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Auger electrons (AEs) represent an intriguing topic in the field of radionuclide therapy. They are emitted by several radionuclides commonly used in nuclear medicine (indium-111, iodine-123, iodine-125), allowing for highly localized energy deposition and thus exerting a radiotoxic effect on specific cellular and sub-cellular targets. However, due to their short range in matter, AEs have had limited use in therapeutic applications so far. In recent years, the synthesis of various radiopharmaceuticals capable of binding to the enzyme poly(ADP-ribose) polymerase 1 has reignited interest in this type of therapy, laying the groundwork for a theranostic approach based on radionuclides emitting AEs. The enzyme PARP-1 operates enzymatically in close proximity to DNA that represents the prime target of radionuclide therapies. Following this trend, several PARP-targeted radiopharmaceuticals for AE-based theranostics have been developed. We provide an updated overview of preclinical studies focused on the applications of this new theranostic approach in glioblastoma, breast, prostate and ovarian carcinoma, and pancreatic adenocarcinoma.

TOPAS-nBio was used to simulate, collision-to-collision, the complete trajectories of electrons in water generated during the explicit simulation of 64Cu decay. S-values and direct damage to the DNA were calculated representing the cell (C) and the cell nucleus (N) with concentric spheres of 5 μm and 4 μm in radius, respectively. The considered 'target'←'source' configurations, including the cell surface (Cs) and cytoplasm (Cy), were: C←C, C←Cs, N←N, N←Cy and N←Cs. Ionization cluster size distributions were also calculated in a cylinder immersed in water corresponding to a DNA segment of 10 base-pairs in length (diameter 2.3 nm, length 3.4 nm), modeling a radioactive point source moving from the central axis to the edge of the cylinder. For that, the first moment (M1) and cumulative probability of having a cluster size of 2 or more ionizations in the cylindrical volume (F2) were obtained. Finally, the direct damage to the DNA was estimated by quantifying double-strand breaks (DSBs) using the clustering algorithm DBSCAN. The S-values obtained with TOPAS-nBio for 64Cu were 7.879 × 10-4 ± 5 × 10-7, 4.351 × 10-4 ± 6 × 10-7, 1.442 × 10-3 ± 1 × 10-6, 2.596 × 10-4 ± 8 × 10-7, 1.127 × 10-4 ± 4 × 10-7 Gy Bq-s-1 for the configurations C←C, C←Cs, N←N, N←Cy and N←Cs, respectively. The difference of these values, compared with previously reported S-values for 64Cu with the code MNCP and software MIRDCell, ranged from -4% to -25% for the configurations N←N and N←Cs, respectively. On the other hand, F2 was maximum with the source at the center of the cylinder 0.373 ± 0.001, and monotonically decreased until reaching a value of 0.058 ± 0.001 at 2.3 nm. The same behavior was observed for M1 with values ranging from 2.188 ± 0.004 to 0.242 ± 0.002. Finally, the DBSCAN algorithm showed that the mean number of DNA DSBs per decay were 0.187 ± 0.001, 0.0317 ± 0.0005, and 0.0125 ± 0.0002 DSB-(Bq-s)-1 for the configurations N←N, N←Cs, and N←Cy, respectively. In conclusion, the results of the S-values show that the absorbed dose strongly depends on the distribution of the radionuclide in the cell, the dose being higher when 64Cu is internalized in the cell nucleus, which is reinforced by the nanodosimetric study by the presence of DNA DSBs attributable to the Auger electrons emitted during the decay of 64Cu.

Abstract Background Auger electron-emitting radionuclides have potential in targeted treatment of small tumors. Thallium-201 (201Tl), 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 201Tl in vitro kinetics, radiotoxicity and potential for targeted molecular radionuclide therapy, and aim to test the hypothesis that 201Tl is radiotoxic only when internalized. Methods Breast cancer MDA-MB-231 and prostate cancer DU145 cells were incubated with 200–8000 kBq/mL [201Tl]TlCl. Potassium concentration varied between 0 and 25 mM to modulate cellular uptake of 201Tl. Cell uptake and efflux rates of 201Tl were measured by gamma counting. Clonogenic assays were used to assess cell survival after 90 min incubation with 201Tl. Nuclear DNA damage was measured with γH2AX fluorescence imaging. Controls included untreated cells and cells treated with decayed [201Tl]TlCl. Results 201Tl 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 201Tl 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 201Tl activity in cells increased, whereas 201Tl 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 201Tl 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. 201Tl at these levels caused on average 3.5–4.6 times more DNA damage per nucleus than control treatments. Conclusions 201Tl reduces clonogenic survival and increases nuclear DNA damage only when internalized. These findings justify further development and evaluation of 201Tl therapeutic radiopharmaceuticals.

Cancer stem cells (CSCs) are resistant to conventional therapy and present a major clinical challenge since they are responsible for the relapse of many cancers, including non-small cell lung cancer (NSCLC). Hence, future successful therapy should also eradicate CSCs. Auger electrons have demonstrated promising therapeutic potential and can induce DNA damage while sparing surrounding cells. Here, we sort primary patient-derived NSCLC cells based on their expression of the CSC-marker CD44 and investigate the effects of cisplatin and a thymidine analog (deoxyuridine) labeled with an Auger electron emitter (125I). We show that the CD44+ populations are more resistant to cisplatin than the CD44− populations. Interestingly, incubation with the thymidine analog 5-[125I]iodo-2′-deoxyuridine ([125I]I-UdR) induces equal DNA damage, G2/M cell cycle arrest, and apoptosis in the CD44− and CD44+ populations. Our results suggest that Auger electron emitters can also eradicate resistant lung cancer CD44+ populations. [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 167Tm in appropriate activities and quality. We report herein on the production of radionuclidically pure 167Tm 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 169Tm 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 104 was shown by utilizing laser resonance ionization and exploiting differences in their vapor pressures. Three 167Tm 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 167Tm/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.

Abstract 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.

The chemical shift of core level binding energies makes electron spectroscopy for chemical analysis (ESCA) a workhorse analytical tool for science and industry. For some elements, close lying and overlapping spectral features within the natural life time broadening restrict applications. We establish how the core level binding energy chemical shift can be picked up experimentally by the additional selectivity through Auger electron photoelectron coincidence spectroscopy (APECS). Coincident measurement of Ni 3p photoemission with different MVV Auger regions from specific decay channels, narrows the 3p core-levels to a width of 1.2 eV, resolves the spin–orbit splitting of 1.6 eV and determines the chemical shift of Ni 3p levels of a Ni(111) single crystal and its oxidized surface layer to 0.6 eV. [ABSTRACT FROM AUTHOR]

Background: Auger electron-emitting radionuclides have potential in targeted treatment of small tumors. Thallium-201 (201Tl), 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 201Tl in vitro kinetics, radiotoxicity and potential for targeted molecular radionuclide therapy, and aim to test the hypothesis that 201Tl is radiotoxic only when internalized. Methods: Breast cancer MDA-MB-231 and prostate cancer DU145 cells were incubated with 200–8000 kBq/mL [201Tl]TlCl. Potassium concentration varied between 0 and 25 mM to modulate cellular uptake of 201Tl. Cell uptake and efflux rates of 201Tl were measured by gamma counting. Clonogenic assays were used to assess cell survival after 90 min incubation with 201Tl. Nuclear DNA damage was measured with γH2AX fluorescence imaging. Controls included untreated cells and cells treated with decayed [201Tl]TlCl. Results: 201Tl uptake in both cell lines reached equilibrium within 90 min and washed out exponentially (t1/2 15 min) after the radioactive medium was exchanged for fresh medium. Cellular uptake of 201Tl 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 201Tl activity in cells increased, whereas 201Tl 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 201Tl 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. 201Tl at these levels caused on average 3.5–4.6 times more DNA damage per nucleus than control treatments. Conclusions: 201Tl reduces clonogenic survival and increases nuclear DNA damage only when internalized. These findings justify further development and evaluation of 201Tl therapeutic radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

[ 177 Lu]Lu-PSMA is an effective class of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response may be partially explained by the presence of micrometastatic deposits, which are energy-sheltered and receive low absorbed radiation with 177 Lu due to the approximately 0.7-mm mean pathlength. 161 Tb has abundant emission of Auger and conversion electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161 Tb has shown in vitro and in vivo efficacy superior to that of 177 Lu. We aim to demonstrate that [ 161 Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 patients with mCRPC. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy (unless medically unsuitable) and androgen receptor pathway inhibitor; prostate-specific membrane antigen-positive disease on [ 68 Ga]Ga-PSMA-11 or [ 18 F]DCFPyL PET/CT (SUV max ≥ 20); no sites of discordance on [ 18 F]FDG PET/CT; adequate bone marrow, hepatic, and renal function; an Eastern Cooperative Oncology Group performance status of no more than 2, and no prior treatment with another radioisotope. The dose escalation is a 3 + 3 design to establish the safety of 3 prespecified activities of [ 161 Tb]Tb-PSMA-I&T (4.4, 5.5, and 7.4 GBq). The maximum tolerated dose will be defined as the highest activity level at which a dose-limiting toxicity occurs in fewer than 2 of 6 participants. The dose expansion will include 24 participants at the maximum tolerated dose. Up to 6 cycles of [ 161 Tb]Tb-PSMA-I&T will be administered intravenously every 6 wk, with each subsequent activity reduced by 0.4 GBq. The coprimary objectives are to establish the maximum tolerated dose and safety profile (Common Terminology Criteria for Adverse Events version 5.0) of [ 161 Tb]Tb-PSMA-I&T. Secondary objectives include measuring absorbed radiation dose (Gy), evaluating antitumor activity (prostate-specific antigen 50% response rate, radiographic and prostate-specific antigen progression-free survival, overall survival, objective response rate), and evaluating pain (Brief Pain Inventory-Short Form) and health-related quality of life (Functional Assessment of Cancer Therapy-Prostate and Functional Assessment of Cancer Therapy-Radionuclide Therapy). Conclusion: Enrollment was completed in February 2024. Patients are still receiving [ 161 Tb]Tb-PSMA-I&T., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract 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 (125I) are used in situ to construct active sites in a nanocatalyst (TiO2) and the application of this method is further extended to cancer catalytic internal radiotherapy (CIRT). The obtained 125I‐TiO2 nanoparticles first construct superficial Ti3+ active sites via the reaction between Ti4+ and AEs. Then Ti3+ stretches and weakens the OH bond of the absorbed H2O, thus enhancing the radiolysis of H2O 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.

This study reports the high-yield production of a novel 133/135La theranostic pair at a 22 MeV proton beam energy as an attractive alternative to the recently introduced 132/135La pair, demonstrating over an order of magnitude production increase of 133/135La (231 ± 8 MBq 133La and 166 ± 5 MBq 135La at End of Bombardment (EOB)) compared to 11.9 MeV production of 132/135La (0.82 ± 0.06 MBq 132La and 19.0 ± 1.2 MBq 135La) for 500 µA·min irradiations. A new sealed solid cyclotron target is introduced, which is fast to assemble, easy to handle, storable, and contains reusable components. Radiolabeling with macrocyclic chelators DOTA and macropa achieved full incorporation, with respective apparent 133La molar activites of 33 ± 5 GBq/µmol and 30 ± 4 GBq/µmol. PET centers with access to a 22 MeV capable cyclotron could produce clinically-relevant doses of 133/135La, via natBa irradiation, as a standalone theranostic agent for PET imaging and Auger electron therapy. With lower positron energies and less energetic and abundant gamma rays than 68Ga, 44Sc and 132La, 133La appears to be an attractive radiometal candidate for PET applications requiring a higher scanning resolution, a relatively long isotopic half-life, ease of handling, and a low patient dose. [ABSTRACT FROM AUTHOR]

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 (125I) are used in situ to construct active sites in a nanocatalyst (TiO2) and the application of this method is further extended to cancer catalytic internal radiotherapy (CIRT). The obtained 125I‐TiO2 nanoparticles first construct superficial Ti3+ active sites via the reaction between Ti4+ and AEs. Then Ti3+ stretches and weakens the OH bond of the absorbed H2O, thus enhancing the radiolysis of H2O 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. [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.

Theoretical aspects are presented for the spin polarization of electrons excited during the impact of spin-polarized He+ ions on a Ni (111) surface. The screening length effects due to the screened Coulomb (Yukawa) potential on spin polarization are explored within the framework of spin-dependent Auger neutralization process. First-order perturbation theory is used to calculate the Auger rates. The incident He+ ions and the metal electrons are spin-polarized so that we will analyze the spin of empty bound state of He+ ions by two possibilities. One is that the spin of empty bound state is parallel to the majority spin in the metal electrons, and the other is that the spin of empty bound state is parallel to the minority spin in the metal electrons. Results are discussed depending on the spin-dependent matrix elements and the neutralization probability of He+ ions with different contributions. [ABSTRACT FROM AUTHOR]

Tatiana A Slastnikova,1,* Andrey A Rosenkranz,1,2,* Natalia B Morozova,3 Maria S Vorontsova,3 Vasiliy M Petriev,4,5 Tatiana N Lupanova,1 Alexey V Ulasov,1 Michael R Zalutsky,6 Raisa I Yakubovskaya,3 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 2Department of Biophysics, Biological Faculty, Lomonosov Moscow State University, 3Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow, 4National Medical Research Radiological Center, Russian Ministry of Health Care, Obninsk, Moscow Region, 5Department of Nuclear Medicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Moscow, Russia; 6Department of Radiology, Duke University Medical Center, Durham, NC, USA *These authors contributed equally to this work Purpose: Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111In for cancer therapy.Methods: Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111In in high specific activity. Cytotoxicity of the 111In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111In-labeled MNT in B16-F1 melanoma tumor-bearing mice.Results: The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111In by serial imaging and significant tumor growth delay (82% growth inhibition) were found.Conclusion: The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111In-NOTA–MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111In-NOTA–MNT suggests further applications of the MNT delivery strategy should be explored. Keywords: nuclear delivery, cancer, melanoma, radionuclide therapy, Auger electrons

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [ 177 Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [ 177 Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [ 177 Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [ 177 Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [ 177 Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [ 177 Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [ 177 Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177 Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Graphical abstract AuNCs-HA exhibited PA imaging guided combined radiotherapy, PDT and PTT trimodalites, leading to effectively synergistic anticancer efficacy. Abstract In this work, we developed a novel multifunctional nanoplatform based on hyaluronic acid modified Au nanocages (AuNCs-HA). The rational design of AuNCs-HA renders the nanoplatform three functionalities: (1) AuNCs-HA with excellent LSPR peak in the NIR region act as contrast agent for enhanced photoacoustic (PA) imaging and photothermal therapy (PTT); (2) the nanoplatform with high-energy rays (X-ray) absorption and auger electrons generation acts as a radiosensitizer for radiotherapy; (3) good photocatalytic property and large surface area make AuNCs-HA a photosensitive agent for photodynamic therapy (PDT). In vivo results demonstrated that AuNCs-HA presented excellent PA imaging performance after intravenous injection, which provided contour, size, and location information of the tumor. Moreover, because AuNCs-HA could combine radiotherapy and phototherapy together, the tumors treated with AuNCs-HA showed complete growth inhibition, comparing to that with each therapy alone. Taken together, our present study demonstrates that AuNCs-HA is of great potential as a multifunctional nanoplatform for PA imaging-guided radio- and photo-therapy of tumor. Statement of Significance In this study, a commendable theranostic nanoplatform based on hyaluronic acid modified AuNCs (AuNCs-HA) was developed. In our approach, the dilute solution of Gold(III) chloride is slowly dripped into Ag nanocubes solution, then the Au nanocages were obtained by redox reaction, and followed by HA modification. We explored them, simultaneously, as radiosensitizers for RT, photosensitizers for PDT, and therapeutic agents for PTT. Compared to that of each therapies alone, the combination of radio-therapy and photo-therapy results in a considerably improved tumor eliminating effect and efficiently inhibited tumor growth. In addition, AuNCs-HA exhibited remarkably strong PA signals for precise identification of the location, size, and boundary of the tumor, thereby facilitating imaging-guided therapy. In brief, our design of AuNCs-HA represents a general and versatile strategy for building up cancer-targeted nanotheranostics with desired synergistic imaging and therapy functionalities. [ABSTRACT FROM AUTHOR]

Radioimmunotherapy (RIT) with anti-CD123 monoclonal antibody CSL360 modified with nuclear translocation sequence (NLS) peptides and labeled with the Auger electron-emitter, 111In (111In-NLS-CSL360) was studied in the prevalent NOD/SCID mouse AML engraftment assay. Significant decreases in CD123+ leukemic cells and impairment of leukemic stem cell self-renewal were achieved with high doses of RIT. However, NOD/SCID mice were very radiosensitive to these doses. At low non-toxic treatment doses, 111In-NLS-CSL360 demonstrated a trend towards improved survival associated with decreased spleen/body weight ratio, an indicator of leukemia burden, and almost complete eradication of leukemia from the bone marrow in some mice.

A comprehensive investigation of the emission characteristics for electrons induced by X-rays of a few hundred eV at grazing-incidence angles on an atomically clean Cu(111) sample during laser excitation is presented. Electron energy spectra due to intense infrared laser irradiation are investigated at the BESSY II slicing facility. Furthermore, the influence of the corresponding high degree of target excitation (high peak current of photoemission) on the properties of Auger and photoelectrons liberated by a probe X-ray beam is investigated in time-resolved pump and probe measurements. Strong electron energy shifts have been found and assigned to space-charge acceleration. The variation of the shift with laser power and electron energy is investigated and discussed on the basis of experimental as well as new theoretical results. [ABSTRACT FROM AUTHOR]

It is evident that 99mTc causes radical-mediated DNA damage due to Auger electrons, which were emitted simultaneously with the known γ-emission of 99mTc. We have synthesized a series of new 99mTc-labeled pyrene derivatives with varied distances between the pyrene moiety and the radionuclide. The pyrene motif is a common DNA intercalator and allowed us to test the influence of the radionuclide distance on damages of the DNA helix. In general, pUC 19 plasmid DNA enables the investigation of the unprotected interactions between the radiotracers and DNA that results in single-strand breaks (SSB) or double-strand breaks (DSB). The resulting DNA fragments were separated by gel electrophoresis and quantified by fluorescent staining. Direct DNA damage and radical-induced indirect DNA damage by radiolysis products of water were evaluated in the presence or absence of the radical scavenger DMSO. We demonstrated that Auger electrons directly induced both SSB and DSB in high efficiency when 99mTc was tightly bound to the plasmid DNA and this damage could not be completely prevented by DMSO, a free radical scavenger. For the first time, we were able to minimize this effect by increasing the carbon chain lengths between the pyrene moiety and the 99mTc nuclide. However, a critical distance between the 99mTc atom and the DNA helix could not be determined due to the significantly lowered DSB generation resulting from the interaction which is dependent on the type of the 99mTc binding motif. The effect of variable DNA damage caused by the different chain length between the pyrene residue and the Tc-core as well as the possible conformations of the applied Tc-complexes was supplemented with molecular dynamics (MD) calculations. The effectiveness of the DNA-binding 99mTc-labeled pyrene derivatives was demonstrated by comparison to non-DNA-binding 99mTcO4–, since nearly all DNA damage caused by 99mTcO4– was prevented by incubating with DMSO. [ABSTRACT FROM AUTHOR]

X-ray photoelectron spectroscopy (XPS) was used to analyze rinsed and not rinsed LiNi0.8Co0.2O2-based high power lithium-ion battery cathodes following calendar-life testing at 60 °C, 60% state-of-charge. XP spectra were obtained using incident monochromatic Al Kα radiation at 0.83401 nm. A survey spectrum together with F 1s, O 1s, C 1s, P 2p and Li 1s are presented. The spectra indicate the principal core level photoelectron and Auger electron signals. [ABSTRACT FROM AUTHOR]

X-ray photoelectron spectroscopy (XPS) was used to analyze rinsed and not rinsed LiNi0.8Co0.2O2-based high power lithium-ion battery cathodes following calendar-life testing at 70 °C, 60% state-of-charge. XP spectra were obtained using incident monochromatic Al Kα radiation at 0.83401 nm. A survey spectrum together with F 1s, O 1s, C 1s, P 2p, and Li 1s are presented. The spectra indicate the principal core level photoelectron and Auger electron signals. [ABSTRACT FROM AUTHOR]

X-ray photoelectron spectroscopy (XPS) was used to analyze rinsed and not rinsed LiNi0.8Co0.2O2-based high power lithium-ion battery cathodes following calendar-life testing at 50 °C, 60% state-of-charge. XP spectra were obtained using incident monochromatic Al Kα radiation at 0.83401 nm. A survey spectrum together with F 1s, O 1s, C 1s, P 2p and Li 1s are presented. The spectra indicate the principal core level photoelectron and Auger electron signals. [ABSTRACT FROM AUTHOR]

X-ray photoelectron spectroscopy (XPS) was used to analyze rinsed and not rinsed LiNi0.8Co0.2O2-based high power lithium-ion battery cathodes following calendar-life testing at 40 °C, 60% state-of-charge. XP spectra were obtained using incident monochromatic Al Kα radiation at 0.83401 nm. A survey spectrum together with F 1s, O 1s, C 1s, P 2p, and Li 1s are presented. The spectra indicate the principal core level photoelectron and Auger electron signals. Both cathodes show only minor nitrogen contamination. [ABSTRACT FROM AUTHOR]

The photoresponse of Cd-doped CuInSe2 (CIS) epitaxial thin films on GaAs(100) was studied using x-ray photoelectron spectroscopy under illumination from a 532 nm laser between sample temperatures of 28-260 °C. The initial, air-exposed surface shows little to no photoresponse in the photoelectron binding energies, the Auger electron kinetic energies or peak shapes. Heating between 50 and 130 °C in the analysis chamber results in enhanced n-type doping at the surface and an increased light-induced binding energy shift, the magnitude of which persists when the samples are cooled to room temperature from 130 °C but which disappears when cooling from 260 °C. Extra negative charge trapped on the Cu and Se atoms indicates deep trap states that dissociate after cooling from 260 °C. Analysis of the Cd modified Auger parameter under illumination gives experimental verification of electron charging on Cd atoms thought to be shallow donors in CIS. The electron charging under illumination disappears at 130 °C but occurs again when the sample is cooled to room temperature. [ABSTRACT FROM AUTHOR]

The dependence of the intensity of X-ray fluorescence on the energy of photons exciting X-ray radiation is considered. For elements with small atomic numbers, the direct ionization of atoms, the major process for the majority of elements of the Periodic Table, is the main only at low energies of primary photons. With the growth of photon energy, the intensity of fluorescence due to photo and Auger electrons arising in the irradiated material increases. This component at certain energy becomes predominant. The further increase in the energy of primary photons leads to the suppression of the ionization of atoms by recoil electron arising in the incoherent (Compton) scattering of primary radiation. The effects of the energy of primary photons on the intensity of X-ray fluorescence for the studied processes differ significantly. The depth of these effects determines their contributions to the formation of the analytical signal. Study of the influence of excitation conditions allows the analyst to intelligently solve problems of the optimization of the X-ray fluorescence determination of elements with small atomic numbers. [ABSTRACT FROM AUTHOR]

A unique analytical method is proposed for local structure analysis via extended X-ray absorption fine structure (EXAFS) spectroscopy. The measurement of electron energy distribution curves at various excitation photon energies using an electron energy analyzer is applied to determine a specific elemental Auger spectrum. To demonstrate the method, the N K-edge EXAFS spectra for a silicon nitride film were obtained via simultaneous measurement of the N KLL Auger and background spectra using dual-energy windows. The background spectrum was then used to remove the photoelectrons and secondary electron mixing in the energy distribution curves. The spectrum obtained following this subtraction procedure represents the `true' N K-edge EXAFS spectrum without the other absorptions that are observed in total electron yield N K-edge EXAFS spectra. The first nearest-neighbor distance (N-Si) derived from the extracted N K-edge EXAFS oscillation was in good agreement with the value derived from Si K-edge analysis. This result confirmed that the present method, referred to as differential electron yield (DEY)-EXAFS, is valid for deriving local surface structure information for low- Z elements. [ABSTRACT FROM AUTHOR]

Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed. [ABSTRACT FROM AUTHOR]

The sintered wire cathode offers a significant improvement in density and uniformity of emission. In the present technique of active sintering, an activator is introduced, which relaxes the sintering temperature of tungsten (W)-wire bunch significantly. The technique also offers well-opened columnar pores with a uniform distribution all across the cross section. The pellets are made out of the sintered bunch of W-wires, each of diameter 50~\mu \textm . The pellets are impregnated using triple carbonates and are integrated with potted heaters. The cathode assemblies are tested in an analytical system containing an anode and an Auger electron spectroscopy facility. The pulse emission measurements revealed that the emission density of these cathodes is higher than twice that of a conventional B-type cathode. This high emission is attributed to a relatively high Ba/W and O/W ratios on the surface as compared with those of a B-type cathode. The Miram curves, generated out of pulse emission data, exhibit sharp temperature-limited fully space charge-limited transition, indicating lower patchiness of emission as compared with that of a B-type. The theoretical studies are carried out to estimate the optimum wire gauge that can produce good coverage and recovery to the ion bombardment. [ABSTRACT FROM AUTHOR]

The electronic structure of a Ti3+ aqueous solution is studied by liquid-jet soft X-ray photoelectron (PE) spectroscopy. Measured valence and Ti 2p core-level binding energies, together with the Ti 2p resonant photoelectron (RPE) spectra and the derived partial electron-yield L-edge X-ray absorption (PEY-XA) spectra, reveal mixing between metal 3d and water orbitals. Specifically, ligand states with metal character are identified through the enhancement of signal intensities in the RPE spectra. An observed satellite 3d peak structure is assigned to several different metal-ligand states. Experimental energies and the delocalized nature of the respective orbitals are supported by ground-state electronic structure calculations. We also show that by choice of the detected Auger-electron-decay channel, from which different PEY-XA spectra are obtained, the experimental sensitivity to the interactions of the metal 3d electrons with the solvent can be varied. The effect of such a state-dependent electronic relaxation on the shape of the PEY-XA spectra is discussed in terms of different degrees of electron delocalization. [ABSTRACT FROM AUTHOR]

We succeed to integrate BaO as a tunneling barrier into Co2FeAl based magnetic tunnel junctions (MTJs). By means of Auger electron spectroscopy it could be proven that the applied annealing temperatures during BaO deposition and afterwards do not cause any diffusion of Ba neither into the lower Heusler compound lead nor into the upper Fe counter electrode. Nevertheless, a negative tunnel magnetoresistance (TMR) ratio of -10% is found for Co2FeAl (24 nm)/BaO (5 nm)/Fe (7 nm) MTJs, which can be attributed to the preparation procedure and can be explained by the formation of Co- and Fe-oxides at the interfaces between the Heusler and the crystalline BaO barrier by comparing with theory. Although an amorphous structure of the BaO barrier seems to be confirmed by high-resolution transmission electron microscopy (TEM), it cannot entirely be ruled out that this is an artifact of TEM sample preparation due to the sensitivity of BaO to moisture. By replacing the BaO tunneling barrier with an MgO/BaO double layer barrier, the electric stability could effectively be increased by a factor of five. The resulting TMR effect is found to be about +20% at room temperature, although a fully antiparallel state has not been realized. [ABSTRACT FROM AUTHOR]

Surface-sensitive analysis via extended X-ray absorption fine-structure (EXAFS) spectroscopy is demonstrated using a thickness-defined SiO2 (12.4 nm)/Si sample. The proposed method exploits the differential electron yield (DEY) method wherein Auger electrons escaping from a sample surface are detected by an electron analyzer. The DEY method removes local intensity changes in the EXAFS spectra caused by photoelectrons crossing the Auger peak during X-ray energy sweeps, enabling EXAFS analysis through Fourier transformation of wide-energy-range spectral oscillations. The Si K-edge DEY X-ray absorption near-edge structure (XANES) spectrum appears to comprise high amounts of SiO2 and low Si content, suggesting an analysis depth, as expressed using the inelastic mean free path of electrons in general electron spectroscopy, of approximately 4.2 nm. The first nearest neighbor (Si-O) distance derived from the Fourier transform of the Si K-edge DEY-EXAFS oscillation is 1.63 Å. This value is within the reported values of bulk SiO2, showing that DEY can be used to detect a surface layer of 12.4 nm thickness with an analysis depth of approximately 4.2 nm and enable `surface EXAFS' analysis using Fourier transformation. [ABSTRACT FROM AUTHOR]