Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods

Abstract

Purpose: Targeted Radionuclide Therapy (TRT) with Auger Emitters (AE) is a technique that allows targeting specific sites on tumor cells using radionuclides. The toxicity of AE is critically dependent on its proximity to the DNA. The aim of this study is to quantify the DNA damage and radiotherapeutic potential of the promising AE radionuclide copper-64 (⁶⁴Cu) incorporated into the DNA of mammalian cells using Monte Carlo track-structure simulations.

Methods: A mammalian cell nucleus model with a diameter of 9.3 μm available in TOPAS-nBio was used. The cellular nucleus consisted of double-helix DNA geometrical model of 2.3 nm diameter surrounded by a hydration shell with a thickness of 0.16 nm, organized in 46 chromosomes giving a total of 6.08 giga base-pairs (DNA density of 14.4 Mbp/μm³). The cellular nucleus was irradiated with monoenergetic electrons and radiation emissions from several radionuclides including ¹¹¹In, ¹²⁵I, ¹²³I, and ^99mTc in addition to ⁶⁴Cu. For monoenergetic electrons, isotropic point sources randomly distributed within the nucleus were modeled. The radionuclides were incorporated in randomly chosen DNA base pairs at two positions near to the central axis of the double-helix DNA model at (1) 0.25 nm off the central axis and (2) at the periphery of the DNA (1.15 nm off the central axis). For all the radionuclides except for ^99mTc, the complete physical decay process was explicitly simulated. For ^99mTc only total electron spectrum from published data was used. The DNA Double Strand Breaks (DSB) yield per decay from direct and indirect actions were quantified. Results obtained for monoenergetic electrons and radionuclides ¹¹¹In, ¹²⁵I, ¹²³I, and ^99mTc were compared with measured and calculated data from the literature for verification purposes. The DSB yields per decay incorporated in DNA for ⁶⁴Cu are first reported in this work. The therapeutic effect of ⁶⁴Cu (activity that led 37% cell survival after two cell divisions) was determined in terms of the number of atoms incorporated into the nucleus that would lead to the same DSBs that 100 decays of ¹²⁵I. Simulations were run until a 2% statistical uncertainty (1 standard deviation) was achieved.

Results: The behavior of DSBs as a function of the energy for monoenergetic electrons was consistent with published data, the DSBs increased with the energy until it reached a maximum value near 500 eV followed by a continuous decrement. For ⁶⁴Cu, when incorporated in the genome at evaluated positions (1) and (2), the DSB were 0.171 ± 0.003 and 0.190 ± 0.003 DSB/decay, respectively. The number of initial atoms incorporated into the genome (per cell) for ⁶⁴Cu that would cause a therapeutic effect was estimated as 3,107 ± 28, that corresponds to an initial activity of 47.1 ± 0.4 × 10^-3 Bq.

Conclusion: Our results showed that TRT with ⁶⁴Cu has comparable therapeutic effects in cells as that of TRT with radionuclides currently used in clinical practice.

Keywords: Auger emitters; DNA; TOPAS-nBio; copper-64; targeted radionuclide therapy.