Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand

Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [²²³Ra]RaCl₂ is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [²²³Ra]Ra²⁺ localizes. To specifically direct [²²³Ra]Ra²⁺ to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [²²³Ra]Ra²⁺ for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [²²³Ra]Ra²⁺ was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [²²³Ra]Ra²⁺ under these conditions. [²²³Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [²²³Ra]RaCl₂, signifying that [²²³Ra][Ra(macropa)] remains intact in vivo. Upon conjugation of macropa to a single amino acid β-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for ²²³Ra, complexing >95% of Ra²⁺ in solution. Furthermore, [²²³Ra][Ra(macropa-β-alanine)] was rapidly cleared from mice and showed low ²²³Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability in vivo for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the β-alanine conjugate with ²²³Ra and its subsequent stability in vivo establishes for the first time the possibility of delivering [²²³Ra]Ra²⁺ to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.

The therapeutic alpha-emitter ²²³Ra can be stably complexed in vivo, creating opportunities for the development of targeted radiopharmaceutical agents with this radionuclide.     

Fr and Ra fixation on some inorganic sorbents or mixed composite ion exchangers

Zinc and nickel hexacyanoferrates (II) present a high affinity for²²³Fr and no retention for²²³Ra in hydrochloric acid solutions with concentrations greater than 0.5N. Hydrated antimony pentoxide is the best sorbent for²²³Ra. Incorporated in a composite exchanger, it could be used for decontamination purposes.     

The determination of mercury by non-flame atomic absorption and fluorescence spectrometry.

An isotopic dilution method has been developed for the determination of ²²⁶Ra and ²²⁸Ra in sea water and sediments with ²²³Ra as a yield tracer. An alternative procedure which obviates the need for ²²³Ra is demonstrated for sediments by the assay of ²²⁴Ra and ²²⁸Th which occur naturally in sediments. In addition, a direct method for β-counting ²²⁸Ra–²²⁸Ac is proposed. Radium, polonium, thorium and uranium isotopes and ²¹⁰Pb are coprecipitated from sea water with aluminum phosphate carrier. The radium and lead-210 are coprecipitated with lead nitrate in sediment leachings. All radium procedures utilize identical chemical isolation and the cathodic electrodeposition of radium. Subsequently, the α-radiation emitted by ²²⁶Ra, ²²³Ra and ²²⁴Ra is determined by pulse-height analysis: the ²²⁸Ra-²²⁸Ac and ²¹⁰Pb-²¹⁰Bi are measured by low background anticoincidence β-counting techniques. This method was used for samples containing 10^-11–0.5 · 10^-12 g of ²²⁶Ra and 10^-13–10^-15 g of ²²⁸Ra and gave a precision of 3–6% and 5–10% respectively, even though radium levels an order of magnitude less can be measured. The ²²⁶Ra method is applicable to all environmental samples, whereas ²²⁸Ra determinations are limited to applications where the ${}^{228}\text{Ra}{}^{226}\text{Ra}$ activity ratio is greater than 0.1. This method is especially attractive for studies of parent-daughter disequilibria.     

Recrystallization of 223Ra with barium sulfate

In this work, the kinetics of barium sulfate recrystallization has been studied in acidic 0.01 mol dm^?3 sodium sulfate solution using ²²³Ra and ¹³³Ba tracers at very low total radium concentration, i.e. less than 10^?13 mol dm^?3. It was found that the system follows the homogeneous recrystallization model and that recrystallization rates, inferred by the decrease of ²²³Ra and ¹³³Ba in the aqueous solution, are fast. Therefore, even at very low concentrations, below the solubility limit, radium will be retained by barium sulfate—a mineral present in the deep underground repository.     

Short-lived <Superscript>224</Superscript>Ra and <Superscript>223</Superscript>Ra isotopes in the Anadyr River–Bering Sea system

The first results of activity measurement of short-lived radium isotopes dissolved in water in the Anadyr River–Bering Sea transit system are presented. The trends of the radionuclide behavior after passage through high-gradient river–coastal sea water mixing zone were identified and the exchange rate of the horizontal mixing was determined. The ²²⁴Ra/²²³Ra activity ratio was used to construct the “radium age” model, which served for estimating the residence time of brackish water in the Anadyr River estuary. The factors affecting this value were elucidated.     

Methodological advances for measuring low-level radium isotopes in seawater

A new approach for quantifying radium isotopes in seawater was developed in advance of the international GEOTRACES program, which has the goal of identifying processes and quantifying fluxes that control the distribution of trace elements and isotopes (TEIs) in the ocean. High-resolution water column samples were collected via a commercially available in situ pump modified to accept multiple filter media including a manganese-oxide (MnO₂) impregnated acrylic cartridge for extracting dissolved radionuclides from seawater. The modifications mitigated prefilter clogging and allowed for up to 1,800 L filtrations in 4 h of pumping. Different MnO₂ cartridge preparation methods were investigated to achieve maximum radium (Ra) extraction efficiency under high sample flow rates. Full-ocean depth profiles were measured for short-lived radium isotopes (²²³Ra and ²²⁴Ra) in shipboard laboratories using a delayed coincidence alpha scintillation counter (RaDeCC). Samples were reanalyzed 4 weeks and 2 months after collection for ²²⁸Th and ²²⁷Ac to correct for supported ²²⁴Ra and ²²³Ra, respectively. Finally, the cartridges were measured on a gamma-ray spectrometer for the long-lived radium isotopes (²²⁶Ra and ²²⁸Ra). Parallel 20 L samples at each pumping depth were collected from Niskin bottles and analyzed via alpha scintillation for ²²⁶Ra to determine radium extraction efficiencies for the cartridges. These modified methods will allow for increased sample throughput, and hence higher spatial resolution for radium isotopes in the ocean. Such resolution will greatly improve the determination of oceanic vertical and horizontal mixing rates over small and large scales, which in turn can be used to calculate fluxes of TEIs into the ocean.     

Intercalibrated radionuclide activities in spiked water samples of the IAEA worldwide open proficiency test

Proficiency testing is one of methods for regularly assessing the accuracy of the analytical data produced by laboratories for particular measurements. In 2008 and 2010, we participated in the IAEA 2008 and 2010 worldwide open proficiency tests on the determination of natural radionuclides in water spiked with ²²⁶Ra, ²³⁴U and ²³⁸U for activity analysis and with ⁹⁰Sr and ²³⁰Th for gross alpha/beta analysis. Feedback statistics from the IAEA final report showed that the radioactivities of all of the samples fell within an acceptable range according to the IAEA. For ²²⁶Ra analysis, our result showed that ²²⁹Th–²²⁵Ra is suitable as a chemical tracer, although there are doubts that different co-precipitation efficient between parent ²²⁹Th and its daughter nuclide ²²⁵Ra in published literature. The impact factors of the analysis results, such as the lower limit of detection, standard substances, the background and efficiency for daily determination, are discussed in detail.     

226Ra, 228Ra and 228Ra/226Ra in surface marine sediment of Malaysia

Surface sediment samples were collected at the West (east coast and west coast of Peninsular Malaysia) and East (Sabah and Sarawak) Malaysia in several expeditions within August 2003 until June 2008 for determining the level of natural radium isotopes. Activity concentrations of ²²⁶Ra and ²²⁸Ra in surface marine sediment at 176 sampling stations were measured. The activity concentrations of both radionuclides in Malaysia (East and West Malaysia) display varied with the range from 9 to 158 Bq/kg dry wt. and 13 to 104 Bq/kg dry wt., respectively. Meanwhile, the ratio distributions of ²²⁸Ra/²²⁶Ra were ranged from 0.62 to 3.75. This indicated that the ratios were slightly high at west coast of Peninsular Malaysia compared to other regions (east coast of Peninsular Malaysia, Sabah and Sarawak). The variation of activity concentrations of ²²⁶Ra and ²²⁸Ra and its ratios were also supported by the statistical analyses of one-way ANOVA and t test at 95 % confidence level, whereby there were proved that the measured values were different between the regions. These different were strictly related to their half-life, potential input sources (included their parents, ²³⁸U and ²³²Th), parent’s characteristic, the geological setting/formation of the study area, environment origin and behavior.     

A 228Ra-212Pb tandem generator for potential application in biomedical studies

A new tandem generator system (cation-exchange generator column coupled to anion-exchange), based on the ²²⁸Ra as starting radionuclide, for ²¹²Pb/²¹²Bi production in the solutions suitable to direct application in biomedical investigations has been developed. Optimum conditions have been found for retention of Ra, Th and Ac parent radionuclides on the cation-exchange column and repeated elution of Pb with subsequent concentration on anion-exchange column using HBr and mixed HBr/CH₃OH solutions. It was shown that Pb/Bi could be eluted from anion — exchange column with a small volume of EDTA, DTPA, NaCl solutions or heated H₂O. The advantages of the tandem generator system for production of short-lived Pb/Bi radionuclides and their application for biomedical studies are discussed.     

<Superscript>226</Superscript>Ra and <Superscript>228</Superscript>Ra determination in environmental samples by alpha-particle spectrometry

A complete methodology for ²²⁶Ra and ²²⁸Ra determination by alpha-particle spectrometry in environmental samples is being applied in our laboratory using ²²⁵Ra as an isotopic tracer. This methodology can be considered highly suitable for the determination of these nuclides when very low absolute limits of detection need to be achieved. The ²²⁶Ra determination can be performed at any time after the isolation of the radium isotopes from the analyzed samples while the ²²⁸Ra determination needs to be carried out at least six months later through the measurement of one of its grand-daughters. The method has been validated by its application to samples with known concentrations of these Ra nuclides, and by comparison with other radiometric methods.     

Measurement of 222Rn and 226Ra in municipal supply tap water to evaluate their radiological impacts

ABSTRACT

Radon (²²²Rn) and its parent radionuclide Radium (²²⁶Ra) are classified as carcinogen. Human exposes to radon in water via inhalation and ingestion, although ingestion is the only way for radium to enter the human body. In this research, tap water collected from Bornova distinct was studied to determine the concentration of radon (²²²Rn) and radium (²²⁶Ra) for evaluating their radiological impact. For this reason, the annual effective doses for ingestion and inhalation were estimated. The measurements were performed using a collector chamber method. The mean concentrations of ²²²Rn and ²²⁶Ra were determined as 0.85 and 0.76 Bq/L, respectively. It can be stated that the ²²²Rn and ²²⁶Ra concentrations of tap waters here are lower than the international reference levels. Obtained concentration levels were applied to estimate annual effective dose due to the inhalation and ingestion. The dose values are also found to be lower than the recommended maximum values. On the other hand, it should be considered that consumption of these waters (2 L) and average radon and radium concentrations of water are the significant factors for estimating doses.     

The determination of radium-226 and radium-228 in soils and plants,using radium-225 as a yield tracer

Recovery of²²⁶Ra in analysis is determined using²²⁵Ra separated by anion exchange from²²⁹Th and²³³U. Radium is coprecipitated with barium, and purified by ion exchange.²²⁶Ra and²¹⁷At (decay product of²²⁵Ra) are measured by α-spectrometry.²²⁸Ra is determined both by β-counting²²⁸Ac and²²⁵Ac separated from²²⁸Ra and²²⁵Ra, and by α-counting its daughters after the decay of²²⁵Ra. Sources for α-spectrometry are prepared by electrodeposition (molecular plating).     

Assessment of 226Ra and 228Ra activity concentration in west coast of India

An investigation on the distribution of ²²⁶Ra and ²²⁸Ra activity concentration in coastal surface sea water from Okha in Gujarat to Ratnagiri in Maharashtra state along the west coast of India was carried out. In-situ pre-concentration technique was used to measure radium isotopes by passing 1,000 L of seawater through MnO₂ impregnated polypropylene filter cartridges at all the locations. ²²⁶Ra was estimated using gamma ray peak of its daughter radionuclides ²¹⁴Bi and ²¹⁴Pb. ²²⁸Ra was estimated from its daughter ²²⁸Ac. In the coastal waters, ²²⁶Ra and ²²⁸Ra activity concentration were observed to be in the range of 1.5–2.9 and 2.5–8.6 Bq m^?3 with a mean of 2.2 and 4.9 Bq m^?3 respectively. The activity of ²²⁸Ra was observed to be more than ²²⁶Ra in all the locations. The variation in spatial distribution of the radium isotopes activity concentration and its ratio with respect to location is discussed in the paper. The radioactive database obtained represents reference values for coastal environment of India.     

Influence of Ba on the electrodeposition of226Ra

A detailed study of the influence of barium on the electrodeposition of²²⁶Ra was made using two different procedures. High yields (80–90%) were attained when the amounts of barium were not very significant. However, the²²⁶Ra yields fell drastically for amounts slightly greater than 0.10–0.15 mg of Ba, according to the electrodeposition procedure. Samples containing trace amounts of barium less than 100–150 g can thus be treated with no barium-radium separation being required.²¹⁰Po was also deposited, although practically no influence of barium on the Po plating was observed. The²²⁵Ra resolution rose uniformly (25 to 55 keV) as the amount of barium rose up to 1 mg. These resolutions allow one to make a direct accurate determination of²²⁶Ra as well as an indirect determination of²²⁴Ra and²²³Ra via measurement of their daughter products.     

On the use of232U and its daughters for the determination of226Ra in water samples

The authors propose a method to determine 226Ra by using a solution of²³²U and its daughters in equilibrium as a tracer.²²⁴Ra of the²³²U solution can be used as yield determinant for²²⁶Ra. The growth of²¹⁴Po from²²⁶Ra and of²¹²Po from²²⁴Ra is measured at different times after the isolation of the radium fraction.     

Application of ICP-QMS for the determination of ultratrace-levels of <Superscript>226</Superscript>Ra in geothermal water and sediment samples

A rapid, accurate and less labor intensive approach to determining ²²⁶Ra in environmental samples was examined; this utilized quadrupole-based inductively coupled plasma mass spectrometry (ICP-QMS). The procedure used chemical separation by ion exchange chromatography to remove most of the matrices after coprecipitation with BaSO₄. The average chemical recovery of the NIST SRM preparation method ranged from 60.5 to 85.9% using ¹³³Ba as internal tracer by gamma counting. This technique was capable of completing a ²²⁶Ra measurement within 3 min. It did not require an in-growth period to allow radon and its progeny to achieve secular equilibrium with the parent ²²⁶Ra as is needed for liquid scintillation analyzer (LSA). The method detection limits for the determination of ²²⁶Ra in geothermal water and sediment samples were 0.02 mBq L⁻¹ (0.558 fg L⁻¹) and 0.10 Bq kg⁻¹ (2.79 fg g⁻¹), respectively. The results obtained with various natural samples and the suitability of the method when applied to various environmental matrices such as geothermal water and sediment are discussed. When ICP-QMS was compared to double-focusing magnetic sector field inductively coupled plasma mass spectrometry (ICP-SFMS), good agreement was obtained with a correlation coefficient, r ² = 0.982.     

Radioactive series disequilibria in underground uranium deposits of the Singhbhum Shear Zone, Eastern India

Radionuclides of the ²³⁸U series (²²⁶Ra, ²¹⁰Pb, ²³⁴Th and ²³⁴U), ²³⁵U series (²²⁷Ac and ²³¹Pa) and ²³²Th series (²²⁸Th and ²²⁸Ra) series were measured by High Resolution Gamma Spectrometry system in twenty-five uranium ore samples from underground uranium deposits in the Singhbhum Shear Zone of Eastern India. The activity concentrations were observed to vary within a wide range in most of the deposits, as is the case in most rocks of crustal origin. The uranium ore from these deposits were not of high ore grade (U concentrations ranged from 0.015 to 0.082%). Activity ratios of key daughter–parent pairs from the decay chains, viz. ²²⁶Ra/²³⁸U, ²²⁶Ra/²¹⁰Pb, ²³¹Pa/²³⁵U, ²²⁷Ac/²³⁵U, ²³⁰Th/²³⁸U, ²³⁴U/²³⁸U, ²²⁶Ra/²³⁰Th and ²²⁸Th/²²⁸Ra indicated migration/accumulation of uranium and radium in some samples. The ²²⁶Ra/²³⁰Th ARs suggested that the deposits were not closed to groundwater movement for a maximum time period of 8ky. Thiel plot of the ²³⁴U/²³⁸U vs. ²³⁰Th/²³⁸U activity ratios indicated uranium accumulation and complex processes of uranium redistribution.     

Measurement of <Superscript>228</Superscript>Ra in the Yellow Sea and East China Sea using the radon emanation method

²²⁸Ra levels in the Yellow Sea and East China Sea were determined using the emanation method. The seawater radium was concentrated using an Mn-fiber and the ²²⁴Ra ingrowth was measured after about half a year when the initial ²²⁴Ra in the sample would have decayed. The ²²⁴Ra activity in the sample was evaluated using the decay dynamics relationship between parent ²²⁸Ra and daughter ²²⁸Th. The concentration and distribution feature of ²²⁸Ra in the Yellow Sea and East China Sea were studied and the ²²⁸Ra concentrations in the surface seawater of the Yellow Sea and the East China Sea were in the range 0.09–15.0 Bq/m³ with an average of 6.84 Bq/m³ during the summer cruise, and in the range 0.09–16.9 Bq/m³ with an average of 6.37 Bq/m³ during the winter cruise. The ²²⁸Ra distribution in the northern Yellow Sea was different from the southern Yellow Sea and East China Sea. The highest ²²⁸Ra activity of surface water was located in the middle of the northern Yellow Sea, but for the southern Yellow Sea and East China Sea, it decreased with increasing distance from China continent.     

222Rn and 226Ra activity concentrations in groundwaters of southern Poland: new data and selected genetic relations

Since 2008, the authors have been conducting research into ²²²Rn and ²²⁶Ra activity concentrations in shallow circulation groundwaters in southern Poland. Measurements have been performed with a liquid-scintillation method and ultra low-level liquid-scintillation spectrometers α/β Quantulus 1220. The research carried out so far has demonstrated that in the Sudetes groundwaters with high activity concentrations of ²²²Rn and ²²⁶Ra are common. In other studied areas in southern Poland no shallow circulation groundwaters with high radon or radium concentrations have been found yet. The conducted research has demonstrated that the activity concentration of ²²²Rn dissolved in shallow circulation groundwaters in the Sudetes depends chiefly on the amount of radon, which after being released as gas from reservoir rocks is dissolved in waters flowing through these rocks. At the same time, the concentration of ²²²Rn dissolved in some shallow circulation groundwaters in the Carpathians is influenced significantly by the amount of radon produced from the decay of its parent ion ²²⁶Ra²⁺ dissolved in these waters.     

Quadrupole moments of radium isotopes from the 7p 2 P 3/2 hyperfine structure in Ra II

The hyperfine structure and isotope shift of^221–226Ra and^212,214Ra have been measured in the ionic (Ra II) transition 7s ² S _1/2–7p ² P _3/2 (λ=381.4 nm). The method of on-line collinear fast-beam laser spectroscopy has been applied using frequency-doubling of cw dye laser radiation in an external ring cavity. The magnetic hyperfine fields are compared with semi-empirical and ab initio calculations. The analysis of the quadrupole splitting by the same method yields the following, improved values of spectroscopic quadrupole moments:Q _s (²²¹Ra)=1.978(7)b,Q _s (²²³Ra)=1.254(3)b and the reanalyzed valuesQ _s (²⁰⁹Ra)=0.40(2)b,Q _s (²¹¹Ra)=0.48(2)b,Q _s (²²⁷Ra)=1.58(3)b,Q _s (²²⁹Ra)=3.09(4)b with an additional scaling uncertainty of ±5%. Furthermore, theJ-dependence of the isotope shift is analyzed in both Ra II transitions connecting the 7s ² S _1/2 ground state with the first excited doublet 7p ² P _1/2 and 7p ² P _3/2.