Modelling Potential Candidates for Targeted Auger Therapy

Abstract

Targeted Auger emitters are being considered as a cancer treatment owing to the high linear energy transfer of Auger electrons. When targeted to cancers, this allows for a highly efficient treatment with a low risk of damage to surrounding healthy tissue. The purpose of this study was to determine the most DNA-damaging Auger emitters from a range of radionuclides, some of which are clinically utilised. A Monte Carlo method-based software (Geant4-DNA version 10.7) was used to determine the energy deposition and number of DNA double-strand breaks from Auger (and internal conversion) electrons imposed on a tetranucleosome. The Auger emitters, ¹¹⁹Sb and ¹⁰³Pd, have similar or slightly greater damaging properties compared to ¹²³I, ¹¹¹In, and ⁸⁹Zr. ^193mPt demonstrated the greatest therapeutic potency. Whilst ¹²⁵I was highly damaging, its relatively long half-life (60 days) makes it less desirable for clinical use. Geant4-DNA modelling identified the radionuclide ^193mPt as being highly favourable for use in radiotherapy.

1. Introduction

The concept of targeted radiotherapy (TRT) involves a selected radionuclide bonded to a targeting molecule to form a radiopharmaceutical designed for the specific cancer being treated. TRT is commonly systemically administered and targets both the primary cancer and metastases. Currently, targeted radiotherapy is predominantly carried out with β⁻-emitters, which have a range of up to 1 cm in tissue and can result in toxicity through normal tissue exposure. Alternatively, the use of radiopharmaceuticals containing alpha or Auger electron emitters has been considered, owing to having a high linear energy transfer (LET). Auger electrons have a range from several nm to ~100 nm [1], requiring proximity malignant cells to be in the proximity of the emitting nucleus for damage to be caused [2,3]. As the targeted radiopharmaceutical is administered, it is taken up at the site of the cancer cell, as shown in Figure 1 [2]. The high linear energy transfer and short range due to having low energies (typically < 50 keV [1,4]) deliver high local doses and limit damage to surrounding healthy cells [3]. These criteria make Auger emitting radionuclides favourable candidates for targeted therapy. Considerations for therapeutic Auger emitters are that they have a half-life of several hours to a few days, decay to a long-lived or (more desirably) a stable daughter nuclide to limit exposure to the patient, can be produced with high activity, and can be easily separated from associated impurities.

The emission of an Auger electron begins when a vacancy is formed in an electron shell, likely through electron capture decay or the emission of an internal conversion electron (a competing process of gamma decay where an atomic electron is emitted with energies characteristic of gamma rays) [3,4]. An electron in a higher orbit decays to fill the vacancy, typically emitting an X-ray in the process. However, there is a probability that another orbital electron will absorb this energy and be ejected as an Auger electron, as shown in Figure 2. As this process leaves a secondary vacancy, this can lead to a cascade of Auger electrons. The energy of the Auger electrons is the energy difference between the relevant electron shells minus the binding energy of the electron. As the Auger electron energy is very low, it possesses a very short penetration depth (several nm to ~100 nm), much less than the dimensions of a cancer cell (~10 µm) [2,4].

Auger electrons primarily cause cell death either by depositing their energy within the DNA structure or indirectly by interacting with water molecules, leading to radiolysis, which creates free radicals. These lead to chemical interactions with the DNA, causing breaks with the covalent bonds. The DNA damage includes single-strand breaks, base damage, cross-linking, and the more lethal double-strand breaks [1]. Double-strand breaks are difficult to repair faithfully and lead to cell death. Monte Carlo methods can be used to model the damage and energy deposition to DNA from Auger electrons emitted by Auger-emitting radionuclides by tracking the motion of charged particles in matter and the resulting nuclear or electromagnetic interactions.

Previous works on modelling the effects of Auger electron damage have led to an understanding of the behaviour of low-energy electrons in DNA geometries [5,6], such as the study performed by H. Nikjoo et al., where Monte Carlo simulations were used to model the damage to DNA induced by the Auger emitter ¹²⁵I [5]. It was found that the lowest energy deposited by charged particles at which ionisation would create a strand break is 17.5 eV, assuming the main transport of particles is through liquid water [5]. This finding has been incorporated into current Monte Carlo codes, such as Geant4-DNA. A study on the Auger emitter ¹²³I, performed by H. Fourie et al. [6], used Geant4-DNA version 9.6 to investigate microdosimetry in DNA. It was observed that targeting the cell nucleus provides the maximum possible dose to the DNA from Auger electrons compared to targeting the cytoplasm. It has also been observed in studies that the damaging properties of low-energy electrons decrease with increasing incident energy and distance from the centre of the DNA strand [7,8].

In the present study, the damage induced to DNA by selected radionuclides (¹¹⁹Sb, ^193mPt, ^195mPt, ¹⁰³Pd, ¹⁹⁷Hg, and ¹¹⁶Tb) is simulated using the Geant4-DNA package. The selected radionuclides met the criteria of having a short half-life or decaying to a long-lived daughter. For example ¹¹⁹Sb ($T_{\frac{1}{2}}=38.19 \mathrm{h}$) and ¹⁹⁷Hg ($T_{\frac{1}{2}}=64.14 \mathrm{h}$) decay via electron capture and ^193mPt ($T_{\frac{1}{2}}=4.33 \mathrm{d}$) decays via an isomeric transition with the daughter ¹⁹³Pt ($T_{\frac{1}{2}}=50 \mathrm{y}$), decaying via electron capture. ^195mPt ($T_{\frac{1}{2}}=4.01 \mathrm{d}$) also decays via isomeric transition to the ground state of ¹⁹⁵Pt, which is stable. The β⁻-emitter, ¹⁶¹Tb ($T_{\frac{1}{2}}=6.89 \mathrm{d}$), also produces an Auger emission per decay with cytotoxic potential. The exception to these criteria is ¹⁰³Pd ($T_{\frac{1}{2}}=16.991 \mathrm{d}$), which decays by electron capture to a short-lived daughter, ^103mRh ($T_{\frac{1}{2}}=56.114 \mathrm{m}\mathrm{i}\mathrm{n}$), which then decays by an isomeric transition to the ground state of ¹⁰³Rh. However, the Auger electron emission and very short half-life of ^103mRh could provide further benefit to treatment using radiopharmaceuticals containing ¹⁰³Pd; thus, they are an interesting inclusion to this study. These theoretically useful but not yet clinically utilised radionuclides will be compared with radionuclides that are already used within nuclear medicine to identify more effective Auger emitters with respect to DNA damage and equivalent dose. The described radionuclides (¹³¹I, ¹²⁵I, ¹²³I, ¹¹¹In, ⁸⁹Zr, and ⁶⁴Cu) are used for diagnostic purposes, as photon emission allows for SPECT. In the case of ⁸⁹Zr, which is currently used in PET due to its β⁺ emission, the electron capture decays to the very short-lived daughter ^89mY ($T_{\frac{1}{2}}=15.633 \mathrm{s}$) and decaying to produce Augers shows the potential for use in cancer treatments. ⁶⁴Cu is also used in PET but shows promise in therapeutic studies due to an alternative electron capture decay, leading to the emission of Auger electrons. The number of Auger electrons emitted per decay for each radionuclide in this study is shown in Table 1.

2. Materials and Methods

Geant4 is a Monte Carlo software framework enabling simulations that track the movement of particles through matter and their interactions. Multiple libraries are pre-compiled containing physical processes (electromagnetic, hadronic, optical), data on radionuclides and particles, materials, and the behaviour of particles, with energies ranging from eV to TeV as they travel through media [13]. Its functionality is designed for application in multiple disciplines, such as high-energy physics and medical physics [14,15].

Geant4-DNA (this study uses version 10.7) is an extension of Geant4 specifically designed for modelling radiation–DNA interactions as applied within the field of medical physics. Included in Geant4-DNA are processes that simulate the behaviour of particles in liquid water, such as charged particles depositing energy in biological molecules and radiolysis using DNA physics libraries [15]. These allow DNA-damaging processes involving ionising radiation to be modelled. Electrons interact with matter via Coulomb interactions. The repulsive forces between the incident electron and valence electrons in the medium can lead to ionisation as the valence electrons are ejected from the atom. These secondary electrons have the potential to contribute to the total damage if in close proximity to the nucleus. Through both processes, the electron loses energy, depositing it into the matter. The range of the electron is the maximum track length of the electron before all its energy has been deposited. Geant4-DNA accounts for these interactions using the G4EmDNAPhysics model. DNA geometries are created by defining the position and elements of individual atoms within the event space to create an atomistic description of the DNA structure surrounded by water. Using this DNA model, single-strand breaks are detected when more than 8.22 eV of energy is deposited in a single strand, as this is the first excitation level of liquid water [16]. A double-strand break is detected if two single-strand breaks occur within ten base pairs of each other. As Auger electrons possess a high linear energy transfer, the primary mechanism of DNA damage comes from direct interactions; however, Geant4-DNA can track the damage induced by chemical processes, such as radiolysis, where free radicals are formed, which interact with the covalent bonds in the DNA structure [15]. The probability of a double-strand break occurring, P, shares a linear relationship with the absorbed dose, D (Gy), and is calculated using [17] as follows:

(1)$P\left(\mathrm{d}\mathrm{o}\mathrm{u}\mathrm{b}\mathrm{l}\mathrm{e} \mathrm{s}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{n}\mathrm{d} \mathrm{b}\mathrm{r}\mathrm{e}\mathrm{a}\mathrm{k}\right)=-{6\times 10}^{-6}{D}^2+{17\times 10}^{-3}D+{3.9\times 10}^{-3}$

pdb4dna is an open-source extension of Geant4-DNA that models the energy deposition and thus damage to DNA molecules induced by ionising radiation down to very low energies [16]. Geometries can be simulated using the protein data bank, allowing for the simulation of an atomistic representation of the DNA structure. The geometry is built by reading pdb files and extrapolating the 3D coordinates of each atom. Simulations in this paper use a tetranucleosome defined by the protein data bank as an unbroken DNA loop between 157 and 240 base pairs with corresponding chromosomes, which is 9 angstroms in length [18].

The 1zbb.pdb file was chosen as it is the largest available DNA structure. This allows for an assessment of the damage delivered to a small section of a strand of DNA delivered by the radionuclides in this study. The geometry is surrounded by a cube of liquid water, as this is the predominant cellular component, with one side equal to 1000 angstroms in length. The simulations in this study assume that the radionuclide is localised within the cell nucleus. The damage to the DNA induced by the most prominent radiation emitted by each selected radionuclide is modelled by introducing a beam of ionising radiation at a distance of 5 angstroms from the centre of the DNA structure. Energy deposition is modelled by observing the electromagnetic interactions between the incident electron and the atoms within the DNA structure. As the electron is scattered, it loses energy, which is deposited into the atom. The energy deposition and damage to DNA induced by the most prominent radiation emitted from each radionuclide have been observed. Each particle beam was simulated with 5,000,000 monoenergetic incidents on the tetranucleosome directed towards the centre of the DNA structure to reduce simulation time and error. This allowed for a more detailed observation of the contributions of Auger electrons and internal conversion electrons by simulating the damage and dose applied to the DNA structure induced by the electron energies emitted by each radionuclide. The equivalent dose, H (Sv), applied by a radionuclide is calculated using the following:

(2)$H=\sum (D\times W_R)$

(3)$D=\frac{E_T}{m}$

where E_T is the total energy absorbed, m is the absorbing mass, and W_R is the weighting factor of the radiation (in this case electrons for electrons W_R = 1). The mass of the DNA geometry used in these simulations is defined in the protein data bank (7.17 × 10⁻²² kg [18]). The energy of electrons is taken from the national nuclear data centre, as Auger electron energies are characteristic of the specific atom they are emitted from [19]. The purpose of these simulations is to assess the damaging properties of novel radionuclides compared with radionuclides currently used in medicine in order to deduce the most potent candidate for further studies in terms of dose and DNA double-strand breaks.

3. Results

Figure 3 shows that due to the high linear energy transfer and lower energies, Auger electrons are stopped at shorter distances in water in comparison to beta particles. This shows that radionuclides that emit electrons with low energies should have the greatest damaging properties to the DNA structure due to the deposition of energy within a localised volume. The data were obtained by simulating the projected length, track length, and total penetration of low-energy electrons in a sphere of liquid water with a radius of 1m, which was compared with data in the NIST ESTAR database [20,21].

The equivalent dose applied to an individual cell by each radionuclide examined was calculated and shown in Figure 4 and Figure 5, respectively. The extremely small mass of the DNA structure in this study gives rise to high dosages, which would not reflect the total absorbed dose applied to a whole cell but to a small structure. Figure 4 shows that ^193mPt deposits the largest dose from the novel radionuclides chosen in this study, with ¹¹⁹Sb and ¹⁰³Pd showing slightly lower doses. ^195mPt, ¹⁶¹Tb, and ¹⁹⁷Hg deposit lower doses due to a higher proportion of electrons with larger energies compared with ^193mPt, ¹¹⁹Sb, and ¹⁰³Pd. Out of the radionuclides currently used in medicine shown in Figure 5, ¹²⁵I deposits the largest dose, with ⁸⁹Zr, ¹¹¹In, and ¹²³I showing similar doses. ¹³¹I is shown to deposit the least energy in this study due to the most prominent electrons being β^- particles, which have a low LET.

The dose rate (dose a patient will receive per unit of time) is crucial for treatment efficacy and is calculated by dividing the total dose by the exposure time.

Since Geant4 does not have a method for measuring the time of simulations, an alternative way of calculating time is used based on the activity (the number of disintegrations per second) of the radionuclide. The dose rate for novel radionuclides in this study is shown in Table 2, and the dose rate for currently used radionuclides is shown in Table 3.

Figure 6 shows the damaging properties of low-energy electrons using the parameters chosen in this study, while Table 4 compares these results with a previous study to show that there is a decrease in the number of double-strand breaks as the energy of the incident electron increases. Comparing Figure 6 with Figure 3 further shows that electrons with a higher LET (lower energies) induce more double-strand breaks in DNA structures.

The number of double-strand breaks expected to be caused by 5,000,000 particles of ionising radiation per electron energy emitted from the novel radionuclides has been simulated and displayed in Figure 7, with Figure 8 showing the damaging properties of currently used radionuclides. Table 5 shows the number of double-strand breaks per decay determined for each radionuclide compared with previous studies. Comparing Figure 7 and Figure 8 with Table 5, ^193mPt is the most damaging radionuclide, producing the largest number of double-strand breaks per decay due to the generation of a high proportion of low-energy electrons. Although ^195mPt has more electrons with a lower LET than ¹²⁵I, it emits the largest number of electrons per decay. Thus, ¹²⁵I and ^195mPt have similar damaging properties per decay. It is clear from this study that the poorest Auger emitters in this study are ¹⁶¹Tb and ¹³¹I due to being β⁻ emitters.

4. Discussion

In this study, the dose from Auger-emitting radionuclides absorbed by the DNA structure was evaluated by measuring the energy deposited into the structure. Another method more commonly used is calculating the cellular S-values, a method established by the Committee on Medical Internal Radiation Dose (MIRD). S-values can be described as the mean absorbed dose per cumulative activity of the radionuclide studied; thus, it is a useful method for understanding dosimetry [31]. This is a widely used method for studying the microdosimetry of Auger emitters in the cell nucleus and cytoplasm. A study by Moradi and Bidabadi [32] evaluated the S-values of several Auger-emitting diagnostic radionuclides, including ¹²³I and ¹²⁵I, and compared them with the widely used ¹³¹I. It was found that ¹²³I and ¹²⁵I can be used as an alternative to ¹³¹I, with the advantages of availability and decreased normal tissue exposure. Another study by N. Falzone and B. Lee et al. [11] calculated the electron spectra for Auger-emitting radionuclides (including ^195mPt, ¹²⁵I, ¹²³I, ¹¹¹In, and ⁸⁹Zr) using the code BrIccEmiss and compared them with the calculations from MIRD. This study also performed simulations on dosimetry and found that ¹²⁵I deposits a larger dose into the cell nucleus when absorbed into either the nucleus or cytoplasm compared to ¹²³I and ¹¹¹In. A study by Hsiao et al. [22] compared dosimetry and DNA damage between the radionuclides ¹²⁵I, ¹¹⁹Sb, and ¹¹¹In. It was found that for both dosimetry and damage, ¹²⁵I showed the greatest potency, followed by ¹¹⁹Sb and ¹¹¹In, respectively. Current limitations in using Auger-emitting radionuclides is the short range of these low-energy electrons, which make it ideal for targeting singular cells; however, further studies would be required to further understand how Auger emitters can be used in treating larger tumors. It has also proven difficult to bond Auger emitters to a suitable carrier molecule that can accurately deliver the radionuclide to the target DNA; therefore, studies have been conducted on the effects of Auger emitters when targeting the cytoplasm and membrane [33].

It is apparent from the simulations that the Auger and conversion electron emissions from ^193mPt have the most potent DNA damaging effect of the radionuclides analysed. Although ^193mPt shows great promise in terms of DNA damage, complications arise due to the half-life of the daughter nuclide ¹⁹³Pt (50 years), as this could further increase the total absorbed dose during treatment. Further studies into the biological half-life of radiopharmaceuticals labelled with ^193mPt could validate the use of this radionuclide in clinical studies. ⁶⁴Cu shows promise with its high damaging properties due to a very low-energy Auger electron emitted from the radionuclide. The radionuclides ¹¹⁹Sb and ¹⁰³Pd (including its daughter, ^103mRh) demonstrate comparable or slightly greater DNA damaging capability to ¹²³I, ¹¹¹In, and ⁸⁹Zr, which are used clinically though not currently for treatment. Although ¹²⁵I is particularly DNA damaging, its longer half-life (60 days) would require bonding to a molecule, giving it a much shorter biological half-life and ensuring that it does not remain in a patient for too long. In the case of double-strand breaks per decay, Table 4 shows ^193m/195mPt and ¹²⁵I to be the more damaging radionuclides, with ¹⁹¹Sb and ¹⁹⁷Hg showing similar damaging properties. This is also in good agreement with the previous literature, and the calculations from MIRD show these radionuclides to be potentially damaging emitters in terms of the number of electrons emitted per decay. As shown in Figure 4 and Figure 6, the damage induced by ^193mPt is caused mostly by conversion electrons. This is due to the metastable state decaying by isomeric transition, as the internal conversion is a competing factor of γ-decay. It is also difficult to distinguish conversion electrons from Auger electrons due to similar energies; therefore, both are considered in electron emissions from the radionuclides. The energy deposited into the DNA by photons (X-rays and γ-rays) emitted from the radionuclides, which are highly penetrating, will be very low due to the close proximity of the radionuclide to the target DNA simulated in this study. However, it is important to note that ionising radiation with higher energies contributes more damage to DNA indirectly, and this is something that would need to be investigated further [34]. It is observed that there is a linear relationship between the number of single-strand breaks and double-strand breaks, and, therefore, a figure containing a number of single-strand breaks contributed by each radionuclide would show a similar trend to Figure 6 and Figure 7 [17]. As there is no experimental data on the characteristic emission of Auger electrons, current simulations use data obtained from Monte Carlo methods. Current limitations in Geant4 only allow DNA simulations in liquid water models and exclude damage to DNA by free radicals produced from radiolysis. The addition of cross-sections of other compounds that make up DNA molecules within the Geant4-DNA code would provide a complete representation of the total damage from Auger emitters.

5. Conclusions

In this study, Geant4 has been used to model the damage induced by DNA to determine the most potent candidates for targeted radiotherapy. From the data obtained, it is apparent that ^193mPt, ^195mPt,¹¹⁹Sb, ⁶⁴Cu, and ¹⁰³Pd/^103mRh are the most damaging. ¹²⁵I is less favourable due to a very long half-life (60 days). Further studies using ^193mPt may be possible if the biological half-life of radiopharmaceuticals containing this radionuclide is found to be short enough to overcome complications due to the long radiological half-life of the decay daughter, ¹⁹³Pt (50 years).

Author Contributions

Conceptualization, L.J.E. and T.A.D.S.; Methodology, C.M.J.B., L.J.E. and M.J.D.R.; Formal analysis, C.M.J.B.; Data curation, C.M.J.B.; Writing—original draft, C.M.J.B.; Writing—review & editing, E.O.A., L.J.E., M.J.D.R. and T.A.D.S.; Supervision, E.O.A., M.J.D.R. and T.A.D.S. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

All data created in this study can be accessed by contacting CMJB via email: [email protected].

Acknowledgments

The authors would like to thank the EPSRC Nuclear Energy Futures Centre for Doctoral Training for their funding of this research and the Draper’s Company in London for their sponsorship of CMJB.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding this paper.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures and Tables

Table 1

The number of Auger electrons emitted by each radionuclide in this study, as calculated from MIRD.

Radionuclide	Number of Auger Electrons Emitted per Decay
119Sb	23.7 [1]
193mPt	27.4 [1]
195mPt	36.6 [1]
103Pd	7.44 [9]
103mRh	5.88 [9]
197Hg	23.2 [1]
161Tb	0.9 [1]
123I	13.7 [1]
125I	23 [1]
131I	1.31 [10]
111In	7.4 [1]
89Zr	9.45 [11]
64Cu	1.8 [12]

Table 2

Dose rate from novel radionuclides applied to the tetranucleosome.

Radionuclide	Dose Rate (GSv/h)	Error
119Sb	1.8	0.2
193mPt	0.91	0.03
195mPt	0.39	0.04
103Pd	0.16	0.02
103mRh	41.77	0.07
197Hg	0.31	0.01
161Tb	0.16	0.03

Table 3

Dose rate applied to the tetranucleosome by radionuclides currently used in nuclear medicine.

Radionuclide	Dose Rate (GSv/h)	Error
131I	0.019	0.005
125I	0.056	0.002
123I	2.548	0.003
111In	0.545	0.002
89Zr	0.551	0.004
64Cu	4.567	0.004

Table 4

The number of strand breaks induced by low-energy electrons of increasing energy compared with the previous work by P. Ahmadi et al., 2017 [7] showing the yield of double-strand breaks for monoenergetic electrons.

This Study		P. Ahmadi et al. Front. Bio. Tech. 2021 [7]
Energy (keV)	No. of Double-Strand Breaks	Energy (keV)	YDSB × 10−11 DSB (Gy·Da)−1
10	$3.4\pm 0.4$	0.1	2.6
15	$8.4\pm 0.2$	0.3	2
20	$8.1\pm 0.3$	0.5	1.2
25	$5.9\pm 0.1$	1	0.87
30	$4.5\pm 0.4$	1.5	0.64
35	$4.7\pm 0.2$	4.5	0.11
40	$3.2\pm 0.1$
45	$2.3\pm 0.1$
50	$1.3\pm 0.1$

Table 5

The number of double-strand breaks per decay induced on the tetranucleosome by the radionuclides in this study compared with the previous literature.

Radionuclide	Number of Double-Strand Breaks per Decay(In This Study)	Number of Double-Strand Breaks per Decay(In Other Works)
119Sb	$0.42\pm 0.03$	0.31 [22]
193mPt	$4.07\pm 0.02$
195mPt	$1.62\pm 0.4$	2.02 [7]
103Pd	$0.07\pm 0.03$
103mRh	$0.07\pm 0.02$
197Hg	$0.28\pm 0.04$
161Tb	$0.05\pm 0.02$
123I	$0.31\pm 0.03$	0.21 [22]0.5 [23]0.4 [24]0.747 [25]1 [26]
125I	$1.54\pm 0.03$	1.57 [7]0.38 [22]1.7 [23]0.979 [25]0.919 [26]1.1 [27]
131I	$0.02\pm 0.01$
111In	$0.11\pm 0.01$	0.2 [22]1.39 [23]3.5 [28]1.3 [29]
89Zr	$0.2\pm 0.05$
64Cu	$0.18\pm 0.04$	0.171 [30]0.19 [30]

References

1. Ku, A.; Facca, V.J.; Cai, Z.; Reilly, R.M. Auger electrons for cancer therapy—A review. EJNMMI Radiopharm. Chem.; 2019; 4, 27. [DOI: https://dx.doi.org/10.1186/s41181-019-0075-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31659527]

2. Dash, A.; Knapp, F.F.; Pillai, M. Targeted radionuclide therapy—An overview. Curr. Radiopharm.; 2013; 6, pp. 152-180. [DOI: https://dx.doi.org/10.2174/18744710113066660023] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24059327]

3. Filosofov, D.; Kurakina, E.; Radchenko, V. Potent candidates for Targeted Auger Therapy: Production and radiochemical considerations. Nucl. Med. Biol.; 2021; 94–95, pp. 1-19. [DOI: https://dx.doi.org/10.1016/j.nucmedbio.2020.12.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33461040]

4. O’Donoghue, J.A.; Wheldon, T.E. Targeted Radiotherapy Using Auger Electron Emitters. Phys. Med. Biol.; 1996; 41, pp. 1973-1992. [DOI: https://dx.doi.org/10.1088/0031-9155/41/10/009]

5. Nikjoo, H.; Martin, R.F.; Charlton, D.E.; Terrissol, M.; Kandaiya, S.; Lobachevsky, P. Modelling of Auger-Induced DNA Damage by Incorporated¹²⁵I. Acta Oncol.; 1996; 35, pp. 849-856. [DOI: https://dx.doi.org/10.3109/02841869609104036] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9004762]

6. Fourie, H.; Newman, R.T.; Slabbert, J.P. Microdosimetry of the Auger emitting 123I radionuclide using Geant4-DNA simulations. Phys. Med. Biol.; 2015; 60, 3333. [DOI: https://dx.doi.org/10.1088/0031-9155/60/8/3333]

7. Ahmadi, P.; Ghandi, M.S.Z.; Shokri, A. Investigation of Auger Emitting Radionuclides Effects in Therapy Using the Geant4-DNA Toolkit: A Simulation Study. Front. Biomed. Technol.; 2021; 8, pp. 79-86. [DOI: https://dx.doi.org/10.18502/fbt.v8i2.6511]

8. Di Maria, S.; Belchior, A.; Pereira, E.; Quental, L.; Oliveira, M.; Mendes, F.; Lavrado, J.; Paulo, A.; Vaz, P. Dosimetry assessment of DNA damage by Auger-emitting radionuclides: Experimental and Monte Carlo studies. Radiat. Phys. Chem.; 2017; 140, pp. 278-282. [DOI: https://dx.doi.org/10.1016/j.radphyschem.2017.01.028]

9. Hindié, E.; Larouze, A.; Alcocer-Ávila, M.; Morgat, C.; Champion, C. Palladium-103 (¹⁰³Pd/^103mRh), a promising Auger-electron emitter for targeted radionuclide therapy of disseminated tumor cells—Absorbed doses in single cells and clusters, with comparison to ¹⁷⁷Lu and ¹⁶¹Tb. Theranostics; 2024; 14, pp. 4318-4330.PMC11303077[DOI: https://dx.doi.org/10.7150/thno.95436] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39113794]

10. Unak, P.; Cetinkaya, B. Absorbed dose estimates at the cellular level for 131I. Appl. Radiat. Isot.; 2005; 62, pp. 861-869. [DOI: https://dx.doi.org/10.1016/j.apradiso.2004.07.013] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15799863]

11. Falzone, N.; Lee, B.Q.; Fernández-Varea, J.M.; Kartsonaki, C.; Stuchbery, A.E.; Kibédi, T.; Vallis, K.A. Absorbed dose evaluation of Auger electron-emitting radionuclides: Impact of input decay spectra on dose point kernels and S-values. Phys. Med. Biol.; 2017; 62, pp. 2239-2253. [DOI: https://dx.doi.org/10.1088/1361-6560/aa5aa4]

12. Bolcaen, J.; Gizawy, M.A.; Terry, S.Y.; Paulo, A.; Cornelissen, B.; Korde, A.; Engle, J.; Radchenko, V.; Howell, R.W. Marshalling the Potential of Auger Electron Radiopharmaceutical Therapy. J. Nucl. Med.; 2023; 64, pp. 1344-1351. [DOI: https://dx.doi.org/10.2967/jnumed.122.265039]

13. Agostinelli, S.; Allison, J.; Amako, K.; Apostolakis, J.; Araujo, H.; Arce, P.; Asai, M.; Axen, D.; Banerjee, S.; Barrand, G. et al. GEANT4—A simulation toolkit. Nucl. Instrum. Methods Phys. Res. Sect. A; 2003; 503, pp. 250-303. [DOI: https://dx.doi.org/10.1016/S0168-9002(03)01368-8]

14. Allison, J.; Amako, K.; Apostolakis, J.; Araujo, H.; Dubois, P.A.; Asai, M.; Barrand, G.; Capra, R.; Chauvie, S.; Chytracek, R. et al. Geant4 developments and applications. IEEE Trans. Nucl. Sci.; 2006; 53, pp. 270-278. [DOI: https://dx.doi.org/10.1109/TNS.2006.869826]

15. Incerti, S.; Baldacchino, G.; Bernal, M.; Capra, R.; Champion, C.; Francis, Z.; Guèye, P.; Mantero, A.; Mascialino, B.; Moretto, P. et al. The geant4-dna project. Int. J. Model. Simul. Sci. Comput.; 2010; 1, pp. 157-178. [DOI: https://dx.doi.org/10.1142/S1793962310000122]

16. Delage, E.; Pham, Q.; Karamitros, M.; Payno, H.; Stepan, V.; Incerti, S.; Maigne, L.; Perrot, Y. PDB4DNA: Implementation of DNA geometry from the protein data bank (PDB) description for Geant4-DNA Monte-Carlo simulations. Comput. Phys. Commun.; 2015; 192, pp. 282-288. [DOI: https://dx.doi.org/10.1016/j.cpc.2015.02.026]

17. Chatzipapas, K.P.; Papadimitroulas, P.; Obeidat, M.; McConnell, K.A.; Kirby, N.; Loudos, G.; Papanikolaou, N.; Kagadis, G.C. Quantification of DNA double-strand breaks using Geant4-DNA. Med. Phys.; 2019; 46, pp. 405-413. [DOI: https://dx.doi.org/10.1002/mp.13290] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30418675]

18. Schalch, T.; Duda, S.; Sargent, D.F.; Richmond, T.J. X-ray structure of a tetranucleosome and its implications for the chromatin fibre. Nature; 2005; 436, pp. 138-141. [DOI: https://dx.doi.org/10.1038/nature03686] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16001076]

19. NNDC Pritychenko, B.; Běták, E.; Singh, B.; Totans, J. Nuclear Sciences References (NSR); National Nuclear Data Center: Upton, NY, USA, 2022; [DOI: https://dx.doi.org/10.18139/nndc.nsr/1866086]

20. Bernal, M.; Bordage, M.; Brown, J.; Davídková, M.; Delage, E.; El Bitar, Z.; Enger, S.; Francis, Z.; Guatelli, S.; Ivanchenko, V. et al. Track structure modeling in liquid water: A review of the Geant4-DNA very low energy extension of the Geant4 Monte Carlo simulation toolkit. Phys. Medica; 2015; 31, pp. 861-874. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26653251][DOI: https://dx.doi.org/10.1016/j.ejmp.2015.10.087]

21. Incerti, S.; Ivanchenko, A.; Karamitros, M.; Mantero, A.; Moretto, P.; Tran, H.N.; Mascialino, B.; Champion, C.; Ivanchenko, V.N.; Bernal, M.A. et al. Comparison of GEANT4 very low energy cross section models with experimental data in water. Med. Phys.; 2010; 37, pp. 4692-4708. [DOI: https://dx.doi.org/10.1118/1.3476457] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20964188]

22. Hsiao, Y.-Y.; Hung, T.-H.; Tu, S.-J.; Tung, C.-J. Fast Monte Carlo simulation of DNA damage induction by Auger-electron emission. Int. J. Radiat. Biol.; 2014; 90, pp. 392-400. [DOI: https://dx.doi.org/10.3109/09553002.2014.892649] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24517473]

23. Ahmadi, P.; Zafarghandi, M.S.; Shokri, A. Calculation of direct geometric model: A simulation study using Geant4-DNA toolkit. Nucl. Instruments Methods Phys. Res. Sect. B Beam Interactions Mater. Atoms; 2020; 483, pp. 22-28. [DOI: https://dx.doi.org/10.1016/j.nimb.2020.08.007]

24. Pomplun, E. 123I: Calaculation of the Auger electron spectrum and assessment of the strand breakage efficiency. Biophys. Asp. Auger Process. Am. Assoc. Phys. Med. Symp. Proc.; 1992; 8, pp. 121-136.

25. Raisali, G.; Mirzakhanian, L.; Masoudi, S.F.; Semsarha, F. Calculation of DNA strand breaks due to direct and indirect effects of Auger electrons from incorporated¹²³I and¹²⁵I radionuclides using the Geant4 computer code. Int. J. Radiat. Biol.; 2013; 89, pp. 57-64. [DOI: https://dx.doi.org/10.3109/09553002.2012.715785] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22892102]

26. Terrissol, M.; Peudon, A.; Kümmerle, E.; Pomplun, E. On the biological efficiency of I-123 and I-125 decay on the molecular level. Int. J. Radiat. Biol.; 2008; 84, pp. 1063-1068. [DOI: https://dx.doi.org/10.1080/09553000802552150] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19061131]

27. Humm, J.; Charlton, D. A new calculational method to assess the therapeutic potential of auger electron emission. Int. J. Radiat. Oncol. Biol. Phys.; 1989; 17, pp. 351-360. [DOI: https://dx.doi.org/10.1016/0360-3016(89)90450-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2753759]

28. Sahu, S.K.; Kassis, A.I.; Makrigiorgos, G.M.; Baranowska-Kortylewicz, J.; Adelstein, S.J. The effects of indium-111 decay on pBR322 DNA. Radiat. Res.; 1995; 141, pp. 193-198. [DOI: https://dx.doi.org/10.2307/3579047] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7838958]

29. Piroozfar, B.; Raisali, G.; Alirezapour, B.; Mirzaii, M. The effect of ¹¹¹In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: A Monte Carlo study using Geant4 toolkit. Int. J. Radiat. Biol.; 2018; 94, pp. 385-393. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29432072][DOI: https://dx.doi.org/10.1080/09553002.2018.1440329]

30. Carrasco-Hernandez, J.; Ramos-Méndez, J.; Padilla-Rodal, E.; Avila-Rodriguez, M.A. Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods. Front. Med.; 2023; 10, 1253746. [DOI: https://dx.doi.org/10.3389/fmed.2023.1253746] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37841004]

31. Bolch, W.E.; Eckerman, K.F.; Sgouros, G.; Thomas, S.R. MIRD Pamphlet No. 21: A Generalized Schema for Radiopharmaceutical Dosimetry—Standardization of Nomenclature. J. Nucl. Med.; 2009; 50, pp. 477-484. [DOI: https://dx.doi.org/10.2967/jnumed.108.056036] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19258258]

32. Moradi, M.S.; Bidabadi, B.S. Micro-dosimetry calculation of Auger-electron-emitting radionuclides mostly used in nuclear medicine using GEANT4-DNA. Appl. Radiat. Isot.; 2018; 141, pp. 73-79. [DOI: https://dx.doi.org/10.1016/j.apradiso.2018.08.019] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30179772]

33. Fourie, H.; Nair, S.; Miles, X.; Rossouw, D.; Beukes, P.; Newman, R.T.; Zeevaart, J.R.; Vandevoorde, C.; Slabbert, J. Estimating the Relative Biological Effectiveness of Auger Electron Emitter 123I in Human Lymphocytes. Front. Phys.; 2020; 8, 567732. [DOI: https://dx.doi.org/10.3389/fphy.2020.567732]

34. Park, Y.; Peoples, A.R.; Madugundu, G.S.; Sanche, L.; Wagner, J.R. Side-by-side comparison of DNA damage induced by low-energy electrons and high-energy photons with solid TpTpT trinu-cleotide. J. Phys. Chem. B; 2013; 117, pp. 10122-10131.PMC3817083[DOI: https://dx.doi.org/10.1021/jp405397m] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23909580]