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The preparation of nanometer-thick molybdenum-99 (99Mo) sources using the droplet deposition method was investigated. The quality of these prepared sources was analyzed using scanning electron microscopy (SEM), electron Rutherford backscattering (ERBS) techniques, and Geant4 simulations. The emitted electrons resulting from the β − -decay of the prepared 99Mo sources, with energies below 2.2 keV, were measured and compared with existing literature data as well as the results obtained from our in-house Monte-Carlo model, BrIccEmis. • Auger electron spectroscopy of medical isotopes. • Electron spectroscopy. • Low energy. • High resolution. [ABSTRACT FROM AUTHOR]

The biological consequences of absorbed radiation doses are ill-defined for radiopharmaceuticals, unlike for external beam radiotherapy (EBRT). A reliable assay that assesses the biological consequences of any radionuclide is much needed. Here, we evaluated the cell-free plasmid DNA assay to determine the relative biological effects of radionuclides such as Auger electron-emitting [67Ga]GaCl 3 or [111In]InCl 3 compared to EBRT. Supercoiled pBR322 plasmid DNA (1.25 or 5 ng/μL) was incubated with 0.5 or 1 MBq [67Ga]GaCl 3 or [111In]InCl 3 for up to 73 h or was exposed to EBRT (137Cs; 5 Gy/min; 0–40 Gy). The induction of relaxed and linear plasmid DNA, representing single and double strand breaks, respectively, was assessed by gel electrophoresis. Chelated forms of 67Ga were also investigated using DOTA and THP. Topological conversion rates for supercoiled-to-relaxed (k sr x ) or relaxed-to-linear (k rl x ) DNA were obtained by fitting a kinetic model. DNA damage increased both with EBRT dose and incubation time for [67Ga]GaCl 3 and [111In]InCl 3. Damage caused by [67Ga]GaCl 3 decreased when chelated. [67Ga]GaCl 3 proved more damaging than [111In]InCl 3 ; 1.25 ng/μL DNA incubated with 0.5 MBq [67Ga]GaCl 3 for 2 h led to a 70% decrease of intact plasmid DNA as opposed to only a 19% decrease for [111In]InCl 3. For both EBRT and radionuclides, conversion rates were slower for 5 ng/μL than 1.25 ng/μL plasmid DNA. DNA damage caused by 1 Gy EBRT was the equivalent to damage caused by 0.5 MBq unchelated [67Ga]GaCl 3 and [111In]InCl 3 after 2.05 ± 0.36 and 9.3 ± 0.77 h of incubation, respectively. This work has highlighted the power of the plasmid DNA assay for a rapid determination of the relative biological effects of radionuclides compared to external beam radiotherapy. It is envisaged this approach will enable the systematic assessment of imaging and therapeutic radionuclides, including Auger electron-emitters, to further inform radiopharmaceutical design and application. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eβ͞av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile. Methods: 161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice. Results: 161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu. Conclusion: 161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC. [ABSTRACT FROM AUTHOR]

The detailed study of single photon multiple ionization processes requires the detection in coincidence of all the electrons emitted from the same ionization event. The advent of magnetic bottle experiments made possible the development of this multi-electron coincidence spectroscopy. First we will briefly review the achievements of this technique. Then we will illustrate more specifically its high sensitivity taking as an example the decay by emission of three Auger electrons of 2p and 2s holes in argon. Our results show that the processes are completely different depending on the initial core hole: the three Auger electrons are emitted dominantly in a simultaneous path for the 2p case, but in cascade for the 2s one. [ABSTRACT FROM AUTHOR]

Purpose:To investigate an enhancement of DNA double-strand break (DSB) induction and cell killing effect by K-shell ionization of phosphorus atoms and Auger electrons on human cell lines. Materials and methods:Induction of DSB, DNA damage responses, cell cycle distributions, and cell killing effects were investigated after exposures of the cells with monochromatic synchrotron radiation soft X-rays of 2153 and 2147 eV, which were the resonance peak and off peak, respectively, of the K-shell photoabsorption of phosphorus. Results:Higher biological effects in the cells irradiated with soft X-rays at 2153 eV than at 2147 eV were observed in (i) the efficiency of 53BP1/γ-H2AX co-localized foci formation per dose and residual number of foci, (ii) prolonged phosphorylation levels of DSB repair and/or cell cycle checkpoint related proteins and G2 arrest, (iii) the cell killing effects at the 10% survival level of normal human fibroblasts, HeLa cells, and human glioblastoma M059K cells (1.2–1.5 times higher) and that of human ataxia telangiectasia mutated (ATM)-defective cells and glioblastoma DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-defective cells (1.2 times). Conclusion:The yield of DSB and partly less-reparable complex DNA damage induction in human cells was enhanced by K-shell photoabsorption of phosphorus and low-energy Auger electrons. [ABSTRACT FROM PUBLISHER]

Purpose: We investigated the effect of incorporation of a nuclear localization signal (NLS) into a conjugate comprising the DNA binding ligand para-iodoHoechst (PIH) and octreotate on its DNA binding and affinity to the somatostatin receptor (SSTR). Confirmation of these properties would support development of similar conjugates labelled with Auger emitters for their potential in Auger endoradiotherapy. Materials and methods: We synthesized conjugates of PIH and octreotate (PO) or PIH and NLS (PN) and a conjugate comprising PIH, NLS and octreotate (PNO). DNA-binding characteristics of PIH and conjugates were assessed using synthetic DNA oligonucleotides employing spectrophotometric titration of ligand solutions with DNA. We used membranes from the type 2 SSTR (SSTR2) overexpressing human non-small cell lung cancer cell line A427-7 to investigate the binding affinity of PNO. Results: We demonstrated PN and PNO retain specific high affinity DNA-binding properties observed for PIH, and acquire an additional non-specific binding capacity. No DNA binding was observed for PO. PNO retains its binding affinity for SSTR. Conclusions: The DNA-binding properties of PNO and its affinity for SSTR suggests that it could potentially be used for tumour-specific delivery of PIH labelled with an Auger emitter in SSTR expressing tumours. [ABSTRACT FROM AUTHOR]

To identify the emergence of the recognition of the potential of the Auger effect for clinical application, and after tracing the salient milestones towards that goal, to evaluate the status quo and future prospects. It was not until 40 years after the discovery of Auger electrons, that the availability of radioactive DNA precursors enabled the biological power, and the clinical potential, of the Auger effect to be appreciated. Important milestones on the path to clinical translation have been identified and reached, but hurdles remain. Nevertheless the potential is still evident, and there is reasonable optimism that the goal of clinical translation is achievable. [ABSTRACT FROM PUBLISHER]

On installation of coincidences of γ-quanta with electrons and with law energy electrons about zero area the spatial correlation of the direction emitting Auger-electrons and electron of internal conversion was investigated at the 152Eu decay. Auger-electrons were registered on eo-electrons of the secondary electron emission (γeICeo-coincidences). It was established, that Auger-electrons of M-series, as well as electrons "shake-off" at β-decay and internal conversion, are strongly correlated at the direction of movement with the direction of movement of basic particle (β-particle, conversion electron), moving together mainly in the forward hemisphere. The intensity of correlated M-Auger radiation in range energy 1000 - 1700 eV is equal to intensity of correlated radiation "shake-off" electron from internal conversion in this range. The assumption, that the presence of spatial correlating Auger-electron and conversion electron caused by current components of electron-electron interaction of particles in the final state is made. [ABSTRACT FROM AUTHOR]

Auger decay spectra of CO subsequent to O 1s ionization with 549.85 eV photons, i.e. close to the top of the shape resonance, are presented. Their comparison with the normal Auger spectrum recorded at a photon energy well above the shape resonance reveals distinct features. In particular, in the energy region of the O 1s-1→b1Πand O 1s-1→a1Σ+ Auger transitions which are well known to consist of vibrational progressions, additional narrow lines are revealed by the spectra recorded at 549.85 eV. In a detailed fit analysis of these Auger spectra it was possible to show that the newly found lines do not exhibit the expected distortions caused by post-collision interaction. This observation identifies these lines as caused by a different mechanism, such as resonant Auger decay processes of doubly excited states. The transitions are assigned using energy and intensity arguments in combination with complementary angular distribution measurements for the Auger electrons. [ABSTRACT FROM AUTHOR]

Purpose: The paper gives an introduction into Interatomic and Intermolecular Coulombic Decay (ICD). ICD is an autoionization process, which contrary to Auger decay involves neighbouring sites of the initial vacancy as an integral part of the decay transition. As a result of ICD, slow electrons are produced which generally are known to be active in radiation damage. The author summarizes the properties of ICD and reviews a number of important experiments performed in recent years. Materials and methods: Intermolecular Coulombic Decay can generally take place in weakly bonded aggregates in the presence of ionizing particles or ionizing radiation. Examples collected here mostly use soft X-rays produced by synchrotron radiation to ionize, and use rare-gas clusters, water clusters or solutes in a liquid jet to observe ICD after irradiation. Results: Intermolecular Coulombic Decay is initiated by single ionization into an excited state. The subsequent relaxation proceeds via an ultra-fast energy transfer to a neighbouring site, where a second ionization occurs. Secondary electrons from ICD have clearly been identified in numerous systems. ICD can take place after primary ionization, as the second step of a decay cascade which also involves Auger decay, or after resonant excitation with an energy which exceeds the ionization potential of the system. Conclusions: ICD is expected to play a role whenever particles or radiation with photon energies above the ionization energies for inner valence electrons are present in weakly bonded matter, e.g., biological tissue. The process produces at the same time a slow electron and two charged atomic or molecular fragments, which will lead to structural changes around the ionized site. [ABSTRACT FROM AUTHOR]

Abstract: In recent years the use of radionuclides in targeted cancer therapy has increased. In this study we have developed a high-current solid target system and demonstrated that by the use of a typical low-energy medical cyclotron, it is possible to produce tens of GBq''s of many unconventional radionuclides relevant for cancer therapy such as 64Cu and 119Sb locally at the hospitals. [Copyright &y& Elsevier]

Abstract: The use of Auger electrons in radionuclide therapy of cancer is a promising tool for specific tumor cell killing of micrometastases and small tumors. The radioisotope 119Sb has recently been identified as a potent Auger-emitter for therapy. We here present a method for producing this isotope using a low-energy cyclotron. With this method, it will be possible to produce clinically relevant amounts of 119Sb radioactivity with high chemical and radionuclidic purity for cancer therapy. [Copyright &y& Elsevier]

Purpose: To determine the mode of killing of B-lymphoma cell lines by 111In-conjugated antibodies (Ab). Materials and methods: Cells were treated with a range of radiolabeled Ab concentrations to produce a level of killing from 80 - 99.9%, as determined by a long-term proliferation assay. On days 1, 2, 3 and 4, apoptosis was evaluated in individual cells by two assays: (i) Mitochondrial function by JC-1 staining; and (ii) presence of cleaved PARP (poly-ADP-ribose-polymerase) by immunofluorescence. Five cell lines were tested, including two non-Burkitt lines, RL and FSCCL. Results: In preliminary experiments, it was realized that the standard JC-1 assay, which is widely used, does not distinguish between apoptotic and necrotic cells. The JC-1 assay becomes useful if it is combined with a stain for lysed cells, Sytox green, and then is able to distinguish between viable, apoptotic and necrotic cells. Of the 5 cell lines tested, only Ramos had a large population of apoptotic cells detected by the modified JC-1 assay, but all four of the other cell lines showed evidence of cleaved PARP, albeit to markedly different degrees. The caspase inhibitor, Z-VAD (N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone), significantly inhibited the killing of Daudi cells. Conclusions: Apoptosis was activated in at least four of the five cell lines tested, and participated in the killing of the cells. Staining for cleaved PARP was much more sensitive than the modified JC-1 assay, for most cell lines, probably because it can detect cells that have already lysed, but which died via apoptosis. In addition, the methodological issues discussed may lead to a better understanding of the role of apoptosis in tumor cell cytotoxicity. [ABSTRACT FROM AUTHOR]

In this study, we try to estimate the relative biological effectiveness (RBE) of low-energy electrons released during the gadolinium neutron capture reaction (157GdNCR) using microdosimetric methods. It is assumed that the 157Gd is uniformly distributed throughout the cells and can be bound to DNAs. The microdosimetric parameters of Gd electrons along with those of carbon ions and protons were calculated using the Geant4-DNA and ROOT software. It was found that for a DNA target, the y D -ratio of carbon ions relative to reference radiation is proportional to the relevant RBE, independent of the radiation quality. Comparing the microdosimetric parameters of Gd electrons with those of carbon ions obtained in a 10-nm target, we evaluated the RBE of Gd electrons. In the case where 157Gd distributed inside of the DNA target, the RBE values of Gd electrons were obtained 2.36 and 2.21 using the modified microdosimetric kinetic model and biological weighting function with specific cell type and end-points, respectively. Although the amount of specific energy of Gd electrons in the DNA target is strongly dependent on the 157Gd distribution relative to the target, the RBE variations to the 157Gd distribution are low. The mean energy deposited of Gd electrons in the DNA target during one 157GdNCR with a value of 220.41 eV (equivalent to 207.73 kGy) is large enough for the induction of double-strand break of DNA. This microdosimetric estimation of the RBE of Gd electrons can be useful for assessing the biological dose of Gd electrons in neutron capture therapy. For other Gd compounds or Auger-electron emitters with heterogeneous distributions inside the cells, by comparing with the results obtained in this study, one can evaluate the RBE of their Auger electrons. • Estimation of the RBE of 157Gd electrons using microdosimetric approach. • calculation of the microdosimetric parameters of 157Gd electrons along with external radiations at nm targets using Geant4-DNA. • The calculated RBE values of 157Gd electrons can be greater than 2 for 157Gd in form of motexafin. • The microdosimetric RBE of the 157Gd electrons can be useful for assessing the biological dose in neutron therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Auger transitions resulting in low energy electron emission from graphene identified using novel Auger-Gamma coincidence spectroscopy. • Low energy Auger electrons from bilayer graphene on copper correlated to deep valence holes in graphene and 2s holes in oxygen. • Obtained spectra of Doppler shifted gamma photons originating exclusively from the annihilation of 1s electrons of O and C. • Demonstrates that the Doppler broadened annihilation gamma spectrum reflects the chemical composition of the topmost atomic layer. We have applied positron annihilation induced Auger-gamma coincidence spectroscopy to identify important mechanisms responsible for the emission of low energy electrons following the sudden creation of holes in bilayer graphene on copper substrate. The novel surface spectroscopic method measures the energy of the Doppler shifted annihilation gamma photon in coincidence with the Auger electron emitted following the relaxation of the hole created by the annihilation of a surface electron with a surface trapped positron. By extracting and theoretically modelling the annihilation gamma spectra coincident with low energy electrons, we associate majority of the intensity in the low energy (7 eV–25 eV) region of the Auger spectrum to electron emission following Auger decays of 2s holes in adsorbed oxygen and deep valence holes in graphene. We provide additional support to this conclusion by showing that most of the Auger electrons with energy less than ∼ 25 eV are coincident with gamma photons with small Doppler shift (511 keV–512 keV) indicating that the primary electron whose annihilation resulted in low energy Auger electron emission had small momentum parallel to the gamma emission direction. On the other hand, majority of the Auger electrons measured in coincidence with the photons having maximum Doppler shift (515 keV–521 keV) were emitted following the decay of core holes (C 1s and O 1s). By selecting annihilation gamma photons coincident only with the O KVV (from surface adsorbed oxygen), C KVV (graphene), and Cu MVV (copper substrate) Auger electrons, we have also experimentally derived the energy spectrum of Doppler shifted gamma photons resulting from the annihilation of positrons with 1s electrons of O, 1s electrons of C and 3p electrons of Cu respectively. Model Doppler broadened gamma spectra produced using ab-initio calculations agree well with the experimentally derived line shapes. This demonstrates the ability of Auger-gamma coincidence method to experimentally resolve the Doppler broadened annihilation gamma spectrum from surfaces into its veiled electronic level constituents which has, heretofore, relied solely on theoretical analysis. Our results also demonstrate that the line shape of the Doppler broadened annihilation gamma peak reflect the chemical composition of the topmost atomic layer and can thus be used to characterize both external and inaccessible surfaces of porous materials. [ABSTRACT FROM AUTHOR]

Abstract: The density matrix approach to treat the resonant coherent excitation of swift ions in oriented crystals is applied for a unified theoretical description of the charge state distribution of relativistic resonant coherently excited ions, their characteristic X-ray radiation and, as a new aspect, the Auger electron production from doubly excited states. [Copyright &y& Elsevier]

Abstract: The high intensity positron source NEPOMUC at the FRM-II in Munich enables measurement times for positron annihilation-induced Auger electron spectroscopy (PAES) of only 2.4h/spectrum, in contrast to usual lab beams with measurement times up to several days. The high electron background due to surrounding experiments in the experimental hall of the FRM-II has been eliminated and hence background free experiments have become possible. Due to this, the signal to noise ratio has been enhanced to 4.5:1, compared to 1:3 with EAES. In addition, a long-term measurement has been performed in order to observe the contamination of a polycrystalline copper foil at 150°C. [Copyright &y& Elsevier]

Internal radiotherapy using Auger-emitting radionuclides is a relatively new technique that presents interesting advantages with respect to external radiotherapy, such as localized tumor efficacy. The aim of this study was to assess the dosimetric effectiveness in irradiating a tumor partitioned in different phenotypes, with different radionuclides directed at each tumor phenotype: 99mTc, 125I, 161Tb, and 177Lu. State of the art Monte Carlo PENELOPE code and ICRP adult female reference voxel phantom (AFP) were used in order to mimic a lung tumor volume composed by four different phenotypes. For each radionuclide above mentioned, the decay modes (accessed through ICRP-107 data files) considered encompassed Auger electrons and β, X and ϒ radiation. Two main radiation therapy scenarios were simulated: i) the entire tumor was irradiated homogenously with each of the radionuclides; ii) each tumor phenotype was filled with a different radionuclide. The optimal dosimetric configuration was studied in terms of Dose Efficiency (DE), defined as tumor-to-healthy dose ratio. The Monte Carlo model was validated by comparing the results of SAF values in AFP and cellular S-values for 125I with the ones present in the bibliography. In the first scenario, calculations showed that the highest DE is reached by 125I. Namely, with 125I a gain dose factor (GDF) of about 2.8, 2.7 and 122.5 could be achieved, with respect to 177Lu, 161Tb, and 99mTc, respectively. In the second scenario, a combination of radionuclides directed to each of the phenotypes can act as enhancement for DE or dose in the tumor tissues, with respect to using only one radionuclide in the 4 tumor phenotypes. According to this study, the hypothetical use of different electron beam qualities directed to different tumor phenotypes of the same tumor could act as a radio-sensitizer and, at the same time, minimize dose to the surrounding healthy tissues. • Feasibility study about dose painting in Targeted Radionuclide Therapy. • Dosimetric assessment considering decays of 99mTc, 125I, 161Tb, and 177Lu. • LungTumor sub division in different volume phenotypes. • Combination of different radionuclides has a dose enhancement effect. • The highest dose to the tumor is achieved by beta radiation. [ABSTRACT FROM AUTHOR]