Radionuclide Production Research Articles

Optimization Processes of Clinical Chelation-Based Radiopharmaceuticals for Pathway-Directed Targeted Radionuclide Therapy in Oncology.

Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, 68Ga and 99mTc are the current standards for diagnostic radionuclides, while 177Lu and 225Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to 225Ac daughters 221Fr and 213Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose-response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses.

EXAMINATION OF THE DYNAMICS OF ANALYZES PERFORMED FOR THE PRESENCE OF RADIONUCLEIDE RESIDUES IN FOOD IN THE PERIOD 2019-2023 IN THE REPUBLIC OF NORTH MACEDONIA

The main focus of this research is to determine the extent of analyzes performed for the presence of radionuclides in food, their dynamics, which radionuclides are present in food, and how much their radioactivity was in the period 2019-2023. The research covers the period from January 01, 2019. until December 31, 2023. The data we used to conduct this research were obtained from the Public Health Institute of R. N. Macedonia. The tests were carried out with accredited methods and by the Regulation on the maximum allowed amounts of radionuclides in food, water, air, land, products, and raw materials of animal and plant origin and objects for general use. Relative numbers and trends are used as statistical methods of work. According to the results, in the period 2019-2023, radionuclides were analyzed in 6065 samples (2711 samples from imports, and 3354 samples from domestic production). The largest amount of radioactivity analyzes were performed in the group of mushrooms (51%) and the group of grain and flour (44%). The scope of analyzes performed for the presence of radionuclide residues in food in R.N. Macedonia shows a downward trend. In the analyzed products, no radioactivity above the limit values was detected (except in 2020 when only in 1 product from the mushroom group - dry morel) detected a value for Cs-137 = 662.8 Bq/kg, and the maximum allowed value is 600 Bq/kg ). It can be concluded from the study that food is safe in terms of the presence of radionuclide residues, but work should be done to increase the volume of analyzes performed for the presence of radionuclides in food, as well as to increase the coverage of different groups of products (fruit, vegetables, coffee, tea, etc.) in which such analyzes would be performed.

Radionuclide characterization and handling strategy of irradiated Fission Product Material (FPM) capsule waste from molybdenum-99 production

Abstract Irradiated FPM Capsule waste is one of the types of radioactive waste generated from Molybdenum-99 (99Mo) production. This 99Mo is a 99mTc parent radionuclide that is used for the diagnosis of human organ disorders. In its production, the capsule is used for the emplacement of uranium target for irradiation in the GA Siwabessy Reactor. Since the beginning of production until now, the irradiated FPM capsules waste are still being stored in the hot cells because no data on their characteristics and handling systems that are necessary for their treatment. However, long-term storage of the FPM capsules waste in the hot cells shall be avoided because it can disrupt the production process of 99Mo and pose radiation risk to workers. The objectives of this research are to characterize radionuclides composition in the FPM capsule waste and identify its appropriate handling system. The radionuclides characterization was carried out using ORIGEN 2.1 software whereas the selection of the handling system was based on the suitability or modification of the available facilities at Radioactive Waste Management Installation (RWMI)-BRIN. The characterization results show that up to a decay time of 50 years, an FPM capsule waste contains activation product radionuclides such as 55Fe, 59Ni, and 63Ni with a total specific activity of 7.11x106 Bq/g. Three FPM capsule waste handling systems were identified that can be implemented at the RWMI facility, namely by using a 350 -liter concrete shell and then storing in an interim storage for low and intermediate-level waste, using a 60-liter stainless-steel canister which is then stored in the interim storage pit for high-level waste, or by modifying the interim storage pit for high-level waste. Radionuclide characterization and appropriate handling systems are required for the safe management of irradiated FPM capsule waste. This FPM capsule waste management is important for human and environmental protection.

Correction factors for induced radioactivity: comparing simplified continuous and periodic irradiation scenarios in medical cyclotron decommissioning.

The use of a Monte Carlo code in the assessment of residual radioactivity for decommissioning of a medical cyclotron facility requires a reasonable approximation to the facility's history of operations. A periodic irradiation scenario simulating the cyclotron's daily operation for radioisotope production is generally considered reasonable, but its implementation in the code's input file can be cumbersome because more than thousands of irradiation cycles must be modeled. In practice, two simplified scenarios with continuous irradiation are commonly used instead: (i) omitting the downtime between two irradiation periods and (ii) extending the irradiation duration across the entire operational lifespan of the facility, albeit with a reduced beam current to maintain workload consistency. A systematic comparison of residual radionuclide productions across various half-lives under these three scenarios was performed. This technical note presents the resulting correction factors for the two simplified continuous irradiation models, enhancing their applicability in estimating radioactive inventories under a range of circumstances.

Scalability study on [133La]LaCl3 production with a focus on potential clinical applications

BackgroundIn recent years, targeted alpha therapy has gained importance in the clinics, and in particular, the alpha-emitter 225Ac plays a fundamental role in this clinical development. Nevertheless, depending on the chelating system no real diagnostic alternative has been established which shares similar chemical properties with this alpha-emitting radionuclide. In fact, the race to launch a diagnostic radionuclide to form a matched pair with 225Ac is still open, and 133La features attractive radiation properties to claim this place. However, in order to enable its translation into clinical use, upscaling of the production of this PET radionuclide is needed.ResultsA study on optimal irradiation parameters, separation conditions and an exhaustive product characterization was carried out. In this framework, a proton irradiation of 2 h, 60 µA and 18.7 MeV produced 133La activities of up to 10.7 GBq at end of bombardment. In addition, the performance of four different chromatographic resins were tested and two optimized purification methods presented, taking approximately 20 min with a 133La recovery efficiencies of over 98%, decay corrected. High radionuclide purity and apparent molar activity was proved, of over 99.5% and 120 GBq/µmol, respectively, at end of purification. Furthermore, quantitative complexation of PSMA-617 and mcp-M-PSMA were obtained with molar activities up to 80 GBq/µmol. In addition, both 133La-radioconjugates offered high stability in serum, of over (98.5 ± 0.3)% and (99.20 ± 0.08)%, respectively, for up to 24 h. A first dosimetry estimation was also performed and it was calculated that an 133La application for imaging with between 350 and 750 MBq would only have an effective dose of 2.1–4.4 mSv, which is comparable to that of 18F and 68Ga based radiopharmaceuticals.ConclusionsIn this article we present an overarching study on 133La production, from the radiation parameters optimization to a clinical dose estimation. Lanthanum-133 activities in the GBq range could be produced, formulated as [133La]LaCl3 with high quality regarding radiolabeling and radionuclide purity. We believe that increasing the 133La availability will further promote the development of radiopharmaceuticals based on macropa or other chelators suitable for 225Ac.Graphical abstract

Neutron activation of stable isotopes in soil and groundwater from a radionuclide production facility, South Africa.

The neutron activation of stable isotopes in environmental matrices, such as soil and groundwater, is a critical aspect of assessing the impact of radionuclide production facilities on the surrounding ecosystem. The envisioned Low-Energy Radioactive Ion Beams (LERIB) facility at the iThemba LABS, South Africa is anticipated to generate significant sources of ionising radiation. The study investigated the possible repercussions of neutron irradiation stemming from the facility, focusing on the activation of stable isotopic compositions in the environment. The investigation employed a combination of experimental and analytical techniques to characterize the neutron activation products in soil and groundwater samples collected from the vicinity. Samples were collected from designated areas for background radiological measurements and were irradiated with neutrons for a period of 1 h. The induced radioactivity measured by the High Purity Germanium detector included 24Na, 22Na, 54Mn, 52Mn, and 46Sc. The application of Darcy's law for groundwater velocity suggests that radionuclides in groundwater will migrate at an average flow velocity of 0.8 m/day. The isotopes with longer half-lives have count rates at background concentrations; therefore, environmental impacts on the site and surrounding communities might be minimal.

Chelator-impregnated polydimethylsiloxane beads for the separation of medical radionuclides

Chelator-impregnated resins have been studied earlier for the chemical separation of elements in aqueous solutions, but issues with their chemical stability have limited their use in the separation of (medical) radionuclides from their respective irradiated targets. We developed a polydimethylsiloxane (PDMS)-based chelator-impregnated resin that showed a high chemical stability against leaching. Several different chelators were tested in this study. After impregnation of the PDMS beads with the di-2-ethylhexylphosphoric acid (D2EHPA) chelator, an in-flow separation study with various radionuclides (Y-90, La-140, and Ac-225) was conducted. These three radionuclides have potential use in nuclear medicine and a production route through irradiation of Sr-, Ba-, and Ra-targets respectively, necessitating their chemical separation. The D2EHPA-impregnated beads achieved high adsorption efficiencies of 99.89% ± 0.14%, 99.50% ± 0.10%, and 98.51% ± 0.25%, for Y-90, La-140, and Ac-225, respectively, while co-adsorption of minor amounts (<3%) of the targets were reported. These results, together with the high chemical stability of the PDMS-based resin, highlight the potential of chelator-impregnated resins in the rapidly growing field of (medical) radionuclide production.

TYtool: A software application for yield and target power optimization in charged particle induced radionuclide production

A software application useful for optimization and maximizing radionuclide production without exceeding the power limits of the target material or holder has been developed. The software (TYtool) can be used for target optimization including yield calculations vs time, thickness, and incident energy, W/mm through the target, and automated target thickness optimization with the Makkonen-Craig & Helariutta − or the novel Yield/Wapproach. TYtool also facilitates graphical representation of many basic plots such as cross section, mass stopping power, activity output, projected range and it is useful for many different particles, reactions, radionuclides via the default cross section data base or the import function for cross section and mass stopping power. The software is available for free at: https://gitlab.com/NM_Karolinska_Solna/TYtool.

Results of modern radiation-hygienic surveys of settlements of Bryansk Oblast of the Russian Federation bordering the Republic of Belarus. Part 3: Radionuclide content in agricultural food products

The third article in a series of publications devoted to the results of studying the current radiation situation in the territories of the Bryansk region bordering the Republic of Belarus presents results of studies of the content of radionuclides (137Cs and 90Sr) in samples of agricultural food products produced in the personal subsidiary plots of the population. The regularities of changing 137Cs and 90Sr content in samples of cow’s milk and potatoes depending on the level of radioactive contamination of the territory were studied; the present values of the quantities characterizing the distribution of the ratio of the activity concentration of radionuclides in agricultural food products to the density of radioactive contamination of the soil of the territory were deter -mined. The ratios of average values of 137Cs activity concentration in milk from stalled and grazing periods for cattle were analyzed. The results of the study show that some dairy product samples (less than 1%) do not meet the radiological safety criterion. Exceedances of the hygienic standards were not found in the studied samples of potatoes, vegetables, and meat of farm animals.

FLUKA simulations of radionuclide yields in oblique targets

In nuclear medicine radionuclides are used in diagnosis and therapy. They can be produced in cyclotrons with different nuclear reactions. Overall goal is the optimization of the yield of the desired radionuclide which is possible by changing different experimental parameters. To test the influence of these parameters to obtain an optimal yield, simulation programs like PHITS and FLUKA can be used. In first studies (see Klink et al. [Testing the suitability of FLUKA and PHITS to predict the outcome of radionuclide production. Radiat. Eff. Defects Solids 2023, 178 (1–2), 111–125]) the experimental yields of nuclide productions were compared with simulation results of different target designs with perpendicular and inclined configuration. In this paper we focus on the effect of inclination since it was one of the problematic cases of the previous study [Klink et al. Testing the suitability of FLUKA and PHITS to predict the outcome of radionuclide production. Radiat. Eff. Defects Solids 2023, 178 (1–2), 111–125]. Different beam profiles were varied in the simulations to determine its influence on the simulated yields. The choice of the beam profile has a great influence on simulating irradiations of inclined targets. With a known beam profile and other experimental conditions, FLUKA can be used to simulate nuclide productions of inclined targets with small deviations compared to the experimental yields. In conclusion, FLUKA can be used to determine the yield of unknown nuclide production with different target designs.

Holocene solar activity inferred from global and hemispherical cosmic-ray proxy records

Variations in solar activity have been proposed to play an important role in recent and past climate change. To study this link on longer timescales, it is essential to know how the Sun has varied over the past millennia. Direct observations of solar variability based on sunspot numbers are limited to the past 400 years, and beyond this we rely on records of cosmogenic radionuclides, such as 14C and 10Be in tree rings and ice cores. Their atmospheric production rates depend on the flux of incoming galactic cosmic rays, which is modulated by Earth’s and the Sun’s magnetic fields, the latter being linked to solar variability. Here we show that accounting for differences in hemispherical production rates, related to geomagnetic field asymmetries, helps resolve so far unexplained differences in Holocene solar activity reconstructions. We find no compelling evidence for long-term variations in solar activity and show that variations in cosmogenic radionuclide production rates on millennial timescales and longer, including the 2,400-year Hallstatt cycle, are explained by variations in the geomagnetic field. Our results also suggest an on-average stronger dipole moment during the Holocene, associated with higher field intensities in the Southern Hemisphere.

Radiological impact of 226Ra, 232Th and 40K in fodders from Penang, Malaysia

The plant acts as an important route for the transfer of radionuclides from the soil to animals, leading to the transfer of radiation to human food products such as beef and milk. Therefore, the level of radioactivity in fodder plays a crucial role in deciding whether cattle may be allowed to graze in a certain area. In this study, the activities of 226Ra, 232Th and 40K were measured via gamma-ray spectrometry on different fodder samples, including napier leaves, rice straw, corn stalks, guinea grass, mixed pasture, palm oil leaves and palm kernel collected from Penang, Malaysia. Theoretical calculations were also conducted to estimate the levels of these radionuclides in caw's products (beef and milk), as well as their potential radiological impact on local consumers. On average, the annual effective dose due to ingestion of radionuclides in milk was 11.39 μSv y−1, whereas in beef it was 5.63 μSv y−1. These values are significantly lower than the worldwide average of 290 μSv y−1. Research confirmed that farmers' usage of the aforementioned feeds did not cause any radiation-related health risks.

Cross sections for the production of radionuclides induced in W targets by high energy carbon ions and protons

Cross sections for the production of radionuclides induced in W targets by high energy carbon ions and protons

Synchronizing the Western Gotland Basin (Baltic Sea) and Lake Kälksjön (central Sweden) sediment records using common cosmogenic radionuclide production variations

Multi-archive studies of climate events and archive-specific response times require synchronous time scales. Aligning common variations in the cosmogenic radionuclide production rate via curve fitting methods provides a tool for the continuous synchronization of natural environmental archives down to decadal precision. Based on this approach, we synchronize 10Be records from Western Gotland Basin (WGB, Baltic Sea) and Lake Kälksjön (KKJ, central Sweden) sediments to the 14C production time series from the IntCal20 calibration curve during the Mid-Holocene period ~6400 to 5200 a BP. Before the synchronization, we assess and reduce non-production variability in the 10Be records by using 10Be/9Be ratios and removing common variability with the TOC record from KKJ sediments based on regression analysis. The synchronizations to the IntCal20 14C production time scale suggest decadal to multi-decadal refinements of the WGB and KKJ chronologies. These refinements reduce the previously centennial chronological uncertainties of both archives to about ± 20 (WGB) and ±40 (KKJ) years. Combining proxy time series from the synchronized archives enables us to interpret a period of ventilation in the deep central Baltic Sea basins from ~6250 to 6000 a BP as possibly caused by inter-annual cooling reducing vertical water temperature gradients allowing deep water formation during exceptionally cold winters.

Xenon photonuclear cross sections for the production of 123I radionuclide

A simple reliable theoretical model for the calculation of total photo-absorption cross sections by atomic nuclei has been presented and applied it to get the relevant data needed for the evaluation of the production rate of 123I radionuclide isotope. Since experimental measurements are not available, the model calculation represents the only source of information. The present results, based on an accurate model of nuclear structure, are in very good agreement with the observed photoabsorption cross sections of Te isotopes, which provide reliable cross sections for the neighboring Xe nuclei, where the usual simple estimates are clearly discordant.

Target Development towards First Production of High-Molar- Activity 44gSc and 47Sc by Mass Separation at CERN-MEDICIS.

The radionuclides 43Sc, 44g/mSc, and 47Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating natTi and natV target materials with protons. Maximizing the production yield of the therapeutic 47Sc in the highest cross section energy range of 24-70 MeV results in the co-production of long-lived, high-γ-ray-energy 46Sc and 48Sc contaminants if one does not use enriched target materials. Mass separation can be used to obtain high molar activity and isotopically pure Sc radionuclides from natural target materials; however, suitable operational conditions to obtain relevant activity released from irradiated natTi and natV have not yet been established at CERN-MEDICIS and ISOLDE. The objective of this work was to develop target units for the production, release, and purification of Sc radionuclides by mass separation as well as to investigate target materials for the mass separation that are compatible with high-yield Sc radionuclide production in the 9-70 MeV proton energy range. In this study, the in-target production yield obtained at MEDICIS with 1.4 GeV protons is compared with the production yield that can be reached with commercially available cyclotrons. The thick-target materials were irradiated at MEDICIS and comprised of metallic natTi, natV metallic foils, and natTiC pellets. The produced radionuclides were subsequently released, ionized, and extracted from various target and ion source units and mass separated. Mono-atomic Sc laser and molecule ionization with forced-electron-beam-induced arc-discharge ion sources were investigated. Sc radionuclide production in thick natTi and natV targets at MEDICIS is equivalent to low- to medium-energy cyclotron-irradiated targets at medically relevant yields, furthermore benefiting from the mass separation possibility. A two-step laser resonance ionization scheme was used to obtain mono-atomic Sc ion beams. Sc radionuclide release from irradiated target units most effectively could be promoted by volatile scandium fluoride formation. Thus, isotopically pure 44g/mSc, 46Sc, and 47Sc were obtained as mono-atomic and molecular ScF 2+ ion beams and collected for the first time at CERN-MEDICIS. Among all the investigated target materials, natTiC is the most suitable target material for Sc mass separation as molecular halide beams, due to high possible operating temperatures and sustained release.

Exploring Aqueous Coordination Chemistry of Highly Lewis Acidic Metals with Emerging Isotopes for Nuclear Medicine.

Nuclear medicine harnesses radioisotopes for the diagnosis and treatment of disease. While the isotopes 99mTc and 111In have enabled the clinical diagnosis of millions of patients over the past 3 decades, more recent clinical translation of numerous 68Ga/177Lu-based radiopharmaceuticals for diagnostic imaging and therapy underscores the clinical utility of metal-based radiopharmaceuticals in mainstream cancer treatment. In addition to such established radionuclides, advancements in radioisotope production have enabled the production of radionuclides with a broad range of half-lives and emission properties of interest for nuclear medicine. Chemical means to form kinetically inert, in vivo-compatible species that can be modified with disease-targeting vectors is imperative. This presents a challenge for radiosiotopes of elements where the aqueous chemistry is still underdeveloped and poorly understood. Here, we discuss our efforts to date in exploring the aqueous, radioactive coordination chemistry of highly Lewis acidic metal ions and how our discoveries apply to the diagnosis and treatment of cancer in preclinical models of disease. The scope of this Account includes approaches to aqueous coordination of to-date understudied highly Lewis acidic metal ions with radioisotopes of emerging interest and the modulation of well-understood coordination environments of radio-coordination complexes to induce metal-catalyzed reactivity for separation and pro-drug applications.First, we discuss the development of seven-coordinate, small-cavity macrocyclic chelator platform mpatcn/picaga as an exemplary case study, which forms robust complexes with 44Sc/47Sc isotopes. Due to the high chemical hardness and pronounced Lewis acidity of the Sc3+ ion, the displacement of ternary ligand H2O by 18/natF- can be achieved to form an inert Sc-18/natF bond. Corresponding coordination complex natSc-18F is in vivo compatible and forms a theranostic tetrad with corresponding 44Sc/47Sc, 177Lu complexes all exhibiting homologous biodistribution profiles. Another exceptionally hard, highly Lewis acidic ion with underdeveloped aqueous chemistry and emerging interest in nuclear medicine is 45Ti4+. To develop de novo approaches to the mononuclear chelation of this ion under aqueous conditions, we employed a fragment-based bidentate ligand screening approach which identified two leads. The screen successfully predicted the formation of [45Ti][Ti(TREN-CAM)], a Ti-triscatechol complex that exhibits remarkable in vivo stability. Furthermore, the fragment-based screen also identified approaches that enabled solid-phase separation of Ti4+ and Sc3+ of interest in streamlining the isotope production of 45Ti and accessing new ways to separate 44Ti/44Sc for the development of a long-lived generator system. In addition to establishing the inert chelation of Ti4+ and Sc3+, we introduce controlled, metal-induced reactivity of corresponding coordination complexes on macroscopic and radiotracer scales. Metal-mediated autolytic amide bond cleavage (MMAAC) enables the temperature-dependent release of high-molar-activity, ready-to-inject radiopharmaceuticals; cleavage is selectively triggered by coordinated trivalent Lewis acid nat/68Ga3+ or Sc3+. Following the scope of reactivity and mechanistic studies, we validated MMAAC for the synthesis of high-molar-activity radiopharmaceuticals to image molecular targets with low expression and metal-mediated prodrug hydrolysis in vivo.This Account summarizes how developing the aqueous coordination chemistry and tuning the chemical reactivity of metal ions with high Lewis acidity at the macroscopic and tracer scales directly apply to the radiopharmaceutical synthesis with clinical potential.

Production of Medical Radionuclides in the Center for Radiopharmaceutical Tumor Research—A Status Report

A new Center for Radiopharmaceutical Cancer Research was established at the Helmholtz-Zentrum Dresden-Rossendorf in 2017 to centralize radionuclide and radiopharmaceutical production, as well as enable chemical and biochemical research. Routine production of several radionuclides was put into operation in recent years. We report on the production methods of radiopharmaceutical radionuclides, in particular 11C, 18F, and radio metals like 61Cu, 64Cu, 67Cu, 67Ga, 131Ba, and 133La that are used regularly. In the discussion, we report typical irradiation parameters and achieved saturation yields.

New directions in nuclear data research for accelerator-based production of medical radionuclides

Extensive nuclear data studies have been carried out over the last 30 years in the context of accelerator-based production of radionuclides, especially at energies below 30 MeV, and the achieved database is fairly good. Yet there are some deficiencies or new needs of data. Those needs are generally associated with new emerging clinical applications of radionuclides, e.g. theranostic approach, bimodal imaging, radioimmuno-therapy, etc. This article gives an overview of on-going nuclear data research utilizing charged-particle accelerators in four directions, namely low-energy region, intermediate energy range, use of the α-particle beam, and utilization of fast neutrons generated at accelerators. Wherever possible, a comparison of experimental data with theoretical estimates is presented and evaluated (standardised) data, if available, are also briefly discussed.

Rapid, high-capacity adsorption of iodine from aqueous environments with amide functionalized covalent organic frameworks

Water pollution from iodine is dangerous to human health because of its long-lived radioisotopes. We show that covalent organic frameworks containing amide groups (COFamides) can quickly remove iodine from water with large adsorption capacities.