Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration

Ashleigh Hull; William Hsieh; Artem Borysenko; William Tieu; Dylan Bartholomeusz; Eva Bezak

doi:10.1186/s41181-023-00209-z

Development of [²²⁵Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration

EJNMMI Radiopharm Chem. 2023 Sep 7;8(1):22. doi: 10.1186/s41181-023-00209-z.

Authors

Ashleigh Hull^{1

2}, William Hsieh^{3

4}, Artem Borysenko⁵, William Tieu⁶, Dylan Bartholomeusz^{4

7}, Eva Bezak^{3

6}

Affiliations

¹ Allied Health and Human Performance Academic Unit, University of South Australia, City East Campus, Cnr North Tce and Frome Road, Adelaide, SA, 5001, Australia. ashleigh.hull@unisa.edu.au.
² Department of PET, Nuclear Medicine & Bone Densitometry, Royal Adelaide Hospital, SA Medical Imaging, Adelaide, SA, 5000, Australia. ashleigh.hull@unisa.edu.au.
³ Allied Health and Human Performance Academic Unit, University of South Australia, City East Campus, Cnr North Tce and Frome Road, Adelaide, SA, 5001, Australia.
⁴ Department of PET, Nuclear Medicine & Bone Densitometry, Royal Adelaide Hospital, SA Medical Imaging, Adelaide, SA, 5000, Australia.
⁵ Radiation Protection Branch, South Australian Environment Protection Authority, Adelaide, SA, 5000, Australia.
⁶ School of Physical Sciences, The University of Adelaide, Adelaide, SA, 5000, Australia.
⁷ Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5000, Australia.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [¹⁷⁷Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [²²⁵Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.

Results: Cell binding and internalisation of [²²⁵Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [²²⁵Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [²²⁵Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [²²⁵Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [²²⁵Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.

Conclusion: [²²⁵Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.

Keywords: Actinium-225; MUC1; Pancreatic ductal adenocarcinoma; Radioimmunotherapy.

Abstract

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