Potential of Gallium-67 as a therapeutic radionuclide

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 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 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

Date of Award	1 Nov 2020
Original language	English
Awarding Institution	King's College London
Supervisor	Philip Blower (Supervisor) & Samantha Terry (Supervisor)