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1.
Nanomedicine (Lond) ; 19(17): 1557-1567, 2024 07 14.
Article in English | MEDLINE | ID: mdl-39011932

ABSTRACT

Aim: Nano-hydroxyapatite (nHA) is a good nanocarrier to load 223Ra, but the low specific activity (sp.act.) of 223Ra@nHA limits its application in medicine. Methods: We proposed a method for preparing nHA using PEG as a template, which significantly increases the sp.act of 223Ra@nHA and a new method to loaded 99mTc for in vivo tracking. Results: The nHA synthesized using PEG as a template was associated with higher sp.act for 223Ra in comparison to nHA with identical particle size and without PEG. The nHA load 99mTc-MDP was associated with higher labeling rate and stability in comparison to 99mTc. Conclusion: All these findings suggest that using PEG as a template and 99mTc-MDP could be the most effective of synthetic 223Ra/99mTc@nHA.


[Box: see text].


Subject(s)
Bone Neoplasms , Durapatite , Particle Size , Radium , Durapatite/chemistry , Humans , Bone Neoplasms/drug therapy , Bone Neoplasms/diagnostic imaging , Radium/chemistry , Polyethylene Glycols/chemistry , Nanoparticles/chemistry , Technetium/chemistry , Cell Line, Tumor , Radiopharmaceuticals/chemistry , Animals , Technetium Tc 99m Medronate/chemistry
2.
J Inorg Biochem ; 256: 112569, 2024 07.
Article in English | MEDLINE | ID: mdl-38701687

ABSTRACT

The clinical success of [223Ra]RaCl2 (Xofigo®) for the palliative treatment of bone metastases in patients with prostate cancer has highlighted the therapeutic potential of α-particle emission. Expanding the applicability of radium-223 in Targeted Alpha Therapy of non-osseous tumors is followed up with significant interest, as it holds the potential to unveil novel treatment options in the comprehensive management of cancer. Moreover, the use of barium radionuclides, like barium-131 and -135m, is still unfamiliar in nuclear medicine applications, although they can be considered as radium-223 surrogates for imaging purposes. Enabling these applications requires the establishment of chelators able to form stable complexes with radium and barium radionuclides. Until now, only a limited number of ligands have been suggested and these molecules have been primarily inspired by existing structures known for their ability to complex large metal cations. However, a systematic inspection of chelators specifically tailored to Ra2+ and Ba2+ has yet to be conducted. This work delves into a comprehensive investigation of a series of small organic ligands, aiming to unveil the coordination preferences of both radium-223 and barium-131/135m. Electronic binding energies of both metal cations to each ligand were theoretically computed via Density Functional Theory calculations (COSMO-ZORA-PBE-D3/TZ2P), while thermodynamic stability constants were experimentally determined for Ba2+-ligand complexes by potentiometry, NMR and UV-Vis spectroscopies. The outcomes revealed malonate, 2-hydroxypyridine 1-oxide and picolinate as the most favorable building blocks to design multidentate chelators. These findings serve as foundation guidelines, propelling the development of cutting-edge radium-223- and barium-131/135m-based radiopharmaceuticals for Targeted Alpha Therapy and theranostics of cancer.


Subject(s)
Radium , Radium/chemistry , Radium/therapeutic use , Humans , Radioisotopes/chemistry , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Barium/chemistry , Alpha Particles/therapeutic use , Chelating Agents/chemistry , Chelating Agents/therapeutic use , Neoplasms/drug therapy , Theranostic Nanomedicine/methods , Metals, Alkaline Earth/chemistry , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/therapeutic use
3.
Environ Pollut ; 352: 124062, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38701963

ABSTRACT

The leaching process of uranium tailings is a typical water-rock interaction. The release of 226Ra from uranium tailings depends on the nuclides outside the intrinsic properties of uranium tailings on the one hand, and is influenced by the water medium on the other. In this paper, a uranium tailings repository in southern China was used as a research object, and uranium tailings at different depths were collected by drilling samples and mixed to analyze the 226Ra occurrence states. Static dissolution leaching experiments of 226Ra under different pH conditions, solid-liquid ratio conditions, and ionic strength conditions were carried out, and the adsorption and desorption behaviours of 226Ra in five representative stratigraphic media were investigated. The results show that 226Ra has a strong adsorption capacity in representative strata, with adsorption distribution coefficient Kd values ranging from 1.07E+02 to 1.29E+03 (mL/g) and desorption distribution coefficients ranging from 4.97E+02 to 2.71E+03 (mL/g), but the adsorption is reversible. The 226Ra in uranium tailings exists mainly in the residual and water-soluble states, and the release of 226Ra from uranium tailings under different conditions is mainly from the water-soluble and exchangeable state fractions. Low pH conditions, low solid-liquid ratio conditions and high ionic strength conditions are favourable to the release of 226Ra from uranium tailings, so the release of 226Ra from uranium tailings can be reduced by means of adjusting the pH in the tailings and setting up a water barrier. The results of this research have important guiding significance for the management of existing uranium tailings ponds and the control of 226Ra migration in groundwater, which is conducive to guaranteeing the long-term safety, stability and sustainability of uranium mining sites.


Subject(s)
Radium , Uranium , Uranium/chemistry , Adsorption , Radium/analysis , Radium/chemistry , China , Soil Pollutants, Radioactive/analysis , Radiation Monitoring , Mining , Water Pollutants, Radioactive/chemistry , Water Pollutants, Radioactive/analysis
4.
Inorg Chem ; 62(50): 20834-20843, 2023 Dec 18.
Article in English | MEDLINE | ID: mdl-37811965

ABSTRACT

Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with 223Ra and 224Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra2+. A moderate log KML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Although macropa-XL could effectively bind 223Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra2+ ion and contributes to the small, but growing, number of chelator development efforts for 223Ra-based TAT.


Subject(s)
Nuclear Medicine , Radium , Humans , Chelating Agents/chemistry , Radium/chemistry , Radioisotopes/chemistry , Cations/chemistry
5.
Colloids Surf B Biointerfaces ; 223: 113174, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36746067

ABSTRACT

The use of targeted alpha therapy (TAT) for bone cancer is increasing each year. Among the alpha radionuclides, radium [223Ra]Ra+2 is the first one approved for bone cancer metastasis therapy. The development of novel radiopharmaceutical based on [223Ra]Ra+2 is essential to continuously increase the arsenal of new TAT drugs. In this study we have developed, characterized, and in vitro evaluated [223Ra] Ra-nano-hydroxyapatite. The results showed that [223Ra] Ra-nano-hydroxyapatite has a dose-response relationship for osteosarcoma cells and a safety profile for human fibroblast cells, corroborating the application as a radiopharmaceutical.


Subject(s)
Bone Neoplasms , Nanostructures , Osteosarcoma , Radium , Humans , Radiopharmaceuticals , Radium/chemistry , Radium/therapeutic use , Bone Neoplasms/drug therapy , Osteosarcoma/drug therapy
6.
Int J Mol Sci ; 22(11)2021 May 27.
Article in English | MEDLINE | ID: mdl-34071854

ABSTRACT

Metastatic castration-resistant prostate cancer (mCRPC) is a progressive and incurable disease with poor prognosis for patients. Despite introduction of novel therapies, the mortality rate remains high. An attractive alternative for extension of the life of mCRPC patients is PSMA-based targeted radioimmunotherapy. In this paper, we extended our in vitro study of 223Ra-labeled and PSMA-targeted NaA nanozeolites [223RaA-silane-PEG-D2B] by undertaking comprehensive preclinical in vitro and in vivo research. The toxicity of the new compound was evaluated in LNCaP C4-2, DU-145, RWPE-1 and HPrEC prostate cells and in BALB/c mice. The tissue distribution of 133Ba- and 223Ra-labeled conjugates was studied at different time points after injection in BALB/c and LNCaP C4-2 tumor-bearing BALB/c Nude mice. No obvious symptoms of antibody-free and antibody-functionalized nanocarriers cytotoxicity and immunotoxicity was found, while exposure to 223Ra-labeled conjugates resulted in bone marrow fibrosis, decreased the number of WBC and platelets and elevated serum concentrations of ALT and AST enzymes. Biodistribution studies revealed high accumulation of 223Ra-labeled conjugates in the liver, lungs, spleen and bone tissue. Nontargeted and PSMA-targeted radioconjugates exhibited a similar, marginal uptake in tumour lesions. In conclusion, despite the fact that NaA nanozeolites are safe carriers, the intravenous administration of NaA nanozeolite-based radioconjugates is dubious due to its high accumulation in the lungs, liver, spleen and bones.


Subject(s)
Immunoconjugates/pharmacokinetics , Nanoparticles , Prostatic Neoplasms/therapy , Radiopharmaceuticals/pharmacokinetics , Radium , Theranostic Nanomedicine , Zeolites , Animals , Antibodies, Monoclonal , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Chemical Phenomena , Chemistry Techniques, Synthetic , Disease Models, Animal , Drug Design , Gene Expression Profiling , Humans , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Isotope Labeling , Male , Mice , Mice, Nude , Molecular Structure , Nanoparticles/chemistry , Prostatic Neoplasms/diagnosis , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/adverse effects , Radiopharmaceuticals/chemistry , Radium/chemistry , Tissue Distribution , Xenograft Model Antitumor Assays , Zeolites/chemistry
7.
Sci Rep ; 11(1): 7389, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33795764

ABSTRACT

To assess the predictive and prognostic aim of interim and end-treatment 18F-fluorocholine PET/CT (FCH-PET/CT) and 99mTc-methilen diphosphonate bone scintigraphy (BS) in patients with castration-resistant prostate cancer and bone metastases (CRPC-BM) treated with Radium 223 dichloride (223Ra). Prospective and multicentre ChoPET-Rad study including 82 patients with CRPC-BM. Baseline, after 3 (interim) and 6 doses (end-treatment) BS and FCH PET/CT were performed in patients who meet the study criteria. Clinical variables, imaging and clinical progression were obtained and their association with progression free survival (PFS), and overall survival (OS) was studied. Agreement between BS and FCH PET/CT response was assessed using Kappa (K) analysis. Median of PFS and OS was 3 and 16 months, respectively. Agreement between interim BS and FCH PET/CT was weak (K: 0.28; p = 0.004). No agreement was observed between end-treatment diagnostic studies. Interim and end-treatment FCH PET/CT were related to PFS (p = 0.011 and p < 0.001, respectively). Therapeutic failure and interim BS and FCH PET/CT showed association with OS (p < 0.001, p = 0.037 and p = 0.008, respectively). Interim and end-treatment FCH PET/CT were good predictors of biochemical progression in patients treated with 223Ra. Therapeutic failure and progression in interim BS or FCH PET/CT were adverse factors for OS.


Subject(s)
Bone Neoplasms/diagnostic imaging , Bone and Bones/diagnostic imaging , Choline/analogs & derivatives , Positron Emission Tomography Computed Tomography/methods , Prostatic Neoplasms/diagnostic imaging , Radium/chemistry , Aged , Bone Neoplasms/secondary , Choline/chemistry , Disease Progression , Disease-Free Survival , Humans , Male , Middle Aged , Molecular Medicine , Multivariate Analysis , Proportional Hazards Models , Prospective Studies , Radioisotopes/chemistry , Reproducibility of Results , Treatment Outcome
8.
PLoS One ; 15(5): e0229452, 2020.
Article in English | MEDLINE | ID: mdl-32357150

ABSTRACT

Most of South Africa's energy is derived from the combustion of coal in pulverized coal-fired power plants (CFPP). However, when compared with the rest of the world, limited information regarding the main radioactive elements (U and Th) and specific radionuclides of interest (K40, Ra226 and Th232) from South African CFPP is available in the public domain. This paper aims to quantify the U, Th and specific radionuclides found in the coal used in selected South African CFPP in comparison to world averages found in literature. The U and Th concentrations were obtained by ICP-MS. The main radionuclides, K40, Ra226 and Th238, were quantified using gamma spectrometry. The U concentration and Th concentrations for the coal used in all the power plants was above the world average of 1.9 mg/kg and 3.2 mg/kg respectively. The coals with the highest Th content originated from the Mpumalanga power plant, while the U content in the Freestate power plant samples was the highest of the three. The concentrations of the K40 were between 88.43±10.75-110.76±8.92 Bq/kg, which are in-line with world averages of 4-785 Bq/kg. Similarly, the Ra226 and Th232 values were between 21.69±2.83-52.63±4.04 Bq/kg and 19.91±1.24-22.97±1.75 Bq/kg respectively, which are also in line with the world averages of 1-206 Bq/kg and 1-170 Bq/kg respectively. Radiological hazard indices such as radium equivalent (Raeq); external hazard index (Hex) and internal hazard index (Hin), that were estimated from these average radionuclide concentrations were less than the prescribed values found in literature. This indicated that no significant health risk was posed by the coal being used from these coal fields.


Subject(s)
Coal/analysis , Power Plants , Soil Pollutants, Radioactive/isolation & purification , Coal Ash/analysis , Humans , Radiation Dosage , Radiation Monitoring , Radioisotopes/chemistry , Radioisotopes/isolation & purification , Radium/chemistry , Radium/isolation & purification , Soil Pollutants, Radioactive/chemistry , South Africa , Spectrometry, Gamma , Thorium/chemistry , Thorium/isolation & purification , Uranium/chemistry , Uranium/isolation & purification
9.
Nucl Med Biol ; 80-81: 65-70, 2020.
Article in English | MEDLINE | ID: mdl-32001104

ABSTRACT

INTRODUCTION: Radiation-induced DNA damage occurs from direct and indirect effects. The induction is influenced by the physical characteristics of the radionuclide, especially its linear energy transfer. Hypoxia reduces the effect of irradiation treatment in tumor cells and leads to poor patient outcomes. High linear energy transfer emitters can overcome this obstacle. Our aim is to demonstrate the influence of hypoxia on the interaction of different radiation qualities with isolated DNA. METHODS: PuC19 Plasmid DNA was irradiated with 223Ra, 188Re, 99mTc and 99mTc-labeled pyrene with and without DMSO under hypoxia or normoxic conditions. DNA damages in form of single-(SSB) and double-strand breaks (DSB) were analyzed by gel electrophoresis. RESULTS: Radiation doses up to 200 Gy of 223Ra, 188Re and 99mTc led to maximal yields of 80% SSB and 30%, 28% and 32% DSB, respectively. Hypoxia had minor effects on damages from 223Ra, but caused a small enhancement in DSB for 188Re and 99mTc. DMSO prevented DSB completely and reduced SSB from the "free" radionuclides to comparable levels. DNA-binding 99mTc-labeled pyrene induced less SSB and DSB compared to [99mTc]TcO4-. However, the incubation with DMSO could prevent the SSB and DSB induction only to a minor extent. CONCLUSIONS: Hypoxia does not limit DNA damage induced by 223Ra, 188Re, 99mTc and 99mTc-labeled pyrene. Dose-dependent radiation effects were comparable for alpha-emitters and both high- and low-energy electron emitters. The radioprotection by DMSO was not influenced by hypoxia. The results indicate the contribution of mainly indirect radiation effects for 99mTc, 188Re and 223Ra. 99mTc-labeled pyrene caused direct DNA damages and Auger-electrons from 99mTc-labeled pyrene are more effective than high-energy electrons or alpha particles. ADVANCES IN KNOWLEDGE: Without the consideration of DNA repair mechanisms, oxygen has no direct influence in radiation-induced DNA damages by different radiation qualities. IMPLICATIONS FOR PATIENT CARE: The short-time stimulation with oxygen during patient radiation could have minor influence compared to constant oxygen flooding to overcome hypoxic barriers.


Subject(s)
Alpha Particles , DNA Breaks/radiation effects , Electrons/therapeutic use , Plasmids/genetics , Pyrenes/chemistry , Pyrenes/pharmacology , Tumor Hypoxia/radiation effects , Dose-Response Relationship, Radiation , Isotope Labeling , Linear Energy Transfer/radiation effects , Radioisotopes/chemistry , Radium/chemistry , Reactive Oxygen Species/metabolism , Rhenium/chemistry , Technetium/chemistry , Tumor Hypoxia/genetics
10.
Environ Sci Process Impacts ; 21(10): 1764-1776, 2019 Oct 16.
Article in English | MEDLINE | ID: mdl-31553335

ABSTRACT

Produced water generated during unconventional oil and gas extractions contains a complex milieu of natural and anthropogenic potentially toxic chemical constituents including arsenic (As), chromium (Cr), and cadmium (Cd), naturally occurring radioactive materials (NORMs) including U and Ra, and a myriad of organic compounds. The human-ecological health risks and challenges associated with the disposal of produced water may be alleviated by understanding geochemical controls on processes responsible for the solubilization of potentially hazardous natural shale constituents to produced water. Here, we investigated, through a series of batch treatments, the leaching behavior of As, Se, Cu, Fe, Ba, Cr, Cd, and radioactive nuclides U, Ra from shale to produced water. Specifically, the effect of four major controls on element mobility was studied: (1) solution pH, (2) ionic strength of the solution, (3) oxic-anoxic conditions, and (4) an additive used in fracking fluid. The mobilization of metals and metalloids from shale was greatest in treatments containing sodium persulfate, an oxidant and a commonly used additive in fracture fluid. In the high ionic strength treatments, dissolved Ba concentrations increased 5-fold compared to low ionic strength treatments. Overall, anoxic conditions superimposed with low pH resulted in the largest increase of dissolved metals and radionuclides such as Ra. Overall, our results suggest that (1) limiting pore water acidification by injection of alkaline fluid in carbonate-low shale and (2) minimizing strong oxidizing conditions in shale formations may result in cost-effective in situ retention of produced water contaminants.


Subject(s)
Hydraulic Fracking , Radioisotopes/analysis , Trace Elements/analysis , Arsenic/analysis , Arsenic/chemistry , Barium/analysis , Barium/chemistry , Cadmium/analysis , Cadmium/chemistry , Chromium/analysis , Chromium/chemistry , Copper/analysis , Copper/chemistry , Hydrogen-Ion Concentration , Iron/analysis , Iron/chemistry , Natural Gas , Osmolar Concentration , Oxygen/analysis , Radioisotopes/chemistry , Radium/analysis , Radium/chemistry , Selenium/analysis , Selenium/chemistry , Trace Elements/chemistry , Uranium/analysis , Uranium/chemistry
11.
Chem Commun (Camb) ; 55(53): 7631-7634, 2019 Jun 27.
Article in English | MEDLINE | ID: mdl-31197298

ABSTRACT

Despite their attractive properties, internal targeted alpha therapies using 223/224Ra are limited to bone-seeking applications. As there is no suitable chelator available, the search for new carriers to stably bind Ra2+ and to connect it to biological target molecules is necessary. Polyoxopalladates represent a class of compounds where Ra2+ can be easily introduced into the Pd-POM core during a facile one-pot preparation. Due to the formation of a protein corona, the connection to other targeting (bio)macromolecules is possible.


Subject(s)
Organometallic Compounds/chemistry , Palladium/chemistry , Polymers/chemistry , Radiopharmaceuticals/chemistry , Radium/chemistry
12.
Molecules ; 24(10)2019 May 18.
Article in English | MEDLINE | ID: mdl-31109077

ABSTRACT

Actinium-225 (225Ac) can be produced with a linear accelerator by proton irradiation of a thorium (Th) target, but the Th also underdoes fission and produces 400 other radioisotopes. No research exists on optimization of the cation step for the purification. The research herein examines the optimization of the cation exchange step for the purification of 225Ac. The following variables were tested: pH of load solution (1.5-4.6); rinse steps with various concentrations of HCl, HNO3, H2SO4, and combinations of HCl and HNO3; various thorium chelators to block retention; MP50 and AG50 resins; and retention of 20-45 elements with different rinse sequences. The research indicated that HCl removes more isotopes earlier than HNO3, but that some elements, such as barium and radium, could be eluted with ≥2.5 M HNO3. The optimal pH of the load solution was 1.5-2.0, and the optimized rinse sequence was five bed volumes (BV) of 1 M citric acid pH 2.0, 3 BV of water, 3 BV of 2 M HNO3, 6 BV of 2.5 M HNO3 and 20 BV of 6 M HNO3. The sequence recovered >90% of 225Ac with minimal 223Ra and thorium present.


Subject(s)
Actinium/chemistry , Cations/chemistry , Chromatography, Ion Exchange , Metals/chemistry , Radium/chemistry , Thorium/chemistry , Acids/chemistry , Chelating Agents/chemistry , Hydrogen-Ion Concentration
13.
Appl Radiat Isot ; 145: 251-257, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30686576

ABSTRACT

At the time of publication, radiopharmaceuticals labelled with thorium-227 are in clinical trials in Europe for the treatment of various types of cancer. In part I of this two-part series the primary standardisation of an aqueous solution of 227Th was reported. In part II, the activity derived from the recommended absolute γ-ray emission intensities have been compared to that from the primary standardisation techniques. This comparison showed a negative bias of 4% in the determined activity per unit mass with an 11% spread in the activities determined for the eight most intense γ-ray emissions (Iγ > 1%) from the 227Th α decay. Using the standardised 227Th, measurements of the characteristic γ-ray emissions from the 223Ra excited states were made using a calibrated HPGe γ-ray spectrometer. This has enabled the absolute intensities of 70 γ ray emissions from the 227Th α-decay to be experimentally determined. A significant improvement over the precision of the recommended normalisation scaling factor has been made, with a value of 12.470 (35) % determined. Typically, the precision of the intensities has been improved by an order of magnitude or greater than current recommended values. The correlation matrices for pairs of the most intense γ-ray emission intensities are presented.


Subject(s)
Radiopharmaceuticals/therapeutic use , Thorium/therapeutic use , Alpha Particles/therapeutic use , Calibration , Gamma Rays/therapeutic use , Humans , Neoplasms/radiotherapy , Radioimmunotherapy/methods , Radioimmunotherapy/standards , Radiopharmaceuticals/standards , Radium/chemistry , Reference Standards , Scintillation Counting , Spectrometry, Gamma , Thorium/standards
14.
Nuklearmedizin ; 57(6): 242-246, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30551225

ABSTRACT

AIM: In this contribution we investigated the potential transfer of an established method for the synthesis of 223Ra-labelled calixarene complexes to a hospital radiopharmaceutical environment. For this purpose, commercially available [223Ra]RaCl2 solution in pharmaceutical grade (Xofigo®) was reacted with three calixarene derivatives. METHODS: A wellestablished two-phase extraction method using a two-phase solvent system was performed for complexation of the radium ions with calixarenes under slightly basic conditions. Moreover, the complexation reaction was conducted in homogenous medium (water / THF) as well as under elevated temperature. RESULTS: The investigated reaction conditions did not allow the isolation of the desired products. Analytical evidence for the presence of radium-calixarene species by means of activity measurement, TLC as well as HPLC could not been proven unambiguously. CONCLUSION: We address the non-conversion of the educts to the large excess of sodium ions in the used Xofigo® solution, what may explain the hampered reaction for all conducted experiments. Finally the transfer of the published complexation concept into a radiopharmaceutical routine environment was not successful. ZIEL: : Ziel der vorliegenden Arbeit ist es, eine bekannte Methode zur Synthese von 223Ramarkierten Calixaren-Komplexen zunächst auf ihre Reproduzierbarkeit zu prüfen und gegebenenfalls für die Anwendung in einem radiopharmazeutischen Arbeitsbereich einer Klinik zu adaptieren. Als Ausgangsnuklid wurde kommerziell verfügbares [223Ra]RaCl2 in pharmazeutischer Qualität (Xofigo®) eingesetzt. Dieses wurde mit verschiedenen Calixarenderivaten umgesetzt. METHODEN: Die Komplexierungsreaktion wurde sowohl mittels einer in der Literatur beschriebenen Zwei-Phasen-Extraktion als auch in einem homogenen Lösungsmittelgemisch (THF/Wasser) bei schwach basischen Bedingungen durchgeführt. Weiterhin wurde die Reaktionstemperatur variiert. RESULTATE: Bei keiner der durchgeführten Umsetzungen konnte die Bildung des postulierten Produkts durch spezifische Analysenmethoden wie Aktivitätsmessung, Radio-Dünnschichtchromatographie-Scans sowie Hochleistungsflüssigkeitschromatographie (HPLC) nachgewiesen werden. SCHLUSSFOLGERUNGEN: Das Ausbleiben der Komplexierung ist wahrscheinlich auf den extrem hohen Überschuss an Natriumionen in der verwendeten Xofigo®-Lösung zurückzuführen. Die Anwendung der publizierten Komplexierungsmethode in einem radiopharmazeutischen Kliniklabor ist nicht möglich.


Subject(s)
Calixarenes/chemistry , Hospitals , Laboratories , Radiopharmaceuticals/chemistry , Radium/chemistry , Radioisotopes/chemistry
15.
Cancer Treat Rev ; 68: 47-54, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29859504

ABSTRACT

With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 (223Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with 223Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical.


Subject(s)
Alpha Particles/therapeutic use , Bone Neoplasms/radiotherapy , Bone Neoplasms/secondary , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Radium/therapeutic use , Animals , Humans , Male , Radium/chemistry
16.
Nucl Med Biol ; 62-63: 1-8, 2018.
Article in English | MEDLINE | ID: mdl-29800797

ABSTRACT

INTRODUCTION: Radium-223 dichloride is the first alpha-particle emitting therapeutic agent approved by FDA and EMA for bone metastatic castration-resistant prostate cancer. We studied its age-dependent biodistribution in mice, and compared it with [99mTc]Tc-MDP and [18F]NaF aiming to identify a potential imaging surrogate to predict [223Ra]RaCl2 whole-body localization. METHODS: Male C57Bl/6 mice dosed with [223Ra]RaCl2 were sacrificed at different time points to explore [223Ra]RaCl2 whole-body distribution. In another experiment, mice at different ages were dosed with [223Ra]RaCl2 to evaluate the aging impact. Finally, [99mTc]Tc-MDP and [18F]NaF were administered to mice, and we compared their biodistributions with [223Ra]RaCl2. Detailed micro-localization of each tracer was visualized using autoradiography and histochemical staining. RESULTS: [223Ra]RaCl2 uptake in bone was rapid and stable. We observed persistent localization at bone epiphyses, as well as the red pulp of the spleen, while its uptake in most soft tissues cleared within 24 h. [223Ra]RaCl2 distribution in soft tissues is similar in all age groups tested, while bone activity significantly decreased with aging. Although the diagnostic tracers cleared much faster from soft tissues than the therapeutic radionuclide, [99mTc]Tc-MDP and [18F]NaF both co-localized with [223Ra]RaCl2 in the skeletal compartment. CONCLUSIONS: Radium-223 localization to the bone is dependent on age-varying factors, which implies that radium-223 dosimetry should take patient age into account. [99mTc]Tc-MDP shows a different biodistribution from [223Ra]RaCl2, both in soft tissues and in bone. [18F]NaF presents a high similarity with [223Ra]RaCl2 in skeletal uptake, which validates the potential of [18F]NaF as an imaging surrogate to predict radium-223 radiotherapeutic distribution in bone.


Subject(s)
Aging/metabolism , Molecular Imaging , Radium/pharmacokinetics , Animals , Male , Mice , Mice, Inbred C57BL , Radioisotopes/chemistry , Radioisotopes/pharmacokinetics , Radium/chemistry , Tissue Distribution
17.
Chemosphere ; 205: 627-634, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29715677

ABSTRACT

To assess radium (226Ra) as a potential indicator of impact in well waters, we investigated its behavior under natural conditions using a case study approach. 226Ra geochemistry was investigated in 67 private wells of southeastern New Brunswick, Canada, a region targeted for potential shale gas exploitation. Objectives were to i) establish 226Ra baseline in groundwater; ii) characterize 226Ra spatial distribution and temporal variability; iii) characterize 226Ra partitioning between dissolved phase and particulate forms in well waters; and iv) understand the mechanisms controlling 226Ra mobility under natural environmental settings. 226Ra levels were generally low (median = 0.061 pg L-1, or 2.2 mBq L-1), stable over time, and randomly distributed. A principal component analysis revealed that concentrations of 226Ra were controlled by key water geochemistry factors: the highest levels were observed in waters with high hardness, and/or high concentrations of individual alkaline earth elements (i.e. Mg, Ca, Sr, Ba), high concentrations of Mn and Fe, and low pH. As for partitioning, 226Ra was essentially observed in the dissolved phase (106 ±â€¯19%) suggesting that the geochemical conditions of groundwater in the studied regions are prone to limit 226Ra sorption, enhancing its mobility. Overall, this study provided comprehensive knowledge on 226Ra background distribution at local and regional scales. Moreover, it provided a framework to establish 226Ra baselines and determine which geochemical conditions to monitor in well waters in order to use this radionuclide as an indicator of environmental impact caused by anthropogenic activities (e.g. unconventional shale gas exploitation, uranium mining, or nuclear generating power plants).


Subject(s)
Environment , Environmental Monitoring/methods , Radium/chemistry , Water Pollutants, Radioactive/chemistry , Water Pollutants, Radioactive/analysis , Water Wells
18.
Molecules ; 23(3)2018 Mar 05.
Article in English | MEDLINE | ID: mdl-29510568

ABSTRACT

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.


Subject(s)
Actinium/therapeutic use , Alpha Particles/therapeutic use , Astatine/therapeutic use , Bismuth/therapeutic use , Neoplasms/radiotherapy , Radioisotopes/therapeutic use , Radiopharmaceuticals/therapeutic use , Radium/therapeutic use , Actinium/chemistry , Astatine/chemistry , Bismuth/chemistry , Chelating Agents/chemistry , Chelating Agents/pharmacokinetics , Dose-Response Relationship, Radiation , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds, 1-Ring/chemistry , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Humans , Neoplasms/pathology , Radiation Dosage , Radioisotopes/chemistry , Radiopharmaceuticals/chemistry , Radium/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics
19.
Chemosphere ; 202: 651-660, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29602097

ABSTRACT

Peat is a complex material with several organic constituents that contribute to its high capacity to retain metals. In the context of uranium mining, peat can accumulate high concentrations of uranium and its decay products such as radium. Hence, interaction with peat appears to be a key factor in the understanding of the geochemical mechanisms controlling the fate of these products. This study aims to determine the sorption properties of two trace elements, U(VI) and 226Ra, on natural organic matter from peat. The presented method was applied to both natural peat samples originating from a mining context, with various contents of organic matter (from 40 to 70%) and detrital loads, and wetland peat with a more than 98% composition of organic matter. In the present study, considering peat material as a sorbent, its reactivity towards metals and other contaminants can be described as that of an ion-exchanger. A relatively simple model of ion-exchange based on the sorption properties of carboxylic sites has been applied with success to describe the sorption of uranium and radium. In the general overview of the different mechanisms able to control the mobility of these radionuclides in a uranium mining context, organic matter is likely one of the main contributors to radionuclide scavenging even under oxic conditions.


Subject(s)
Radium/chemistry , Soil/chemistry , Uranium/chemistry , Water Pollutants, Radioactive/chemistry , Mining , Radium/analysis , Uranium/analysis , Water Pollutants, Radioactive/analysis , Wetlands
20.
Regul Toxicol Pharmacol ; 92: 245-250, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29277438

ABSTRACT

Black sand samples collected from Baltim beaches (Kafr El-Sheikh governorate) in Egypt on the Mediterranean Sea shore were analyzed radiometrically and evaluated using a nondestructive gamma ray spectroscopic techniques. The natural radionuclides of 226Ra, 232Th and 40K in the black sand samples were identified and quantified. It is found that the activity concentrations for 226Ra, 232Th and 40K in different eleven sites (S1S11) were found within the ranges of 28-322, 91-308 and 81-339 Bq/kg, respectively. Moreover, different radiological hazardous parameters (absorbed dose rate, annual effective dose equivalent, radium activity, annual gonadal dose equivalent and excess lifetime cancer risk) were calculated. The results show that these values are greater than the permissible values due to increasing the activity concentrations of the primordial radionuclides 226Ra, 232Th and 40K. The dose rate for radiation emitted at 1 m from the surface of land was measured directly and the results shown that all sites emit radiation doses more than the international permissible value (57 nGy/h) especially at three sites which around 340 nGy/h. These values are important to establish baseline levels of this environmental radioactivity to detect any upcoming change for the local population and resorts people. The relatively high dose rate will be considered as a spa for the physical therapy such as treatment of some skin diseases and rheumatoid.


Subject(s)
Potassium Radioisotopes/chemistry , Radiation Monitoring/methods , Radioisotopes/chemistry , Radium/chemistry , Soil Pollutants, Radioactive/analysis , Thorium/chemistry , Environmental Monitoring/methods , Gamma Rays , Mediterranean Sea , Radiation Dosage , Radioactivity
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