Mr. Krisanat Chuamsaamarkkee) Date 4 Table of Contents ABSTRACT .................................................................................................................................... 2 STATEMENT OF AUTHORSHIP ................................................................................................... 4 TABLE OF CONTENTS ................................................................................................................. 5 TABLE OF FIGURES ..................................................................................................................... 9 TABLE OF TABLES ..................................................................................................................... 17 ACKNOWLEDGEMENTS ............................................................................................................ 20 ABBREVIATIONS ........................................................................................................................ 22 CHAPTER 1 INTRODUCTION .................................................................................................... 25 1.1 INTRODUCTION ......................................................................................................................................... 25 1.2 THYROID .................................................................................................................................................. 28 1.2.1 Thyroid Anatomy ...................................................................................................................... 28 1.2.2 Thyroid Histology ...................................................................................................................... 29 1.2.3 Thyroid Hormones Synthesis and Physiology ........................................................................... 30 1.2.4 Iodine Kinetics and Sodium Iodide Symporter (NIS) ................................................................. 32 1.2.5 Radionuclide Imaging of Thyroid Gland .................................................................................... 33 1.2.6 Radionuclide Therapeutic of Thyroid Gland ............................................................................. 35 1.3 MICROSCOPIC AND MACROSCOPIC DOSIMETRY IN NUCLEAR MEDICINE ................................................................ 36 1.3.1 Macroscopic Dosimetry in Nuclear Medicine ........................................................................... 36 1.3.2 Microscopic Dosimetry in Nuclear Medicine ............................................................................ 36 1.4 THESIS OVERVIEW ..................................................................................................................................... 38 CHAPTER 2 QUANTITATIVE IMAGING WITH THE NANOSCAN SPECT/CT .......................... 39 2.1 INTRODUCTION ........................................................................................................................................