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Radionuclide therapy employing alpha emitters holds great potential for personalized cancer treatment. However, certain challenges remain when designing alpha radiopharmaceuticals, including the lack of stability of used radioconjugates due to nuclear decay events. In this work, ultrasmall silver telluride nanoparticles with a core diameter of 2.1 nm were prepared and radiolabeled with lead‐212 using a chelator‐free method with a radiolabeling efficiency of 75%. The results from the in vitro radiochemical stability assay indicated a very high retention of bismuth‐212 despite the internal conversion effects originating from the decay of 212Pb. To further evaluate the potential of the nanoparticles, they were radiolabeled with indium‐111, and their cell uptake and subcellular distribution were determined in 2D U87 cells, showing accumulation in the nucleus. Although not intentional, it was observed that the indium‐111‐radiolabeled nanoparticles induced efficient tumor cell killing, which was attributed to the Auger electrons emitted by indium‐111. Combining the results obtained in this work with other favorable properties such as fast renal clearance and the possibility to attach targeting vectors on the surface of the nanoparticles, all well‐known from the literature, these ultra‐small silver telluride nanoparticles provide exciting opportunities for the design of theragnostic radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

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.

Ion-induced secondary electron emission of surfaces occurs in all gas discharges which have contact to surfaces such as electrodes or chamber walls. These secondary electrons (SEs) play an important role, for instance, in the performance of DC discharges, RF discharges and magnetron sputtering discharges. SE generation can be separated into potential electron emission (PEE) due to the neutralization of the incident ion upon impact and kinetic electron emission (KEE) due to the electronic stopping of the penetrating ion in the solid. SE due to neutralization is usually described by Auger processes and the density of states of the electrons in the solid, whereas KEE scales with the electronic stopping of the ion in the solid, as being calculated by ion collision simulations. The measurement of the energy distribution of the SEs of three metals (Al, Ti, Cu) and their oxides reveals the occurrence of Auger peaks, which are not reflected by standard models such as the Hagstrum model. Instead, in this paper, a model is proposed describing these Auger peaks by Auger neutralization of holes created by the collision cascade of the incident ion. This shows decent agreement. The contribution of Auger peaks in the metals Al and Ti is very significant, whereas it is negligible in the case of Cu. The implication of these energy distributions to the performance of magnetron sputtering discharges is discussed. [ABSTRACT FROM AUTHOR]

Non-targeted effects, including bystander and systemic effects, play a crucial role during Auger targeted radionuclide therapy. Here, we investigated whether small extracellular vesicles (sEVs) produced by irradiated cells could contribute to the bystander cytotoxic effects in vitro and also to therapeutic efficacy in vivo, after their injection in tumor xenografts. B16F10 melanoma donor cells were exposed to radiolabeled antibodies (Auger radioimmunotherapy, RIT) for 48 h or to X-rays (donor cells). Then, donor cells were incubated with fresh medium for 2 h to prepare conditioned medium (CM) that was transferred onto recipient cells for bystander effect assessment, or used for sEVs enrichment. Resulting sEVs were incubated in vitro with recipient cells for determining bystander cytotoxicity, or injected in B16F10 melanoma tumors harbored by athymic and C57BL/6 mice. In vitro analysis of bystander cytotoxic effects showed that CM killed about 30–40% of melanoma cells. SEVs isolated from CM contributed to this effect. Moreover, the double-stranded DNA (dsDNA) content was increased in sEVs isolated from CM of exposed cells compared to control (not exposed), but the difference was significant only for the X-ray condition. These results were supported by immunodetection of cytosolic dsDNA in donor cells, a phenomenon that should precede dsDNA enrichment in sEVs. However, sEVs cytotoxicity could not be detected in vivo. Indeed, in athymic and in immunocompetent mice that received four intratumoral injections of sEVs (1/day), tumor growth was not delayed compared with untreated controls. Tumor growth was slightly (not significantly) delayed in immunocompetent mice treated with sEVs from X-ray-exposed cells, and significantly with sEVs purified from CM collected after 48 h of incubation. These results highlight the need to determine the optimal conditions, including radiation absorbed dose and sEVs collection time, to obtain the strongest cytotoxic effects. This study demonstrates that sEVs could play a role during Auger RIT through bystander effects in vitro. No systemic effects were observed in vivo, under our experimental conditions. However, X-rays experiments showed that sEVs collection time might be influencing the nature of sEVs, a parameter that should also be investigated during Auger RIT. [ABSTRACT FROM AUTHOR]

To examine the reliability to model cellular S-values for the Auger electron (AE) emitters, 111In, 197Hg and 197mHg with MCNP6 and their relative dose deposition in subcellular targets. A model cell was defined as four concentric spheres consisting of the nucleus (N), cytoplasm (Cy), cell and nuclear membranes (CM, NM) in which radionuclides distributed homogeneously. The transport of AE, conversion electrons and photons were simulated by MCNP6 to calculate cellular S values (SN←CM, SN←Cy, SN←NM, SN←N, SCM←CM, SNM←NM). SN←CM, SN←Cy and SN←N were also calculated with MIRDcell. MIRDcell and MCNP6-calculated SN←N were in excellent agreement, but a slight discrepancy on SN←Cy and SN←CM was observed. The ratios of SCM←CM or SNM←NM vs. SN←N were 9.7–51.0 or 10.5–37.4, 7.9–41.8 or 8.4–31.8 and 7.2–36.9 or 8.0–28.1 for 111In, 197Hg, 197mHg, respectively. The mean S(197Hg)/S(111In) and S(197mHg)/S(111In) were 2.5 ± 0.5 and 2.5 ± 0.6, respectively. Cellular S-values were reliably calculated with MCNP6. 197Hg and 197mHg deposit two-fold more doses than 111In at the subcellular scale. All AE emitters deposit a higher self-dose in the CM and NM than in the N, which warrants studies on the effects of targeting the CM and NM by AE emitters. [ABSTRACT FROM AUTHOR]

Auger electrons can be highly radiotoxic when they are used to irradiate specific molecular sites. This has spurred basic science investigations of their radiobiological effects and clinical investigations of their potential for therapy. Focused symposia on the biophysical aspects of Auger processes have been held quadrennially. This 9th International Symposium on Physical, Molecular, Cellular, and Medical Aspects of Auger Processes at Oxford University brought together scientists from many different fields to review past findings, discuss the latest studies, and plot the future work to be done. This review article examines the research in this field that was published during the years 2015–2019 which corresponds to the period since the last meeting in Japan. In addition, this article points to future work yet to be done. There have been a plethora of advancements in our understanding of Auger processes. These advancements range from basic atomic and molecular physics to new ways to implement Auger electron emitters in radiopharmaceutical therapy. The highly localized doses of radiation that are deposited within a 10 nm of the decay site make them precision tools for discovery across the physical, chemical, biological, and medical sciences. [ABSTRACT FROM AUTHOR]

Thallium-201 is an Auger electron-emitting radionuclide with significant potential for targeted molecular radiotherapy of cancer. It stands out among other Auger electron emitters by releasing approximately 37 Auger and Coster-Kronig electrons per decay, which is one of the highest numbers in its category. It has also a convenient half-life of 73 h, a stable daughter product, established production methods, and demonstrated high in vitro radiotoxicity. However, its full potential in targeted radiotherapy remains unexplored, primarily due to the lack of available efficient chelators for [ 201 Tl]Tl + or [ 201 Tl]Tl 3+ . This study aims to assess texaphyrin for macrocycle chelation of [ 201 Tl]Tl 3+ . Texaphyrins are known for effective binding of trivalent metals with similar ionic radii, such as indium and gadolinium. Optimization of [ 201 Tl]Tl + to [ 201 Tl]Tl 3+ oxidation and subsequent chelation with texaphyrin-lipid conjugate were assessed using thin-layer chromatography. The formation and stability of nonradioactive Tl-texaphyrin-lipid complexes were confirmed by UV-Vis spectroscopy and ultrahigh performance liquid chromatography-mass spectrometry. [ 201 Tl]Tl/Tl-texaphyrin-lipid nanoparticles (nanotexaphyrins) were assembled by using a microfluidic system, and their morphology and stability were evaluated by using dynamic light scattering and transmission electron microscopy. The uptake of these nanotexaphyrins in lung cancer and ovarian cancer cells was evaluated using both radioactive and nonradioactive methods. The conversion of [ 201 Tl]Tl + to [ 201 Tl]Tl 3+ in 0.25 M HCl achieved an average yield of 91.8 ± 3.1%, while the highest radiolabeling yield of the texaphyrin-lipid with [ 201 Tl]Tl 3+ was 25.5 ± 4.5%. Tl-texaphyrin-lipid conjugates were stable at room temperature for at least 72 h. These conjugates were successfully assembled into homogeneous nanotexaphyrins with an average hydrodynamic diameter of 147.4 ± 1.4 nm. Throughout a 72 h period, no changes in size or polydispersity of the synthesized nanoparticles were observed. [ 201 Tl]Tl-nanotexaphyrins were synthesized with an average radiochemical purity of 77.4 ± 10.3% and a yield of 5.1 ± 4.4%. The release of [ 201 Tl]Tl + from [ 201 Tl]Tl-nanotexaphyrins in phosphate-buffered saline exhibited a time- and temperature-dependent pattern, with a faster release observed at 37 °C than at room temperature. Additionally, the uptake of Tl-nanotexaphyrins and [ 201 Tl]Tl-nanotexaphyrins in cancer cells was similar to that of unbound Tl + and [ 201 Tl]Tl + . This is the first time that texaphyrins have been investigated as chelators for radiothallium. Although [ 201 Tl]Tl-nanotexaphyrins were found to be thermodynamically and kinetically unstable, we successfully synthesized stable texaphyrin-lipid complexes with nat Tl 3+ . This opens up opportunities for further refinements in the nanotexaphyrin-lipid structure to enhance [ 201 Tl]Tl 3+ stability and prevent its reduction to a 1+ oxidation state. Future research should consider further modifications to the texaphyrin structure or using texaphyrins without the lipid component.

In Auger electron spectroscopy (AES), the spectral background is mainly due to inelastic scattering of Auger electrons that lose their kinetic energy in a sample bulk. To investigate the spectral components within this background for SiO2(19.3 nm)/Si(100) with known layer thickness, X-ray absorption spectroscopy (XAS) was used in the partial-electron-yield (PEY) mode at several electron kinetic energies to probe the background of the Si KLL Auger peak. The Si K-edge PEY-XAS spectra constituted of both Si and SiO2 components at each kinetic energy, and their component fractions were approximately the same as those derived from the simulated AES background for the same sample structure. The contributions of Auger electrons originating from layers at different depths to the inelastic background could thus be identified experimentally. [ABSTRACT FROM AUTHOR]

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.

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

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]

The possibility of applying magnetite nanoparticles for the purpose of improving the efficiency of cancer-tumor suppression during X-ray brachytherapy treatment is considered. The proposed role of the nanoparticles is to enhance the dose of ionizing radiation, absorbed by the tumor, into which the injection of solution containing such particles is carried out. These particles possess several properties that make them useful for the targeted delivery of radiation to tumors. Magnetite nanoparticles are biodegradable and magnetic and can emit secondary radiation when irradiated with an external source. In this work, the dose distribution around a magnetite particle 10 nm in diameter, immersed into water and irradiated by monochromatic X-rays with energies in the range from 4 to 60 keV is calculated. In this case, water can be considered as a good enough equivalent of biological tissue for model computations. Using Monte Carlo computations with the Geant4 program package, it is shown that under such conditions, an increase in the dose absorbed by water on account of the generation of X-ray fluorescence radiation really takes place; however the spatial region, where such enhancement is rather high, is quite small. To apply the method effectively, one would need to deliver such nanoparticles directly into the cell nucleus. [ABSTRACT FROM AUTHOR]

Purpose: The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods: The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results: In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs. [ABSTRACT FROM AUTHOR]

Many in the microelectronics field view tunneling field-effect transistors (TFETs) as society's best hope for achieving a >10× power reduction for electronic devices; however, despite a decade of considerable worldwide research, experimental TFET results have significantly underperformed simulations and conventional MOSFETs. To explain the discrepancy between TFET experiments and simulations, we investigate the parasitic leakage current due to Auger generation, an intrinsic mechanism that cannot be mitigated with improved material quality or better device processing. We expose the intrinsic link between the Auger and band-to-band tunneling rates, highlighting the difficulty of increasing one without the other. From this link, we show that Auger generation imposes a fundamental limit on ultimate TFET performance. [ABSTRACT FROM AUTHOR]

An Auger-electron-photoion coincidence (AEPICO) method has been applied to study the stability and dissociation dynamics of dicationic states after the N K-shell photoionization of nitrogen molecules. From time-of-flight and kinetic energy analyses of the product ions, we have obtained coincident Auger spectra associated with metastable states of N2++ ions and dissociative states leading to N2++ → N+ + N+ and N++ + N. To investigate the production of dissociative states, we present two-dimensional AEPICO maps which reveal the correlations between the binding energies of the Auger final states and the ion kinetic energy release. These correlations have been used to determine the dissociation limits of individual Auger final states. [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.

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

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]

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 [201Tl]Tl(I) to chelatable [201Tl]Tl(III) and identify challenges in stable chelation of thallium to support future synthesis of effective [201Tl]-labelled radiopharmaceuticals. A plasmid pBR322 assay was carried out to determine the DNA damaging properties of [201Tl]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 [201Tl]Tl(III) radiolabelling efficacy and complex stability. Isolated plasmid studies demonstrated that [201Tl]Tl(III) can induce single and double-stranded DNA breaks. Iodo-beads, iodogen and trichloroisocyanuric acid enabled more than 95% conversion from [201Tl]Tl(I) to [201Tl]Tl(III) under conditions compatible with future biomolecule radiolabelling (mild pH, room temperature and post-oxidation removal of oxidising agent). Although chelation of [201Tl]Tl(III) was possible with EDTA, DTPA and DOTA, only radiolabeled DOTA showed good stability in serum. Decay of [201Tl]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 [201Tl]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 [201Tl]Tl(III) complexes is required. [Display omitted] [ABSTRACT FROM AUTHOR]

Photoemission yield (the number of emitted electrons per incoming photon) is one of the fundamental properties of solid materials but is not yet well constrained for the lunar surface for photon energies >∼20 eV. In this study, we constrain this yield for incident photons with energies of ∼10–500 eV with data from the Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun (ARTEMIS) mission along with solar irradiance spectra from Version 2 of the Flare Irradiance Spectral Model. We also report the first oxygen Auger electron observations at the Moon by the ARTEMIS spacecraft, which provides a unique feature to identify photoelectrons emitted from the lunar surface. With lunar photoelectron observations identified in both Earth's magnetotail lobes and the solar wind for four selected days, we infer a lower bound of 10−3 in yield for photon energies >∼20 eV. However, our investigation also reveals an uncertainty over ∼4 orders of magnitude in derived yields with a sensitivity study, owing to a poorly constrained photoelectron energy probability function. This uncertainty motivates future experiments on lunar samples to better characterize the lunar surface charging environment. Plain Language Summary: The photoemission yield (the number of emitted electrons per incoming photon) is one of the fundamental properties of solid materials, but not yet well constrained for the lunar surface for photon energies >∼20 eV (electron volts). A better understanding of lunar surface photoemission yield is also important for characterizing the lunar electrostatic charging environment, as lunar photoelectrons contribute to one of the dominant currents at/near the lunar surface. This study utilizes measurements from the Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun mission and also full solar irradiance spectra from a model to determine this yield. While we can infer a lower bound in yield for photon energies >∼20 eV, we find an uncertainty over ∼4 orders of magnitude in derived yields, which motivates future experiments on lunar samples to better characterize the yield function. Key Points: We make the first report of oxygen Auger electron observations at the Moon by the Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun spacecraftWe infer a lower bound of 10−3 in photoemission yield of the lunar surface for photon energies >∼20 eVUncertainties over four orders of magnitude in yields are found, motivating future experiments on lunar samples for a better understanding [ABSTRACT FROM AUTHOR]

Phosphorus (P) is an n-type dopant for conductive silicon nanocrystals (Si-nc's), the electrical activation of which may be monitored through a non-radiative Auger recombination process that quenches the Si-nc luminescence. We investigated this quenching mechanism through electrical measurements of Si-nc's. Infrared-excited Auger electron emission as the non-radiative process was directly probed and the dynamics of the process are determined from a frequency response analysis. To explain the dynamics, we propose a model in which Auger electrons with a low kinetic energy establish a local inter-nanocrystal conductance and the repetition of this local conductance results in a constant photocurrent ("linkage emission"). This emission becomes significant by electron filling in the Si-nc's owing to the electrical activation of P, which is consistent with observed luminescence quenching behavior. We found that the IR photo-excited emission is distinct from the thermally induced hopping conduction and show that confined, rather than trapped, charges are the source of the Auger electrons. Thus, the process consumes both confined charges and the recombination energy for Auger emission, which explains the luminescence quenching mechanism of Si-nc:P. [ABSTRACT FROM AUTHOR]

Treatment of glioblastomas (GBM) using the Auger electron emitting compound [125I]5-Iodo-2′-deoxyuridine ([125I]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. A patient-derived GBM cancer stem cell (CSC)-enriched cell line, grown as neurospheres, was employed to evaluate DNA-incorporation of [125I]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 [125I]I-UdR were also investigated by a CellTiter-Blue assay. The highest general increase in [125I]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 [125I]I-UdR compared to [125I]I-UdR alone at all activity concentrations tested. MTX was redundant when combined with 400 and 500 Bq/ml [125I]I-UdR. TMZ was effective in combination with either [125I]I-UdR alone or with both thymidylate synthase inhibitors combined with 50–100 Bq/ml [125I]I-UdR. Overall, our study revealed a higher incorporation and therapeutic effect of [125I]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 [125I]I-UdR in combination with the thymidylate synthase inhibitors. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

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 z0 (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. z0 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, z0 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. [ABSTRACT FROM AUTHOR]

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 165Er and 155Tb for Auger Therapy and SPECT imaging, respectively. [Display omitted] [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.

Interatomic Coulombic decay (ICD) is an efficient and ultrafast radiationless decay mechanism which can be initiated by removal of an electron from the inner-valence shell of an atom or molecule. Generally, the ICD mechanism is prevailed in weakly bound clusters. A very promising approach, known as CAP/EOM-CC, consists of the combination of complex absorbing potential (CAP) with the equation-of-motion coupled-cluster (EOM-CC) method, is applied for the first time to study the nature of the ICD mechanism. We have applied this technique to determine the lifetime of an auto-ionized, inner-valence excited state of the NeH2O, Ne(H2O)2, and Ne(H2O)3 systems. The lifetime is found to be very short and decreases significantly with the number of neighboring water molecules. [ABSTRACT FROM AUTHOR]

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]

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 (125I and 111In) and β− particle emitters (177Lu, 131I and 90Y), 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 177Lu, 131I and 90Y 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, 125I delivered a greater absorbed dose per decay than 111In 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 177Lu (2.41·10−2 µGy·Bq−1·s−1) and 131I (2.46·10−2 µGy·Bq−1·s−1) are higher than for 90Y (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 177Lu and 131I compared to 90Y, 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, 177Lu and 131I delivered absorbed doses higher than 90Y. In view of real irradiation of MALCs, such a work may be useful to select suited radionuclides and to help explain the biological effects. [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.