Biodistribution and imaging of an hsp90 ligand labelled with 111In and 67Ga for imaging of cell death

Ivan Ho Shon; Divesh Kumar; Chithradevi Sathiakumar; Paula Berghofer; Khang Van; Andrew Chicco; Philip J Hogg

doi:10.1186/s13550-020-0590-x

Biodistribution and imaging of an hsp90 ligand labelled with ¹¹¹In and ⁶⁷Ga for imaging of cell death

EJNMMI Res. 2020 Jan 20;10(1):4. doi: 10.1186/s13550-020-0590-x.

Authors

Ivan Ho Shon^{1

2

3}, Divesh Kumar⁴, Chithradevi Sathiakumar⁵, Paula Berghofer⁶, Khang Van⁵, Andrew Chicco⁷, Philip J Hogg⁸

Affiliations

¹ Department of Nuclear Medicine and PET, Prince of Wales Hospital, Randwick, 2031, NSW, Australia. i.hoshon@unsw.edu.au.
² The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia. i.hoshon@unsw.edu.au.
³ Prince of Wales Clinical School, University of New South Wales, Sydney, 2052, NSW, Australia. i.hoshon@unsw.edu.au.
⁴ Department of Nuclear Medicine and PET, Fiona Stanley Hospital, Murdoch, 6150, WA, Australia.
⁵ Department of Nuclear Medicine and PET, Liverpool Hospital, Liverpool, NSW, 2170, Australia.
⁶ LifeSciences Division, Australian Nuclear Science and Technology Organisation, New Illawarra Road, Lucas Heights, Sydney, NSW, 2234, Australia.
⁷ Department of Medical Physics, Westmead Hospital, Westmead, NSW, 2145, Australia.
⁸ The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.

Abstract

Background: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated at the γ-glutamyl residue with fluorophores and radio-isotopes is able to image dead and dying cells in vitro and in vivo by binding to intracellular 90-kDa heat shock proteins (hsp90) when cell membrane integrity is compromised. The ability to image cell death has potential clinical impact especially for early treatment response assessment in oncology. This work aims to assess the biodistribution and tumour uptake of diethylene triamine pentaacetic acid GSAO labelled with ¹¹¹In ([¹¹¹In]In-DTPA-GSAO) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid GSAO labelled with ⁶⁷Ga ([⁶⁷Ga]Ga-DOTA-GSAO) in a murine subcutaneous tumour xenograft model and estimate dosimetry of [⁶⁷Ga]Ga-DOTA-GSAO.

Results: There was good tumour uptake of both [¹¹¹In]In-DTPA-GSAO and [⁶⁷Ga]Ga-DOTA-GSAO (2.44 ± 0.26% injected activity per gramme of tissue (%IA/g) and 2.75 ± 0.34 %IA/g, respectively) in Balb c nu/nu mice bearing subcutaneous tumour xenografts of a human metastatic prostate cancer cell line (PC3M-luc-c6). Peak tumour uptake occurred at 2.7 h post injection. [¹¹¹In]In-DTPA-GSAO and [⁶⁷Ga]Ga-DOTA-GSAO demonstrated increased uptake in the liver (4.40 ± 0.86 %IA/g and 1.72 ± 0.27 %IA/g, respectively), kidneys (16.54 ± 3.86 %IA/g and 8.16 ± 1.33 %IA/g) and spleen (6.44 ± 1.24 %IA/g and 1.85 ± 0.44 %IA/g); however, uptake in these organs was significantly lower with [⁶⁷Ga]Ga-DOTA-GSAO (p = 0.006, p = 0.017 and p = 0.003, respectively). Uptake of [⁶⁷Ga]Ga-DOTA-GSAO into tumour was higher than all organs except the kidneys. There was negligible uptake in the other organs. Excretion of [⁶⁷Ga]Ga-DOTA-GSAO was more rapid than [¹¹¹In]In-DTPA-GSAO. Estimated effective dose of [⁶⁷Ga]Ga-DOTA-GSAO for an adult male human was 1.54 × 10^{- 2} mSv/MBq.

Conclusions: [⁶⁷Ga]Ga-DOTA-GSAO demonstrates higher specific uptake in dead and dying cells within tumours and lower uptake in normal organs than [¹¹¹In]In-DTPA-GSAO. [⁶⁷Ga]Ga-DOTA-GSAO may be potentially useful for imaging cell death in vivo. Dosimetry estimates for [⁶⁷Ga]Ga-DOTA-GSAO are acceptable for future human studies. This work also prepares for development of ⁶⁸Ga GSAO radiopharmaceuticals.

Keywords: Cell death; Gallium-67; Indium-111; Radionuclide imaging.