Exploring Auger electron-emitting radionuclides for targeted DNA damage in mismatch repair-deficient cells: a theoretical study of 99Rh- and 123I-labeled metalloinsertors.

Abstract

Purpose: Preserving the integrity of the genome is critical to healthy cellular growth and development. Under normal circumstances, the eukaryotic mismatch repair (MMR) machinery is effective at detecting DNA polymerase errors and maintaining the fidelity of the genome. However, cells with inactivated MMR machinery are prone to the accumulation of mutations and tumorigenesis. This study explores the theoretical potential of rhodium-99- and iodine-123-labeled DNA metalloinsertors as Auger electron-emitting radiotherapeutics for cancers characterized by MMR deficiency.

Materials and methods: A Monte Carlo code was developed in MATLAB^® to obtain Auger electron energy spectra for ⁹⁹Rh and ¹²³I. Using Geant4 track structure simulations, we determined the difference in effectiveness of these two Auger electron-emitting radionuclides in direct damage to DNA and the ability to produce double strand break damage (dsb) to the DNA comparing two different constructors 'G4EmDNAPhysics_option2' and 'G4EmDNAPhysics_option4'.

Results: Differences in the Auger electron emission spectra of ⁹⁹Rh and ¹²³I arise from their electronic structure: ¹²³I favors more complex cascades and ultra-low-energy electrons, while ⁹⁹Rh produces electrons with energies more suited to DNA damage. Despite similar total electron yields, the emissions of ⁹⁹Rh are more effective at causing dsb (0.71 vs. 0.60 dsb/decay for ⁹⁹Rh and ¹²³I, respectively, using constructor 'G4EmDNAPhysics_option2' and 0.81 dsb/decay for ⁹⁹Rh vs. 0.71 dsb/decay for ¹²³I when using 'G4EmDNAPhysics_option4'.

Conclusion: This theoretical study leverages both simulation and comparative analyses to identify ⁹⁹Rh as a promising Auger electron-emitting nuclide for radiotheranostics, as it offers superior DNA damage efficacy compared to ¹²³I.