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In this work, the feasibility of XPS analysis using locally generated Al Ka radiation has been demonstrated. Both photo and Auger-electron signals can be obtained from a single, sub-micrometre, particle, achieving the aim of chemical state identification by means of the Auger parameter. The results, demonstrated in this work using copper particles on an aluminium substrate, suggest that the technique, with further development, will be valuable for those concerned with the health hazards of nano-particles in general. [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]

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, cell membrane. Therefore, radioimmunoconjugates (RIC) have been developed for specific tumour cell targeting and transportation to the nucleus. Herein, we assessed, in A-431CEA-luc and SK-OV-31B9 cancer cells that express low and high levels of HER2 receptors, two 111In-RIC consisting of the anti-HER2 antibody trastuzumab conjugated to NLS or TAT peptides for nuclear delivery. We found that NLS and TAT peptides improved the nuclear uptake of 111In-trastuzumab conjugates, but this effect was limited and non-specific. Moreover, it did not result in a drastic decrease of clonogenic survival. Indium-111 also contributed to non-specific cytotoxicity in vitro due to conversion electrons (30% of the cell killing). Comparison with [125I]I-UdR showed that the energy released in the cell nucleus by increasing the RIC's nuclear uptake or by choosing an AEE that releases more energy per decay should be 5 to 10 times higher to observe a significant therapeutic effect. Therefore, new Auger-based radiopharmaceuticals need to be developed. [ABSTRACT FROM AUTHOR]

Thulium-167 is a promising radionuclide for nuclear medicine applications with potential use for both diagnosis and therapy ("theragnostics") in disseminated tumor cells and small metastases, due to suitable gamma-line as well as conversion/Auger electron energies. However, adequate delivery methods are yet to be developed and accompanying radiobiological effects to be investigated, demanding the availability of 167 Tm in appropriate activities and quality. We report herein on the production of radionuclidically pure 167 Tm from proton-irradiated natural erbium oxide targets at a cyclotron and subsequent ion beam mass separation at the CERN-MEDICIS facility, with a particular focus on the process efficiency. Development of the mass separation process with studies on stable 169 Tm yielded 65 and 60% for pure and erbium-excess samples. An enhancement factor of thulium ion beam over that of erbium of up to several 10 4 was shown by utilizing laser resonance ionization and exploiting differences in their vapor pressures. Three 167 Tm samples produced at the IP2 irradiation station, receiving 22.8 MeV protons from Injector II at Paul Scherrer Institute (PSI), were mass separated with collected radionuclide efficiencies between 11 and 20%. Ion beam sputtering from the collection foils was identified as a limiting factor. In-situ gamma-measurements showed that up to 45% separation efficiency could be fully collected if these limits are overcome. Comparative analyses show possible neighboring mass suppression factors of more than 1,000, and overall 167 Tm/Er purity increase in the same range. Both the actual achieved collection and separation efficiencies present the highest values for the mass separation of external radionuclide sources at MEDICIS to date., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heinke, Chevallay, Chrysalidis, Cocolios, Duchemin, Fedosseev, Hurier, Lambert, Leenders, Marsh, van der Meulen, Sprung, Stora, Tosato, Wilkins, Zhang and Talip.)

Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. "match" oligonucleotides complementary to the telomerase RNA template subunit (hTR) and "scramble" (control) oligonucleotides were conjugated to diethylenetriamine pentaacetate (DTPA) for 111 In-labeling. AuNPs (15.5 nm) were decorated with a monofunctional layer of oligonucleotides (ON-AuNP) or a multifunctional layer of oligonucleotides, PEG(polethylene glycol)800-SH (to reduce AuNP aggregation) and the cell-penetrating peptide Tat (ON-AuNP-Tat). Match-AuNP enhanced the cellular uptake of radiolabeled oligonucleotides while retaining the ability to inhibit telomerase activity. The addition of Tat to AuNPs increased nuclear localization. 111 In-Match-AuNP-Tat induced DNA double-strand breaks and caused a dose-dependent reduction in clonogenic survival of telomerase-positive cells but not telomerase-negative cells. hTR inhibition has been reported to sensitize cancer cells to ionizing radiation, and 111 In-Match-AuNP-Tat therefore holds promise as a vector for delivery of radionuclides into cancer cells while simultaneously sensitizing them to the effects of the emitted radiation.

161 Tb has decay properties similar to those of 177 Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply 161 Tb in a clinical setting and to investigate the feasibility of visualizing the physiologic and tumor biodistributions of 161 Tb-DOTATOC. Methods: 161 Tb was shipped from Paul Scherrer Institute, Villigen-PSI, Switzerland, to Zentralklinik Bad Berka, Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In 2 separate studies, 596 and 1,300 MBq of 161 Tb-DOTATOC were administered to a 35-y-old male patient with a metastatic, well-differentiated, nonfunctional malignant paraganglioma and a 70-y-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphy images were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed using a recently established protocol and visually analyzed. Patients were observed for adverse events after the application of 161 Tb-DOTATOC. Results: The radiolabeling of DOTATOC with 161 Tb was readily achieved with a high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of 161 Tb-DOTATOC in the liver, kidneys, spleen, and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in bones and liver. The application of 161 Tb-DOTATOC was well tolerated, and no related adverse events were reported. Conclusion: This study demonstrated the feasibility of imaging even small metastases after the injection of relatively low activities of 161 Tb-DOTATOC using γ-scintigraphy and SPECT/CT. On the basis of this essential first step in translating 161 Tb to clinics, further efforts will be directed toward the application of 161 Tb for therapeutic purposes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: 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 [ 67 Ga]GaCl 3 or [ 111 In]InCl 3 compared to EBRT., Methods: Supercoiled pBR322 plasmid DNA (1.25 or 5 ng/μL) was incubated with 0.5 or 1 MBq [ 67 Ga]GaCl 3 or [ 111 In]InCl 3 for up to 73 h or was exposed to EBRT ( 137 Cs; 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 67 Ga 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., Results: DNA damage increased both with EBRT dose and incubation time for [ 67 Ga]GaCl 3 and [ 111 In]InCl 3 . Damage caused by [ 67 Ga]GaCl 3 decreased when chelated. [ 67 Ga]GaCl 3 proved more damaging than [ 111 In]InCl 3 ; 1.25 ng/μL DNA incubated with 0.5 MBq [ 67 Ga]GaCl 3 for 2 h led to a 70% decrease of intact plasmid DNA as opposed to only a 19% decrease for [ 111 In]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 [ 67 Ga]GaCl 3 and [ 111 In]InCl 3 after 2.05 ± 0.36 and 9.3 ± 0.77 h of incubation, respectively., Conclusions: 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., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Shown in this paper is the influence of channeling effect on formation of the signal for low- and high-energy Auger-electrons observed in monocrystalline silicon. It has been ascertained the anisotropic (wave-like) character of the yield value for lowenergy Auger-electrons in silicon, when changing the angle of acting initial radiation during sample rotation. [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]

165Er, a pure Auger-electron emitter, could be an attractive candidate for targeted radionuclide therapy. Auger electrons possess short penetration paths with high linear energy transfer. In this study, experimental cross-sections of the 165Ho(p, n)165Er nuclear reaction were measured and targets irradiated with protons using Injector II cyclotron at Paul Scherrer Institute (Switzerland) and the 18 MeV medical cyclotron laboratory at the University Hospital in Bern. A purification method was developed in order to obtain 165Er suitable for in vivo applications. • A new method for the production of 165Er was devised. • Cross section measurements were performed to determine production potential. • Proton irradiations took place at two facilities. • Chemical separation ensured a radionuclidically pure product. • Complications to this method were looked at critically and improvements proposed. [ABSTRACT FROM AUTHOR]

Background: Auger electron-emitting radionuclides have potential in targeted treatment of small tumors. Thallium-201 ( 201 Tl), a gamma-emitting radionuclide used in myocardial perfusion scintigraphy, decays by electron capture, releasing around 37 Auger and Coster-Kronig electrons per decay. However, its therapeutic and toxic effects in cancer cells remain largely unexplored. Here, we assess 201 Tl in vitro kinetics, radiotoxicity and potential for targeted molecular radionuclide therapy, and aim to test the hypothesis that 201 Tl is radiotoxic only when internalized., Methods: Breast cancer MDA-MB-231 and prostate cancer DU145 cells were incubated with 200-8000 kBq/mL [ 201 Tl]TlCl. Potassium concentration varied between 0 and 25 mM to modulate cellular uptake of 201 Tl. Cell uptake and efflux rates of 201 Tl were measured by gamma counting. Clonogenic assays were used to assess cell survival after 90 min incubation with 201 Tl. Nuclear DNA damage was measured with γH2AX fluorescence imaging. Controls included untreated cells and cells treated with decayed [ 201 Tl]TlCl., Results: 201 Tl uptake in both cell lines reached equilibrium within 90 min and washed out exponentially (t 1/2 15 min) after the radioactive medium was exchanged for fresh medium. Cellular uptake of 201 Tl in DU145 cells ranged between 1.6 (25 mM potassium) and 25.9% (0 mM potassium). Colony formation by both cell lines decreased significantly as 201 Tl activity in cells increased, whereas 201 Tl excluded from cells by use of high potassium buffer caused no significant toxicity. Non-radioactive TlCl at comparable concentrations caused no toxicity. An estimated average 201 Tl intracellular activity of 0.29 Bq/cell (DU145 cells) and 0.18 Bq/cell (MDA-MB-231 cells) during 90 min exposure time caused 90% reduction in clonogenicity. 201 Tl at these levels caused on average 3.5-4.6 times more DNA damage per nucleus than control treatments., Conclusions: 201 Tl reduces clonogenic survival and increases nuclear DNA damage only when internalized. These findings justify further development and evaluation of 201 Tl therapeutic radiopharmaceuticals.

Introduction: Thallium-201 is a radionuclide that has previously been used clinically for myocardial perfusion scintigraphy. Although in this role it has now been largely replaced by technetium-99 m radiopharmaceuticals, thallium-201 remains attractive in the context of molecular radionuclide therapy for cancer micrometastases or single circulating tumour cells. This is due to its Auger electron (AE) emissions, which are amongst the highest in total energy and number per decay for AE-emitters. Currently, chemical platforms to achieve this potential through developing thallium-201-labelled targeted radiopharmaceuticals are not available. Here, we describe convenient methods to oxidise [ 201 Tl]Tl(I) to chelatable [ 201 Tl]Tl(III) and identify challenges in stable chelation of thallium to support future synthesis of effective [ 201 Tl]-labelled radiopharmaceuticals., Methods: A plasmid pBR322 assay was carried out to determine the DNA damaging properties of [ 201 Tl]Tl(III). A range of oxidising agents (ozone, oxygen, hydrogen peroxide, chloramine-T, iodogen, iodobeads, trichloroisocyanuric acid) and conditions (acidity, temperature) were assessed using thin layer chromatography. Chelators EDTA, DTPA and DOTA were investigated for their [ 201 Tl]Tl(III) radiolabelling efficacy and complex stability., Results: Isolated plasmid studies demonstrated that [ 201 Tl]Tl(III) can induce single and double-stranded DNA breaks. Iodo-beads, iodogen and trichloroisocyanuric acid enabled more than 95% conversion from [ 201 Tl]Tl(I) to [ 201 Tl]Tl(III) under conditions compatible with future biomolecule radiolabelling (mild pH, room temperature and post-oxidation removal of oxidising agent). Although chelation of [ 201 Tl]Tl(III) was possible with EDTA, DTPA and DOTA, only radiolabeled DOTA showed good stability in serum., Conclusions: Decay of [ 201 Tl]Tl(III) in proximity to DNA causes DNA damage. Iodobeads provide a simple, mild method to convert thallium-201 from a 1+ to 3+ oxidation state and [ 201 Tl]Tl(III) can be chelated by DOTA with moderate stability. Of the well-established chelators evaluated, DOTA is most promising for future molecular radionuclide therapy using thallium-201; nevertheless, a new generation of chelating agents offering resistance to reduction and dissociation of [ 201 Tl]Tl(III) complexes is required., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Treatment of glioblastomas (GBM) using the Auger electron emitting compound [ 125 I]5-Iodo-2'-deoxyuridine ([ 125 I]I-UdR), combined with the thymidylate synthase inhibitor methotrexate (MTX) and concomitant chemotherapy with temozolomide (TMZ) has recently shown very promising therapeutic effects in vitro and in vivo in animals. The aim of the current study was to investigate if the therapeutic effects of this multimodal treatment strategy could be further increased by the thymidylate synthase inhibitor, 5-fluoro-2'-deoxyuridine (F-UdR), in comparison to MTX, and if the co-treatment should be given in a neoadjuvant or adjuvant setting., Methods: A patient-derived GBM cancer stem cell (CSC)-enriched cell line, grown as neurospheres, was employed to evaluate DNA-incorporation of [ 125 I]I-UdR, determined by a DNA precipitation assay, using either pre-treatment or co-treatment with MTX or F-UdR. The therapeutic effects in the CSC-enriched cell line after exposure to various combinations of MTX, F-UdR, TMZ and [ 125 I]I-UdR were also investigated by a CellTiter-Blue assay., Results: The highest general increase in [ 125 I]I-UdR incorporation was observed with F-UdR co-treatment, which resulted in approx. 2.5-fold increase in the DNA-associated activity. Also the cell viability was significantly decreased when F-UdR was combined with [ 125 I]I-UdR compared to [ 125 I]I-UdR alone at all activity concentrations tested. MTX was redundant when combined with 400 and 500 Bq/ml [ 125 I]I-UdR. TMZ was effective in combination with either [ 125 I]I-UdR alone or with both thymidylate synthase inhibitors combined with 50-100 Bq/ml [ 125 I]I-UdR., Conclusions: Overall, our study revealed a higher incorporation and therapeutic effect of [ 125 I]I-UdR when GBM cells were co-treated with F-UdR compared to MTX. The therapeutic effects were further increased when TMZ was combined with [ 125 I]I-UdR in combination with the thymidylate synthase inhibitors., Advances in Knowledge and Implications for Patient Care: Auger electron therapy in combination with thymidylate synthase inhibition and concomitant chemotherapy has the potential to become a future therapeutic treatment option for patients with glioblastoma., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: For the past two decades, high-Z nanoparticles have been of high interest to improve the therapeutic outcomes of radiation therapy, especially for low-energy x-rays. Monte Carlo (MC) simulations have been used to evaluate the boost of dose deposition induced by Auger electrons near the nanoparticle surface, by calculating average energy deposition at the nanoscale. In this study, we propose to go beyond average quantities and quantify the stochastic nature of energy deposition at such a scale. We present results of probability density of the specific energy (restricted to ionization, excitation and electron attachment events) in cylindrical nanotargets of height and radius set at 10 nm. This quantity was evaluated for nanotargets located within 200 nm around 5-50 nm gold nanoparticles (GNPs), for 20-90 keV photon irradiation., Methods: This nanodosimetry study was based on the MC simulation MDM that allows tracking of electrons down to thermalization energy. We introduced a new quantity, namely the probability enhancement ratio (PER), by estimating the probability of imparting to nanotargets a restricted specific energy larger than a threshold z 0 (1, 10, and 20 kGy), normalized to the probability for pure water. The PER was calculated as a function of the distance between the nanotarget and the GNP surface. The threshold values were chosen in light of the biophysical model NanOx that predicts cell survival by calculating local lethal events based on the restricted specific energy and an effective local lethal function. z 0 then represents a threshold above which the nanotarget damages induce efficiently cell death., Results: Our calculations showed that the PER varied a lot with the GNP radius, the photon energy, z 0 and the distance of the GNP to the nanotarget. The highest PER was 95 when the nanotarget was located at 5 nm from the GNP surface, for a photon energy of 20 keV, a threshold of 20 kGy, and a GNP radius of 50 nm. This enhancement dramatically decreased with increasing GNP-nanotarget distances as it went below 1.5 for distances larger than 200 nm., Conclusions: The PER seems better adapted than the mean dose deposition to describe the formation of biological damages. The significant increase of the PER within 200 nm around the GNP suggests that severe damages could occur for biological nanotargets located near the GNP. These calculations will be used as an input of the biophysical model NanOx to convert PER into estimation of radiation-induced cell death enhanced by GNPs., (© 2020 American Association of Physicists in Medicine.)

Production of medical radionuclides with ISOL facilities is a unique production method that may provide access to preclinical quantities of some rare and potent radionuclides for nuclear medicine. Particularly attention over the past years was focused on several promising candidates for Targeted Radionuclides Therapy (TRT). With this review, we provide some perspectives of using the TRIUMF ISOL facility (ISAC) to produce medical radionuclides for TRT application and highlight our current effort to collect of 165 Er and 155 Tb for Auger Therapy and SPECT imaging, respectively., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Targeted Radionuclide Therapies (TRTs) based on Auger emitting radionuclides have the potential to deliver extremely selective therapeutic payloads on the cellular level. However, to fully exploit this potential, suitable radionuclides need to be applied in combination with appropriate delivery systems. In this review, we summarize the state-of-the-art production, purification, chelation and applications of two promising candidates for Targeted Auger Therapy, namely antimony- 119 ( 119 Sb) and mercury-197 ( 197 Hg). Both radionuclides have great potential to become efficient tools for TRT. We also highlight our current progress on the production of both radionuclides at TRIUMF and the University of Wisconsin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Small-scale dosimetry studies generally consider an artificial environment where the tumors are spherical and the radionuclides are homogeneously biodistributed. However, tumor shapes are irregular and radiopharmaceutical biodistributions are heterogeneous, impacting the energy deposition in targeted radionuclide therapy. To bring realism, we developed a dosimetric methodology based on a three-dimensional in vitro model of follicular lymphoma incubated with rituximab, an anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin lymphomas, which might be combined with a radionuclide. The effects of the realistic geometry and biodistribution on the absorbed dose were highlighted by comparison with literature data. Additionally, to illustrate the possibilities of this methodology, the effect of different radionuclides on the absorbed dose distribution delivered to the in vitro tumor were compared., Methods: The starting point was a model named multicellular aggregates of lymphoma cells (MALC). Three MALCs of different dimensions and their rituximab biodistribution were considered. Geometry, antibody location and concentration were extracted from selective plane illumination microscopy. Assuming antibody radiolabeling with Auger electron ( 125 I and 111 In) and β - particle emitters ( 177 Lu, 131 I and 90 Y), we simulated energy deposition in MALCs using two Monte Carlo codes: Geant4-DNA with "CPA100" physics models for Auger electron emitters and Geant4 with "Livermore" physics models for β - particle emitters., Results: MALCs had ellipsoid-like shapes with major radii, r, of ~0.25, ~0.5 and ~1.3 mm. Rituximab was concentrated in the periphery of the MALCs. The absorbed doses delivered by 177 Lu, 131 I and 90 Y in MALCs were compared with literature data for spheres with two types of homogeneous biodistributions (on the surface or throughout the volume). Compared to the MALCs, the mean absorbed doses delivered in spheres with surface biodistributions were between 18% and 38% lower, while with volume biodistribution they were between 15% and 29% higher. Regarding the radionuclides comparison, the relationship between MALC dimensions, rituximab biodistribution and energy released per decay impacted the absorbed doses. Despite releasing less energy, 125 I delivered a greater absorbed dose per decay than 111 In in the r ~ 0.25 mm MALC (6.78·10 -2 vs 6.26·10 -2  µGy·Bq -1 ·s -1 ). Similarly, the absorbed doses per decay in the r ~ 0.5 mm MALC for 177 Lu (2.41·10 -2  µGy·Bq -1 ·s -1 ) and 131 I (2.46·10 -2  µGy·Bq -1 ·s -1 ) are higher than for 90 Y (1.98·10 -2  µGy·Bq -1 ·s -1 ). Furthermore, radionuclides releasing more energy per decay delivered absorbed dose more uniformly through the MALCs. Finally, when considering the radiopharmaceutical effective half-life, due to the biological half-life of rituximab being best matched by the physical half-life of 177 Lu and 131 I compared to 90 Y, the first two radionuclides delivered higher absorbed doses., Conclusion: In the simulated configurations, β - emitters delivered higher and more uniform absorbed dose than Auger electron emitters. When considering radiopharmaceutical half-lives, 177 Lu and 131 I delivered absorbed doses higher than 90 Y. In view of real irradiation of MALCs, such a work may be useful to select suited radionuclides and to help explain the biological effects., (© 2020 American Association of Physicists in Medicine.)

Excess electrons play important roles for the construction of superficial active sites on nanocatalysts. However, providing excess electrons to nanocatalysts in vivo is still a challenge, which limits the applications of nanocatalysts in biomedicine. Herein, auger electrons (AEs) emitted from radionuclide 125 ( 125 I) are used in situ to construct active sites in a nanocatalyst (TiO 2 ) and the application of this method is further extended to cancer catalytic internal radiotherapy (CIRT). The obtained 125 I-TiO 2 nanoparticles first construct superficial Ti 3+ active sites via the reaction between Ti 4+ and AEs. Then Ti 3+ stretches and weakens the O-H bond of the absorbed H 2 O, thus enhancing the radiolysis of H 2 O molecules and generating hydroxyl radicals (•OH). All in vitro and in vivo results demonstrate a good CIRT performance. These findings will broaden the application of radionuclides and introduce new perspectives to nanomedicine., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

The rationale of boron (10B) neutron capture therapy (BNCT) is based on the high thermal neutron capture cross section of 10B and the limited maximum range (about one cell diameter) of the high LET fission products of the boron neutron capture (NC) reaction. The resulting radiochemical damage is confined to the cell containing the BNC reaction. Although other nuclides have higher thermal neutron capture cross sections than 10B, NC by such nuclides results in the emission of highly penetrating gamma rays. However, gadolinium-157 (157Gd) n-gamma reaction is also accompanied by some internal conversion and, by implication, Auger electron emission. Irradiation of Gd3+-DNA complexes with thermal neutrons results in the induction of DNA double-strand (ds) breaks, but the effect is largely abrogated in the presence of EDTA. Thus, by analogy with the effects of decay of Auger electron-emitting isotopes such as 125I, the Gd NC event must take place in the close proximity of DNA in order to induce a DNA ds break. It is proposed that 157Gd-DNA ligands therefore have potential in NCT. The thermal neutron capture cross section of 157Gd, a nonradioactive isotope, is more than 50 times that of 10B. [ABSTRACT FROM AUTHOR]

Background: Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. 111In, 67Ga, 99mTc, 195mPt, 125I and 123I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment. Results: AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. 125I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (125I and 123I) or radiometal chelation (111In, 67Ga, 99mTc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using 111In-DTPA-octreotide and 125I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with 125I-mAb 425, with minimal normal tissue toxicity. Conclusions: Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision. [ABSTRACT FROM AUTHOR]

Synchrotron generated monochromatic X-rays can be precisely tuned to the K-shell energy of high Z materials resulting in the release of the Auger electrons. In this work, we have employed this mechanism to destruct tumor spheroids. We first loaded gadolinium onto the surface of mesoporous silica nanoparticles (MSNs) producing gadolinium-loaded MSN (Gd-MSN). When Gd-MSN was added to the tumor spheroids, we observed efficient uptake and uniform distribution of Gd-MSN. Gd-MSN also can be taken up into cancer cells and localize to a site just outside of the cell nucleus. Exposure of the Gd-MSN containing tumor spheroids to monochromatic X-ray beams resulted in almost complete destruction. Importantly, this effect was observed at an energy level of 50.25 keV, but not with 50.0 keV. These results suggest that it is possible to use precisely tuned monochromatic X-rays to destruct tumor mass loaded with high Z materials, while sparing other cells. Our experiments point to the importance of nanoparticles to facilitate loading of gadolinium to tumor spheroids and to localize at a site close to the nucleus. Because the nanoparticles can target to tumor, our study opens up the possibility of developing a new type of radiation therapy for cancer. [ABSTRACT FROM AUTHOR]

Introduction: Our objective was to evaluate the effectiveness and normal tissue toxicity of nimotuzumab labeled with the Auger electron (AE)-emitter, 111 In ([ 111 In]In-Bn-DTPA-nimotuzumab) for radioimmunotherapy (RIT) of human triple-negative breast cancer (TNBC) or trastuzumab-resistant HER2-positive BC tumors overexpressing epidermal growth factor receptors (EGFR) in athymic mice., Methods: Normal tissue toxicity was studied in non-tumor-bearing Balb/c mice i.v. administered 9.0 or 28.6 MBq (3 mg/kg) of [ 111 In]In-Bn-DTPA-nimotuzumab, unlabeled nimotuzumab (3 mg/kg) or normal saline. A complete blood cell count (CBC) and serum alanine aminotransferase (ALT) and creatinine (Cr) were measured at 14 days. Body weight was monitored. RIT studies were performed in CD-1 athymic mice engrafted s.c. with MDA-MB-468 human TNBC tumors or TrR1 HER2-positive but trastuzumab-resistant BC tumors. Mice were i.v. administered two amounts (15.5 MBq; 3 mg/kg) of [ 111 In]In-Bn-DTPA-nimotuzumab separated by 14 days. Control mice received unlabeled Bn-DTPA-nimotuzumab (3 mg/kg) or anti-HER2 [ 111 In]In-Bn-DTPA-trastuzumab or normal saline. Tumor growth and body weight were measured for 6 weeks. A tumor growth index (TGI) and body weight index (BWI) were calculated to compare the tumor size and body weight post-treatment with the pre-treatment values. A tumor doubling ratio (TDR) was calculated for each treatment group compared to control mice receiving normal saline., Results: There was no loss of body weight or decreased red blood cells (RBC) or platelets (PLT) or increased serum ALT or Cr in Balb/c mice administered 9.0 or 28.6 MBq (3 mg/kg) of [ 111 In]In-Bn-DTPA-nimotuzumab compared to mice treated with unlabeled Bn-DTPA-nimotuzumab (3 mg/kg) or normal saline. There was a significant decrease in white blood cell (WBC) counts in Balb/c mice receiving 28.6 MBq but not 9.0 MBq of [ 111 In]In-Bn-DTPA-nimotuzumab. Based on these results, an administered amount of 15.5 MBq (3 mg/kg) was selected for RIT studies. Administration of two amounts (15.5 MBq; 3 mg/kg) separated by 14 days to CD-1 athymic mice with s.c. MDA-MB-468 xenografts strongly inhibited tumor growth. The TDR for mice treated with [ 111 In]In-Bn-DTPA-nimotuzumab was 2.15 compared to control mice receiving normal saline. In contrast, treatment with unlabeled Bn-DTPA-nimotuzumab or [ 111 In]In-Bn-DTPA-trastuzumab had no significant effect on tumor growth (TDR = 0.96 and 1.08, respectively). RIT with [ 111 In]In-Bn-DTPA-nimotuzumab also strongly inhibited the growth of TrR1 tumors in athymic mice (TDR = 2.13) compared to unlabeled Bn-DTPA-nimotuzumab (TDR = 0.91). There were no losses in body weight over 6 weeks in tumor bearing mice receiving [ 111 In]In-Bn-DTPA-nimotuzumab, unlabeled Bn-DTPA-nimotuzumab, [ 111 In]In-Bn-DTPA-trastuzumab or normal saline., Conclusions: [ 111 In]In-Bn-DTPA-nimotuzumab was effective for treatment of TNBC or trastuzumab-resistant HER2-positive human BC tumors in mice that overexpress EGFR at administered amounts that caused no decrease in body weight or normal tissue toxicity in non-tumor-bearing Balb/c mice., Advances in Knowledge and Implications for Patient Care: Our results suggest that Auger electron RIT with [ 111 In]In-Bn-DTPA-nimotuzumab may provide a novel therapeutic option for patients with TNBC or trastuzumab-resistant HER2-positive BC that overexpresses EGFR. The low normal tissue toxicity of this approach may allow combination with other targeted therapies such as antibody-drug conjugates (ADCs)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Molecular radiotherapy exploiting short-range Auger electron-emitting radionuclides has potential for targeted cancer treatment and, in particular, is an attractive option for managing micrometastatic disease. Here, an approach using chelator-trastuzumab conjugates to target radioactivity to breast cancer cells was evaluated as a proof-of-concept to assess the suitability of 67 Ga as a therapeutic radionuclide., Methods: THP-trastuzumab and DOTA-trastuzumab were synthesised and radiolabelled with Auger electron-emitters 67 Ga and 111 In, respectively. Radiopharmaceuticals were tested for HER2-specific binding and internalisation, and their effects on viability (dye exclusion) and clonogenicity of HER2-positive HCC1954 and HER2-negative MDA-MB-231 cell lines was measured. Labelled cell populations were studied by microautoradiography., Results: Labelling efficiencies for [ 67 Ga]Ga-THP-trastuzumab and [ 111 In]In-DOTA-trastuzumab were 90% and 98%, respectively, giving specific activities 0.52 ± 0.16 and 0.61 ± 0.11 MBq/μg (78-92 GBq/μmol). At 4 nM total antibody concentration and 200 × 10 3 cells/mL, [ 67 Ga]Ga-THP-trastuzumab showed higher percentage of cell association (10.7 ± 1.3%) than [ 111 In]In-DOTA-trastuzumab (6.2 ± 1.6%; p = 0.01). The proportion of bound activity that was internalised did not differ significantly for the two tracers (62.1 ± 1.4% and 60.8 ± 15.5%, respectively). At 100 nM, percentage cell binding of both radiopharmaceuticals was greatly reduced compared to 4 nM and did not differ significantly between the two (1.2 ± 1.0% [ 67 Ga]Ga-THP-trastuzumab and 0.8 ± 0.9% for [ 111 In]In-DOTA-trastuzumab). Viability and clonogenicity of HER2-positive cells decreased when each radionuclide was incorporated into cells by conjugation with trastuzumab, but not when the same level of radioactivity was confined to the medium by omitting the antibody conjugation, suggesting that 67 Ga needs to be cell-bound or internalised for a therapeutic effect. Microautoradiography showed that radioactivity bound to individual cells varied considerably within the population., Conclusions: [ 67 Ga]Ga-THP-trastuzumab reduced cell viability and clonogenicity only when cell-bound, suggesting 67 Ga holds promise as a therapeutic radionuclide as part of a targeted radiopharmaceutical. The causes and consequences of non-homogeneous uptake among the cell population should be explored., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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 161 Tb (T 1/2  = 6.89 days; Eβ ͞ av Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.177 Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile., Methods: 161 Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161 Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177 Lu-PSMA-617. The effects of 161 Tb-PSMA-617 and 177 Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161 Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice., Results: 161 Tb-PSMA-617 and 177 Lu-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 161 Tb-PSMA-617 as compared to the effect obtained with the same activities of 177 Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161 Tb-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 161 Tb-PSMA-617 and 177 Lu-PSMA-617 indicated the anticipated superiority of 161 Tb over 177 Lu., Conclusion: 161 Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177 Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161 Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161 Tb-PSMA-617 for the treatment of mCRPC.

Rotational streaking by a circularly polarized THz field of Auger electrons generated by a short extreme ultraviolet (XUV) or x-ray pulse is theoretically investigated. The character of the streaking pattern depends on three main parameters: the duration of the XUV pulse, the Auger decay time-of-life and the period of the THz field. Different cases with various interrelations of these parameters are discussed. Examples of the patterns are calculated within the strong field approximation. Correspondence between the angular streaking of electrons in the processes of photoionization and Auger ionization is considered. Retrieval of the Auger decay parameters from the circular streaking spectrum is discussed. [ABSTRACT FROM AUTHOR]

A tenet of time-resolved spectroscopy is "faster laser pulses for shorter timescales". Here, we suggest turning this paradigm around, and slowing down the system dynamics via repeated measurements, to do spectroscopy on longer timescales. This is the principle of the quantum Zeno effect. We exemplify our approach with the Auger process, and find that repeated measurements increase the core-hole lifetime, redistribute the kinetic energy of Auger electrons, and alter entanglement formation. We further provide an explicit experimental protocol for atomic Li, to make our proposal concrete. [ABSTRACT FROM AUTHOR]

Ultra-fast x-ray-dynamic experimental subsystem is a facility which can provide femtosecond hard x-ray sources using a femtosecond laser interacting with plasmas. By utilizing these ultra-fast x-rays as a probe, combined with a naturally synchronized driver laser as a pump, we can perform dynamic studies on samples with a femtosecond time resolution. This subsystem with a four-dimensional ultra-high spatiotemporal resolution is a powerful tool for studies of the process of photosynthesis, Auger electron effects, lattice vibrations, etc. Compared with conventional x-ray sources based on accelerators, this table-top laser-driven x-ray source has significant advantages in terms of the source size, pulse duration, brightness, flexibility, and economy. It is an effective supplement to the synchrotron light source in the ultrafast detection regime. [ABSTRACT FROM AUTHOR]

A classical approach to the description of angular momentum transfer between the Auger electron and photoelectron in post-collision interaction is worked out. The results of the classical approach coincide with the quantum mechanical ones at the photoionization threshold. Besides, the approach developed provides a description of angular momentum transfer beyond the photoionization threshold. In particular, it is suitable in the energy region of comparable velocities of two emitted electrons. [ABSTRACT FROM AUTHOR]

Auger electrons emitted after nuclear decay have potential application in targeted cancer therapy. For this purpose it is important to know the Auger electron yield per nuclear decay. In this work we describe a measurement of the ratio of the number of conversion electrons (emitted as part of the nuclear decay process) to the number of Auger electrons (emitted as part of the atomic relaxation process after the nuclear decay) for the case of 125I. Results are compared with Monte-Carlo type simulations of the relaxation cascade using the BrIccEmis code. Our results indicate that for 125I the calculations based on rates from the Evaluated Atomic Data Library underestimate the K Auger yields by 20%. [ABSTRACT FROM AUTHOR]

The half-lives of 135La and 132La were determined via serial gamma spectroscopy, and the half-life of 135La was further determined by a high-precision ionization-chamber measurement. The results are 18.91(2) hr for 135La and 4.59(4) hr for 132La compared with the previously compiled values of 19.5(2) hr and 4.8(2) hr, respectively. These lanthanum isotopes comprise a medically interesting system with positron emitter 132La and Auger-electron emitter 135La forming a theranostic pair for internal diagnostics and therapeutics. The precise half-lives are necessary for proper evaluation of their value in medicine and for a more representative tabulation of nuclear data. [ABSTRACT FROM AUTHOR]