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

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

CONCLUSION

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