An approach to assessing the contribution of the high LET effect in strategies for Auger endoradiotherapy

Abstract

Purpose: The interest in exploiting Auger emitters in cancer therapy stems from their high linear energy transfer (LET)-type radiation damage to DNA. However, the design of Auger-emitter labeled vehicles that target the Auger cascade specifically to the DNA of tumour cells is challenging. Here we suggest a possible approach to evaluate tumour-targeting Auger-labeled conjugates by assessing the impact of a radioprotector known to be effective in protecting from low LET radiation, but not high LET radiation. Given some similarity between the energy spectrum of Auger electrons and that of secondary electrons from soft X-rays, we report the results of radioprotection experiments with 25 kVp X-rays.

Materials and methods: Clonogenic survival curves for cultured human keratinocytes were established for three different irradiation conditions: ¹³⁷Cs γ-rays, 25 kVp X-rays and 320 kVp X-rays, and the effect of including a new radioprotector, denoted “2PH”, was investigated.

Results: The extent of radioprotection by 2PH was comparable for all radiation conditions, although RBE was higher (about 1.7) for soft X-rays.

Conclusions: Radioprotectors like 2PH will help to evaluate Auger endoradiotherapy strategies, by determining the relative contributions of the high-LET effects (not protected), compared to other components, such as Auger electrons not effectively targeted to DNA.

Keywords:

• Auger emitters
• high LET
• DNA damage
• DNA-binding radioprotectors

Acknowledgments

The authors acknowledge funding from Sirtex Medical, Australia, pursuant to a Licensing Agreement with PeterMacCallum Cancer Centre through to end-June 2017.

Disclosure statement

Four authors, RFM, JW, PL, and CS are inventors on the patent (WO2011/123890) that disclosed the synthesis and properties of 2PH. The ownership of the IP associated with the patent was assigned by the Peter MacCallum Cancer Centre in 2018 to RFM, on behalf of the inventors. The authors have no other declarations of potential conflict of interest.

Additional information

Funding

The Present work was financially supported by Sirtex Medical Australia.

Notes on contributors

Pavel Lobachevsky

Pavel Lobachevsky, PhD, Research Fellow, Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, Parkville, VIC, Australia. Current position: Principal, Advanced Analytical Technologies, Melbourne, VIC, Australia.

Colin Skene

Colin Skene, PhD, Research Fellow, School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville, VIC, Australia.

Laura Munforte

Laura Munforte, BSc (Hons), Research Officer, Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, Parkville, VIC, Australia.

Andrea Smith

Andrea Smith, PhD, Senior Research Officer, Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, Parkville, VIC, Australia.

Jonathan White

Jonathan White, PhD, Professor of Chemistry, School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville, VIC, Australia.

Roger F. Martin

Roger F. Martin, PhD, Lab Head, Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, Parkville, VIC, Australia. Honorary Professorial Fellow, School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville, VIC, Australia.