A reverse 230U/226Th radionuclide generator for targeted alpha therapy applications.

PURPOSE: Thorium-226 (half-life 30.6 m) is a radionuclide of interest for use in targeted alpha therapy applications. Due to its short half-life, 226Th must be provided through a radionuclide generator system from its parent 230U (20.8 d). Furthermore, as the half-life of 226Th is very short, it should be provided in a form that is directly amenable to use in biomedical applications. METHODS: A reverse radionuclide generator system was developed employing a DGA extraction chromatography column. A 230U/226Th parent/daughter solution in equilibrium is added to a DGA column in >6 M HCl. The parent 230U is eluted first in 0.1 M HNO3 followed by elution of 226Th in 0.1 M citrate buffer pH 5. RESULTS: Thorium-226 was recovered from the radionuclide generator column with >96% yield. Greater than 99.5% of the 230U parent was isolated for reuse in the generator. Long term evaluation over six weeks demonstrated consistent supply of 226Th with greater than 99.5% radionuclidic purity. The only contaminant found in the final product was 230U (<0.5%). CONCLUSIONS: The reverse radionuclide generator described herein was shown to be a feasible method for providing 226Th in high yield, purity and in a chemical form that is amenable for direct use in biomedical applications.

Evaluation of antihyperglycemic potential of homeopathic medicines Insulinum, Pancreatinum and Uranium nitricum in Streptozotocin Induced diabetic rats

IntroductionDiabetes Mellitusis an emerging endocrine and metabolic disorder which has affected millions of people globally. Homeopathic system of medicine uses ultra-molecular doses for treatment of Diabetes Mellitus. Homeopathic medicines are prepared from plant, mineral, sarcodes,nosodes and animal parts. Insulinum 6 CH, Pancreatinum 6CH and Uranium nitricum 6 CHareused in homeopathy for treatment of Diabetes Mellitus. However,no preclinical studies have been investigated for the anti-diabetic effect and its safety.MethodsHomeopathic medicines Insulinum 6CH, Pancreatinum 6CHandUranium nitricum6CH(1012)dilution factor were used to examine antihyperglycemic effects in streptozotocin induced diabetic rats. After 28 daysoftreatment,bodyweight, Hematology, Biochemistry (serum glucose, urea, creatinine, SGPT, SGOT, ALP, Triglyceride and HDL-cholesterol), Oral Glucose Tolerance Test, HbA1C with histopathologyof (Liver, Kidney, Pancreas) weremeasured.ResultsAfter Streptozotocin induction, the animals have shown significant increase in the fasting blood glucose level (p<0.01) as compared to normal control animals. Treatment with homeopathic medicine Insulinum 6CH, Pancreatinum 6CHandUranium nitricum6CHpotency showed significant decrease in levels of Glucose (p<0.05), OGTT, Total protein (P<0.001), ALP (P<0.05), Cholesterol (P<0.001), SGPT (P<0.001), SGOT (p<0.01), Urea, HbA1C as compared to diabetic animal.ConclusionsIn the present study homeopathic medicine Insulinum 6CH, Pancreatinum 6CH andUranium nitricum6CHpotency exhibitantihyperglycemic effects in streptozotocin induced diabetic rats.(AU)

Production of 230U/226Th for targeted alpha therapy via proton irradiation of 231Pa.

(230)U and its daughter nuclide (226)Th are novel therapeutic nuclides for application in targeted alpha-therapy of cancer. We have investigated the feasibility of producing (230)U/(226)Th via proton irradiation of (231)Pa according to the reaction (231)Pa(p,2n)(230)U. The experimental excitation function for this reaction is reported for the first time. Cross sections were measured using thin targets of (231)Pa prepared by electrodeposition and (230)U yields were analyzed using alpha-spectrometry. Beam parameters (energy and intensity) were determined both by calculation using a mathematical model based on measured beam orbits and beam current integrator and by parallel monitor reactions on copper foils using high-resolution gamma-spectrometry and IAEA recommended cross-section data. The measured cross sections are in good agreement with model calculations using the EMPIRE-II code and are sufficiently high for the production of (230)U/(226)Th in clinically relevant amounts. A highly effective separation process was developed to isolate clinical grade (230)U from irradiated protactinium oxide targets. Product purity was assessed using alpha- and gamma-spectrometry as well as ICPMS.

Cross-sections of the reaction 232Th(p,3n)230Pa for production of 230U for targeted alpha therapy.

(230)U/(226)Th is a promising novel alpha-emitter system for application in targeted alpha therapy of cancer. The therapeutic nuclides can be produced by proton irradiation of natural (232)Th according to the reaction (232)Th(p,3n)(230)Pa, followed by subsequent beta decay of (230)Pa to (230)U. In this study, the experimental excitation function for the (232)Th(p,3n)(230)Pa reaction up to 34 MeV proton energy has been measured using the stacked-foil technique. The proton energies in the various foils were calculated with the SRIM 2003 code and gamma-ray spectrometry was used to measure the activities of the various radioisotopes produced. The measured cross-sections are in good agreement with selected literature values and with model calculations using the EMPIRE II code. The reaction (232)Th(p,3n)(230)Pa allows the production of carrier-free (230)U in clinically relevant levels.

Acute chemical toxicity of uranium.

Although human experience with uranium spans more than 200 years, the LD50 for acute intake in humans has not been well established. Large acute doses of uranium can produce death from chemical toxicity in rats, guinea pigs, and other small experimental animals, with variation in sensitivity among species. However, there has never been a death attributable to uranium poisoning in humans, and humans seem to be less sensitive to both acute and chronic toxic effects of uranium than other mammalian species studied. Highly relevant data on uranium toxicity in humans are available from the experience of persons administered large doses of uranium for therapy of diabetes and from acute accidental inhalation intakes. Although the data on which to establish oral and inhalation acute LD50 for uranium in humans are sparse, they are adequate to conclude that the LD50 for oral intake of soluble uranium compounds exceeds several grams of uranium and is at least 1.0 g for inhalation intakes. For intakes of uranium compounds of lesser solubility, acute LD50 values are likely to be significantly greater. It is suggested that 5 g be provisionally considered the acute oral LD50 for uranium in humans. For inhalation intakes of soluble compounds of uranium, 1.0 g of uranium is proposed as the provisional acute inhalation LD50.

Dose distributions in a human head phantom for neutron capture therapy using moderated neutrons from the 2.5 meV proton-7Li reaction or from fission of 235U.

The feasibility of neutron capture therapy (NCT) using an accelerator-based neutron source of the 7Li(p,n) reaction produced by 2.5 MeV protons was investigated by comparing the neutron beam tailored by both the Hiroshima University radiological research accelerator (HIRRAC) and the heavy water neutron irradiation facility in the Kyoto University reactor (KUR-HWNIF) from the viewpoint of the contamination dose ratios of the fast neutrons and the gamma rays. These contamination ratios to the boron dose were estimated in a water phantom of 20 cm diameter and 20 cm length to simulate a human head, with experiments by the same techniques for NCT in KUR-HWNIF and/or the simulation calculations by the Monte Carlo N-particle transport code system version 4B (MCNP-4B). It was found that the 7Li(p,n) neutrons produced by 2.5 MeV protons combined with 20, 25 or 30 cm thick D20 moderators of 20 cm diameter could make irradiation fields for NCT with depth-dose characteristics similar to those from the epithermal neutron beam at the KUR-HWNIF.

Uranium-loaded apoferritin with antibodies attached: molecular design for uranium neutron-capture therapy.

A method is described to deliver 235U to tumors; the isotope would then be fissioned by incident neutrons, producing localized lethal radiation sufficient for therapy. Apoferritin was loaded with an average of approximately 800 238U atoms per molecule. Stability of the loaded apoferritin in solution was improved, so that only 8% loss of uranium occurred after 8 days at pH 7. Fab' antibody fragments were covalently attached to the uranium-loaded apoferritin, and the immunoreactivity of the conjugate was 92% of that for antibody alone. Such bio-uranium constructions should provide significant advantages over boronated antibodies to meet the requirements for clinical neutron-capture therapy.

Neutron capture therapy with 235U seeds.

A combination of brachytherapy and neutron capture therapy has been evaluated using 235U metal seeds and external neutron beam irradiation. When thermal neutrons are absorbed by 235U, high-energy neutrons and gamma rays are produced and some of these deposit energy in surrounding tissue. A Monte Carlo program, using the code MCNP, has been used to evaluate two sizes of 235U seeds in a water phantom. The results of flux suppression around the seeds and dose distributions are illustrated and discussed. The results show that high doses can be delivered in a relatively short time by using 235U seeds with neutron capture therapy. This therapy with multiple needles or seeds can be envisioned as a substitute for traditional brachytherapy to give an effective killing dose.