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Title: Potential of Gallium-67 as a therapeutic radionuclide
Author: Bin Othman, Faiz
ISNI:       0000 0004 9357 5259
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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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 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. In 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 projectlooked 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 warrantsfurther investigations for better understanding of its therapeutic capacity.
Supervisor: Blower, Philip John ; Terry, Samantha Yorna Armstrong Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available