AbstractGallium-67 (67Ga) produces Auger electrons with energy range between 0.95 keV and 9.46 keV . 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 . 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
|Philip Blower (Supervisor) & Samantha Terry (Supervisor)