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Sample records for alpha-particle-emitting radioimmunoconjugate 227th-rituximab

  1. Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate 227Th-rituximab

    International Nuclear Information System (INIS)

    The anti-CD20 antibody rituximab labelled with the α-particle-emitting radionuclide 227Th is of interest as a radiotherapeutic agent for treatment of lymphoma. Complete regression of human lymphoma Raji xenografts in 60% of mice treated with 200 kBq/kg 227Th-rituximab has been observed. To evaluate possible late side effects of 227Th-rituximab, the long-term radiotoxicity of this potential radiopharmaceutical was investigated. BALB/c mice were injected with saline, cold rituximab or 50, 200 or 1,000 kBq/kg 227Th-rituximab and followed for up to 1 year. In addition, nude mice with Raji xenografts treated with various doses of 227Th-rituximab were also included in the study. Toxicity was evaluated by measurements of mouse body weight, white blood cell (WBC) and platelet counts, serum clinical chemistry parameters and histological examination of tissues. Only the 1,000 kBq/kg dosage resulted in decreased body weight of the BALB/c mice. There was a significant but temporary decrease in WBC and platelet count in mice treated with 400 and 1,000 kBq/kg 227Th-rituximab. Therefore, the no-observed-adverse-effect level (NOAEL) was 200 kBq/kg. The maximum tolerated activity was between 600 and 1,000 kBq/kg. No significant signs of toxicity were observed in histological sections in any examined tissue. There were significantly (p 227Th-rituximab or non-labelled antibody when compared with control mice. The maximum tolerated dose to bone marrow was between 2.1 and 3.5 Gy. Therapeutically relevant dose levels of 227Th-rituximab were well tolerated in mice. Bone marrow suppression, as indicated by decrease in WBC count, was the dose-limiting radiotoxicity. These toxicity data together with anti-tumour activity data in a CD20-positive xenograft mouse model indicate that therapeutic effects could be obtained with relatively safe dosage levels of the radioimmunoconjugate. (orig.)

  2. Treatment of HER2-Expressing Breast Cancer and Ovarian Cancer Cells With Alpha Particle-Emitting 227Th-Trastuzumab

    International Nuclear Information System (INIS)

    Purpose: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate 227Th-p-isothiocyanato-benzyl-DOTA-trastuzumab (227Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of 227Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene. Methods and Materials: Clonogenic survival and cell growth rates of breast cancer cells treated with 227Th-trastuzumab were compared with rates of cells treated with nonbinding 227Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated. Results: SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml 227Th-trastuzumab for 1 h at 4oC, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines. Conclusions: Clinically relevant activity concentrations of 227Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of 227Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with 227Th-trastuzumab.

  3. The biokinetics of alpha-particle emitting radiopharmaceuticals

    International Nuclear Information System (INIS)

    The past two decades have seen wide interest in the application of alpha-particle emitting radionuclides for targeted endoradiotherapy and a large number of compounds labeled with 211At (T1/2 7.21 h), 212Bi (T1/2 1 h) or 213Bi (T1/2 0.78 h) have been studied. Knowledge of the biokinetic behaviour of such agents is important both for their optimal clinical exploitation and for general radiological protection purposes. Animal studies of the distribution and retention of 211At compounds, including ionic astatide, substituted aromatic compounds and labelled monoclonal antibodies, have provided new information on the biochemistry of astatine. With respect the thyroid gland the uptake of the astatide ion has been shown to be very much lower than that of the iodide ion. Less information is available for 212Bi-labelled radiopharmaceuticals. The available data for both 211At and 212Bi radiopharmaceuticals are reviewed. Cautious generic biokinetic models for inorganic and simple organic compounds of 211At and 212Bi; for [211At]-, and [212Bi]-biphosphonates and for [211At]-, and [212Bi]-monoclonal antibodies, are proposed for use in general radiological protection when compound-specific data are not available. (orig.)

  4. The biokinetics of alpha-particle emitting radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, D.M. [School of Chemistry, Cardiff Univ., Cardiff (United Kingdom); Duffield, J.R. [Faculty of Applied Sciences, Univ. of the West of England, Bristol (United Kingdom)

    2005-07-01

    The past two decades have seen wide interest in the application of alpha-particle emitting radionuclides for targeted endoradiotherapy and a large number of compounds labeled with {sup 211}At (T{sup 1}/{sub 2} 7.21 h), {sup 212}Bi (T{sup 1}/{sub 2} 1 h) or {sup 213}Bi (T{sup 1}/{sub 2} 0.78 h) have been studied. Knowledge of the biokinetic behaviour of such agents is important both for their optimal clinical exploitation and for general radiological protection purposes. Animal studies of the distribution and retention of {sup 211}At compounds, including ionic astatide, substituted aromatic compounds and labelled monoclonal antibodies, have provided new information on the biochemistry of astatine. With respect the thyroid gland the uptake of the astatide ion has been shown to be very much lower than that of the iodide ion. Less information is available for {sup 212}Bi-labelled radiopharmaceuticals. The available data for both {sup 211}At and {sup 212}Bi radiopharmaceuticals are reviewed. Cautious generic biokinetic models for inorganic and simple organic compounds of {sup 211}At and {sup 212}Bi; for [{sup 211}At]-, and [{sup 212}Bi]-biphosphonates and for [{sup 211}At]-, and [{sup 212}Bi]-monoclonal antibodies, are proposed for use in general radiological protection when compound-specific data are not available. (orig.)

  5. Bismuth-212-labeled anti-Tac monoclonal antibody: alpha-particle-emitting radionuclides as modalities for radioimmunotherapy

    International Nuclear Information System (INIS)

    Anti-Tac, a monoclonal antibody directed to the human interleukin 2 (IL-2) receptor, has been successfully conjugated to the alpha-particle-emitting radionuclide bismuth-212 by use of a bifunctional ligand, the isobutylcarboxycarbonic anhydride of diethylenetriaminepentaacetic acid. The physical properties of 212Bi are appropriate for radioimmunotherapy in that it has a short half-life, deposits its high energy over a short distance, and can be obtained in large quantities from a radium generator. Antibody specific activities of 1-40 microCi/microgram (1 Ci = 37 GBq) were achieved. Specificity of the 212Bi-labeled anti-Tac was demonstrated for the IL-2 receptor-positive adult T-cell leukemia line HUT-102B2 by protein synthesis inhibition and clonogenic assays. Activity levels of 0.5 microCi or the equivalent of 12 rad/ml of alpha radiation targeted by anti-Tac eliminated greater than 98% the proliferative capabilities of HUT-102B2 cells with more modest effects on IL-2 receptor-negative cell lines. Specific cytotoxicity was blocked by excess unlabeled anti-Tac but not by human IgG. In addition, an irrelevant control monoclonal antibody of the same isotype labeled with 212Bi was unable to target alpha radiation to cell lines. Therefore, 212Bi-labeled anti-Tac is a potentially effective and specific immunocytotoxic reagent for the elimination of IL-2 receptor-positive cells. These experiments thus provide the scientific basis for use of alpha-particle-emitting radionuclides in immunotherapy

  6. Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of {alpha}-particle-emitting {sup 211}At-labeled trastuzumab

    Energy Technology Data Exchange (ETDEWEB)

    Boskovitz, Abraham; McLendon, Roger E.; Okamura, Tatsunori [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Sampson, John H. [Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States)], E-mail: zalut001@mc.duke.edu

    2009-08-15

    Introduction: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of {alpha}-particle emitting {sup 211}At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. Methods: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 {mu}Ci {sup 211}At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 {mu}Ci {sup 211}At-labeled trastuzumab or saline. In Experiment 3, animals received 28 {mu}Ci {sup 211}At-labeled trastuzumab, 30 {mu}Ci {sup 211}At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. Results: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 {mu}Ci {sup 211}At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 {mu}Ci {sup 211}At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with {sup 211}At-labeled TPS3.2 and {sup 211}At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the {sup 211}At-trastuzumab-treated groups. Conclusion: Intrathecal {sup 211}At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

  7. Radioiodinated iodophenyl maleimide: A potential radioimmunoconjugate with low in vivo deiodination

    International Nuclear Information System (INIS)

    The conceptual design and feasibility of a new sulfhydryl radiolabeled agent, N-(4-[125I]iodophenyl)maleimide, as a potential radioimmunoconjugate is described. The distribution of bovine serum albumin when labeled with 131I by the chloramine-T oxidation procedure or with 125I by maleimide conjugation was studied in normal female Fischer rats. The 125I-iodophenylmaleimide labeled bovine serum albumin showed significantly lower thyroid uptake (1.03% injected dose) and hence greater stability than the 131I labeled bovine serum albumin (4.85% injected dose) at 24 h. This promising result indicates need for further evaluation of iodophenylmaleimide as a potential radioimmunoconjugate. (orig.)

  8. Alpha-particle emitting 213Bi-anti-EGFR immunoconjugates eradicate tumor cells independent of oxygenation.

    Directory of Open Access Journals (Sweden)

    Christian Wulbrand

    Full Text Available Hypoxia is a central problem in tumor treatment because hypoxic cells are less sensitive to chemo- and radiotherapy than normoxic cells. Radioresistance of hypoxic tumor cells is due to reduced sensitivity towards low Linear Energy Transfer (LET radiation. High LET α-emitters are thought to eradicate tumor cells independent of cellular oxygenation. Therefore, the aim of this study was to demonstrate that cell-bound α-particle emitting (213Bi immunoconjugates kill hypoxic and normoxic CAL33 tumor cells with identical efficiency. For that purpose CAL33 cells were incubated with (213Bi-anti-EGFR-MAb or irradiated with photons with a nominal energy of 6 MeV both under hypoxic and normoxic conditions. Oxygenation of cells was checked via the hypoxia-associated marker HIF-1α. Survival of cells was analysed using the clonogenic assay. Cell viability was monitored with the WST colorimetric assay. Results were evaluated statistically using a t-test and a Generalized Linear Mixed Model (GLMM. Survival and viability of CAL33 cells decreased both after incubation with increasing (213Bi-anti-EGFR-MAb activity concentrations (9.25 kBq/ml-1.48 MBq/ml and irradiation with increasing doses of photons (0.5-12 Gy. Following photon irradiation survival and viability of normoxic cells were significantly lower than those of hypoxic cells at all doses analysed. In contrast, cell death induced by (213Bi-anti-EGFR-MAb turned out to be independent of cellular oxygenation. These results demonstrate that α-particle emitting (213Bi-immunoconjugates eradicate hypoxic tumor cells as effective as normoxic cells. Therefore, (213Bi-radioimmunotherapy seems to be an appropriate strategy for treatment of hypoxic tumors.

  9. Assessment of gamma, beta and alpha-particle-emitting nuclides in marine samples

    International Nuclear Information System (INIS)

    Depending on the physical properties of radionuclides different systems must be used for their measurement. Most convenient is if gamma spectrometry can be used by germanium, Silicon or Scintillation detectors (eg. NaI). If, however, the main emission consists of beta or alpha particles or low-energy photons as is the case for radionuclides decaying by electron capture, radiochemical separation and specific source preparations must be undertaken. In such cases also the radiochemical yield must be determined. The radiochemical part mainly follows the lines presented by prof. T. Jaakkola, Department of Radiochemistry, Helsinki, Finland, at a course in radioecology in Lurid, 1991. For very long-lived radionuclides other methods such as mass spectrometry are superior although often associated with sophisticated expensive instrumentation. (author)

  10. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    International Nuclear Information System (INIS)

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies

  11. Low-level measurement of alpha-particle emitting nuclei in ceramics and lead

    International Nuclear Information System (INIS)

    Nearly all natural materials contain trace quantities of uranium (U) and thorium (Th) and their daughter nuclides, many of which emit α-particles in their decay. Lead, at the end of the U-decay chain, typically contains some radioactive 210Pb which is chemically inseparable from the other Pb isotopes. α-particle emission from these decays can affect sensitive electronic components, such as memory chips or processors. Measurement of α-particle emitters can be accomplished by direct detection of the α-particles (which typically provides no positive identification of the emitting isotope because of energy loss in the sample) or by low-background γ-ray spectroscopy (which does provide positive identification via characteristic γ-rays). The latter is by far the best method for screening kg-sized samples of materials like ceramics, aluminum, iron, or copper. The difference between α counting and γ-ray spectroscopy is less for measuring 210Pb in Pb since the 46.5 keV characteristic γ-rays directly following the 210Pb decay are strongly absorbed and both methods are limited to thin layers. This paper discusses these two cases and concludes that a large n-type germanium γ-ray spectrometer is probably the best overall system for both measurements. (author)

  12. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Adams, Gregory P.

    2004-11-24

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies.

  13. High molecular mass radioimmunoconjugates are promising for intraperitoneal α-emitter immunotherapy due to prolonged retention in the peritoneum

    International Nuclear Information System (INIS)

    Introduction: Therapeutic efficacy of intraperitoneal radioimmunotherapy is dependent on the time of retention of the radioimmunoconjugates within the peritoneal cavity. Therefore, the aim of this study was to investigate intraperitoneal retention of Fab, IgG and IgM radioimmunoconjugates. Methods: Female Balb/c mice were injected with 213Bi- or 111In-labeled IgM, IgG and recombinant Fab conjugates intraperitoneally or intravenously. At different time points after injection, whole body distribution of radionuclides was imaged using a gamma camera. Distribution of radionuclides in selected organs was determined via γ-counting after sacrifice. Biological half-lives of the conjugates were calculated from whole body activities. Results: After i.p. injection 213Bi-Fab rapidly accumulated in the kidneys indicative of glomerular filtration and reabsorption. Accumulation of 213Bi-IgG in the kidneys was significantly lower. 213Bi-IgM showed a striking accumulation in the liver 180 min after i.p. injection. 111In-IgG persisted in the circulation up to 72 h both after i.p. and i.v. injection. 111In-IgM showed a continuous accumulation in the liver. Moreover, 111In-IgM was significantly higher 24 h after i.v. injection than i.p. injection both in liver and spleen. These differences could be confirmed via scintigraphy. After injection of 111In-IgG differences in scintigraphic images between i.v. and i.p. were clearly visible only at 3 h. Biological half lives were 24 h, 45 h and 165 h for 111In-IgM, 111In-Fab and 111In-IgG, respectively. Conclusions: Retention of radioimmunoconjugates in the peritoneal cavity positively correlates with the molecular mass of the antibody. Therefore, IgM radioimmunoconjugates should be preferably used in radioimmunotherapy of free floating tumor cells and small tumor cell clusters in the ascites of the peritoneal cavity.

  14. Biodistribution and Dosimetry of 177Lu-tetulomab, a New Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

    OpenAIRE

    Repetto-Llamazares, Ada H. V.; Larsen, Roy H.; Mollatt, Camilla; Lassmann, Michael; Dahle, Jostein

    2013-01-01

    The biodistribution of the anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab (177Lu-DOTA-HH1) was evaluated. Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-tetraxetan-rituximab and free 177Lu in nude mice implanted with Daudi lymphoma xenografts. The data showed that 177Lu-tetulomab had a relevant stability and tumor targeting properties in the human lymphoma model. The half-life of 177Lu allowed significant tumor to normal tissue ratios to be obtained indicatin...

  15. In Vitro Cytotoxicity of Low-Dose-Rate Radioimmunotherapy by the Alpha-Emitting Radioimmunoconjugate Thorium-227-DOTA-Rituximab

    International Nuclear Information System (INIS)

    Purpose: To determine whether the low-dose-rate α-particle-emitting radioimmunoconjugate 227Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. Methods and Materials: CD20-positive lymphoma cell lines were treated with 227Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with 227Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. Results: There was a specific targeted effect on cell growth of the 227Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with 227Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL 227Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 105 to 107 cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy α-particle radiation from 227Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. Conclusions: The low-dose-rate radioimmunoconjugate 227Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

  16. First In Vivo Evaluation of Liposome-encapsulated 223Ra as a Potential Alpha-particle-emitting Cancer Therapeutic Agent

    Energy Technology Data Exchange (ETDEWEB)

    Jonasdottir, Thora J.; Fisher, Darrell R.; Borrebaek, Jorgen; Bruland, Oyvind S.; Larsen, Roy H.

    2006-09-13

    Liposomes carrying chemotherapeutics have had some success in cancer treatment and may be suitable carriers for therapeutic radionuclides. This study was designed to evaluate the biodistribution of and to estimate the radiation doses from the alpha emitter 223Ra loaded into pegylated liposomes in selected tissues. 223Ra was encapsulated in pegylated liposomal doxorubicin by ionophore-mediated loading. The biodistribution of liposomal 223Ra was compared to free cationic 223Ra in Balb/C mice. We showed that liposomal 223 Ra circulated in the blood with an initial half-time in excess of 24 hours, which agreed well with that reported for liposomal doxorubicin in rodents, while the blood half-time of cationic 223Ra was considerably less than one hour. When liposomal 223 Ra was catabolized, the released 223Ra was either excreted or taken up in the skeleton. This skeletal uptake increased up to 14 days after treatment, but did not reach the level seen with free 223Ra. Pre-treatment with non-radioactive liposomal doxorubicin 4 days in advance lessened the liver uptake of liposomal 223 Ra. Dose estimates showed that the spleen, followed by bone surfaces, received the highest absorbed doses. Liposomal 223 Ra was relatively stable in vivo and may have potential for radionuclide therapy and combination therapy with chemotherapeutic agents.

  17. Relativistic alpha-particles emitted in Fe-emulsion interactions at 1.7 A GeV

    International Nuclear Information System (INIS)

    Relativistic α-particles have been studied in 423 Fe-emulsion interactions at 1.7 A Gev. Comparisons of the observed angular distribution with that from 16O-emulsion reactions at 2.1 A GeV reveal that more α particles are observed at large angles in the Fe-emulsion reactions. The α particles with large angles connot be explained by fragmentation from a clean cut spectator. Comparison of the experimental data with moving relativistic Boltzmann distributions shows that a single Boltzmann distribution cannot fit the fragmentation peak and the tail simultaneously. A thermal source (fireball) explaining the tail part of the distribution need to be formed by a mechanism other than simple clean cut participant-spectator picture. A large transverse momentum transfer to spectator before fragmentation may explain the tail. (author)

  18. Hit rates and radiation doses to nuclei of bone lining cells from alpha-particle-emitting radionuclides

    Science.gov (United States)

    Polig, E.; Jee, W. S.; Kruglikov, I. L.

    1992-01-01

    Factors relating the local concentration of a bone-seeking alpha-particle emitter to the mean hit rate have been determined for nuclei of bone lining cells using a Monte Carlo procedure. Cell nuclei were approximated by oblate spheroids with dimensions and location taken from a previous histomorphometric study. The Monte Carlo simulation is applicable for planar and diffuse labels at plane or cylindrical bone surfaces. Additionally, the mean nuclear dose per hit, the dose mean per hit, the mean track segment length and its second moment, the percentage of stoppers, and the frequency distribution of the dose have been determined. Some basic features of the hit statistics for bone lining cells have been outlined, and the consequences of existing standards of radiation protection with regard to the hit frequency to cell nuclei are discussed.

  19. Targeted Cancer Therapy with a Novel Anti-CD37 Beta-Particle Emitting Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

    OpenAIRE

    Repetto-Llamazares, Ada H V; Larsen, Roy H.; Sebastian Patzke; Fleten, Karianne G; David Didierlaurent; Alexandre Pichard; Jean Pierre Pouget; Jostein Dahle

    2015-01-01

    177Lu-DOTA-HH1 (177Lu-HH1) is a novel anti-CD37 radioimmunoconjugate developed to treat non-Hodgkin lymphoma. Mice with subcutaneous Ramos xenografts were treated with different activities of 177Lu-HH1, 177Lu-DOTA-rituximab (177Lu-rituximab) and non-specific 177Lu-DOTA-IgG1 (177Lu-IgG1) and therapeutic effect and toxicity of the treatment were monitored. Significant tumor growth delay and increased survival of mice were observed in mice treated with 530 MBq/kg 177Lu-HH1 as compared with mice ...

  20. A Potential Radioimmunoconjugate 177Lu-DOTA-Bz-(h-R3) for Radioimmunotherapy of EGFR Overexpressing Tumors: Labeling Optimization and in vitro and in vivo Evaluations in Tumor Models

    Czech Academy of Sciences Publication Activity Database

    Beckford, Denis R.; Beran, Miloš; Eigner-Henke, Kateřina; Lázničková, A.; Lázníček, M.; Melichar, František

    2010-01-01

    Roč. 37, - (2010), S295-S295. ISSN 1619-7070. [23rd Annual Congress of the European-Association-of- Nuclear - Medicine (EANM). 09.10.2009-13.10.2010, Vienna] R&D Projects: GA MŠk OE08018 Institutional research plan: CEZ:AV0Z10480505 Keywords : Radioimmunoconjugate * EGFR * Tumor Subject RIV: FR - Pharmacology ; Medidal Chemistry

  1. Radio-immunoconjugated, Dox-loaded, surface-modified superparamagnetic iron oxide nanoparticles (SPIONs) as a bioprobe for breast cancer tumor theranostics

    International Nuclear Information System (INIS)

    In this research, we develop dual modality molecular imaging and also radio-immunotherapy (RIT) bioprobes, in the form of modified superparamagnetic iron oxide nanoparticles (SPIONs) conjugated to radiolabeled antibodies, for PET and MRI of HER2 expressing cancers as well as a PH sensitive drug carrier by embedded an anticancer agent for cancer therapeutic applications. The bioprobes were developed by conjugating 64Cu labeled trastuzumab (herceptin) and rituximab (Anti CD-20) antibodies to modified SPIONs. The SPIONs were modified with carboxymethyl chitosan and functionalized with acrylic acid (AA). Also, with the purpose of identifying more effective bifunctional chelator (BFC), we compared the properties of novel BFC, p-NO2-Bn-PCTA with the commonly used DOTA-NHS for radio-immunoconjugate preparations. Moreover, a chemotherapy drug, doxorubicin, was then loaded onto engineered nanoparticles for targeted intracellular drug delivery and selective cancer cell killing. Resulting radio-immunoconjugated-SPIONs were evaluated for molecular imaging and effective targeting of the HER2+ receptors in SKBR3 cell lines and breast tumor bearing Balb/C mice. Therefore, our biocompatible SPIONs could serve as a promising multifunctional theranostics nanoplatform in dual modality imaging guided RIT of HER2 overexpressing cancer applicable to drug delivery and controlled drug release for trigger both intrinsic and extrinsic pathways of apoptosis. (author)

  2. Targeted Cancer Therapy with a Novel Anti-CD37 Beta-Particle Emitting Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma.

    Directory of Open Access Journals (Sweden)

    Ada H V Repetto-Llamazares

    Full Text Available 177Lu-DOTA-HH1 (177Lu-HH1 is a novel anti-CD37 radioimmunoconjugate developed to treat non-Hodgkin lymphoma. Mice with subcutaneous Ramos xenografts were treated with different activities of 177Lu-HH1, 177Lu-DOTA-rituximab (177Lu-rituximab and non-specific 177Lu-DOTA-IgG1 (177Lu-IgG1 and therapeutic effect and toxicity of the treatment were monitored. Significant tumor growth delay and increased survival of mice were observed in mice treated with 530 MBq/kg 177Lu-HH1 as compared with mice treated with similar activities of 177Lu-rituximab or non-specific 177Lu-IgG1, 0.9% NaCl or unlabeled HH1. All mice injected with 530 MBq/kg of 177Lu-HH1 tolerated the treatment well. In contrast, 6 out of 10 mice treated with 530 MBq/kg 177Lu-rituximab experienced severe radiation toxicity. The retention of 177Lu-rituximab in organs of the mononuclear phagocyte system was longer than for 177Lu-HH1, which explains the higher toxicity observed in mice treated with 177Lu-rituximab. In vitro internalization studies showed that 177Lu-HH1 internalizes faster and to a higher extent than 177Lu-rituximab which might be the reason for the better therapeutic effect of 177Lu-HH1.

  3. 177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

    Directory of Open Access Journals (Sweden)

    Ada H V Repetto-Llamazares

    Full Text Available CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL and chronic lymphocytic leukemia cells (CLL. The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin. The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.

  4. Development of the method for treatment for bone metastasis by using disequilibrium-type alpha particle emitting in vivo generator: 227Th-EDTMP

    International Nuclear Information System (INIS)

    To evaluate the efficacy of an alpha emitting radiopharmaceutical, 227Th-EDTMP for treatment of bone metastasis, 1) the process of bone metastasis on rats were monitored by radiography and gamma scintigraphy, and 2) 227Th-EDTMP were administered to bone metastasis model rats and assessed its palliation effect by von Frey filament test and measured tumor size. Two weeks after tumor cell inoculation, rats showed osteolytic change on cell inoculated site and bone lesion was detected by scintigraphy. In the therapy study, the rats showed no toxic effect by 227Th-EDTMP. However, the tumor volume size was increased with time and the bone pain palliation was comparable to control groups. Further experiment was necessary. (author)

  5. High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a 177Lu-based CD22-specific radioimmunoconjugate and rituximab

    International Nuclear Information System (INIS)

    Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter 177Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A''-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of 177Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1null) interleukin-2 receptor common gamma chain (IL2r γ null) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. 177Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A''-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the 177Lu-labelled anti-CD22 IgG than of 177Lu-labelled rituximab. Treatment with 177Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with 177Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with 177Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL. (orig.)

  6. High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a {sup 177}Lu-based CD22-specific radioimmunoconjugate and rituximab

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Tobias; Boetticher, Benedikt; Keller, Armin; Schlegelmilch, Anne; Jaeger, Dirk; Krauss, Juergen [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); Mier, Walter; Kraemer, Susanne; Leotta, Karin [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); Sauter, Max; Haberkorn, Uwe [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); Grosse-Hovest, Ludger [University of Tuebingen, Department of Immunology, Tuebingen (Germany); Arndt, Michaela A.E. [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); German Cancer Research Center (DKFZ), Immunotherapy Program, National Center for Tumor Diseases, Heidelberg (Germany)

    2016-03-15

    Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter {sup 177}Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A''-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of {sup 177}Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1{sup null}) interleukin-2 receptor common gamma chain (IL2r γ {sup null}) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. {sup 177}Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A''-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the {sup 177}Lu-labelled anti-CD22 IgG than of {sup 177}Lu-labelled rituximab. Treatment with {sup 177}Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with {sup 177}Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with {sup 177}Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for

  7. 123I-labeled HIV-1 tat peptide radioimmunoconjugates are imported into the nucleus of human breast cancer cells and functionally interact in vitro and in vivo with the cyclin-dependent kinase inhibitor, p21WAF-1/Cip-1

    International Nuclear Information System (INIS)

    To evaluate the internalization and nuclear translocation of 123I-tat-peptide radioimmunoconjugates in MDA-MB-468 breast cancer cells and their ability to interact with the cyclin-dependent kinase inhibitor, p21WAF-1/Cip-1. Peptides [GRKKRRQRRRPPQGYGC] harboring the nuclear-localizing sequence from HIV tat domain were conjugated to anti-p21WAF-1/Cip-1 antibodies. Immunoreactivity was assessed by Western blot using lysate from MDA-MB-468 cells exposed to EGF to induce p21WAF-1/Cip-1. Internalization and nuclear translocation were measured. The ability of tat-anti-p21WAF-1/Cip-1 to block G1-S phase arrest in MDA-MB-468 cells caused by EGF-induced p21WAF-1/Cip-1 was evaluated. Tumor and normal tissue uptake were determined at 48 h p.i. in athymic mice implanted s.c. with MDA-MB-468 xenografts injected intratumorally with EGF. There was 13.4±0.2% of radioactivity internalized by MDA-MB-468 cells incubated with 123I-tat-anti-p21WAF-1/Cip-1 and 34.6±3.1% imported into the nucleus. Tat-anti-p21WAF-1/Cip-1(8 μM) decreased the proportion of EGF-treated cells in G1 phase from 81.9±0.7% to 46.1±0.7% (p1 phase fraction to that of unexposed cells (25.8±0.2%). Non-specific tat-mouse IgG did not block EGF-induced G1-S phase arrest. Tumor uptake of radioactivity was higher in mice injected with EGF to induce p21WAF-1/Cip-1 than in mice not receiving EGF (3.1±0.4% versus 1.8±0.2% ID/g; p=0.04). Western blot analysis of tumors revealed a threefold increase in the p21WAF-1/Cip-1/β-actin ratio. We conclude that intracellular and nuclear epitopes in cancer cells can be functionally targeted with tat-radioimmunoconjugates to exploit many more epitopes for imaging and radiotherapeutic applications than have previously been accessible. (orig.)

  8. The human polynucleotide kinase/phosphatase (hPNKP) inhibitor A12B4C3 radiosensitizes human myeloid leukemia cells to Auger electron-emitting anti-CD123 111In-NLS-7G3 radioimmunoconjugates

    International Nuclear Information System (INIS)

    Introduction: Leukemia stem cells (LSCs) are believed to be responsible for initiating and propagating acute myeloid leukemia (AML) and for causing relapse after treatment. Radioimmunotherapy (RIT) targeting these cells may improve the treatment of AML, but is limited by the low density of target epitopes. Our objective was to study a human polynucleotide kinase/phosphatase (hPNKP) inhibitor that interferes with DNA repair as a radiosensitizer for the Auger electron RIT agent, 111In-NLS-7G3, which recognizes the CD123+/CD131- phenotype uniquely displayed by LSCs. Methods: The surviving fraction (SF) of CD123+/CD131- AML-5 cells exposed to 111In-NLS-7G3 (33–266 nmols/L; 0.74 MBq/μg) or to γ-radiation (0.25-5 Gy) was determined by clonogenic assays. The effect of A12B4C3 (25 μmols/L) combined with 111In-NLS-7G3 (16–66 nmols/L) or with γ-radiation (0.25–2 Gy) on the SF of AML-5 cells was assessed. The density of DNA double-strand breaks (DSBs) in the nucleus was measured using the γ-H2AX assay. Cellular dosimetry was estimated based on the subcellular distribution of 111In-NLS-7G3 measured by cell fractionation. Results: Binding of 111In-NLS-7G3 to AML-5 cells was reduced by 2.2-fold in the presence of an excess (1 μM) of unlabeled NLS-7G3, demonstrating specific binding to the CD123+/CD131- epitope. 111In-NLS-7G3 reduced the SF of AML-5 cells from 86.1 ± 11.0% at 33 nmols/L to 10.5 ± 3.6% at 266 nmols/L. Unlabeled NLS-7G3 had no significant effect on the SF. Treatment of AML-5 cells with γ-radiation reduced the SF from 98.9 ± 14.9% at 0.25 Gy to 0.03 ± 0.1% at 5 Gy. A12B4C3 combined with 111In-NLS-7G3 (16–66 nmols/L) enhanced the cytotoxicity up to 1.7-fold compared to treatment with radioimmunoconjugates alone and was associated with a 1.6-fold increase in DNA DSBs in the nucleus. A12B4C3 enhanced the cytotoxicity of γ-radiation (0.25–0.5 Gy) on AML-5 cells by up to 1.5-fold, and DNA DSBs were increased by 1.7-fold. Exposure to 111In-NLS-7G3

  9. Experimental Treatment of Bladder Cancer with Bi-213-anti-EGFR MAb

    International Nuclear Information System (INIS)

    Therapy of non-muscle-invasive bladder cancer (carcinoma in situ) comprises transurethral resection of the tumour and subsequent instillation of the chemotherapeutic drug mitomycin C in order to eradicate remaining tumour cells. Yet 15 – 40% of treated patients relapse within 5 years. Therefore, new therapeutic strategies to combat tumour recurrence are needed. Alpha-particle emitting radionuclides efficiently kill single tumour cells or small tumour cell clusters. Because the epidermal growth factor receptor (EGFR) is overexpressed on bladder cancer cells, conjugates composed of the alpha-emitter Bi-213 and the anti-EGFR antibody matuzumab should provide a powerful drug to eliminate disseminated bladder cancer cells. Therefore, the aims of our study were (i) to analyse the cytotoxic effects of Bi-213-anti-EGFR radioimmunoconjugates at the cellular level, (ii) to evaluate therapeutic efficacy of intravesically applied Bi-213- anti-EGFR-Mab in a nude mouse model with intravesical human bladder cancer xenografts, (iii) to compare Bi- 213-anti-EGFR-Mab efficacy with chemotherapy using mitomycin C and (iv) to demonstrate that radioimmunotherapy is not toxic to cells of the bladder wall and of the kidneys

  10. Bismuth 213-labeled anti-CD45 radioimmunoconjugate to condition dogs for nonmyeloablative allogeneic marrow grafts

    Energy Technology Data Exchange (ETDEWEB)

    Sandmaier, B M.(Fred Hutchinson Cancer Research Center, Seattle, WA); Bethge, W A.(Fred Hutchinson Cancer Research Center, Seattle, WA); Wilbur, D. Scott (Washington, Univ Of); Hamlin, Donald K.(Washington, Univ Of); Santos, E B.(Fred Hutchinson Cancer Research Center, Seattle, WA); Brechbiel, M W.(National Cancer Institute, National Institutes of Health, Bethesda, MD); Fisher, Darrell R.(BATTELLE (PACIFIC NW LAB)); Storb, R. (Fred Hutchinson Cancer Research Center)

    2002-01-01

    To lower treatment-related mortality and toxicity of conventional marrow transplantation, a nonmyeloablative regimen using 200 cGy total-body irradiation (TBI) and mycophenolate mofetil (MMF) combined with cyclosporine (CSP) for postgrafting immunosuppression was developed. To circumvent possible toxic effects of external- beam gamma irradiation, strategies for targeted radiation therapy were investigated. We tested whether the short-lived (46 minutes) alpha-emitter Bi-213 conjugated to an anti-CD45 monoclonal antibody (mAb) could replace 200 cGy TBI and selectively target hematopoietic tissues in a canine model of nonmyeloablative DLA-identical marrow transplantation. Biodistribution studies using iodine 123-labeled anti-CD45 mAb showed uptake in blood, marrow, lymph nodes, spleen, and liver. In a dose-escalation study, 7 dogs treated with the Bi-213-anti-CD45 conjugate (Bi-213 dose, 0.1-5.9 mCi/kg[3.7-218 MBq/kg]) without marrow grafts had no toxic effects other than a mild, reversible suppression of blood counts. On the basis of these studies, 3 dogs were treated with 0.5 mg/kg Bi-213-labeled anti-CD45 mAb (Bi-213 doses, 3.6, 4.6, and 8.8 mCi/kg[133, 170, and 326 MBq/kg]) given in 6 injections 3 and 2 days before grafting of marrow from DLA-identical littermates. The dogs also received MMF (10 mg/kg subcutaneously twice daily the day of transplantation until day 27 afterward) and CSP (15 mg/kg orally twice daily the day before transplantation until 35 days afterward). Therapy was well tolerated except for transient elevations in levels of transaminases in 3 dogs, followed by, in one dog, ascites. All dogs achieved prompt engraftment and stable mixed hematopoietic chimerism, with donor contributions ranging from 30% to 70% after more than 27 weeks of follow-up. These results form the basis for additional studies in animals and the design of clinical trials using Bi-213 as a nonmyeloablative conditioning regimen with minimal toxicity.

  11. Small animal PET imaging of TAG-72 expressing tumor using 68Ga-NOTA-3E8 Fab radioimmunoconjugate

    International Nuclear Information System (INIS)

    The tumor-associated glycoprotein TAG-72 is express ed in the majority of human adenocarcinomas but is rarely expressed in most normal tissues, which makes it a potential target for the diagnosis and therapy of a variety of human cancer. 3E8 is anti-TAG-72 humanized antibody. Antibody fragments have some advantages such as improved pharmacokinetics and reduced immunogenicity compared to whole IgG. 68Ga is a short-lived positron emitter (t1/268 min; β+, 88%) that is produced, independent from a cyclotron, by a 68Ge/68Ga generator. The parent nuclide 68Ge has a long half-life (270.8 day), allowing its use as a generator for more than 1 year. A 68Ga is labeled with antibodies through bifunctional chelators, which allows possible kit formulation and which wide availability of the nuclear imaging agents. In this study, Fab fragment of anti-TAG-72 humanized Ab (3E8) was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4, 7-triacetic acid (p-SCN-Bn-NOTA) and radiolabeled with 68Ga and acquire small animal PET image

  12. Preparation of a pure [sup 99m]Tc-F(ab')[sub 2] radioimmunoconjugate by direct labeling methods

    Energy Technology Data Exchange (ETDEWEB)

    Griffiths, G.L.; Jones, A.L.; Hansen, H.J. (Immunomedics Inc., Morris Plains, NJ (United States)); Goldenberg, D.M. (Center for Molecular Medicine and Immunology, Newark, NJ (United States))

    1994-05-01

    Intact IgG and Fab' can be labeled directly with [sup 99m]Tc to give quantitative incorporation of radioactivity into the protein. With F(ab')[sub 2] the reductive conditions yield a mixture of [sup 99m]Tc-F(ab')[sub 2] and [sup 99m]Tc-Fab'. We now report a direct labeling method to produce only [sup 99m]Tc-F(ab')[sub 2] in quantitative yield and contaminated with [sup 99m]Tc-Fab'. The properties, stability and biodistribution of the [sup 99m]Tc-F(ab')[sub 2] have been compared to [sup 99m]Tc-Fab'. This new technology will allow us to compare technetium direct-labeled IgG, F(ab')[sub 2] and Fab' derivatives of the same antibody for radioimmunodetection. (author).

  13. Comparative uptakes and biodistributions of internalizing vs. noninternalizing copper-64 radioimmunoconjugates in cell and animal models of colon cancer

    International Nuclear Information System (INIS)

    Copper-64-labeled monoclonal antibodies (mAbs) have previously demonstrated unexpectedly effective tumor control in rodent models of cancer at relatively low tumor-absorbed radiation doses. This property has been associated with delivery platforms resulting in cellular internalization. The purpose of the present studies was to evaluate the in vitro internalization and in vivo distribution of a two-antibody model of 64Cu radioimmunotherapy (RIT) in the same cell and animal models of cancer. Biodistributions of an internalizing antibody, cBR96, and a noninternalizing antibody, cT84.66, labeled with 64Cu, were obtained in nude mice bearing LS174T colon carcinoma xenografts from 15 min to 48 h. The 64Cu-DOTA-cBR96 conjugate demonstrated rapid tumor uptake, reaching 20.2% ID/g at 3 h and peaking at 35.4% ID/g by 24 h. Tumor accumulation of 64Cu-DOTA-cT84.66 was more gradual, 8.19% ID/g at 3 h and 43.8% ID/g by 24 h, but maximum uptake was not statistically different from 64Cu-DOTA-cBR96. Mouse xenograft dosimetry was estimated to be 1128 rad/mCi (304.9 mGy/MBq) for 64Cu-DOTA-cBR96 and 1409 rad/mCi (380.5 mGy/MBq) for 64Cu-DOTA-cT84.66. In LS174T cells, internalized radioactivity increased by a factor of 3.8 over 4 h for 64Cu-DOTA-cBR96, but remained unchanged 64Cu-DOTA-cT84.66. When normalized to uptake at 1 h, cellular efflux of 64Cu was essentially identical for both mAbs. The biodistributions and tumor dosimetry of these internalizing and noninternalizing radiolabeled mAbs were sufficiently similar for direct comparison of the therapeutic efficacies of low doses of 64Cu RIT agents in the same animal model of cancer

  14. 213Bi-anti-EGFR radioimmunoconjugates and X-ray irradiation trigger different cell death pathways in squamous cell carcinoma cells

    International Nuclear Information System (INIS)

    Introduction: Treatment of patients with squamous cell carcinoma of head and neck is hampered by resistance of tumor cells to irradiation. Additional therapies enhancing the effect of X-ray irradiation may be beneficial. Antibodies targeting EGFR have been shown to improve the efficacy of radiation therapy. Therefore, we analyzed cytotoxicity of 213Bi-anti-EGFR immunoconjugates in combination with X-ray irradiation. Methods: The monoclonal anti-EGFR antibody matuzumab was coupled to CHX-A”-DTPA forming stable complexes with 213Bi. Cytotoxicity of X-ray radiation, of treatment with 213Bi-anti-EGFR monoclonal antibodies (MAb) or of a combined treatment regimen was assayed using cell proliferation and colony formation assays in UD-SCC5 cells. Key proteins of cell-cycle arrest and cell death were examined by Western blot analysis. Cell cycle analysis was performed by flow cytometry. DNA double-strand breaks were detected via γH2AX and quantified using Definiens™ software. Results: Irradiation with X-rays or treatment with 213Bi-anti-EGFR-MAb resulted in median lethal dose (LD50) values of 12 Gy or 130 kBq/mL, respectively. Treatment with 37 kBq/mL of 213Bi-anti-EGFR-MAb or 2 Gy of X-rays had only little effect on colony formation of UD-SCC5 cells. In contrast, a combined treatment regimen (37 kBq/mL plus 2 Gy) significantly decreased colony formation and enhanced the formation of DNA double-strand breaks. As revealed by flow cytometry, radiation treatments caused accumulation of cells in the G0/G1 phase. Both treatment with 213Bi-anti-EGFR immunoconjugates and application of the combined treatment regimen triggered activation of genes of signaling pathways involved in cell-cycle arrest and induction of apoptosis like p21/Waf, GADD45, Puma and Bax, which were only marginally modulated by X-ray irradiation of cells. Conclusions: 213Bi-anti-EGFR-MAb enhances cytotoxicity of X-ray irradiation in UD-SCC5 cells most probably due to effective induction of DNA double-strand breaks. Induction of genes involved in cell-cycle arrest and cell death is almost exclusively due to 213Bi-anti-EGFR-MAb and seems to be independent of p53 function

  15. Site-specific conjugation of HIV-1 tat peptides to IgG: a potential route to construct radioimmunoconjugates for targeting intracellular and nuclear epitopes in cancer

    International Nuclear Information System (INIS)

    Our objective was to study the cellular and nuclear uptake of 123I-mouse IgG (123I-mIgG) linked to peptides [GRKKRRQRRRPPQGYGC] harbouring the membrane-translocating and nuclear import sequences of HIV-1 tat protein. Carbohydrates on mIgG were oxidized by NaIO4, then reacted with a 40-fold excess of peptides. Displacement of binding of anti-mouse IgG (Fab specific; α-mFab) to 123I-mIgG by tat-mIgG or mIgG was compared. Internalization and nuclear translocation of 123I-tat-mIgG in MDA-MB-468, MDA-MB-231 or MCF-7 breast cancer cells were measured. The immunoreactivity of imported tat-mIgG was evaluated by measuring binding of 123I-α-mFab to cell lysate and by displacement of binding of 123I-mIgG to α-mFab by cell lysate. Biodistribution and nuclear uptake of 123I-tat-mIgG, 123I-mIgG and 123I-tat were compared in mice bearing s.c. MDA-MB-468 tumours. There was a 15-fold decrease in affinity of α-mFab for tat-mIgG compared with mIgG. Internalized radioactivity imported into the nucleus for 123I-tat-mIgG in MDA-MB-468, MDA-MB-231 and MCF-7 cells was 61.5±0.6%, 60.3±3.6% and 64.7±1.0%, respectively. The binding of 123I-α-mFab to lysate from MDA-MB-468 cells importing tat-mIgG was 17-fold higher than that for cells not exposed to tat-mIgG. Imported tat-mIgG competed with tat-mIgG for displacement of binding of 123I-mIgG to α-mFab. Conjugation of mIgG to tat peptides did not change tissue distribution. Nuclear localization for 123I-tat-mIgG in MDA-MB-468 tumours was 28.1±5.6%, and for liver, spleen and kidneys it was 41.7±2.7%, 13.8±0.8% and 36.9±3.3%, respectively. (orig.)

  16. High efficiency charged-particle spectrometer using gridded ionization chamber for fast-neutron induced reactions

    International Nuclear Information System (INIS)

    A high efficiency charged particle spectrometer for fast neutron induced reactions has been developed using a gridded-ionization chamber taking advantage of its large solid angle and capability of energy-angle determination. It is characterized by high stopping-power and low background to be applicable for alpha-particles emitted by 15 MeV neutrons and protons for MeV incident neutrons. The spectrometer has been applied successfully for (n, alpha) and (n, p) reactions. (orig.)

  17. Health Risk Evaluations for Ingestion Exposure of Humans to Polonium-210

    OpenAIRE

    Scott, Bobby R.

    2007-01-01

    The incident in London during November 2006 involving a lethal intake by Mr. Alexander Litvinenko of the highly-radioactive, alpha-particles-emitting polonium-210 (Po-210) isotope, presumably via ingestion, sparked renewed interest in the area of Po-210 toxicity to humans. This paper is the result of assembling and interpreting existing Po-210 data within the context of what is considered a reliable risk model (hazard-function [HF] model) for characterizing the risk of death from deterministi...

  18. Open problems in formation and decay of composite systems in heavy ion reactions

    Indian Academy of Sciences (India)

    G Viesti; V Rizzi; M Barbui; D Fabris; M Lunardon; G Nebbia; S Moretto; S Pesente; M Cinausero; E Fioretto; G Prete; D Shetty

    2001-08-01

    New highly exclusive experiments in the field of formation and decay of composite systems in heavy ion reactions are presented. Dynamical effects are reviewed in the light of recent works on the role of the / asymmetry between projectile and target. The possibility of extracting directly from the experimental data the emission barrier of alpha particles emitted from highly excited nuclei is discussed. Finally, the first experimental evidence of double giant resonance excitation in fusion-evaporation reaction is presented.

  19. Is the Double Giant Dipole Resonance Process Responsible for Alpha Emission in Ternary Fission?

    Institute of Scientific and Technical Information of China (English)

    HAN Hong-Yin(韩洪银); WAND Yi-Hua(王屹华); G.Mouze

    2001-01-01

    The Monte Carlo program built on the double giant dipole resonance model proposed by Mouze et al. [Nuovo Cimento A 110(1997)1097] was employed to calculate the energy spectrum of alpha particles emitted in the spontaneous ternary fission of 252Cf. It has been found that in the case of the zero orbital angular momentum of alpha particles in the alpha decay of the fragments, the measured alpha spectrum can be reproduced approximately by the model without any adjustable parameter.

  20. Derivation of a novel formula for α-decay half-life

    International Nuclear Information System (INIS)

    Based on the basic principle of quantal decay of particle, we derive a formula of logarithm of decay half-life of an alpha particle emitting from a radioactive nucleus. The process of decay is understood as the transition of the particle from an isolated quasi-bound state to a scattering state. In this picture, the decay width is a resonance width in the system consisting of an α-cluster and the residual nucleus

  1. Particle detectors based on InP Schottky diodes

    International Nuclear Information System (INIS)

    A study of electrical properties and detection performance of Indium Phosphide detector structures with Schottky contacts prepared on high purity p-type InP was performed. Schottky barrier detectors were prepared by vacuum evaporation of Pd on p-type epitaxial layers grown on Zn-doped p-type substrates. The detection performance of the detectors was characterized by the measurement of pulse-height spectra with alpha particles emitted from 241Am source at room temperature. The influence of the quality of p-type epitaxial layers on the charge-collection efficiency and energy resolution in the full-width half-maximum is discussed.

  2. Alpha emitters activity measurement using the defined solid angle method

    International Nuclear Information System (INIS)

    The defined solid angle counting method can reach a very high accuracy, specially for heavy ions as alpha particles emitted by a radioactive source. The activity measurement of such sources with a relative uncertainty of the order of 0.01% is investigated. Such an accuracy is available only under suitable conditions: the radiation emitted by the source must be isotropic and all the particles emitted in the effective solid angle must be detected. The efficiency detection value must be equal to unity and phenomena such as absorption or scattering must be null. It is shown that corrections often become necessary. All parameters which can influence the measurements are studied

  3. Development of low level alpha particle counting system

    International Nuclear Information System (INIS)

    Much attention has been paid to the trace analysis of uranium and thorium contained in the base material of LSI or VLSI, since the so-called ''soft-error'' of the memory device was known to be due to alpha particles emitted from these radioactive elements. We have developed an apparatus to meet the needs of estimating such a very small quantity of U and Th of the level of ppb, by directly counting alpha particles using a gas-flow type proportional counter. This method requires no sophisticated analytical skill, and the accuracy of the result is satisfactory. The instrumentation and some application of this apparatus are described. (author)

  4. Analysis of a liquid sample residue using in situ alpha spectrometry

    International Nuclear Information System (INIS)

    Three in situ alpha spectrometry methods were demonstrated to rapidly detect alpha-particle emitting radionuclides from a liquid sample. The liquid containing natU and 241Am was evaporated under an infrared lamp and the residue was analyzed in a vacuum and at ambient air pressure. The residue was too thick to determine activities of individual nuclides, but their identification and activity ratio calculations were possible. U and 241Am behaved differently during the liquid dry off, which led to alpha peaks of different shape. This finding should be taken into account for preparing future spectrum unfolding programs. (author)

  5. Detection of alpha particles with undoped poly (ethylene naphthalate)

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Hidehito, E-mail: hidehito@rri.kyoto-u.ac.jp [Kyoto University, 2, Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Shirakawa, Yoshiyuki; Kitamura, Hisashi [National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); Sato, Nobuhiro; Takahashi, Sentaro [Kyoto University, 2, Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan)

    2014-03-01

    There has been recent interest in the use of undoped, aromatic-ring polymers as organic scintillation materials for radiation detectors. Here, we characterise the response of poly (ethylene naphthalate) (PEN) to alpha particles. The energy response to 5486 keV alpha particles emitted from {sup 241}Am was 554±45 keV electron equivalents (keVee), with an energy resolution of 11.2±0.1%. The energy response to 6118 keV alpha particles emitted from {sup 252}Cf was 618±45 keVee, with a resolution of 8.8±0.1%. It is also important to characterise the refractive index because it determines how efficiently light propagates in scintillation materials to the photodetector. By taking into account the PEN emission spectrum, it was revealed that its effective refractive index was 1.70. Overall, the results indicate that PEN has potential as a scintillation material for the detection of alpha particles. - Highlights: • PEN is characterised as a scintillation material for alpha particles. • The effective refractive index for PEN is 1.70 in its emission spectrum. • The response to 5486 (6118) keV alpha particles was 554±45 (618±45) keVee. • The energy resolution for 5486 (6118) keV alpha particles was 11.2±0.1 (8.8±0.1) %. • This work will stimulate future use of PEN for radiation detection.

  6. Analysis of radioactive impurities in alumina and silica used for electronic materials

    International Nuclear Information System (INIS)

    It has been established that soft error of high precision electronic circuits can be induced by alpha-particles emitted from the naturally occurring radioactive impurities such as U, Th. As the electronic circuits have recently become lower dimension and higher density, these alpha-particle emitting radioactive impurities have to be strictly controlled. The aim of this study is to develop of NAA(Neutron Activation Analysis) and gamma-spectrometry to improve the analytical sensitivity(ng/g) and precision of U and Th. New NAA methods have been established using the HTS(Hydraulic Transfer System) irradiation facility which has been used to produce radioisotopes for industries and medicines instead of PTS(Pneumatic Transfer System) irradiation facility which has been used in general NAA. When the ultra-trace impurities have to be analyzed by NAA, background gamma-ray spectra induced from 222Rn and its progeny nuclides in air is serious problem. This unstable background has been eliminated or stabilized by the use of a nitrogen purging system. Ultra trace amounts of U(0.1ng/g) and Th(0.01ng/g) in alumina ball and high purity silica used for EMC could be analyzed by the use of HTS-NAA and low background gamma-spectrometry

  7. NAA and low-background Υ- spectrometry for the analysis of U and Th in high purity silica used in electronic devices

    International Nuclear Information System (INIS)

    It has been established that soft error of high precision electronic circuits can be induced by alpha particle emitted from the naturally occurring radioactive impurities such as U and Th. Silica has used in electronic industries as the base materials and impurities must be controlled strictly. Recently, electronic circuits have become lower dimension and higher density, so alpha-particle emitting radioactive impurities have to be strictly controlled. The objective of the present study was to develop of NAA and gamma-spectrometry for the sensitive (ng/g) and precise analysis of U and Th. A new NAA method has been established using the HTS irradiation facility which has been used to produce radioisotopes for industries and medicines. When the ultratrace impurities have to be analyzed by NAA, background gamma-ray spectra induced from 222Rn and its progeny nuclides in atmosphere are serious problem. This unstable background was eliminated and stabilized by the use of a nitrogen purging system. By the use of HTS-NAA and low background gamma-spectrometry ultratrace amounts of U (0.1ng/g) and Th (0.01ng/g) in high purity silica could be analyzed

  8. In vivo evaluation of a lead-labeled monoclonal antibody using the DOTA ligand

    International Nuclear Information System (INIS)

    The aim of this study was to assess the utility of a radioimmunoconjugate containing a lead radionuclide for therapy and scintigraphy applications. The radioimmunoconjugate evaluated consisted of a bifunctional DOTA ligand and monoclonal antibody (MAb) B72.3 using athymic mice bearing LS-174T tumors, human colon carcinoma xenografts. In the studies reported here, the lead-203-DOTA complex itself was first demonstrated to have in vivo stability. MAb B72.3 was then conjugated with the DOTA ligand and labeled with 203Pb, and the immunoreactivity of B72.3 was maintained. The localization of the radioimmunoconjugate to tumor tissue and other select organs paralleled that of DOTA-125I-B72.3, suggesting a similar metabolic pattern of the two radioimmunoconjugates. Thus, the DOTA-metal complex does not alter the behavior of the radioimmunoconjugate. Tumor localization of the 203Pb-DOTA-B72.3 conjugate was demonstrated with biodistribution studies as well as immunoscintigraphy studies. Such data highlight the stability of a lead radionuclide in the DOTA ligand. The suitability of this chelation chemistry for labeling radioimmunoconjugates with a lead radionuclide now makes its application in nuclear medicine a feasible proposition. (orig.)

  9. Light-particle emission in reactions induced with carbon and oxygen ions

    International Nuclear Information System (INIS)

    Preliminary results are presented from three different experiments in which light particles emitted during the course of heavy-ion-induced reactions have been studied. The common primary motivation for undertaking these studies was to determine the nature and extent of nonequilibrium particle emission. The three experiments involved measurements of energies, angular correlations, and multiplicities of neutrons or alpha particles emitted in coincidence with deeply inelastic products or with evaporation residues produced as follows: neutrons from reactions of 16O with 93Nb at 12.9 MeV/u; alphas produced in the same system; and neutrons produced in 12C reactions with 158Gd and in 13C reactions with 157Gd at about 12.4 MeV/u. 3 figures

  10. Flow-cytometric measurements of somatic cell mutations in Thorotrast patients

    International Nuclear Information System (INIS)

    Exposure to ionizing radiation is a well-recognized risk factor for cancer development. Because ionizing radiation can induce mutations, an accurate way of measuring somatic mutation frequencies could be a useful tool for evaluating cancer risk. In the present study, we have examined in vivo somatic mutation frequencies at the erythrocyte glycophorin A and T-cell receptor loci in 18 Thorotrast patients. These persons have been continuously irradiated with alpha particles emitted from the internal deposition of thorium dioxide and thus have increased risks of certain malignant tumors. When compared with controls, the Thorotrast patients showed a significantly higher frequency of mutants at the lymphocyte T-cell receptor loci but not at the erythrocyte glycophorin A loci. (author)

  11. Room temperature particle detectors based on indium phosphide

    Energy Technology Data Exchange (ETDEWEB)

    Yatskiv, R., E-mail: yatskiv@ufe.c [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Praha 8 (Czech Republic); Grym, J.; Zdansky, K. [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Praha 8 (Czech Republic); Pekarek, L. [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Praha 8 (Czech Republic); Institute of Physics, Academy of Sciences of the Czech Republic, Na Slovance 2, 18221 Praha 8 (Czech Republic)

    2010-01-01

    A study of electrical properties and detection performance of particle detectors based on bulk InP and semiconducting LPE layers operated at room temperature is presented. Bulk detectors were fabricated on semi-insulating InP crystals grown by liquid-encapsulated Czochralski (LEC) technique. High purity InP layers of both n- and p-type conductivity were used to fabricate detector structures with p-n junction. The detection performance of particle detectors was measured by pulse-height spectra with alpha particles emitted from {sup 241}Am source at room temperature. Better noise properties were achieved for detectors with p-n junctions due to better quality contacts on p-type layers.

  12. Room temperature particle detectors based on indium phosphide

    Science.gov (United States)

    Yatskiv, R.; Grym, J.; Zdansky, K.; Pekarek, L.

    2010-01-01

    A study of electrical properties and detection performance of particle detectors based on bulk InP and semiconducting LPE layers operated at room temperature is presented. Bulk detectors were fabricated on semi-insulating InP crystals grown by liquid-encapsulated Czochralski (LEC) technique. High purity InP layers of both n- and p-type conductivity were used to fabricate detector structures with p-n junction. The detection performance of particle detectors was measured by pulse-height spectra with alpha particles emitted from 241Am source at room temperature. Better noise properties were achieved for detectors with p-n junctions due to better quality contacts on p-type layers.

  13. Particle detectors based on semiconducting InP epitaxial layers

    Science.gov (United States)

    Yatskiv, R.; Grym, J.; Zdansky, K.

    2011-01-01

    A study of electrical properties and detection performance of two types of Indium Phosphide detector structures was performed: (i) with p-n-junction and (ii) with Schottky contact prepared on high purity p-type InP. The p-n junction detectors were based on a high purity InP:Pr layers of both n- and p- type conductivity with carrier concentration on the order of 1014 cm-3 grown on Sn doped n-type substrate. Schottky barrier detectors were prepared by vacuum evaporation of Pd on high purity p-type epitaxial layer grown on Mn doped p-type substrate. The detection performance of particle detectors was measured by pulse-height spectra with alpha particles emitted from 241Am source at room temperature.

  14. Room temperature particle detectors based on indium phosphide

    International Nuclear Information System (INIS)

    A study of electrical properties and detection performance of particle detectors based on bulk InP and semiconducting LPE layers operated at room temperature is presented. Bulk detectors were fabricated on semi-insulating InP crystals grown by liquid-encapsulated Czochralski (LEC) technique. High purity InP layers of both n- and p-type conductivity were used to fabricate detector structures with p-n junction. The detection performance of particle detectors was measured by pulse-height spectra with alpha particles emitted from 241Am source at room temperature. Better noise properties were achieved for detectors with p-n junctions due to better quality contacts on p-type layers.

  15. Particle detectors based on semiconducting InP epitaxial layers

    Energy Technology Data Exchange (ETDEWEB)

    Yatskiv, R; Grym, J; Zdansky, K, E-mail: yatskiv@ufe.cz [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Praha 8 (Czech Republic)

    2011-01-15

    A study of electrical properties and detection performance of two types of Indium Phosphide detector structures was performed: (i) with p-n-junction and (ii) with Schottky contact prepared on high purity p-type InP. The p-n junction detectors were based on a high purity InP:Pr layers of both n- and p- type conductivity with carrier concentration on the order of 10{sup 14} cm{sup -3} grown on Sn doped n-type substrate. Schottky barrier detectors were prepared by vacuum evaporation of Pd on high purity p-type epitaxial layer grown on Mn doped p-type substrate. The detection performance of particle detectors was measured by pulse-height spectra with alpha particles emitted from {sup 241}Am source at room temperature.

  16. Particle detectors based on semiconducting InP epitaxial layers

    International Nuclear Information System (INIS)

    A study of electrical properties and detection performance of two types of Indium Phosphide detector structures was performed: (i) with p-n-junction and (ii) with Schottky contact prepared on high purity p-type InP. The p-n junction detectors were based on a high purity InP:Pr layers of both n- and p- type conductivity with carrier concentration on the order of 1014 cm-3 grown on Sn doped n-type substrate. Schottky barrier detectors were prepared by vacuum evaporation of Pd on high purity p-type epitaxial layer grown on Mn doped p-type substrate. The detection performance of particle detectors was measured by pulse-height spectra with alpha particles emitted from 241Am source at room temperature.

  17. Evaluation of soft errors rate in a commercial memory EEPROM

    International Nuclear Information System (INIS)

    Soft errors are transient circuit errors caused by external radiation. When an ion intercepts a p-n region in an electronic component, the ionization produces excess charges along the track. These charges when collected can flip internal values, especially in memory cells. The problem affects not only space application but also terrestrial ones. Neutrons induced by cosmic rays and alpha particles, emitted from traces of radioactive contaminants contained in packaging and chip materials, are the predominant sources of radiation. The soft error susceptibility is different for different memory technology hence the experimental study are very important for Soft Error Rate (SER) evaluation. In this work, the methodology for accelerated tests is presented with the results for SER in a commercial electrically erasable and programmable read-only memory (EEPROM). (author)

  18. Classical behavior in quantum systems: the case of straight tracks in a cloud chamber

    CERN Document Server

    Teta, Alessandro

    2009-01-01

    The aim of this review is to discuss in a pedagogical way the problem of the emergence of a classical behavior in certain physical systems which, in principle, are correctly described by quantum mechanics. It is stressed that the limit $\\hbar \\to 0$ is not sufficient and the crucial role played by the environment must be taken into account. In particular it is recalled the old problem raised by Mott in 1929 (\\cite{m}) concerning the straight tracks observed in a cloud chamber, produced by an $\\alpha$-particle emitted by a source in the form of a spherical wave. The conceptual relevance of the problem for a clearer understanding of the classical limit is discussed in a historical perspective. Moreover a simple mathematical model is proposed, where the result of Mott is obtained in a rigorous mathematical way.

  19. Compact Raman Lidar Measurement of Liquid and Vapor Phase Water Under the Influence of Ionizing Radiation

    Science.gov (United States)

    Shiina, Tatsuo; Chigira, Tomoyuki; Saito, Hayato; Manago, Naohiro; Kuze, Hiroaki; Hanyu, Toshinori; Kanayama, Fumihiko; Fukushima, Mineo

    2016-06-01

    A compact Raman lidar has been developed for studying phase changes of water in the atmosphere under the influence of ionization radiation. The Raman lidar is operated at the wavelength of 349 nm and backscattered Raman signals of liquid and vapor phase water are detected at 396 and 400 nm, respectively. Alpha particles emitted from 241Am of 9 MBq ionize air molecules in a scattering chamber, and the resulting ions lead to the formation of liquid water droplets. From the analysis of Raman signal intensities, it has been found that the increase in the liquid water Raman channel is approximately 3 times as much as the decrease in the vapor phase water Raman channel, which is consistent with the theoretical prediction based on the Raman cross-sections. In addition, the radius of the water droplet is estimated to be 0.2 μm.

  20. Study of the odd-${A}$, high-spin isomers in neutron-deficient trans-lead nuclei with ISOLTRAP

    CERN Multimedia

    Herfurth, F; Blaum, K; Beck, D; Kowalska, M; Schwarz, S; Stanja, J; Huyse, M L; Wienholtz, F

    We propose to measure the excitation energy of the $\\frac{13^{+}}{2}$ isomers in the neutron-deficient isotopes $^{193,195,197}$Po with the ISOLTRAP mass spectrometer. The assignment of the low- and high-spin isomers will be made by measuring the energy of the $\\alpha$- particles emitted in the decay of purified beams implanted in a windmill system. Using $\\alpha$-decay information, it is then also possible to determine the excitation energy of the similar isomers in the $\\alpha$-daughter nuclei $^{189,191,193}$Pb, $\\alpha$-parent nuclei $^{197,199,201}$Rn, and $\\alpha$-grand-parent nuclei $^{201,203,205}$Ra. The polonium beams are produced with a UC$_{\\textrm{x}}$ target and using the RILIS.

  1. Compact Raman Lidar Measurement of Liquid and Vapor Phase Water Under the Influence of Ionizing Radiation

    Directory of Open Access Journals (Sweden)

    Shiina Tatsuo

    2016-01-01

    Full Text Available A compact Raman lidar has been developed for studying phase changes of water in the atmosphere under the influence of ionization radiation. The Raman lidar is operated at the wavelength of 349 nm and backscattered Raman signals of liquid and vapor phase water are detected at 396 and 400 nm, respectively. Alpha particles emitted from 241Am of 9 MBq ionize air molecules in a scattering chamber, and the resulting ions lead to the formation of liquid water droplets. From the analysis of Raman signal intensities, it has been found that the increase in the liquid water Raman channel is approximately 3 times as much as the decrease in the vapor phase water Raman channel, which is consistent with the theoretical prediction based on the Raman cross-sections. In addition, the radius of the water droplet is estimated to be 0.2 μm.

  2. Determination of uranium and thorium contents inside different materials using track detectors and mean critical angles

    CERN Document Server

    Misdaq, M A; Ktata, A; Merzouki, A; Youbi, N

    1999-01-01

    The critical angles of the CR-39 (theta sub c) and LR-115 type II (theta sub c ') solid state nuclear track detectors (SSNTD) for detecting alpha-particles emitted by the uranium and thorium series have been evaluated by calculating the corresponding ranges of the emitted alpha-particles in different material samples and in the SSNTD studied. The influence of the emitted alpha-particles initial and residual energies on the critical angles of the SSNTD studied has been investigated. The uranium and thorium contents of different geological samples have been evaluated by exploiting data obtained for the critical angles of the CR-39 and LR-115 type II solid state nuclear track detectors and measuring the corresponding densities of tracks.

  3. Pre-mining variation of alpha activity intake in shells of fresh water mussels

    Energy Technology Data Exchange (ETDEWEB)

    Kvasnicka, J.; McNally, P.; McKay, T. (Northern Territory Dept. of Mines and Energy, Darwin (Australia)); Allison, H. (Office of the Supervising Scientist for the Alligator Rivers Region, Sydney (Australia)); Bywater, J. (Ranger Uranium Mines Proprietary Ltd., Chatswood (Australia))

    1985-04-01

    Specific alpha activity distribution in fresh water mussel shells has been studied for mussels collected from several billabongs in the uranium province in the Northern Territory. Track etch detector Kodak LR-115 was exposed to alpha particles emitted from surface areas of shells previously dated by growth-rings counting procedures. The annual average alpha activity was calculated from alpha emission track etch densities corresponding to the dated areas on the shell surfaces. An interesting correlation between the annual rainfall and corresponding annual average shell activity was observed. The results demonstrated that this method could indicate aspects of variations in natural pre-mining radiation background of billabongs which are the source of some of the traditional diet components, such as mussels, for local aboriginals. The evaluation of the future influence of uranium mining on the levels of radiation likely to be taken up into diet components must take careful consideration of these observed variations in natural background radiation.

  4. Development of the MICROMEGAS Detector for Measuring the Energy Spectrum of Alpha Particles by using a 241-Am Source

    CERN Document Server

    Kim, Do Yoon; Shin, Jae Won; Park, Tae-Sun; Hong, Seung-Woo; Andriamonje, Samuel; Kadi, Yacine; Tenreiro, Claudio

    2016-01-01

    We have developed MICROMEGAS (MICRO MEsh GASeous) detectors for detecting {\\alpha} particles emitted from an 241-Am standard source. The voltage applied to the ionization region of the detector is optimized for stable operation at room temperature and atmospheric pressure. The energy of {\\alpha} particles from the 241-Am source can be varied by changing the flight path of the {\\alpha} particle from the 241 Am source. The channel numbers of the experimentally-measured pulse peak positions for different energies of the {\\alpha} particles are associated with the energies deposited by the alpha particles in the ionization region of the detector as calculated by using GEANT4 simulations; thus, the energy calibration of the MICROMEGAS detector for {\\alpha} particles is done. For the energy calibration, the thickness of the ionization region is adjusted so that {\\alpha} particles may completely stop in the ionization region and their kinetic energies are fully deposited in the region. The efficiency of our MICROMEGA...

  5. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors

    Directory of Open Access Journals (Sweden)

    Chatal Jean-Francois

    2009-09-01

    Full Text Available Radioimmunotherapy (RIT has been proven effective in the treatment of radiosensitive non-Hodgkin lymphoma but, for radioresistant solid tumors, new approaches are necessary to improve the clinical effectiveness. A real improvement has been the introduction of the pretargeting technology which appeared to be able to significantly increase tumor-to-normal organ uptake ratios.Another very promising approach consists in associating RIT with other treatment modalities. Finally the use of alpha particle-emitting radionuclides such as astatin-211 or bismuth-213 (alpha-RIT should allow to efficiently eradicate disseminated microscopic clusters of tumor cells or isolated tumor cells which fit well with the short path length of alpha particles.

  6. ATMS_Phase_II: a standalone code for counting non-overlapping high-density nuclear tracks

    Science.gov (United States)

    Khayat, Omid

    2014-02-01

    In this paper we focus on counting and density measurements of non-overlapping high-density nuclear track images. This paper is a continuum of another paper of the author introducing ATMS software which has been particularly developed for overlapping nuclear tracks. Here, as the second phase of the ATMS software, a hybrid algorithm is presented for counting the tracks according to user parameter initialization, template inserting and correlation estimation to initially detect nuclear track candidates, then to evaluate geometrical and contextual features of track candidates and finally a decision-making process according to the user's sensitivity considerations. The presented hybrid algorithm is verified and validated by a database containing 100 randomly selected Alpha track images captured from the surface of CR-39 polycarbonate detectors irradiated by environmental Alpha particles emitted from Rn-222 near a copper mine around Anarak city.

  7. Acrylic purification and coatings

    CERN Document Server

    ,

    2012-01-01

    Radon (Rn) and its decay daughters are a well-known source of background in direct WIMP detection experiments, as either a Rn decay daughter or an alpha particle emitted from a thin inner surface layer of a detector could produce a WIMP-like signal. Different surface treatment and cleaning techniques have been employed in the past to remove this type of contamination. A new method of dealing with the problem has been proposed and used for a prototype acrylic DEAP-1 detector. Inner surfaces of the detector were coated with a layer of ultra pure acrylic, meant to shield the active volume from alphas and recoiling nuclei. An acrylic purification technique and two coating techniques are described: a solvent-borne (tested on DEAP-1) and solvent-less (being developed for the full scale DEAP-3600 detector).

  8. Pre-mining variation of alpha activity intake in shells of fresh water mussels

    International Nuclear Information System (INIS)

    Specific alpha activity distribution in fresh water mussel shells has been studied for mussels collected from several billabongs in the uranium province in the Northern Territory. Track etch detector Kodak LR-115 was exposed to alpha particles emitted from surface areas of shells previously dated by growth-rings counting procedures. The annual average alpha activity was calculated from alpha emission track etch densities corresponding to the dated areas on the shell surfaces. An interesting correlation between the annual rainfall and corresponding annual average shell activity was observed. The results demonstrated that this method could indicate aspects of variations in natural pre-mining radiation background of billabongs which are the source of some of the traditional diet components, suvh as mussels, for local aboriginals. The evaluation of the future influence of uranium mining on the levels of radiation likely to be taken up into diet components must take careful consideration of these observed variations in natural background radiation

  9. Sodium-iodide symporter (NIS)-mediated accumulation of [211At]astatide in NIS-transfected human cancer cells

    International Nuclear Information System (INIS)

    The cellular expression of the sodium iodide symporter (NIS) has been shown to confer iodide-concentrating capacity in non-thyroid cell types. We examined the role of NIS in the uptake of the alpha-particle emitting radiohalide [211At]astatide in the UVW human glioma cell line transfected to express NIS. [211At]Astatide uptake is shown to be NIS-dependent, with characteristics similar to [131I]iodide uptake. These studies suggest [211At]astatide as a possible alternative radionuclide to [131I]iodide for NIS-based endoradiotherapy, and provide a model for the study of [211At]astatide behavior at a cellular level

  10. Non-linear relationship of cell hit and transformation probabilities in low dose of inhaled radon progenies

    CERN Document Server

    Balásházy, Imre; Madas, Balázs Gergely; Hofmann, Werner

    2013-01-01

    Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or in support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions, which are characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterize the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a funct...

  11. New approach to spectrum analysis. Iterative Monte Carlo simulations and fitting

    International Nuclear Information System (INIS)

    A novel spectrum analysis code which combines the Monte Carlo simulations with spectrum fitting is introduced. The shapes used in the fitting are obtained from the simulations. The code is developed especially to analyze complex alpha particle energy spectra - such as those obtained from non-processed air filters, swipe samples or isolated particles emitting alpha radiation. In addition to activities of the nuclides present in the sample, the code can provide source characterization. In particular, the code can be used to characterize samples of nuclear material, i.e. those containing fissionable isotopes such as 235U or 239Pu. In the present paper we illustrate the use of the code to identify and quantify alpha-particle emitting isotopes in a depleted U projectile found in Kosovo. (author)

  12. Rutherford Experiment

    CERN Multimedia

    This experiment, carried out by Ernest Rutherford in 1910, revolutionised understanding of the structure of matter, showing that almost all the mass of an atom is concentrated in a very small, positively charged nucleus. Alpha particles emitted at bombard a thin gold foil. A detector records the number of alpha particles crossing the foil per second. The number is displayed on the counter and updated every minute. Alpha particles are helium nuclei, they consist of 2 protons and 2 neutrons. Rotate the central knob to change the angle between the foil and the detector. The number of alpha particles detected depends on the angle. Most of the alpha particles travel straight through the foil because the gold atoms are mainly empty space. However some hit the atomic nucleus and are deflected.

  13. Investigation of radon emanation along a seismic fault

    International Nuclear Information System (INIS)

    In order to identify premonitory signs that might be useful for earthquake prediction, the behaviour of terrestrial gases has been extensively studied in recent years in seismically active areas. Soil gas concentration, and in particular, the measurement of subsurface radon may prove to be useful in forecasting eruptions. In this context, a project on earthquake prediction research is operating along the Chlef seismic fault located west of Algiers (Algeria). Radon measuring stations have been planted along the geological fault of the October 1980 devastating earthquake in the region. Plastic nuclear track detectors are used to record alpha particles emitted by radon and its daughters. Every three to four weeks the detectors are replaced, processed and analysed, hence a continuous time sequence of the radon gas is recorded. This paper presents the field results obtained in terms of temporal variation of radon concentration correlated with the meteorological and seismic data of the region. (author)

  14. A new method for evaluating annual absorbed gamma dose rates in an archaeological site by combining the SSNTD technique with Monte Carlo simulations

    Energy Technology Data Exchange (ETDEWEB)

    Misdaq, M.A.; Fahde, K.; Erramli, H. [Nuclear Physics and Techniques Laboratory, Faculty of Sciences Semlalia, B.P. S15, University Cadi Ayyad, Marrakech (Morocco); Mikdad, A. [National Institute of Archaeology and Patrimony, Rabat (Morocco); Rzama, A.; Yousif Charif, M.L. [National Centre of Radioprotection, Rabat (Morocco)

    1998-10-01

    Uranium and thorium contents in different layers of an archaeological site have been determined by using CR-39 and LR-115 type II solid state nuclear track detectors (SSNTD) and calculating the probabilities for {alpha}-particles emitted by the uranium and thorium series to reach and be registered on the SSNTD films. A new method has been developed based on calculating the self-absorption coefficient of the gamma-photons emitted by the uranium ({sup 238}U), thorium ({sup 232}Th) and their corresponding decay products as well as the potassium-40 ({sup 40}K) isotope for evaluating the annual absorbed gamma dose rates in the considered material samples. Results obtained have been compared with data obtained by using the TL dosimetry and Bell's methods. Ceramic samples belonging to the studied archaeological site have been dated.

  15. A new method for evaluating annual absorbed gamma dose rates in an archaeological site by combining the SSNTD technique with Monte Carlo simulations

    CERN Document Server

    Misdaq, M A; Erramli, H; Mikdad, A; Rzama, A; Yousif-Charif, M L

    1998-01-01

    Uranium and thorium contents in different layers of an archaeological site have been determined by using CR-39 and LR-115 type II solid state nuclear track detectors (SSNTD) and calculating the probabilities for alpha-particles emitted by the uranium and thorium series to reach and be registered on the SSNTD films. A new method has been developed based on calculating the self-absorption coefficient of the gamma-photons emitted by the uranium ( sup 2 sup 3 sup 8 U), thorium ( sup 2 sup 3 sup 2 Th) and their corresponding decay products as well as the potassium-40 ( sup 4 sup 0 K) isotope for evaluating the annual absorbed gamma dose rates in the considered material samples. Results obtained have been compared with data obtained by using the TL dosimetry and Bell's methods. Ceramic samples belonging to the studied archaeological site have been dated.

  16. Angular correlation between the heavy fragments and the light charged particles in tripartition of 236U and 252Cf

    International Nuclear Information System (INIS)

    The energy distributions and relative intensities of protons, deuterons, tritons and alpha-particles emitted along the fission axis during thermal neutron fission of 236U are measured simultaneously with the energies of the two fission fragments. The mass distributions of the fragments, the total kinetic energy (TKE), the dependence of the mean TKE on the fragment mass, as well as the mean kinetic energy dependence of polar particles on the fragment mass and energy are deduced from these data. Although some experimental results agree remarkably well with the hypothesis that polar particles are evaporated in-flight from fission fragments, the general conclusion is that these particles are emitted according to some other mechanism

  17. Traversal of cells by radiation and absorbed fraction estimates for electrons and alpha particles

    International Nuclear Information System (INIS)

    Consideration of the pathlength which radiation traverses in a cell is central to algorithms for estimating energy deposition on a cellular level. Distinct pathlength distributions occur for radionuclides: (1) uniformly distributed in space about the cell (referred to as μ-randomness); (2) uniformly distributed on the surface of the cell (S-randomness); and (3) uniformly distributed within the cell volume (I-randomness). For a spherical cell of diameter d, the mean pathlengths are 2/3d, and 3/4d, respectively, for these distributions. Algorithms for simulating the path of radiation through a cell are presented and the absorbed fraction in the cell and its nucleus are tabulated for low energy electrons and alpha particles emitted on the surface of spherical cells. The algorithms and absorbed fraction data should be of interest to those concerned with the dosimetry of radionuclide-labeled monoclonal antibodies. 8 references, 3 figures, 2 tables

  18. Improved radioimmunotherapy of hematologic malignancies. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1996-08-15

    Experiments were performed to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells. An attempt was made to examine in vivo the effects of lysosomotropic amines and thioamides on the retention of radiolabeled monoclonal antibodies by tumor cells. Experiments also examined the impact of newer radioiodination techniques on the metabolic degradation of radioiodinated antibodies, and on the radioimmunoscintigraphy and radioimmunotherapy of neoplasms. The endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with I-131, In-111, and Y-90 were compared. The utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer was investigated.

  19. Improved radioimmunotherapy of hematologic malignancies. Final technical report

    International Nuclear Information System (INIS)

    Experiments were performed to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells. An attempt was made to examine in vivo the effects of lysosomotropic amines and thioamides on the retention of radiolabeled monoclonal antibodies by tumor cells. Experiments also examined the impact of newer radioiodination techniques on the metabolic degradation of radioiodinated antibodies, and on the radioimmunoscintigraphy and radioimmunotherapy of neoplasms. The endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with I-131, In-111, and Y-90 were compared. The utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer was investigated

  20. Alpha particle emitters in cancer therapy: establishing the rationale and overcoming the difficulties

    International Nuclear Information System (INIS)

    Full text: Once a tumor has metastasized, the possibility of cure is significantly diminished, if not excluded. Since metastatic spread arises due to the release of single tumor cells or tumor cell clusters, treatment regimens following an overt metastasis must include agents that eradicate individual tumor cells and cell clusters or that prevent their dissemination. Alpha particles may be highly effective in eradicating rapidly accessible disease. The effectiveness of alpha particles arises because the amount of energy deposited per unit distance traveled (linear energy transfer or LET) is approximately 400 times greater than that of beta particles (80 keV/μm vs. 0.2 keV/μm). Each traversal of an alpha particle through a cell nucleus results in a very highly ionizing track. Cell survival studies have shown that alpha-particle killing is independent of oxygenation state or cell-cycle during irradiation and that as few as 1 to 6 tracks across the nucleus may result in cell death. Most studies with alpha-particle emitting radionuclides for therapy have examined either bismuth-212 or astatine-211. Both radionuclides are short-lived with 61 minute and 7.2 hour half-lives, respectively, yielding intermediates with 3-minute and 32 year half-lives, respectively. Both emit alpha particles whose range is 40 to 80 μm. Alpha-particle emitting radionuclides have been attached to antibodies against tumor cell associated antigen. Antibodies have been the most widely used vehicle for delivery of alpha particles due to their specificity. Bismuth-212 has demonstrated a significant curative potential with minimal toxicity. In an ascites tumor mouse model, specific targeting and 80% cure following injection of Bi-212-labeled antibody has been observed (Macklis RM et al, Science, 240:1024-1026, 1988). It is important to define the realm of applicability for alpha particle emitting radionuclides. The short half-life of most currently available radionuclides, limits their use to

  1. Gas-flow detector for uranium contamination on finned-can surface of a reactor fuel

    International Nuclear Information System (INIS)

    This gas-flow detector is a gridded proportional-counter specially designed for detecting uranium contamination on the finned-can surface of a reactor fuel. A conventional proportional-counter constructed only by a cathode and collector can hardly detect alpha particles emitted from uranium which is contaminated on rugged surfaces such as those of the fins of a reactor-fuel can because of the lack of uniformity of the electric field near the surface. This is the reason why we have constructed the gridded proportional-counter. This counter comprises the fuel, a grid, collectors and a cathode which are cylindrical in construction and arranged coaxially. The fuel is placed in the centre of the grid and negative voltage is applied. The space between the fuel and the grid serves as an ion-collecting space. The grid is made of fine parallel tungsten wires which are constructed cylindrically around the fuel and connected to ground potential. The collectors are 16 fine tungsten wires constructed similarly to the grid, but each wire is electrically insulated from the others. Through 50-kΩ resistors all collectors are connected together and to positive high voltage via a feeding resistor. The space between the grid, the collectors and the cathode serves as a gas-multiplication space just like a conventional proportional-counter. Each 50-kΩ resistor separates the stray capacity of the connected collector from the others. The detector output is coupled with a low input-impedance-current amplifier. The low inputimpedance also lessens the bad influence of the stray capacity of the input circuitry. These result in a good S/N ratio and allow the sensitive detection of alpha particles. Before measurement, the counter is first evacuated by a rotary pump and then PR gas (A: 90%, Methane: 10%) is admitted. By the use of this new equipment we have successfully detected alpha particles emitted from 1 x 10-5 g natural-uranium contamination of the finned-can surface of a Calder Hall

  2. Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide bi-DTPA-[F3]2 into the nucleus of tumor cells.

    Directory of Open Access Journals (Sweden)

    Enken Drecoll

    Full Text Available BACKGROUND: Alpha-particle emitting isotopes are effective novel tools in cancer therapy, but targeted delivery into tumors is a prerequisite of their application to avoid toxic side effects. Peritoneal carcinomatosis is a widespread dissemination of tumors throughout the peritoneal cavity. As peritoneal carcinomatosis is fatal in most cases, novel therapies are needed. F3 is a tumor homing peptide which is internalized into the nucleus of tumor cells upon binding to nucleolin on the cell surface. Therefore, F3 may be an appropriate carrier for alpha-particle emitting isotopes facilitating selective tumor therapies. PRINCIPAL FINDINGS: A dimer of the vascular tumor homing peptide F3 was chemically coupled to the alpha-emitter (213Bi ((213Bi-DTPA-[F3](2. We found (213Bi-DTPA-[F3](2 to accumulate in the nucleus of tumor cells in vitro and in intraperitoneally growing tumors in vivo. To study the anti-tumor activity of (213Bi-DTPA-[F3](2 we treated mice bearing intraperitoneally growing xenograft tumors with (213Bi-DTPA-[F3](2. In a tumor prevention study between the days 4-14 after inoculation of tumor cells 6x1.85 MBq (50 microCi of (213Bi-DTPA-[F3](2 were injected. In a tumor reduction study between the days 16-26 after inoculation of tumor cells 6x1.85 MBq of (213Bi-DTPA-[F3](2 were injected. The survival time of the animals was increased from 51 to 93.5 days in the prevention study and from 57 days to 78 days in the tumor reduction study. No toxicity of the treatment was observed. In bio-distribution studies we found (213Bi-DTPA-[F3](2 to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213Bi-DTPA-[F3](2 is found due to renal excretion. CONCLUSIONS/SIGNIFICANCE: In conclusion we report that (213Bi-DTPA-[F3](2 is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be

  3. Contribution of waterborne radon to home air quality

    International Nuclear Information System (INIS)

    Radon-222 is a member of the uranium decay chain and is formed from the decay of radium-226. Radon and its decay products emit alpha particles during the decay process. If radon is inhaled, alpha particles emitted from inhaled radon and its daughters increase the risk of lung cancer. Radon is soluble in water; thus when radon comes in contact with groundwater it dissolves. The radon concentration in groundwater may range from 100 pCi/L to 1,000,000 pCi/L. When water with a high radon level is used in the home, radon is released from the water to the air and thus can increase indoor air radon concentration. Considering the estimated health risk from radon in public water supply systems, EPA has proposed a maximum contaminant level (MCL) of 300 pCi/L for radon in public drinking water supplies. To address the health risks of radon in water and the proposed regulations, the American Water Works Association Research Foundation (AWWARF) initiated a study to determine the contribution of waterborne radon to radon levels in indoor household air

  4. Room-temperature particle detectors with guard rings based on semi-insulating InP co-doped with Ti and Zn

    Energy Technology Data Exchange (ETDEWEB)

    Yatskiv, R. [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Praha 8 (Czech Republic)], E-mail: yatskiv@ufe.cz; Zdansky, K. [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Praha 8 (Czech Republic); Pekarek, L. [Institute of Physics, Academy of Sciences of the Czech Republic, Na Slovance 2, 18221 Praha 8 (Czech Republic)

    2009-01-21

    Particle detectors made with a guard-ring (GR) electrode, operating at room temperature, have been studied. The detectors were fabricated on a semi-insulating InP crystal co-doped with Ti and Zn, grown using the Liquid-Encapsulated Czochralski technique. The detection performance of the particle detectors was evaluated using alpha particles emitted from a {sup 241}Am source. Good detector performance has been achieved with measured charge-collection efficiencies of 99.9% and 98.2% and FWHM energy resolutions of 0.9% and 2.1%. The measurements were carried out at 230 K for negative and positive bias voltages of the irradiated electrode. The good performance is due to the SI properties of the material which has been achieved by doping with suitable Ti atoms and co-doping with a low concentration of Zn acceptors, sufficient to fully compensate shallow donors. Electron and hole charge-collection efficiencies (CCEs) were measured at various temperatures. At room temperature, unlike at low temperature (T<250 K), the hole CCE was better than the electron CCE, which can be explained by the presence of electron-trapping centres in InP with a temperature-dependent capture rate.

  5. Room-temperature particle detectors with guard rings based on semi-insulating InP co-doped with Ti and Zn

    International Nuclear Information System (INIS)

    Particle detectors made with a guard-ring (GR) electrode, operating at room temperature, have been studied. The detectors were fabricated on a semi-insulating InP crystal co-doped with Ti and Zn, grown using the Liquid-Encapsulated Czochralski technique. The detection performance of the particle detectors was evaluated using alpha particles emitted from a 241Am source. Good detector performance has been achieved with measured charge-collection efficiencies of 99.9% and 98.2% and FWHM energy resolutions of 0.9% and 2.1%. The measurements were carried out at 230 K for negative and positive bias voltages of the irradiated electrode. The good performance is due to the SI properties of the material which has been achieved by doping with suitable Ti atoms and co-doping with a low concentration of Zn acceptors, sufficient to fully compensate shallow donors. Electron and hole charge-collection efficiencies (CCEs) were measured at various temperatures. At room temperature, unlike at low temperature (T<250 K), the hole CCE was better than the electron CCE, which can be explained by the presence of electron-trapping centres in InP with a temperature-dependent capture rate.

  6. Impact of Pr on the properties of InP based layers for light sources and detectors

    Energy Technology Data Exchange (ETDEWEB)

    Prochazkova, Olga; Grym, Jan; Zavadil, Jiri; Zdansky, Karel; Yatskiv, Roman [Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Chaberska 57, 18251 Prague (Czech Republic)

    2009-12-15

    We report the optimization of LPE growth technique for the preparation of InP and GaInAsP high quality and high purity layers by using Pr purification effect. We have found that Pr addition into the growth melt leads to the reduction of the layer defect density by a half order of magnitude and carrier concentrations diminished to 10{sup 14} cm{sup -3}. Three types of p-n junction based radiation detection structures were prepared and their detection performance was assessed by using {alpha}-particles emitted from the {sup 241}Am radioactive source. The type III structure, utilizing the p-n junction with both components grown with Pr addition, exhibits the highest charge collection efficiency. Pr admixture was also exploited in the preparation of quaternary GaInAsP(Pr) active region in the double heterostructure GaInAsP/InP emitting at 1200 nm. Purification effect of Pr addition is demonstrated by measuring impurity concentrations deduced from C-V curves and by low temperature PL spectra. (copyright 2009 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  7. Room-temperature particle detectors with guard rings based on semi-insulating InP co-doped with Ti and Zn

    Science.gov (United States)

    Yatskiv, R.; Zdansky, K.; Pekarek, L.

    2009-01-01

    Particle detectors made with a guard-ring (GR) electrode, operating at room temperature, have been studied. The detectors were fabricated on a semi-insulating InP crystal co-doped with Ti and Zn, grown using the Liquid-Encapsulated Czochralski technique. The detection performance of the particle detectors was evaluated using alpha particles emitted from a 241Am source. Good detector performance has been achieved with measured charge-collection efficiencies of 99.9% and 98.2% and FWHM energy resolutions of 0.9% and 2.1%. The measurements were carried out at 230 K for negative and positive bias voltages of the irradiated electrode. The good performance is due to the SI properties of the material which has been achieved by doping with suitable Ti atoms and co-doping with a low concentration of Zn acceptors, sufficient to fully compensate shallow donors. Electron and hole charge-collection efficiencies (CCEs) were measured at various temperatures. At room temperature, unlike at low temperature ( T<250 K), the hole CCE was better than the electron CCE, which can be explained by the presence of electron-trapping centres in InP with a temperature-dependent capture rate.

  8. On the Analytic Estimation of Radioactive Contamination from Degraded Alphas

    CERN Document Server

    Kadel, Richard W

    2016-01-01

    The high energy spectrum of alpha particles emitted from a single isotope uniformly contaminating a bulk solid has a flat energy spectrum with a high end cutoff energy equal to the maximal alpha kinetic energy ($T_{\\alpha}$) of the decay. In this flat region of the spectrum, we show the surface rate $r_b\\text{\\,(Bq/keV-cm}^{2})$ arising from a bulk alpha contamination $\\rho_b$ (Bq/cm$^3$) from a single isotope is given by $r_b =\\rho_b \\Delta R/ 4 \\Delta E $, where $\\Delta E = E_1-E_2>0\\ $ is the energy interval considered (keV) in the flat region of the spectrum and $\\Delta R = R_2-R_1$, where $R_2$ ($R_1$) is the amount of the bulk material (cm) necessary to degrade the energy of the alpha from $T_{\\alpha}$ to $E_2$ ($E_1$). We compare our calculation to a rate measurement of alphas from $^{147}$Sm, ($15.32\\%\\,\\pm\\,0.03\\%$ of Sm($nat$) and half life of $(1.06\\,\\pm\\,0.01)\\times\\,10^{11} \\text{yr}$, and find good agreement, with the ratio between prediction to measurement of $100.2\\%\\pm 1.6\\%\\,\\text{(stat)}\\pm...

  9. Production of high-purity radium-223 from legacy actinium-beryllium neutron sources.

    Science.gov (United States)

    Soderquist, Chuck Z; McNamara, Bruce K; Fisher, Darrell R

    2012-07-01

    Radium-223 is a short-lived alpha-particle-emitting radionuclide with potential applications in cancer treatment. Research to develop new radiopharmaceuticals employing (223)Ra has been hindered by poor availability due to the small quantities of parent actinium-227 available world-wide. The purpose of this study was to develop innovative and cost-effective methods to obtain high-purity (223)Ra from (227)Ac. We obtained (227)Ac from two surplus actinium-beryllium neutron generators. We retrieved the actinium/beryllium buttons from the sources and dissolved them in a sulfuric-nitric acid solution. A crude actinium solid was recovered from the solution by coprecipitation with thorium fluoride, leaving beryllium in solution. The crude actinium was purified to provide about 40 milligrams of actinium nitrate using anion exchange in methanol-water-nitric acid solution. The purified actinium was then used to generate high-purity (223)Ra. We extracted (223)Ra using anion exchange in a methanol-water-nitric acid solution. After the radium was separated, actinium and thorium were then eluted from the column and dried for interim storage. This single-pass separation produces high purity, carrier-free (223)Ra product, and does not disturb the (227)Ac/(227)Th equilibrium. A high purity, carrier-free (227)Th was also obtained from the actinium using a similar anion exchange in nitric acid. These methods enable efficient production of (223)Ra for research and new alpha-emitter radiopharmaceutical development. PMID:22697483

  10. Radon as a medicine. Therapeutic effectiveness, biological mechanism and comparative risk assessment

    International Nuclear Information System (INIS)

    Proofs of the therapeutic efficiency of balneological radon applications administered to patients suffering from rheumatic diseases, investigations into the biological action mechanism associated with the alpha particles emitted by radon and its radioactive daughter products, and the comparative risk assessment of radon treatment and medicinal pain therapy have been the research projects whose results are summarized in this book. Controlled clinical studies, if possible performed as prospective, randomized and placebo-controlled double blind studies, have given evidence that the therapeutic effects of balneological radon applications - long-lasting pain reduction and reduced consumption of medicines compared with controls - are significantly persisting over many post-treatment months. The molecular and cellular mechanism of action underlying these long-lasting therapeutic effects has been identified as the down-regulation of cellular immune responses, initiated by cellular apoptosis sequential to low alpha particle doses and by the subsequent release of anti-inflammatory cytokines. The unwanted side-effects of non-steroidal anti-rheumatic drug treatments have to be compared with the absence of side effects from the balneological radon applications which merely involve radiation doses well below the mean value and the fluctuation width of the annual doses attributable to everybody's natural radiation exposure.

  11. The metabolism of radiohafnium in rats and hamsters: a possible analog of plutonium for metabolic studies

    International Nuclear Information System (INIS)

    The metabolism of radiohafnium (175Hf + 181Hf) was studied in male Sprague-Dawley rats and Chinese hamsters for periods of up to 168 days. The results were compared with similar data for 239Pu in the same rat strain. In rats and hamsters the radiohafnium organ distribution was skeleton greater than skin greater than muscle greater than liver at about 7 days postinjection. Retention of radiohafnium and plutonium was similar in plasma and liver, as were the retention times observed for other organs: Absorption of radiohafnium from the gastrointestinal tract of rats was less than 0.05%. Biochemical studies showed that the radiohafnium was bound mainly to the iron-transport protein, transferrin, in blood plasma and in the liver cytosol of both the rat and the hamster, as has been observed also for plutonium. The metabolic behavior of radiohafnium mimics, to a large extent, that of plutonium, and it is suggested that radiohafnium can serve as a non-alpha-particle-emitting analog of plutonium for metabolic, biochemical, and selected human investigations

  12. Detection of hidden explosives by using tagged neutron beams with sub-nanosecond time resolution

    International Nuclear Information System (INIS)

    Non-destructive inspection of luggage has been simulated in laboratory conditions by using a 14 MeV tagged neutron beam and BaF2 scintillation detectors (Tagged Neutron Inspection System, TNIS). The tagged neutron beam is produced by detecting the associated alpha particle emitted in the D+T reaction by means of a YAP:Ce scintillator. The TNIS intrinsic time resolution has been measured to be δt=0.9 ns [FWHM], which allows inspection of a minimum voxel of 5 cm depth along the neutron flight path. This characteristic is demonstrated by identifying graphite and water samples hidden inside a hard plastic suitcase filled with background material. Finally, explosive devices such as small anti-personnel or anti-tank landmines have been inspected when placed inside the suitcase. In the case of relatively large explosive objects such as an anti-tank landmine, the system is capable of testing directly the TNT charge inside the device, separating this material from the external plastic case. Further developments of the TNIS concept are discussed

  13. The energy spectra and double-differential cross-sections for p+92,94,95,96,97,98,100Mo reactions at the incident energies from threshold to 200 MeV

    International Nuclear Information System (INIS)

    Highlights: • The energy spectra for composite particle emissions are calculated by the nuclear models. • The double differential cross-sections for composite particle emitted are calculated. • The improved Iwamoto-Harada model for composite particles emitted is accommodated. • The Pauli principle in the calculation of exciton state densities is accommodated. • The calculated results agree well with experimental data. - Abstract: The energy spectra and double-differential cross sections of neutron, proton, deuteron, triton, helium and alpha-particle emitted are studied by the exciton model including the improved Iwamoto–Harada model. All cross sections, angular distributions, energy spectra and double-differential cross sections are consistently calculated and analyzed for p+92,94,95,96,97,98,100Mo reactions at the incident proton energies below 200 MeV by using nuclear theoretical models which integrate the optical model, the intra-nuclear cascade model, direct, pre-equilibrium and equilibrium reaction theories. The theoretically calculated results are compared with existing experimental data

  14. Phase I Rinal Report: Ultra-Low Background Alpha Activity Counter

    Energy Technology Data Exchange (ETDEWEB)

    Warburton, W.K.

    2005-07-22

    In certain important physics experiments that search for rare-events, such as neutrino or double beta decay detections, it is critical to minimize the number of background events that arise from alpha particle emitted by the natural radioactivity in the materials used to construct the experiment. Similarly, the natural radioactivity in materials used to connect and package silicon microcircuits must also be minimized in order to eliminate ''soft errors'' caused by alpha particles depositing charges within the microcircuits and thereby changing their logic states. For these, and related reasons in the areas of environmental cleanup and nuclear materials tracking, there is a need that is important from commercial, scientific, and national security perspectives to develop an ultra-low background alpha counter that would be capable of measuring materials' alpha particle emissivity at rates well below 0.00001 alpha/cm{sup 2}/hour. This rate, which corresponds to 24 alpha particles per square meter per day, is essentially impossible to achieve with existing commercial instruments because the natural radioactivity of the materials used to construct even the best of these counters produces background rates at the 0.005 alpha/cm{sup 2}/hr level. Our company (XIA) had previously developed an instrument that uses electronic background suppression to operate at the 0.0005 0.005 alpha/cm{sup 2}/hr level. This patented technology sets up an electric field between a large planar sample and a large planar anode, and fills the gap with pure Nitrogen. An alpha particle entering the chamber ionizes the Nitrogen, producing a ''track'' of electrons, which drift to the anode in the electric field. Tracks close to the anode take less than 10 microseconds (us) to be collected, giving a preamplifier signal with a 10 us risetime. Tracks from the sample have to drift across the full anode-sample gap and produce a 35 us risetime signal. By

  15. Alpha-emitting radioisotopes production for radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Chun, Kwon Soo [Korea Institutet of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2007-02-15

    This review discusses the production of alpha-particle-emitting radionuclides in radioimmunotherapy. Radioimmunotherapy labeled with alpha-particle is expected to be very useful for the treatment of monocellular cancer (e.g. leukemia) and micrometastasis at an early stage, residual tumor remained in tissues after chemotherapy and tumor resection, due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha particle. Despite of the expected effectiveness of alpha-particle in radioimmunotherapy, its clinical research has not been activated by the several reasons, shortage of a suitable a-particle development and a reliable radionuclide production and supply system, appropriate antibody and chelator development. Among them, the establishment of radionuclide development and supply system is a key factor to make an alpha-immunotherapy more popular in clinical trial. Alpha-emitter can be produced by several methods, natural radionuclides, reactor irradiation, cyclotron irradiation, generator system and elution. Due to the sharply increasing demand of {sup 213}Bi, which is a most promising radionuclide in radioimmunotherapy and now has been produced with reactor, the cyclotron production system should be developed urgently to meet the demand.

  16. Selective elimination in vitro of alloresponsive T cells to human transplantation antigens by toxin or radionuclide conjugated anti-IL-2 receptor (Tac) monoclonal antibody

    International Nuclear Information System (INIS)

    The human allogeneic mixed lymphocyte reaction is the in vitro correlate of graft rejection. Cytotoxic effector cells generated during an allogeneic mixed lymphocyte reaction were previously shown to express the human p55 IL-2 receptor subunit, whereas resting cells do not express this receptor peptide. In this study, we asked whether Pseudomonas exotoxin or bismuth-212 (an alpha-particle emitting radionuclide) coupled to the anti-IL-2 receptor mAb, anti-Tac, were able to selectively eliminate alloresponsive cells generated during an allogeneic mixed lymphocyte reaction. After assembly, anti-Tac immunoconjugates retained their binding integrity, specificity, and selectivity. Deletion of alloresponsive cells was shown by the removal of alloproliferating cells as assessed by quantitating cell recovery and by measurement of thymidine incorporation into newly synthesized DNA. Both toxin and radionuclide immunoconjugates eliminated established cytotoxic effector cells generated in an allogeneic mixed lymphocyte reaction, while leaving intact the PHA-inducible mitogenic response of the nonactivated cells. The addition of excess anti-Tac blocked all of the effects of these cytotoxic reagents. The therapeutic reagents in vitro were most effective when added just prior to the peak of the alloproliferative response, when receptor expression would be close to maximum. Thus, anti-Tac conjugated either with toxin or radionuclide is effective in vitro in specifically eliminating cytotoxic effector cells

  17. Phase I Final Report: Ultra-Low Background Alpha Activity Counter

    International Nuclear Information System (INIS)

    In certain important physics experiments that search for rare-events, such as neutrino or double beta decay detections, it is critical to minimize the number of background events that arise from alpha particle emitted by the natural radioactivity in the materials used to construct the experiment. Similarly, the natural radioactivity in materials used to connect and package silicon microcircuits must also be minimized in order to eliminate ''soft errors'' caused by alpha particles depositing charges within the microcircuits and thereby changing their logic states. For these, and related reasons in the areas of environmental cleanup and nuclear materials tracking, there is a need that is important from commercial, scientific, and national security perspectives to develop an ultra-low background alpha counter that would be capable of measuring materials' alpha particle emissivity at rates well below 0.00001 alpha/cm2/hour. This rate, which corresponds to 24 alpha particles per square meter per day, is essentially impossible to achieve with existing commercial instruments because the natural radioactivity of the materials used to construct even the best of these counters produces background rates at the 0.005 alpha/cm2/hr level. Our company (XIA) had previously developed an instrument that uses electronic background suppression to operate at the 0.0005 0.005 alpha/cm2/hr level. This patented technology sets up an electric field between a large planar sample and a large planar anode, and fills the gap with pure Nitrogen. An alpha particle entering the chamber ionizes the Nitrogen, producing a ''track'' of electrons, which drift to the anode in the electric field. Tracks close to the anode take less than 10 microseconds (us) to be collected, giving a preamplifier signal with a 10 us risetime. Tracks from the sample have to drift across the full anode-sample gap and produce a 35 us risetime signal. By analyzing the preamplifier signals with a digital signal processor we

  18. Inverse-kinematics study of 78Kr + 40Ca at 10 AMeV

    Directory of Open Access Journals (Sweden)

    Henry E.

    2015-01-01

    Full Text Available The CHIMERA multi-detector array at LNS Catania has been used to study the inverse-kinematics reaction of 78Kr + 40Ca at a bombarding energy of 10 A MeV. Analysis of the experimental data focused on a class of selected events consistent with the complete fusion and subsequent binary split of the of the reacting system. This class of events features a broad A, Z distribution of fission fragments centered about symmetric fission while exhibiting relative velocities significantly higher than given by Viola systematics. The center-of-mass angular distribution (dσ/dΘ of the fission fragments exhibit an unexpected anisotropy inconsistent with a compound-nucleus reaction and indicates a dynamic fusion-fission like process. The observed angular distribution features an asymmetric forward-backward peaking most prevalent for mass-asymmetric events. Furthermore, the more massive fragment of mass-asymmetric events appears to emerge preferentially in the forward direction, along the beam axis, in analogy to dynamic fragmentation of projectile-like fragments. Analysis of the angular distribution of alpha particles emitted from these fission fragments suggests the events are associated mostly with central collisions.

  19. Proceedings of transuranium elements

    International Nuclear Information System (INIS)

    The identification of the first synthetic elements was established by chemical evidence. Conclusive proof of the synthesis of the first artificial element, technetium, was published in 1937 by Perrier and Segre. An essential aspect of their achievement was the prediction of the chemical properties of element 43, which had been missing from the periodic table and which was expected to have properties similar to those of manganese and rhenium. The discovery of other artificial elements, astatine and francium, was facilitated in 1939-1940 by the prediction of their chemical properties. A little more than 50 years ago, in the spring of 1940, Edwin McMillan and Philip Abelson synthesized element 93, neptunium, and confirmed its uniqueness by chemical means. On August 30, 1940, Glenn Seaborg, Arthur Wahl, and the late Joseph Kennedy began their neutron irradiations of uranium nitrate hexahydrate. A few months later they synthesized element 94, later named plutonium, by observing the alpha particles emitted from uranium oxide targets that had been bombarded with deuterons. Shortly thereafter they proved that is was the second transuranium element by establishing its unique oxidation-reduction behavior. The symposium honored the scientists and engineers whose vision and dedication led to the discovery of the transuranium elements and to the understanding of the influence of 5f electrons on their electronic structure and bonding. This volume represents a record of papers presented at the symposium

  20. Alpha particle radiography of ants using a 244Cm alpha source

    International Nuclear Information System (INIS)

    Alpha particles emitted from a radioisotope 244Cm were used for the radiography of ants. Cellulose nitrate films, LR-115 from Kodak Pathe, were used as solid state nuclear track detectors to make the radiographs. Alpha particles of energies from 3.5 to 5.5 MeV were obtained by varying the air spacing between the 244Cm and the sample with stainless steel spacers of thickness from 2.4 to 0.5 cm to slow the 5.81 MeV alpha particles from the 244Cm by air. The resulting radiographs of the ants put on the LR-115 films and irradiated by alpha particles of different energies show that only the profiles of the ants were obtained when the ants were exposed to alpha particles of energies lower than 3.5 MeV, and almost all parts of the ant except a portion in the head were penetrated by alpha particles of energies higher than 5.0 MeV to register high density alpha tracks on the LR-115. The details of the internal organs of the ant can be shown clearly by radiography with alpha particles of energies between 4.0 and 5.0 MeV. (author)

  1. Depleted uranium instead of lead in munitions: the lesser evil

    International Nuclear Information System (INIS)

    Uranium has many similarities to lead in its exposure mechanisms, metabolism and target organs. However, lead is more toxic, which is reflected in the threshold limit values. The main potential hazard associated with depleted uranium is inhalation of the aerosols created when a projectile hits an armoured target. A person can be exposed to lead in similar ways. Accidental dangerous exposures can result from contact with both substances. Encountering uranium fragments is of minor significance because of the low penetration depth of alpha particles emitted by uranium: they are unable to penetrate even the superficial keratin layer of human skin. An additional cancer risk attributable to the uranium exposure might be significant only in case of prolonged contact of the contaminant with susceptible tissues. Lead intoxication can be observed in the wounded, in workers manufacturing munitions etc; moreover, lead has been documented to have a negative impact on the intellectual function of children at very low blood concentrations. It is concluded on the basis of the literature overview that replacement of lead by depleted uranium in munitions would be environmentally beneficial or largely insignificant because both lead and uranium are present in the environment. (opinion)

  2. Depleted uranium instead of lead in munitions: the lesser evil.

    Science.gov (United States)

    Jargin, Sergei V

    2014-03-01

    Uranium has many similarities to lead in its exposure mechanisms, metabolism and target organs. However, lead is more toxic, which is reflected in the threshold limit values. The main potential hazard associated with depleted uranium is inhalation of the aerosols created when a projectile hits an armoured target. A person can be exposed to lead in similar ways. Accidental dangerous exposures can result from contact with both substances. Encountering uranium fragments is of minor significance because of the low penetration depth of alpha particles emitted by uranium: they are unable to penetrate even the superficial keratin layer of human skin. An additional cancer risk attributable to the uranium exposure might be significant only in case of prolonged contact of the contaminant with susceptible tissues. Lead intoxication can be observed in the wounded, in workers manufacturing munitions etc; moreover, lead has been documented to have a negative impact on the intellectual function of children at very low blood concentrations. It is concluded on the basis of the literature overview that replacement of lead by depleted uranium in munitions would be environmentally beneficial or largely insignificant because both lead and uranium are present in the environment. PMID:24594921

  3. Preliminary Study of Natural Alpha Particle Track Areal Distribution Behind Eyeglasses Obstacles

    International Nuclear Information System (INIS)

    Plastic nuclear track detectors are widely used to register tracks of alpha particles emitted from radon gas nuclei and radioactive daughter nuclei. Eye glasses, finger rings, necklaces and many other accessories intimately accompany most people. The eyeglasses may modify the surface distribution of alpha particle pass spots just behind them. There may be some effects due to the earth's magnetic field on the motion of the charged alpha particle emitters (radon ions). In metallic frames of the eyeglasses, the earth's magnetic field and charged radio-ions enforce free electrons to move setting electric current, which reduces the magnetic field at the frame. Being weak at the frame and stronger on both sides away, the magnetic field lines may form a magnetic trap of some charged radio-ions in the air. The polymer Solid State Nuclear Track Detector (SSNTD) CR-39 which is a polyalyl diglycol carbonate is used to register alpha particles behind the eyeglasses obstacles. Remarkable decrease in alpha track density was noticed in CR-39 registration due both to glass and magnetic screening. The obtained results call for more studies on all metallic tools used or possessed in mines and non-ventilated underground cavities.

  4. Osteosarcoma induction by plutonium-239, americium-241 and neptunium-237 : the problem of deriving risk estimates for man

    International Nuclear Information System (INIS)

    Spontaneous bone cancer (osteosarcoma) represents only about 0.3% of all human cancers, but is well known to be inducible in humans by internal contamination with radium-226 and radium-224. plutonium-239, americium-241 and neptunium-237 form, or will form, the principal long-lived alpha particle emitting components of high activity waste and burnt-up nuclear fuel elements. These three nuclides deposit extensively in human bone and although, fortunately, no case of a human osteosarcoma induced by any of these nuclides is known, evidence from animal studies suggests that all three are more effective than radium-226 in inducing osteosarcoma. The assumption that the ratio of the risk factors, the number of osteosarcoma expected per 10000 person/animal Gy, for radium-226 and any other bone-seeking alpha-emitter will be independent of animal species has formed the basis of all the important studies of the radiotoxicity of actinide nuclides in experimental animals. The aim of this communication is to review the risk factors which may be calculated from the various animal studies carried out over the last thirty years with plutonium-237, americium-241 and neptunium-237 and to consider the problems which may arise in extrapolating these risk factors to homo sapiens

  5. Interaction of alpha particles at the cellular level - Implications for the radiation weighting factor

    International Nuclear Information System (INIS)

    Since low dose effects of alpha particles are produced by cellular hits in a relatively small fraction of exposed cells, the present study focuses on alpha particle interactions in bronchial epithelial cells following exposure to inhaled radon progeny. A computer code was developed for the calculation of microdosimetric spectra, dose and hit probabilities for alpha particles emitted from uniform and non-uniform source distributions in cylindrical and Y-shaped bronchial airway geometries. Activity accumulations at the dividing spur of bronchial airway bifurcations produce hot spots of cellular hits, indicating that a small fraction of cells located at such sites may receive substantially higher doses. While presently available data on in vitro transformation frequencies suggest that the relative biological effectiveness for alpha particles ranges from about 3 to 10, the effect of inhomogeneous activity distributions of radon progeny may slightly increase the radiation weighting factor relative to a uniform distribution. Thus a radiation weighting factor of about 10 may be more realistic than the current value of 20, at least for lung cancer risk following inhalation of short-lived radon progeny. (authors)

  6. Detection of hidden explosives by using tagged neutron beams with sub-nanosecond time resolution

    Energy Technology Data Exchange (ETDEWEB)

    Pesente, Silvia; Nebbia, Giancarlo; Lunardon, Marcello; Viesti, Giuseppe E-mail: giuseppe.viesti@pd.infn.it; Sudac, Davorin; Nad, Karlo; Blagus, Sasha; Valkovic, Vladivoj

    2004-10-01

    Non-destructive inspection of luggage has been simulated in laboratory conditions by using a 14 MeV tagged neutron beam and BaF{sub 2} scintillation detectors (Tagged Neutron Inspection System, TNIS). The tagged neutron beam is produced by detecting the associated alpha particle emitted in the D+T reaction by means of a YAP:Ce scintillator. The TNIS intrinsic time resolution has been measured to be {delta}t=0.9 ns [FWHM], which allows inspection of a minimum voxel of 5 cm depth along the neutron flight path. This characteristic is demonstrated by identifying graphite and water samples hidden inside a hard plastic suitcase filled with background material. Finally, explosive devices such as small anti-personnel or anti-tank landmines have been inspected when placed inside the suitcase. In the case of relatively large explosive objects such as an anti-tank landmine, the system is capable of testing directly the TNT charge inside the device, separating this material from the external plastic case. Further developments of the TNIS concept are discussed.

  7. Fluorine concentrations in teeth studied by /sup 19/F(p,α/sub o/)/sup 16/O nuclear reaction

    International Nuclear Information System (INIS)

    The fluorine concentrations has been determined in the enamel, dentine and cementum of a significative set of dental samples (healthy, fluorotic and decayed), by using /sup 19/F(rho,α/sub o/) /sup 16/O reaction, in the resonant region around 1350 KeV proton beam, and by recording the alpha particles emitted at 6.9 MeV. CrF/sub 3/ samples, as standard thin and thick films, has been used for quantitative analysis. In these films protons (0.5 / 1.5 MeV) and helium (4.0 / 7.0 MeV) stopping powers are very similar to those in dental tissue, supposed as hydroxyapatite (Ca/sub 10/(PO/sub 4/)/sub 6/(OH)/sub 2/). Fluorine depth profiles show an accumulation in the first superficial layers (1 / 2 μm) and about a factor two reduction at 4 / 5 μm. Results show an average concentration of surface fluorine in the healthy enamel of the order of 10/sup -3/ g/g (for 1 g of hydroxyapatite), concentration about ten times higher in fluorotic enamel and very low concentration, close to the minimum detectable limit (MDL = 0.3 mg/g), in the carried zones

  8. Updated estimates of the proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionising radiation

    International Nuclear Information System (INIS)

    The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionising radiation, such as was experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily upon studies of the Japanese A-bomb survivors imply that low-level exposure to ionising radiation, including to ubiquitous natural background radiation, also raises the risk of childhood leukaemia. In a recent paper (Wakeford et al 2009 Leukaemia 23 770-6) we estimated the proportion of childhood leukaemia incidence in Great Britain attributable to natural background radiation to be about 20%. In this paper we employ the two sets of published leukaemia risk models used previously, but use recently published revised estimates of natural background radiation doses received by the red bone marrow of British children to update the previous results. Using the newer dosimetry we calculate that the best estimate of the proportion of cases of childhood leukaemia in Great Britain predicted to be attributable to this source of exposure is 15-20%, although the uncertainty associated with certain stages in the calculation (e.g. the nature of the transfer of risk between populations and the pertinent dose received from naturally occurring alpha-particle-emitting radionuclides) is significant. The slightly lower attributable proportions compared with those previously derived by Wakeford et al (Leukaemia 2009 23 770-6) are largely due to the lower doses (and in particular lower high LET doses) for the first year of life.

  9. Updated estimates of the proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionising radiation

    Energy Technology Data Exchange (ETDEWEB)

    Little, Mark P [Department of Epidemiology and Public Health, Imperial College, London W2 1PG (United Kingdom); Wakeford, Richard [Dalton Nuclear Institute, University of Manchester, Pariser Building-G Floor, PO Box 88, Sackville Street, Manchester M60 1QD (United Kingdom); Kendall, Gerald M [Childhood Cancer Research Group, Richards Building, University of Oxford, Old Road Campus, Oxford OX3 7LG (United Kingdom)], E-mail: mark.little@imperial.ac.uk

    2009-12-01

    The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionising radiation, such as was experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily upon studies of the Japanese A-bomb survivors imply that low-level exposure to ionising radiation, including to ubiquitous natural background radiation, also raises the risk of childhood leukaemia. In a recent paper (Wakeford et al 2009 Leukaemia 23 770-6) we estimated the proportion of childhood leukaemia incidence in Great Britain attributable to natural background radiation to be about 20%. In this paper we employ the two sets of published leukaemia risk models used previously, but use recently published revised estimates of natural background radiation doses received by the red bone marrow of British children to update the previous results. Using the newer dosimetry we calculate that the best estimate of the proportion of cases of childhood leukaemia in Great Britain predicted to be attributable to this source of exposure is 15-20%, although the uncertainty associated with certain stages in the calculation (e.g. the nature of the transfer of risk between populations and the pertinent dose received from naturally occurring alpha-particle-emitting radionuclides) is significant. The slightly lower attributable proportions compared with those previously derived by Wakeford et al (Leukaemia 2009 23 770-6) are largely due to the lower doses (and in particular lower high LET doses) for the first year of life.

  10. Cancer hazard from inhaled plutonium

    International Nuclear Information System (INIS)

    The best estimate of the lung cancer potential in humans for inhaled insoluble compounds of plutonium (such as PuO2 particles) has been grossly underestimated by such authoritative bodies as the International Commission on Radiological Protection and the British Medical Research Council. Calculations are presented of lung cancer induction by 239Pu as insoluble particles and for deposited reactor-grade Pu. The reason for the gross underestimate of the carcinogenic effects of Pu by ICRP or the British Medical Research Council (BMRC) is their use of a totally unrealistic idealized model for the clearance of deposited Pu from the lungs and bronchi plus their non-recognition of the bronchi as the true site for most human lung cancers. The erroneous model used by such organizations also fails totally to take into account the effect of cigarette-smoking upon the physiological function of human lungs. Plutonium nuclides, such as 239Pu, or other alpha particle-emitting nuclides, in an insoluble form represent an inhalation cancer hazard in a class some 100,000 times more potent than the potent chemical carcinogens, weight for weight. The already-existing lung cancer data for beagle dogs inhaling insoluble PuO2 particles is clearly in order of magnitude agreement with calculations for humans

  11. Radon as a medicine. Therapeutic effectiveness, biological mechanism and comparative risk assessment

    Energy Technology Data Exchange (ETDEWEB)

    Deetjen, Peter; Falkenbach, Albrecht; Harder, Dietrich; Joeckel, Hans; Kaul, Alexander; Philipsborn, Henning von

    2014-07-01

    Proofs of the therapeutic efficiency of balneological radon applications administered to patients suffering from rheumatic diseases, investigations into the biological action mechanism associated with the alpha particles emitted by radon and its radioactive daughter products, and the comparative risk assessment of radon treatment and medicinal pain therapy have been the research projects whose results are summarized in this book. Controlled clinical studies, if possible performed as prospective, randomized and placebo-controlled double blind studies, have given evidence that the therapeutic effects of balneological radon applications - long-lasting pain reduction and reduced consumption of medicines compared with controls - are significantly persisting over many post-treatment months. The molecular and cellular mechanism of action underlying these long-lasting therapeutic effects has been identified as the down-regulation of cellular immune responses, initiated by cellular apoptosis sequential to low alpha particle doses and by the subsequent release of anti-inflammatory cytokines. The unwanted side-effects of non-steroidal anti-rheumatic drug treatments have to be compared with the absence of side effects from the balneological radon applications which merely involve radiation doses well below the mean value and the fluctuation width of the annual doses attributable to everybody's natural radiation exposure.

  12. Does long term exposure to radon gas influence the properties of polymeric waterproof materials?

    International Nuclear Information System (INIS)

    The technical state of buildings and the quality of the indoor environment depend on the quality of the waterproofing course and on the properties of the insulating materials that are applied, in particular on their durability, long-term functional reliability and resistance to corrosive effects of the subsoil. Underground water chemistry and soil bacteria are well-known corrosive agents. Our investigations indicate that the ageing process of waterproof materials can be significantly accelerated by alpha particles emitted by radon and radon progenies which are present in soil gas. Materials commonly available on the building market, e.g. LDPE and HDPE of various densities, PVC, TPO (thermoplastic polyolefin), PP (polypropylene) and EPDM were selected for our experimental study. The preliminary results for 3-year exposure to radon gas show a decrease in tensile strength to 60%, elongation to 80% and hardness to 95% for samples based on PE. The diffusion coefficient of radon for samples based on PVC decreased to 20% of the initial value after 1-year exposure to radon and soil bacteria. - Highlights: • Long-term exposure of waterproof materials to radon and soil bacteria. • Changes in mechanical properties shown. • Major changes in diffusion coefficient of radon found for PVC

  13. Preparation of thin {alpha}-particle sources using poly-pyrrole films functionalized by a chelating agent; Preparation de sources minces d'emetteurs alpha a l'aide de films de polypyrrole fonctionnalises par un ligand chelatant

    Energy Technology Data Exchange (ETDEWEB)

    Mariet, C. [CEA Saclay, INSTN, Institut National des Sciences et Techniques Nucleaires, 91 - Gif-sur-Yvette (France); Universite Pierre et Marie Curie, 75 - Paris (France)

    2000-07-01

    This work takes place in the scope of analysis of the {alpha}-particle emitting elements U, Pu and Am present in compound environmental matrix like sols and sediments. The samples diversity and above all the {alpha}-ray characteristics require the analyst to implement a sequence of chemical steps in which the more restricting is the actinides concentration in a uniform and thin layer en allowing an accurately measure of alpha activity. On this account, we studied a new technique for radioactive sources preparation based on tow steps: preparation of a thin film as source support; incorporation of radioactive elements by a chelating extraction mechanism. The thin films were obtained through electro-polymerization of pyrrole monomer functionalized by an chelating ligand able to extract actinides from concentrated acidic solutions. Polymerization conditions of this monomer were perfected, then obtained films were characterized from a physico-chemical point of view. We point out their extracting properties were comparable to (retention capacity, distribution coefficient) to those of usual ion-exchange resins. The underscore of uranyl and americium nitrate complexes formed in the thin layer allowed to calculate the extraction constants in case acid extraction is negligible. Thanks to this results, the values of the coefficients distribution D{sub U} and D{sub Am} could be provided for all nitric solutions in which acid extraction is negligible. Optimal actinides retention conditions in the polymer were defined and used to settle a protocol for plutonium analysis in environmental samples. (author)

  14. Instrument for measuring total alpha particle energies of alpha emitters in ambient air

    Energy Technology Data Exchange (ETDEWEB)

    Kronenberg, S.; Brucker, G.J.; Cummings, B.; Bechtel, E.; Gentner, F.; Horne, S

    2000-11-11

    This paper describes the design, fabrication, testing and evaluation of a self-reading, carbon fiber, electrometer-type instrument. It is used for measuring the total energy of alpha particles emitted in air by progenies of {sup 222}Rn ({sup 218}Po, {sup 214}Pb, and {sup 214}Bi), and sometimes by other types of alpha emitters (e.g. {sup 212}Pb, {sup 238}U, and {sup 239}Pu). The purpose of these measurements is to assess the energy delivered by alpha emission from these sources to the lung tissue. A sample (charged progenies attached to aerosols) is collected on filter paper from a known volume of air and placed on the instrument. The discharge rate indicates the alpha energy in MeV l{sup -1} of air per min that is produced by the alpha emitters. The calibration procedure shows that the instrument has an energy sensitivity for alpha particles of 800.5 MeV/scale unit. The range of the readout scale is 30 units. Measurements of alpha contamination in air were made using this instrument in buildings, private homes and in a standard chamber. The value of the radon concentration in this chamber is traceable back to the US Environmental Protection Agency (EPA) and to the National Institute of Standards and Technology (NIST)

  15. Development and implementation of methodology for radium analysis by alpha spectrometry: preliminary results

    International Nuclear Information System (INIS)

    Alpha spectrometry is one of the most sensitive techniques for radium determination and allows simultaneous measurement of different radium isotopes. The determination of alpha particle-emitting radionuclides in environmental samples by alpha spectrometry requires careful chemical procedures to obtain enough thin sources to provide high quality spectra in which well separated peaks appear. Therefore, determinations by α- spectrometry require radiochemical separation of the element from the matrix, followed by preparation of suitable radioactive sources to obtain high resolution α-spectra in order to minimize peak overlap, and the use of appropriate tracers to determine the chemical yields of the radiochemical sample processing. In this paper, a radiochemical procedure is been developed to 228Ra, 226Ra and 224Ra determination in geological samples, such as rocks, soils, sediments, and waters. The main aim is to include an additional and simple step for the purification of radium within general procedure commonly used in our laboratory for uranium and thorium isotope determination in geological samples. For that reason, we are making several experiments involving direct 226Ra tracer electrodeposition onto stainless steel, as well as ion-exchange chromatography using 225Ra (T1/2 = 14.9 days) as yield tracer. Results showed that chemical recovery of direct electrodeposition of ten aliquots varied between 97 ± 4 % and 104 ± 5 %, with a mean value of 100 ± 1 %, implying in a very small loss in this step. (author)

  16. Simulation study on the measurements of diffusion coefficients in solid materials by short-lived radiotracer beams

    CERN Document Server

    Jeong, S C; Kawakami, H

    2003-01-01

    We have examined, by a computer simulation, an on-line measurement of diffusion coefficients by using a short-lived alpha particle emitter, sup 8 Li (half life of 0.84s), as a radiotracer. The energy spectra of alpha particles emitted from diffusing sup 8 Li primarily implanted in the sample of LiAl ar simulated as a measure of the diffusion of sup 8 Li in the sample. As a possible time sequence for the measurement, a time cycle of 6s, i.e. the implantation of sup 8 Li for 1.5s and subsequent diffusion for 4.5s, is supposed. The sample is primarily set on a given temperature for the measurement. The time-dependent yields of alpha particles during the time cycle reveal the possibility to measure the diffusion coefficient with an accuracy of 10% if larger than 1 x 10 sup - sup 9 cm sup 2 /s, by the comparison with the experimental spectra measured at the temperature, i.e. at a certain diffusion coefficient. (author)

  17. Does long term exposure to radon gas influence the properties of polymeric waterproof materials?

    Science.gov (United States)

    Navratilova Rovenska, Katerina; Jiranek, Martin; Kokes, Pavel; Wasserbauer, Richard; Kacmarikova, Veronika

    2014-01-01

    The technical state of buildings and the quality of the indoor environment depend on the quality of the waterproofing course and on the properties of the insulating materials that are applied, in particular on their durability, long-term functional reliability and resistance to corrosive effects of the subsoil. Underground water chemistry and soil bacteria are well-known corrosive agents. Our investigations indicate that the ageing process of waterproof materials can be significantly accelerated by alpha particles emitted by radon and radon progenies which are present in soil gas. Materials commonly available on the building market, e.g. LDPE and HDPE of various densities, PVC, TPO (thermoplastic polyolefin), PP (polypropylene) and EPDM were selected for our experimental study. The preliminary results for 3-year exposure to radon gas show a decrease in tensile strength to 60%, elongation to 80% and hardness to 95% for samples based on PE. The diffusion coefficient of radon for samples based on PVC decreased to 20% of the initial value after 1-year exposure to radon and soil bacteria.

  18. Initial evaluation of 227Th-p-benzyl-DOTA-rituximab for low-dose rate α-particle radioimmunotherapy

    International Nuclear Information System (INIS)

    Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with β-emitting isotopes. In contrast to β-emitters, the shorter range and high linear energy transfer (LET) of α particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of α-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The α-emitting radioimmunoconjugate 227Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the α-particle-emitting nuclide 227Th alone, the chelated form, 227Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate 227Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of 227Th-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the 227Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of 227Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with 227Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of 227Th-DOTA-p-benzyl-rituximab

  19. Formulation and Characterization of “Ready to Use” 1B4M-DTPA-rituximab for Lu-177 Labeling

    OpenAIRE

    Gorgieva, Darinka; Smilkov, Katarina; Janevik-Ivanovska, Emilija

    2014-01-01

    Investigations for NHL treatment are oriented towards radiolabelled therapeutics. This research focuses on formulation and characterization of a new, ready to label immunoconjugate, 1B4M-DTPA-rituximab, which is suitable for labeling with Lu-177. The conjugation was performed using 20-fold molar excess of the bifunctional chelating agent, 1B4M-DTPA and subsequent lyophilization. The characterization of the (radio)immunoconjugate was performed using SE-HPLC, SDS-PAGE and MALDI-TOF-...

  20. 131I–Tositumomab in lymphoma

    OpenAIRE

    Cheung, M.C.; MacEachern, J.A.; Haynes, A.E.; Meyer, R.M.; Imrie, K.; ,

    2009-01-01

    Radioimmunoconjugates are radioisotope-bound monoclonal antibodies that target radiation specifically to sites of lymphoma involvement. Initial studies of 131I–tositumomab in non-Hodgkin lymphoma (nhl) have suggested benefit in patients with relapsed or refractory indolent disease. However, the routine adoption of this agent is tempered by concerns about associated toxicities and unclear long-term benefit. Based on a comprehensive search for studies on 131I–tositumomab use in lymphoma, this s...

  1. Radioimmunotherapy for lymphoma - analysis of clinical trials and treatment algorithms

    International Nuclear Information System (INIS)

    Ibritumomab, an 90Yttrium (90Y) labelled radioimmunoconjugate, is registered in Europe to treat follicular lymphomas. Its mode of action combines the selectivity of monoclonal antibodies with the efficiency of radiotherapy, making it a unique and useful therapeutic agent. This paper is for haemato-oncologists with a decent practice in lymphoma therapy, who have not yet used ibritumomab themselves. It summarizes clinical trials with radioimmunotherapy, indicating clinical situations where it may be specifically useful. (author)

  2. Improved radioimmunotherapy of hematologic malignancies

    International Nuclear Information System (INIS)

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides (131Iodine, 111Indium, 90Yttrium, 99mTechnetium, 186Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer

  3. Improved radioimmunotherapy of hematologic malignancies

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  4. Improved radioimmunotherapy of hematologic malignancies. [Final report

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  5. Astatine-211 Pathway from Radiochemistry to Clinical Investigation

    International Nuclear Information System (INIS)

    Particularly in clinical settings where tumour burden is low and cancers are located in close proximity to essential normal tissue structures, α-particle emitting radionuclides can offer significant advantages for targeted radionuclide therapy. One of the first alpha emitters to be evaluated for this purpose is the 7.2-h half-life radiohalogen Astatine-211 (211At). From a commercialization-potential perspective 211At, is less appealing than the longer half-life alpha particle emitters Radium-223, Actinium-225 and Thorium-227, which have become the focus of many laboratories. However, if methods for providing a better supply of 211At could be developed, this alpha emitter would be the radionuclide of choice for many potential therapeutic applications. With regard to the production of 211At, this can be readily be accomplished by bombarding natural bismuth targets with 28−29.5 MeV alpha particles via the 209Bi(α,2n)211At reaction. The goal is to utilize an alpha particle beam energy that provides the required balance for maximizing 211At production while minimizing creation of 210At, which is problematic because of its 138.4-day half life alpha-particle emitting daughter, 210Po. For most intended clinical applications, alpha particle beam energy of about 29 MeV offers the best compromise between maximizing yield and providing 211At with sufficient radionuclidic purity for clinical use. Clinically relevant levels of 211At have been produced at several institutions using both internal and external cyclotron targets

  6. Multi-parametric approach towards the assessment of radon and thoron progeny exposures

    International Nuclear Information System (INIS)

    Conventionally, the dosimetry is carried out using radon and thoron gas concentration measurements and doses have been assigned using assumed equilibrium factors for the progeny species, which is inadequate pertaining to the variations in equilibrium factors and possibly due to significant thoron. In fact, since the true exposures depend upon the intricate mechanisms of progeny deposition in the lung, therefore an integrated approach for the assessment of progeny is essential. In this context, the recently developed deposition based progeny concentration measurement techniques (DTPS: Direct Thoron progeny sensors and DRPS: Direct Radon progeny sensors) appear to be best suited for radiological risk assessments both among occupational workers and general study populations. DTPS and DRPS consist of aluminized mylar mounted LR115 type passive detectors, which essentially detects the alpha particles emitted from the deposited progeny atoms on the detector surface. It gives direct measure of progeny activity concentrations in air. DTPS has a lower limit of detection limit of 0.1 Bq/m3 whereas that for DRPS is 1 Bq/m3, hence are perfectly suitable for indoor environments. These DTPS and DRPS can be capped with 200-mesh type wire-screen to measure the coarse fraction of the progeny concentration and the corresponding coarse fraction deposition velocities as well as the time integrated fine fraction. DTPS and DRPS can also be lodged in an integrated sampler wherein the wire-mesh and filter-paper are arranged in an array in flow-mode, to measure the fine and coarse fraction concentration separately and simultaneously. The details are further discussed in the paper

  7. Long-Range Alpha Particle Emission in the Fission of U235 by 3-MeV Neutrons

    International Nuclear Information System (INIS)

    The energy and angular distribution of long-range alpha particles emitted in the fission of U235 induced by 3-MeV neutrons have been measured. The alpha panicles were detected by solid-state detector and the fission fragments were detected by a gas scintillation counter. The neutrons were produced by the T (p, n) He3 reaction using a 5.5- MeV Van de Graaff accelerator. About 3000 fission events accompanied by the emission of a high-energy alpha panicle were recorded. The most probable energy of the alpha particles is between 15-16 MeV. and the energy distribution has a full width at half maximum of about D MeV, which is the same as observed in tliermal- neutron fission. The angular distribution of the long-range alpha panicles with respect to the incident neutron direction was found to be forward-peaked, in agreement with previous work on alpha emission in 14-MeV neutron-induced fission of LP. At angles of 0° and 90° with respect to the incident neutron direction the alpha panicles were detected with an angular spread of about ± 25°. The anisotropy [Nα(0°)/ Nα(90°)] was found to be 1.320 ± 0.12. This value is in agreement with the anisotropy calculated on the basis of statistical evaporation of panicles. The results of the present investigation are consistent with the hypothesis that the emission of long-range alpha panicles in fission is an evaporation process. The implications of the results of this work and of other recent investigations on long-range alpha emission are discussed. (author)

  8. APSTNG: Associated particle sealed-tube neutron generator studies for arms control. Final report on NN-20 Project ST220

    Energy Technology Data Exchange (ETDEWEB)

    Rhodes, E.; Dickerman, C.E.; Brunner, T.; Hess, A.; Tylinski, S.

    1994-12-01

    Argonne National Laboratory has performed research and development on the use of Associated Particle Sealed-Tube Neutron Generator (APSTNG) technology for treaty verification and non-proliferation applications, under funding from the DOE Office of Nonproliferation and National Security. Results indicate that this technology has significant potential for nondestructively detecting elemental compositions inside inspected objects or volumes. The final phase of this project was placement of an order for commercial procurement of an advanced sealed tube, with its high-voltage supply and control systems. Procurement specifications reflected lessons learned during the study. The APSTNG interrogates a volume with a continuous 14-MeV neutron flux. Each neutron is emitted coincident with an {open_quotes}associated{close_quotes} alpha-particle emitted in the opposite direction. Thus detection of an alpha-particle marks the emission of a neutron in a cone opposite to that defined by the alpha detector. Detection of a gamma ray coincident with the alpha indicates that the gamma was emitted from a neutron-induced reaction inside the neutron cone: the gamma spectra can be used to identify fissionable materials and many isotopes having an atomic number larger than that of boron. The differences in gamma-ray and alpha-particle detection times yield a coarse measurement of the distance along the cone axis from the APSTNG emitter to each region containing the identified nuclide. A position-sensitive alpha detector would permit construction of coarse three-dimensional images. The source and emission-detection systems can be located on the same side of the interrogated volume. The neutrons and gamma rays are highly penetrating. A relatively high signal-to-background ratio allows the use of a relatively small neutron source and conventional electronics.

  9. An optical readout TPC (O-TPC) for studies in nuclear astrophysics with gamma-ray beams at HI{gamma}S{sup 1}

    Energy Technology Data Exchange (ETDEWEB)

    Gai, M; Zimmerman, W R; Kading, T J; Seo, P-N; Young, A H [LNS at Avery Point, University of Connecticut, Groton, CT 06340-6097 (United States); Ahmed, M W; Stave, S C; Henshaw, S S; Martel, P P; Weller, H R [TUNL, Dept. of Physics, Duke University, Durham, NC 27708 (United States); Breskin, A; Chechik, R [Dept. of Particle Physics, Weizmann Institute of Science, 76100 Rehovot (Israel); Bromberger, B; Dangendorf, V; Tittelmeier, K [Physikalisch-Technische Bundesanstalt, 38116 Braunschweig (Germany); Delbar, Th [Universite Catholique de Louvain, 1348 Louvain-la-Neuve (Belgium); III, R H France [Georgia College and State University, CBX 82, Milledgeville, GA 31061 (United States); McDonald, J E R, E-mail: moshe.gai@yale.edu [Dept. of Physics, Yale University, New Haven, CT 06520-8124 (United States)

    2010-12-15

    We report on the construction, tests, calibrations and commissioning of an Optical Readout Time Projection Chamber (O-TPC) detector operating with a CO{sub 2}(80%) + N{sub 2}(20%) gas mixture at 100 and 150 Torr. It was designed to measure the cross sections of several key nuclear reactions involved in stellar evolution. In particular, a study of the rate of formation of oxygen and carbon during the process of helium burning will be performed by exposing the chamber gas to intense nearly mono-energetic gamma-ray beams at the High Intensity Gamma Source (HI{gamma}S) facility. The O-TPC has a sensitive target-drift volume of 30x30x21 cm{sup 3}. Ionization electrons drift towards a double parallel-grid avalanche multiplier, yielding charge multiplication and light emission. Avalanche-induced photons from N{sub 2} emission are collected, intensified and recorded with a Charge Coupled Device (CCD) camera, providing two-dimensional track images. The event's time projection (third coordinate) and the deposited energy are recorded by photomultipliers and by the TPC charge-signal, respectively. A dedicated VME-based data acquisition system and associated data analysis tools were developed to record and analyze these data. The O-TPC has been tested and calibrated with 3.183 MeV alpha-particles emitted by a {sup 148}Gd source placed within its volume with a measured energy resolution of 3.0%. Tracks of alpha and {sup 12}C particles from the dissociation of {sup 16}O and of three alpha-particles from the dissociation of {sup 12}C have been measured during initial in-beam test experiments performed at the HI{gamma}S facility at Duke University. The full detection system and its performance are described and the results of the preliminary in-beam test experiments are reported.

  10. Determination of alpha dose rate profile at the HLW nuclear glass/water interface

    Science.gov (United States)

    Mougnaud, S.; Tribet, M.; Rolland, S.; Renault, J.-P.; Jégou, C.

    2015-07-01

    Alpha irradiation and radiolysis can affect the alteration behavior of High Level Waste (HLW) nuclear glasses. In this study, the way the energy of alpha particles, emitted by a typical HLW glass, is deposited in water at the glass/water interface is investigated, with the aim of better characterizing the dose deposition at the glass/water interface during water-induced leaching mechanisms. A simplified chemical composition was considered for the nuclear glass under study, wherein the dose rate is about 140 Gy/h. The MCNPX calculation code was used to calculate alpha dose rate and alpha particle flux profiles at the glass/water interface in different systems: a single glass grain in water, a glass powder in water and a water-filled ideal crack in a glass package. Dose rate decreases within glass and in water as distance to the center of the grain increases. A general model has been proposed to fit a dose rate profile in water and in glass from values for dose rate in glass bulk, alpha range in water and linear energy transfer considerations. The glass powder simulation showed that there was systematic overlapping of radiation fields for neighboring glass grains, but the water dose rate always remained lower than the bulk value. Finally, for typical ideal cracks in a glass matrix, an overlapping of irradiation fields was observed while the crack aperture was lower than twice the alpha range in water. This led to significant values for the alpha dose rate within the crack volume, as long as the aperture remained lower than 60 μm.

  11. In vitro experimental {sup 211}At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin

    Energy Technology Data Exchange (ETDEWEB)

    Petrich, Thorsten; Korkmaz, Zekiye; Krull, Doris; Meyer, Geerd J.; Knapp, Wolfram H. [Hanover University School of Medicine, Department of Nuclear Medicine, Hanover (Germany); Froemke, Cornelia [Hanover University School of Medicine, Department of Biometry, Hanover (Germany)

    2010-05-15

    Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair. We labelled anti-CD33 antibodies with the alpha-emitter {sup 211}At and compared survival of leukaemic HL-60 and K-562 cells treated with the {sup 211}At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free {sup 211}At. The mean labelling ratio of {sup 211}At-labelled antibodies was 1:1,090 {+-} 364 (range: 1:738-1:1,722) in comparison to 2-3:1 for GO. Tumour cell binding of {sup 211}At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. {sup 211}At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after {sup 211}At-anti-CD33 (1:1,090) versus GO (1:1) treatment. Our results suggest that {sup 211}At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase {sup 211}At-anti-CD33 therapeutic effects. (orig.)

  12. Targeted Radiolabeled Compounds in Glioma Therapy.

    Science.gov (United States)

    Cordier, Dominik; Krolicki, Leszek; Morgenstern, Alfred; Merlo, Adrian

    2016-05-01

    Malignant gliomas of World Health Organization (WHO) grades II-IV represent the largest entity within the group of intrinsic brain tumors and are graded according to their pathophysiological features with survival times between more than 10 years (WHO II) and only several months (WHO IV). Gliomas arise from astrocytic or oligodendrocytic precursor cells and exhibit an infiltrative growth pattern lacking a clearly identifiable tumor border. The development of effective treatment strategies of the invasive tumor cell front represents the main challenge in glioma therapy. The therapeutic standard consists of surgical resection and, depending on the extent of resection and WHO grade, adjuvant external beam radiotherapy or systemic chemotherapy. Within the last decades, there has been no major improvement of the prognosis of patients with glioma. The consistent overexpression of neurokinin type 1 receptors in gliomas WHO grades II-IV has been used to develop a therapeutic substance P-based targeting system. A substance P-analogue conjugated to the DOTA or DOTAGA chelator has been labeled with different alpha-particle or beta-particle emitting radionuclides for targeted glioma therapy. The radiopharmaceutical has been locally injected into the tumors or the resection cavity. In several clinical studies, the methodology has been examined in adjuvant and neoadjuvant clinical settings. Although no large controlled series have so far been generated, the results of radiolabeled substance P-based targeted glioma therapy compare favorably with standard therapy. Recently, labeling with the alpha particle emitting Bi-213 has been found to be promising due to the high linear energy transfer and the very short tissue range of 0.08mm. Further development needs to focus on the improvement of the stability of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within the prognostically critical infiltrative

  13. Experimental models in the rat for the assessment of local and systemic behaviour and decorporation of MOX after contamination by wounding

    International Nuclear Information System (INIS)

    Accidental contamination of nuclear industry workers by alpha particle-emitting actinides (plutonium; Pu, americium; Am) can occur after wounding. Transfer from the wound depends on contaminant physicochemical properties, wound type and anatomical location. These factors and wound activity levels direct the ensuing medical approaches. The principal objective of this research program, carried out in the Laboratoire de Radio-Toxicologie (CEA/DSV) in collaboration with AREVA NC, was to establish models of actinide-contaminated wounds in the rat using multidisciplinary approaches. Rats were contaminated by MOX (7.1% Pu by mass) or Pu nitrate or Am nitrate, either by subcutaneous implantation of an agarose gel containing the radioelement or following incision of the hind limb muscles. Actinide urinary excretion, wound, tissue levels and effects of decorporant regimens including wound excision were evaluated. In both experimental models following MOX contamination, urinary Am excretion was greater than Pu, and bone Pu and Am retention increased significantly with time. Moreover after Pu or Am nitrate contamination, Am excretion and tissue retention was greater than Pu again reflecting the higher solubility of Am. Coherent with the insoluble nature of oxide forms, tissue Am or Pu levels were much lower after MOX compared to those seen after nitrates. Wound site actinide retention was also much higher after MOX contamination. Repeated systemic DTPA increased actinide urinary excretion and decreased tissue retention, as did single or repeated local DTPA. Pu urinary excretion was transiently increased after wound excision but no further Pu organ retention was observed. In conclusion, several different experimental models have been developed in the rat to simulate actinide wound contamination. Information obtained on Pu and Am behavior either at the wound site or at distant organs allowed the discrimination between different physicochemical actinide forms and evaluation of

  14. On the analytic estimation of radioactive contamination from degraded alphas

    Science.gov (United States)

    Kadel, R. W.

    2016-03-01

    The high energy spectrum of alpha particles emitted from a single isotope uniformly contaminating a bulk solid has a flat energy spectrum with a high end cutoff energy equal to the maximal alpha kinetic energy (Tα) of the decay. In this flat region of the spectrum, we show the surface rate rb (Bq keV-1cm-2) arising from a bulk alpha contamination ρb (Bq cm-3) from a single isotope is given by rb =ρb Δ R/ 4 Δ E , where Δ E = E1-E2>0 is the energy interval considered (keV) in the flat region of the spectrum and Δ R = R2-R1, where R2 (R1) is the amount of the bulk material (cm) necessary to degrade the energy of the alpha from Tα to E2 (E1). We compare our calculation to a rate measurement of alphas from 147Sm, (15.32 ± 0.03% of Sm(nat) and half life of (1.06 ± 0.01)× 1011 yr [1]), and find good agreement, with the ratio between prediction to measurement of 100.2%± 1.6% (stat)± 2.1% (sys). We derive the condition for the flat spectrum, and also calculate the relationship between the decay rate measured at the surface for a [near] surface contamination with an exponential dependence on depth and a second case of an alpha source with a thin overcoat. While there is excellent agreement between our implementation of the sophisticated Monte Carlo program SRIM [2] and our intuitive model in all cases, both fail to describe the measured energy distribution of a 148Gd alpha source with a thin (~200μg cm-2) Au overcoat. We discuss possible origins of the disagreement and suggest avenues for future study.

  15. Final Report for grant entitled "Production of Astatine-211 for U.S. Investigators"

    Energy Technology Data Exchange (ETDEWEB)

    Wilbur, Daniel Scott

    2012-12-12

    Alpha-particle emitting radionuclides hold great promise in the therapy of cancer, but few alpha-emitters are available to investigators to evaluate. Of the alpha-emitters that have properties amenable for use in humans, 211At is of particular interest as it does not have alpha-emitting daughter radionuclides. Thus, there is a high interest in having a source of 211At for sale to investigators in the US. Production of 211At is accomplished on a cyclotron using an alpha-particle beam irradiation of bismuth metal. Unfortunately, there are few cyclotrons available that can produce an alpha particle beam for that production. The University of Washington has a cyclotron, one of three in the U.S., that is currently producing 211At. In the proposed studies, the things necessary for production and shipment of 211At to other investigators will be put into place at UW. Of major importance is the efficient production and isolation of 211At in a form that can be readily used by other investigators. In the studies, production of 211At on the UW cyclotron will be optimized by determining the best beam energy and the highest beam current to maximize 211At production. As it would be very difficult for most investigators to isolate the 211At from the irradiated target, the 211At-isolation process will be optimized and automated to more safely and efficiently obtain the 211At for shipment. Additional tasks to make the 211At available for distribution include obtaining appropriate shipping vials and containers, putting into place the requisite standard operating procedures for Radiation Safety compliance at the levels of 211At activity to be produced / shipped, and working with the Department of Energy, Isotope Development and Production for Research and Applications Program, to take orders, make shipments and be reimbursed for costs of production and shipment.

  16. Radon integral measurement system

    International Nuclear Information System (INIS)

    The Radon Integral Measurement System (SMIR) is a device designed specially to detect, to count and to store the data of the acquisition of alpha particles emitted by Radon-222 coming from the underground. The system includes a detection chamber, a radiation detector, a digital system with bateries backup and an auxiliary photovoltaic cell. A personal computer fixes the mode in which the system works, transmitting the commands to the system by the serial port. The heart of the system is a microprocesor working with interrupts by hardware. Every external device to the microprocessor sends his own interrupt request and the microprocessor handles the interrupts with a defined priority. The system uses a real time clock, compatible with the microprocessor, to take care of the real timing and date of the acquisition. A non volatile RAM is used to store data of two bytes every 15 minutes along 41 days as a maximum. After the setting up to the system by the computer, it can operate in stand alone way for up 41 days in the working place without the lose of any data. If the memory is full the next data will be written in the first locations of the memory. The memory is divided in pages corresponding every one of this to a different day of the acquisition. The counting time for every acquisition can be programmed by the user from 15 minutes to 65535 minutes but it is recommended to use a small time not to reach the limit of 65535 counts in every acquisition period. We can take information of the system without affecting the acquisition process in the field by using a lap top computer, then the information can be stored in a file. There is a program in the computer that can show the information in a table of values or in a bar graph. (Author)

  17. An optical readout TPC (O-TPC) for studies in nuclear astrophysics with gamma-ray beams at HIγS1

    International Nuclear Information System (INIS)

    We report on the construction, tests, calibrations and commissioning of an Optical Readout Time Projection Chamber (O-TPC) detector operating with a CO2(80%) + N2(20%) gas mixture at 100 and 150 Torr. It was designed to measure the cross sections of several key nuclear reactions involved in stellar evolution. In particular, a study of the rate of formation of oxygen and carbon during the process of helium burning will be performed by exposing the chamber gas to intense nearly mono-energetic gamma-ray beams at the High Intensity Gamma Source (HIγS) facility. The O-TPC has a sensitive target-drift volume of 30x30x21 cm3. Ionization electrons drift towards a double parallel-grid avalanche multiplier, yielding charge multiplication and light emission. Avalanche-induced photons from N2 emission are collected, intensified and recorded with a Charge Coupled Device (CCD) camera, providing two-dimensional track images. The event's time projection (third coordinate) and the deposited energy are recorded by photomultipliers and by the TPC charge-signal, respectively. A dedicated VME-based data acquisition system and associated data analysis tools were developed to record and analyze these data. The O-TPC has been tested and calibrated with 3.183 MeV alpha-particles emitted by a 148Gd source placed within its volume with a measured energy resolution of 3.0%. Tracks of alpha and 12C particles from the dissociation of 16O and of three alpha-particles from the dissociation of 12C have been measured during initial in-beam test experiments performed at the HIγS facility at Duke University. The full detection system and its performance are described and the results of the preliminary in-beam test experiments are reported.

  18. Radiation effects in moist-air systems and the influence of radiolytic product formation on nuclear waste glass corrosion

    International Nuclear Information System (INIS)

    Ionizing radiation may affect the performance of glass in an unsaturated repository site by interacting with air, water vapor, or liquid water to produce a variety of radiolytic products. Tests were conducted to examine the effects of radiolysis under high gas/liquid ratios. Results indicate that nitrate is the predominant radiolytic product produced following both gamma and alpha radiation exposure, with lesser amounts of nitrite and carboxylic acids. The formation of nitrogen acids during exposure to long-lived, alpha-particle-emitting transuranic elements indicates that these acids may play a role in influencing nuclear waste form reactions in a long-term unsaturated disposal scenario. Experiments were also conducted with samples that simulate the composition of Savannah River Plant nuclear waste glasses. Radiolytic product formation in batch tests (340 m-1, 90 C) resulted in a small increase in the release rates of many glass components, such as alkali and alkaline earth elements, although silicon and uranium release rates were slightly reduced indicating an overall beneficial effect of radiation on waste form stability. The radiolytic acids increased the rate of ion exchange between the glass and the thin film of condensate, resulting in accelerated corrosion rates for the glass. The paragenetic sequence of alteration phases formed on both the irradiated and nonirradiated glass samples reacted in the vapor hydration tests matches closely with those developed during volcanic glass alteration in naturally occurring saline-alkaline lake systems. This correspondence suggests that the high temperatures used in these tests have not changed the underlying glass reaction mechanism relate to that which controls glass reactions under ambient surficial conditions

  19. Abscopal induction of leukaemia and osteosarcoma following administration of alpha-emitting radionuclides

    Energy Technology Data Exchange (ETDEWEB)

    Lord, B.I. (Paterson Institute for Cancer Research, Christie Hospital Manchester, Manchester (United Kingdom))

    2008-12-15

    Alpha-particle-emitting, bone-seeking radionuclides can induce leukaemia and/ or osteosarcoma in mice. Furthermore, plutonium-239, given to male mice before mating with normal females, while not directly leading to leukaemia in the progeny does lead to enhanced susceptibility to leukaemogenic agents. In the first case, the amounts of radionuclide are very small in experimental terms; and zero in the case of transgenerational activity. In both cases, the development of the disorders is remote in time and location relative to that of the contaminating radionuclide, making interpretation of the mechanisms and estimation of radiation risk problematic. It is necessary, then, to address questions involving the basis of haemopoiesis itself. Cellular kinetics of the development of blood from the pluripotent stem cells to the mature functional cells are outlined, describing compensatory proliferation mechanisms and extensive movement of cells throughout the marrow space. The locations of potential oncogenic target cells are identified and the nature of the stromal microenvironment that regulates haemopoiesis is defined. Plutonium-239, given to male mice, targets spermatogenesis at the stem cell level leaving unidentified damage that is inherited by his offspring. This leaves the offspring susceptible to a leukaemogenic agent encountered later in life. The characteristics of this, corroborated by consideration of the cellular kinetics, are of an inherited genomic instability. Cells of the microenvronment, inheriting the same genetic damage, probably act in the role of an enhancing 'bystander'. In adult mice, the mechanisms are different. Bone turnover results in radioactivity being gradually transported through the marrow by long-lived macrophages. A model based on temporal microdistributions of activity, defining specific target cell regions, is able to illustrate that considering bone marrow as a uniform mass of cells is inadequate to describe the observed

  20. Radiation effects in moist-air systems and the influence of radiolytic product formation on nuclear waste glass corrosion

    Energy Technology Data Exchange (ETDEWEB)

    Wronkiewicz, D.J.; Bates, J.K.; Buck, E.C.; Hoh, J.C.; Emery, J.W. [Argonne National Lab., IL (United States). Chemical Technology Div.; Wang, L.M. [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Geology

    1997-07-01

    Ionizing radiation may affect the performance of glass in an unsaturated repository site by interacting with air, water vapor, or liquid water to produce a variety of radiolytic products. Tests were conducted to examine the effects of radiolysis under high gas/liquid ratios. Results indicate that nitrate is the predominant radiolytic product produced following both gamma and alpha radiation exposure, with lesser amounts of nitrite and carboxylic acids. The formation of nitrogen acids during exposure to long-lived, alpha-particle-emitting transuranic elements indicates that these acids may play a role in influencing nuclear waste form reactions in a long-term unsaturated disposal scenario. Experiments were also conducted with samples that simulate the composition of Savannah River Plant nuclear waste glasses. Radiolytic product formation in batch tests (340 m{sup {minus}1}, 90 C) resulted in a small increase in the release rates of many glass components, such as alkali and alkaline earth elements, although silicon and uranium release rates were slightly reduced indicating an overall beneficial effect of radiation on waste form stability. The radiolytic acids increased the rate of ion exchange between the glass and the thin film of condensate, resulting in accelerated corrosion rates for the glass. The paragenetic sequence of alteration phases formed on both the irradiated and nonirradiated glass samples reacted in the vapor hydration tests matches closely with those developed during volcanic glass alteration in naturally occurring saline-alkaline lake systems. This correspondence suggests that the high temperatures used in these tests have not changed the underlying glass reaction mechanism relate to that which controls glass reactions under ambient surficial conditions.

  1. Studies of heavy ion reactions and transuranic nuclei. Progress report, August 1, 1983-August 31, 1984

    International Nuclear Information System (INIS)

    The status of the current understanding of the microscopic mechanisms operating in damped nuclear reactions is reviewed. Several experimental and conceptual problems of attempts to determine the nuclear interaction potential for distances inside the fusion barrier are discussed. An explanation of the unexpectedly large angular anisotropies of fragments from fission of heavy systems produced at large spins has been found in terms of the statistical scission model. In this model, the phase space available to the final deformed fission fragments governs the fission probability. Processes associated with incomplete linear-momentum transfer have been studied for 292-MeV 20Ne-induced fission with targets of 165Ho, 181Ta, 197Au, 209Bi, and 238U. Preequilibrium neutron emission has been studied in central and peripheral 165Ho + 20Ne and 165Ho + 12C collisions at bombarding energies between 11 and 25 MeV/nucleon. In preparation of kinematically complete coincidence experiments, a fast, position-sensitive avalanche detector with a large active area has been developed. The theoretical framework of the statistical scission model for fission has been reconsidered. Exclusive measurements were made of alpha particles emitted in the damped reaction 165Ho + 56Fe at E/sub Lab/ = 465 MeV. The data were interpreted with the aid of rather detailed Monte Carlo evaporation simulations. As part of an extensive coincidence study of equilibration mechanisms in damped reactions, inclusive measurements of projectile-like and fusion-fission-like fragments have been performed for the 197Au + 51V system at E/sub Lab/ = 447 MeV. The damped reaction features have been interpreted in terms of phenomenological reaction models

  2. Individual variation in p53 and Cip1 expression profiles in normal human fibroblast strains following exposure to high-let radiation

    Energy Technology Data Exchange (ETDEWEB)

    Carpenter, T.R.; Johnson, N.F.; Gilliland, F.D. [Univ. of New Mexico, Albuquerque, NM (United States)] [and others

    1995-12-01

    Exposure to {alpha}-particles emitted by radon progeny appears to be the second-leading cause of lung cancer mortality. However, individual susceptibility to the carcinogenic effects of {alpha}-particles remains poorly characterized. Variation in susceptibility to cancer produced by certian classes of DNA-damaging chemicals is suspected to involve differences in metabolic activation and detoxication. Susceptibility to {alpha}-particle-induced cancer may involve variations in capacity or opportunity to repair DNA damage. Subtle variations in DNA repair capacity would more likely explain radon-related lung cancer susceptibility. The p53 tumor suppressor protein accumulates as a cellular response to DNA damage from ionizing radiation and regulates arrest in the G{sub 1} portion of the cell cycle. Arrest in G{sub 1} portion of the cell cycle. While upstream regulation of p53 protein stability is poorly understood, variations in the ability to accumulate p53 following DNA damage represent potential variations in lung cancer susceptibility related to radon progeny. Further, transcription of the cell-cycle regulatory gene Cip1 is regulated by p53 and increases following ionizing radiation. Therefore, variations in the expression of Cip1 following {alpha}-particle exposure may also be a susceptibility factor in radon-related lung cancers. The purpose of the present investigation was to measure p53 and Cip1 protein induction following {alpha}-particle exposure of fibroblast lines from nine individuals to determine if there were significant variations. The expression of Cip1 protein indicates the differences in response are biologically relevant.

  3. Enhanced efficacy of combined {sup 213}Bi-DTPA-F3 and paclitaxel therapy of peritoneal carcinomatosis is mediated by enhanced induction of apoptosis and G2/M phase arrest

    Energy Technology Data Exchange (ETDEWEB)

    Vallon, Mario; Seidl, Christof; Blechert, Birgit; Li, Zhoulei; Gaertner, Florian C.; Senekowitsch-Schmidtke, Reingard; Essler, Markus [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Gilbertz, Klaus-Peter [German Armed Forces, Institute of Radiobiology, Munich (Germany); Baumgart, Anja [Technische Universitaet Muenchen, III. Medical Department, Munich (Germany); Aichler, Michaela; Feuchtinger, Annette; Walch, Axel K. [Helmholtz Zentrum Muenchen, Institute of Pathology, Neuherberg (Germany); Bruchertseifer, Frank; Morgenstern, Alfred [Institute for Transuranium Elements, European Commission, Joint Research Centre, Karlsruhe (Germany)

    2012-12-15

    Targeted therapy with {alpha}-particle emitting radionuclides is a promising new option in cancer therapy. Stable conjugates of the vascular tumour-homing peptide F3 with the {alpha}-emitter {sup 213}Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined {sup 213}Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either {sup 213}Bi-DTPA-F3 or paclitaxel both in vitro and in vivo. Cytotoxicity of treatment with {sup 213}Bi-DTPA-F3 and paclitaxel, alone or in combination, was assayed towards OVCAR-3 cells using the alamarBlue assay, the clonogenic assay and flow cytometric analyses of the mode of cell death and cell cycle arrest. Therapeutic efficacy of the different treatment options was assayed after repeated treatment of mice bearing intraperitoneal OVCAR-3 xenograft tumours. Therapy monitoring was performed by bioluminescence imaging and histopathologic analysis. Treatment of OVCAR-3 cells in vitro with combined {sup 213}Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either {sup 213}Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with {sup 213}Bi-DTPA-F3 (1.85 MBq) and paclitaxel (120 {mu}g) as demonstrated by bioluminescence imaging and histopathologic investigation of tumour spread on the mesentery of the small and large intestine. Moreover, mean survival of xenograft mice that received combined therapy with {sup 213}Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either {sup 213}Bi-DTPA-F3 or paclitaxel alone. Combined treatment with {sup 213}Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application. (orig.)

  4. I. Excluded Volume Effects in Ising Cluster Distributions and Nuclear Multifragmentation II. Multiple-Chance Effects in Alpha-Particle Evaporation

    Energy Technology Data Exchange (ETDEWEB)

    Breus, Dimitry E.

    2005-05-16

    In Part 1, geometric clusters of the Ising model are studied as possible model clusters for nuclear multifragmentation. These clusters may not be considered as non-interacting (ideal gas) due to excluded volume effect which predominantly is the artifact of the cluster's finite size. Interaction significantly complicates the use of clusters in the analysis of thermodynamic systems. Stillinger's theory is used as a basis for the analysis, which within the RFL (Reiss, Frisch, Lebowitz) fluid-of-spheres approximation produces a prediction for cluster concentrations well obeyed by geometric clusters of the Ising model. If thermodynamic condition of phase coexistence is met, these concentrations can be incorporated into a differential equation procedure of moderate complexity to elucidate the liquid-vapor phase diagram of the system with cluster interaction included. The drawback of increased complexity is outweighted by the reward of greater accuracy of the phase diagram, as it is demonstrated by the Ising model. A novel nuclear-cluster analysis procedure is developed by modifying Fisher's model to contain cluster interaction and employing the differential equation procedure to obtain thermodynamic variables. With this procedure applied to geometric clusters, the guidelines are developed to look for excluded volume effect in nuclear multifragmentation. In part 2, an explanation is offered for the recently observed oscillations in the energy spectra of {alpha}-particles emitted from hot compound nuclei. Contrary to what was previously expected, the oscillations are assumed to be caused by the multiple-chance nature of {alpha}-evaporation. In a semi-empirical fashion this assumption is successfully confirmed by a technique of two-spectra decomposition which treats experimental {alpha}-spectra has having contributions from at least two independent emitters. Building upon the success of the multiple-chance explanation of the oscillations, Moretto

  5. Studies on the atomic and molecular processes produced by alpha emitters in gaseous media using track detection

    International Nuclear Information System (INIS)

    The main purpose of the studies consists in obtaining new and reliable experimental data on certain atomic and molecular physical processes which take place at low speed or/and very low amounts, such as: diffusion, adherence, fallout, etc. of the alpha emitters in gaseous media. By using the track analysis method, most experimental data can be visualized by optical microscopy, so that reliable qualitative and quantitative investigations can be performed. In the first stage, the alpha track method was used. Two plastic detectors were used: CR - 39 (Page, England) and RL - 115 types 1 and 2 (Kodak, France). For these detectors new etching conditions were developed. In the present stage, a calibration of CR - 39 and RL - 115 track detectors for the alpha particles emitted from gaseous radionuclides, particularly for 222 Rn and its alpha descendants, is performed. For this purpose the track detectors were suspended in tight vessels and the following alpha emitter sources were used: - a diuranate source calibrated in uranium prepared in our laboratory; - a calibrated 226 Ra solution; - sources calibrated in 222 Rn and 226 Ra. The amounts and activities of each alpha decay product of these sources are calculated using a radioactive accumulation computation programme UURASE based on the Bateman general equation. The alpha particle ranges were calculated using the TRIM computation programme. In the future stages of this investigation the following studies will be performed: - the diffusion of gaseous alpha emitters; - the sorption of alpha emitter gases and aerosols on different materials; - 222 Rn monitoring in dwelling houses and working places and the implementation of the alpha track method in the National Networks for surveillance of the environmental alpha radioactivity. (authors)

  6. Radon monitoring in gas turbine and thermal power station; A comparative study

    International Nuclear Information System (INIS)

    Background: In this study, measurement of indoor radon and its progeny levels was carried out in gas turbine power station in Haryana (India), where natural gas is used as fuel. For comparison, the results of a study carried out in thermal power plant in Haryana are also presented. Radon being a ubiquitous air pollutant has global impact and its monitoring in the environment at work places is essential from health and hygiene point of view. Materials and methods: LR-115, type- II (Kodak Pathe, France), plastic track detectors commonly known as solid state nuclear track detectors were used to measure the radon concentration over long integrated times. Alpha particles emitted from radon cause radiation damage tracks, which were subsequently revealed by chemical etching in NaOH. These alpha tracks registered were counted by optical microscope at suitable magnification and converted into radon concentration. Results: The radon levels measured at various locations were moderate to high and thus unsafe from health point of view. The potential alpha energy concentration, radon levels (EEC), annual exposure, annual effective dose in the gas turbine power plant varied from 4.14 mWL to 26.7 mWL, 38.3 Bq m-3 to 247.6 Bq m-3, 0.17 WLM to 1.10 WLM and 0.66 mSv respectively. Conclusion: In gas turbine power plant, the radon levels were found to be lower as compared with thermal power plant. In thermal power plant a lot of coal is being burnt which contains radionuclides. Coal fired plants release more radioactive waste which is hazardous into the air than gas power plants of equivalent capacity

  7. A kinematically complete, interdisciplinary, and co-institutional measurement of the 19F(α,n) cross section for nuclear safeguards science

    Energy Technology Data Exchange (ETDEWEB)

    Peters, W. A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States); Smith, M. S. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Pittman, S. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Thompson, S. J. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Clement, R. R. C. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Cizewski, J. A. [Rutgers Univ., New Brunswick, NJ (United States); Pain, S. D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Febbraro, M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Michigan, Ann Arbor, MI (United States); Chipps, K. A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Burcher, S. [Rutgers Univ., New Brunswick, NJ (United States); Manning, B. [Rutgers Univ., New Brunswick, NJ (United States); Reingold, C. [Rutgers Univ., New Brunswick, NJ (United States); Avetisyan, R. [Univ. of Notre Dame, IN (United States); Battaglia, A. [Univ. of Notre Dame, IN (United States); Chen, Y. [Univ. of Notre Dame, IN (United States); Long, A. [Univ. of Notre Dame, IN (United States); Lyons, S. [Univ. of Notre Dame, IN (United States); Marley, S. T. [Univ. of Notre Dame, IN (United States); Seymour, C. [Univ. of Notre Dame, IN (United States); Siegl, K. T. [Univ. of Notre Dame, IN (United States); Smith, M. K. [Univ. of Notre Dame, IN (United States); Strauss, S. [Univ. of Notre Dame, IN (United States); Talwar, R. [Univ. of Notre Dame, IN (United States); Bardayan, D. W. [Univ. of Notre Dame, IN (United States); Gyurjinyan, A. [Univ. of Notre Dame, IN (United States); Smith, K. [Univ. of Tennessee, Knoxville, TN (United States); Thornsberry, C.; Thompson, P.; Madurga, M. [Univ. of Tennessee, Knoxville, TN (United States); Stech, E. [Univ. of Notre Dame, IN (United States); Tan, W. P. [Univ. of Notre Dame, IN (United States); Wiescher, M. [Univ. of Notre Dame, IN (United States); Ilyushkin, S. [Colorado School of Mines, Golden, CO (United States); Tully, Z. [Tennessee Technological Univ., Cookeville, TN (United States); Grinder, M. M. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-05-01

    Alpha particles emitted from the decay of uranium in a UF6 matrix can interact with fluorine and generate neutrons via the 19F(α,n)22Na reaction. These neutrons can be used to determine the uranium content in a UF6 storage cylinder. The accuracy of this self-interrogating, non-destructive assay (NDA) technique is, however, limited by the uncertainty of the 19F(α,n)22Na cross section. We have performed complementary measurements of the 19F(α,n)22Na reaction with both 4He and 19F beams to improve the precision of the 19F(α,n)22Na cross section over the alpha energy range that encompasses common actinide alpha decay needed for NDA studies. We have determined an absolute cross section for the 19F(α,n)22Na reaction to an average precision of 7.6% over the alpha energy range of 3.9 – 6.7 MeV. We utilized this cross section in a simulation of a 100 g spherical UF6 assembly and obtained a change in neutron emission rate values of approximately 10-12%, and a significant (factor of 3.6) decrease in the neutron emission rate uncertainty (from 50-51% to 13-14%), compared to simulations using the old cross section. Our new absolute cross section enables improved interpretations of NDAs of containers of arbitrary size and configuration.

  8. Modeling of biodistribution of 90 Y-DOTA-hR3 by using artificial intelligence techniques

    International Nuclear Information System (INIS)

    In this work the biodistribution of radioimmunoconjugate 90Y-DOTA-hR3 was modeled by using an artificial neural network. In vivo stability of 90Y-DOTA-hR3 was determined in healthy male Wistar rats at 4, 24 and 48 hours, in different organs. A model describing the relationship between, by one hand, the incorporated dose and, by the other hand, organ and time was developed by using a multilayer perceptron neural network. Adjusted model was analyzed by several statistical tests. Outcomes shown that proposed neural model describes the relationship between the studied variables in a proper way. (Author)

  9. Preparation and radiolabeling of a lyophilized (kit) formulation of DOTA-rituximab with 90Y and 111In for domestic radioimmunotherapy and radioscintigraphy of Non-Hodgkin’s Lymphoma

    OpenAIRE

    Gholipour, Nazila; Jalilian, Amir Reza; Khalaj, Ali; Johari-Daha, Fariba; Yavari, Kamal; Sabzevari, Omid; Khanchi, Ali Reza; AKHLAGHI, MEHDI

    2014-01-01

    Background On the basis of results of our previous investigations on 90Y-DTPA-rituximab and in order to fulfil national demands to radioimmunoconjugates for radioscintigraphy and radioimmunotherapy of Non-Hodgkin’s Lymphoma (NHL), preparation and radiolabeling of a lyophilized formulation (kit) of DOTA-rituximab with 111In and 90Y was investigated. Methods 111In and 90Y with high radiochemical and radionuclide purity were prepared by 112Cd (p,2n)111In nuclear reaction and a locally developed ...

  10. Development and evaluation of copper-67 and samarium-153 labeled conjugates for tumor radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, S.C.; Mausner, L.F.; Mease, R.C.; Meinken, G.E.; Joshi, V.; Kolsky, K.; Sweet, M.; Steplewski, Z.

    1995-02-01

    The potential of utilizing receptor-specific agents such as monoclonal antibodies (MAb), and MAb-derived smaller molecules, as carriers of radionuclides for the selective destruction of tumors has stimulated much research activity. The success of such applications depends on many factors, especially the tumor binding properties of the antibody reagent, the efficiency of labeling and in-vivo stability of the radioconjugate and, on the careful choice of the radionuclide best suited to treat the tumor under consideration. The radiolabeled antibody technique for radioimmunotherapy (RIT), however, has experienced many limitations, and its success has not matched the expectations that were raised more than a decade ago. The problems that have been identified include: (i) degradation of antibody immunoreactivity resulting from chemical manipulations required for labeling; (ii) lack of suitable radioisotopes and methods for stable attachment of the radiolabel; (iii) in-vivo instability of the radioimmunoconjugates; (iv) excessive accumulation of activity in non-target locations; and (v) lack of radioimmunoconjugate accessibility to cells internal to a tumor mass. A careful choice of the radionuclide(s) best suited to treat the tumor under consideration is one of the most important requirements for successful radioimmunotherapy. This study evaluates copper 67 and samarium 153 for tumor radioimmunotherapy.

  11. Terbium-149, a novel α-emitter for radioimmunotherapy of melanoma and leukaemia

    International Nuclear Information System (INIS)

    Because of their short range, high linear energy transfer (LET) and high relative biological effectiveness (RBE), α-emitters are particularly promising in the treatment of micrometastases by killing cells in transit (Go phase) and in preangiogenic lesions sparing normal cells and bone marrow (the dose limiting organ), if conjugated to a 'smart' carrier (radioimmunoconjugate). 149Tb, the α-emitting radiolanthanide, was successfully produced on tandem accelerator at Australian National University by irradiating 142Nd and studied by us for the first time for its possible use in the treatment of cancer with its high α-energy of 4.0 MeV and high LET of 243 keV/μm. 152Tb and 153Sm are used for optimising the technique for radiolabelling anti-melanoma and anti- leukaemia antibodies, viz. 9.2.27 and WM-53, respectively, using the bifunctional chelator, bicyclic anhydride of diethylene triamine pentaacetic acid (cDTPAa) to form the radioimmunoconjugate (RIC). The RIC was subjected to quality control based on radiochemical purity, serum stability, and flow-cytometry studies. The biological effectiveness of these conjugates being evaluated by in vitro and in vivo experiments. The former are based on cell survival studies by 3H-thymidine incorporation test, and the latter by biodistribution studies in tumour models in nude mice using human melanoma cell lines MM-138

  12. Development of radioinmunoconjugate 90Y-DOTA-nimotuzumab-Fab for therapy of EGFR over expressing tumors

    International Nuclear Information System (INIS)

    Many monoclonal antibodies conjugated with 1,4,7,10-tetraaza cyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) and radiolabeled with 90Y, have been used for radioimmunotherapy. As know IgG molecules are heavy proteins with a molecular weight of approximately 150 kDa. Accordingly, intact IgG antibodies may have significant slow kinetics biodistribution and severely limited properties of tissue penetration. Antibody fragments labeled with radio metals could be promising radiopharmaceuticals for imaging and non-invasive therapy due to its high affinity to the tumor, the lack of effector function and rapid pharmacokinetic. In this work, the nimotuzumab Fab fragment was obtained by cleavage with papain in molar excess. After separating the reaction mixture in three steps using affinity, size exclusion and ion exchange chromatography; the Fab fragment showed high values of purity, integrity and identity. The Fab fragment was derivatized with DOTA and labeled with 90Y. The radioimmunoconjugate with high radiochemical yield was assessed by in vitro stability with an excess of 50mM DTPA. The development of 90Y-DOTA-Nimotuzumab-Fab radioimmunoconjugate allows to count on as a potential agent for radioimmunotherapy. (Author)

  13. Skeletal dosimetry models for alpha-particles for use in molecular radiotherapy

    Science.gov (United States)

    Watchman, Christopher J.

    Molecular radiotherapy is a cancer treatment methodology whereby a radionuclide is combined with a biologically active molecule to preferentially target cancer cells. Alpha-particle emitting radionuclides show significant potential for use in molecular radiotherapy due to the short range of the alpha-particles in tissue and their high rates of energy deposition. Current radiation dosimetry models used to assess alpha emitter dose in the skeleton were developed originally for occupational applications. In medical dosimetry, individual variability in uptake, translocation and other biological factors can result in poor correlation of clinical outcome with marrow dose estimates determined using existing skeletal models. Methods presented in this work were developed in response to the need for dosimetry models which account for these biological and patient-specific factors. Dosimetry models are presented for trabecular bone alpha particle dosimetry as well as a model for cortical bone dosimetry. These radiation transport models are the 3D chord-based infinite spongiosa transport model (3D-CBIST) and the chord-based infinite cortical transport model (CBICT), respectively. Absorbed fraction data for several skeletal tissues for several subjects are presented. Each modeling strategy accounts for biological parameters, such as bone marrow cellularity, not previously incorporated into alpha-particle skeletal dosimetry models used in radiation protection. Using these data a study investigating the variability in alpha-particle absorbed fractions in the human skeleton is also presented. Data is also offered relating skeletal tissue masses in individual bone sites for a range of ages. These data are necessary for dose calculations and have previously only been available as whole body tissue masses. A revised 3D-CBIST model is also presented which allows for changes in endosteum thickness to account for revised target cell location of tissues involved in the radiological

  14. Determination of alpha dose rate profile at the HLW nuclear glass/water interface

    International Nuclear Information System (INIS)

    Highlights: • The nuclear glass/water interface is studied. • The way the energy of alpha particles is deposited is modeled using MCNPX code. • A model giving dose rate profiles at the interface using intrinsic data is proposed. • Bulk dose rate is a majoring estimation in alteration layer and in surrounding water. • Dose rate is high in small cracks; in larger ones irradiated volume is negligible. - Abstract: Alpha irradiation and radiolysis can affect the alteration behavior of High Level Waste (HLW) nuclear glasses. In this study, the way the energy of alpha particles, emitted by a typical HLW glass, is deposited in water at the glass/water interface is investigated, with the aim of better characterizing the dose deposition at the glass/water interface during water-induced leaching mechanisms. A simplified chemical composition was considered for the nuclear glass under study, wherein the dose rate is about 140 Gy/h. The MCNPX calculation code was used to calculate alpha dose rate and alpha particle flux profiles at the glass/water interface in different systems: a single glass grain in water, a glass powder in water and a water-filled ideal crack in a glass package. Dose rate decreases within glass and in water as distance to the center of the grain increases. A general model has been proposed to fit a dose rate profile in water and in glass from values for dose rate in glass bulk, alpha range in water and linear energy transfer considerations. The glass powder simulation showed that there was systematic overlapping of radiation fields for neighboring glass grains, but the water dose rate always remained lower than the bulk value. Finally, for typical ideal cracks in a glass matrix, an overlapping of irradiation fields was observed while the crack aperture was lower than twice the alpha range in water. This led to significant values for the alpha dose rate within the crack volume, as long as the aperture remained lower than 60 μm

  15. Radioactive contamination and health risk assessment due to burning of coal in thermal energy generation

    International Nuclear Information System (INIS)

    Full text: Radon being a ubiquitous air pollutant has global impact and its monitoring in the environment at work places is essential from health and hygiene point of view. In thermal power plants, a lot of coal is burnt which contains radionuclides which are released into the environment and are hazardous. Radon is the main culprit in the local radioactive contamination of the environment due to burning of coal in thermal energy generation. It has been reported by several researchers (Nikl and Vegvari 1992, Bodizs et al. 1992) that the concentrations of the isotopes U 238 and Ra 226 become 3-5 times more than those in the coal itself in the coal slag and fly ash obtained by burning the coal in coal fired power plants. Several researchers have reported radon levels in thermal power plants (Bodizs et al. 1992, Rawat et al. 1991, Nikl and Vevgari 1992, Papastefanou and Charalanbous 1979, Kant et al. 2001). Keeping in view the environmental pollution caused due to the burning of coal in thermal power stations, there is an upsurge in the establishment of nuclear and gas turbine power stations in recent times. An increased share of gas and nuclear in power generation could lead to lower emissions. Also, considerable emphasis is being laid on developing non-polluting and renewable energy sources like water, air, solar energy and others. In this study, measurement of radon and its progeny levels was carried out over long integrated times in thermal power plant in Haryana by using LR-115, Type- II (Kodak Pathe, France), plastic track detectors commonly known as solid state nuclear track detectors (SS NTDs). Alpha particles emitted from radon cause radiation damage tracks, which were subsequently revealed by chemical etching in NaOH. These alpha tracks registered were counted by optical microscope at suitable magnification and converted into radon concentration. The findings indicate that it is very important to carry out these studies and the results of the full study will

  16. Study of Astatine (III) reactions with O, S and N ligands in solution

    International Nuclear Information System (INIS)

    Full text of publication follows. Astatine (At, Z=85: [Xe]4f145d106s26p5) belongs to the halogen group and is located below iodine in the periodic table. One of its isotopes (211At) appears promising as a therapeutic agent in nuclear medicine (Ref.1) owing to the energy of the alpha particles emitted during the disintegration of its nucleus and its short physical half-life (7.2 h). Since there are no stable isotopes of astatine, the chemistry of this element remains poorly understood. Generally, At is supposed to behave as a halogen (Ref.2) but it has been shown recently in our group that astatine presents a metallic behaviour in aqueous solution: it notably exists as At+ and AtO+ species under the oxidation states +I and +III (Ref.3). At the present time, the number of studies dealing with the complexation properties of the cationic forms of astatine remains limited (Ref.4), owing to its low availability. In this work, we have investigated the reactions of AtO+ species with different hetero-atomic (N, S, O) model ligands. A combined approach based on experimental and theoretical studies has been used (Ref.5). On account of the difficulties of experimental investigations of astatine species, the reactivity of AtO+ was explored using a competition method founded on astatine distributions between two distinct phases. Furthermore, for each AtO+/ ligand complex, the nature of the species formed and the associated thermodynamic constants were determined by computational modeling (DFT calculations). In this framework, an original computational methodology was developed to take into account the specificities of astatine, notably the associated relativistic effects. The computed equilibrium constants have been confronted with the experimental results. This comparison demonstrates an outstanding coherence between experience and theory. Furthermore, the analysis of the results shows a key role of solvent effects on astatine chemistry. Lastly, a specific reactivity for the

  17. Microdosimetric measurements for radiotherapy and radiation protection

    International Nuclear Information System (INIS)

    Neutrons produced by bombarding a 4 mm thick beryllium target with deuterons of 30 MeV and 70 MeV proton beams are used for a clinical trials of radiotherapy in NIRS cyclotron facility. Microdosimetric measurements for neutrons and protons were carried out using a tissue-equivalent (TE) proportional counters, and LET-1/2-SW counter and LET-5-SW counter. The TE gas employed is the propane based mixture, and pressure of 67.7 torr provided an effective sphere diameter of 2 μm for LET-1/2-SW counter. Alpha particles emitted from Cm-244 have an energy of approximatey 5.8 MeV, and the energy loss in a 2 μm path length of propane based TE gas was calculated to be 79.2 keV/μm. For the improvement of S/N ratio, a probetype charge sensitive pre-amplifier built in a first stage FET was used. Electronic signals were amplified and processed with a homemade spectroscopy logarithmic amplifier and a multichannel analyzer. The logarithmic amplifier made it possible to measure the dose distributions in lineal energy from less than 50 eV/μm to 2000 keV/μm at the same time. The number of pulse as a function of lineal energy in logarithm was stored and then processed with a personal computer (PC-9801). The measurement were also made on mixed radiation fields of neutron and proton and gamma-rays in order to investigate the variation of dose distribution in lineal energy. The differential distribution of dose in lineal energy, d(y) = y·n(y) was normalized to yield the fraction of dose deposited per unit of lineal energy. On the basis of these distributions, the dose-averaged LET and the average quality factor for radiations outside the primary beams was determined by using calculated with separately d(y)-distribution of a Photon fields. (author)

  18. The alpha immunotherapy - A successful solution in cancer treatment

    International Nuclear Information System (INIS)

    Full text: Radiation has been used in cancer therapy for many years. While, in the past the treatment involved mainly use of relatively low energy beta-emitters, more recently it was shown that isotopes emitting alpha particles have been more effective and selective against blood-borne cancers, widespread tumors and residual cells remaining after surgical intervention. This study shows that radioimmunotherapy (RIT) with α emitters may be therapeutically more effective than RIT with conventional β emitters. In the process of designing and developing the radioimmunotherapy procedures, the selection of the isotope is a major factor. This selection depends on a number of criteria and parameters, affecting usefulness and feasibility. Usefulness is directly related to the radiological performance of the ionising radiation in relation to tissue and its morphology, with a major distinction between the effects of alpha and beta-particles. Usefulness is also related to the pharmacodynamic performance of the isotope-carrier (e.g. antibody) complex, where the proper choice of isotope radiodecay half-life is essential. Feasibility depends on availability of the components in the isotope-ligand-carrier complex, and also on convenience and safety aspects in the preparation and the handling of the materials as well as in their application in patients. Alpha immunotherapy is based on emission of alpha particles by radionuclides. Due to its short physical t1/2, 213Bi appears to be especially suitable for use in conjunction with fast-clearing fragments; its 440-keV α emission also can be used for quantitation by external scintigraphy. Bismuth-213, a short-lived alpha particle emitting radionuclide, is generated from the decay of 225Ac, which has a half-life of 10 days. The development of a clinical 225Ac/213Bi generator and the preparation of a 213Bi radiolabeled antibody for radioimmunotherapy of leukemia is reported. Alpha emitting radionuclides are amongst the most promising

  19. Therapeutic efficacy and toxicity of {sup 225}Ac-labelled vs. {sup 213}Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

    Energy Technology Data Exchange (ETDEWEB)

    Essler, Markus; Gaertner, Florian C.; Blechert, Birgit; Senekowitsch-Schmidtke, Reingard; Seidl, Christof [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Neff, Frauke [Helmholtz Zentrum Muenchen, Institute of Pathology, Neuherberg (Germany); Bruchertseifer, Frank; Morgenstern, Alfred [Institute for Transuranium Elements, European Commission, Joint Research Centre, Karlsruhe (Germany)

    2012-04-15

    Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with {sup 225}Ac and {sup 213}Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of {sup 225}Ac-DOTA-F3 in comparison with that of {sup 213}Bi-DTPA-F3. ID{sub 50} values of {sup 213}Bi-DTPA-F3 and {sup 225}Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology. ID{sub 50} values of {sup 213}Bi-DTPA-F3 and {sup 225}Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 x 10{sup 7} MDA-MB-435 cells. Therapy with 6 x 1.85 kBq of {sup 225}Ac-DOTA-F3 or 6 x 1.85 MBq of {sup 213}Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived {sup 213}Bi (t{sub 1/2} 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of {sup 225}Ac-DOTA-F3 (t{sub 1/2} 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with {sup 225}Ac-DOTA-F3 (43%) and with {sup 213}Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10-30% of animals after treatment with {sup 225}Ac-DOTA-F3 or {sup 213}Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. Therapy with both {sup 225}Ac-DOTA-F3 and {sup 213}Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both

  20. A Study of Primary Collision Dynamics in Inverse-Kinematics Reaction of 78Kr on 40Ca at a Bombarding Energy of 10 MeV per Nucleon

    Science.gov (United States)

    Henry, Eric M.

    The CHIMERA multi-detector array at LNS Catania has been used to study the inverse-kinematics reaction of 78Kr + 40Ca at a bombarding energy of 10 A MeV. The multi-detector is capable of detecting individual products of the collision essential for the reconstruction of the collision dynamics. This is the first time CHIMERA has been used at low-energy, which offered a unique challenge for the calibration and interpretation of experimental data. Initial interrogation of the calibrated data revealed a class of selected events characterized by two coincident heavy fragments (atomic number Z>3) that together account for the majority of the total mass of the colliding system. These events are consistent with the complete fusion and subsequent binary split (fission) of a composite nucleus. The observed fission fragments are characterized by a broad A, Z distribution and are centered about symmetric fission while exhibiting relative velocities significantly higher than given by Viola systematics. Additional analysis of the kinematic relationship between the fission fragments was performed. Of note, is that the center-of-mass angular distribution (dsigma/dtheta) of the fission fragments exhibits an unexpected anisotropy inconsistent with a compound-nucleus reaction. This anisotropy is indicative of a dynamic fusion/fission-like process. The observed angular distribution features a forward-backward anisotropy most prevalent for mass-asymmetric events. Furthermore, the more massive fragment of mass-asymmetric events appears to emerge preferentially in the forward direction, along the beam axis. Analysis of the angular distribution of alpha particles emitted from these fission fragments suggests the events are associated mostly with central collisions. The observations associated with this subset of events are similar to those reported for dynamic fragmentation of projectile-like fragments, but have not before been observed for a fusion/fission-like process. Comparisons to

  1. Study of spatial distribution of thoron progeny in a room using direct thoron progeny sensors

    International Nuclear Information System (INIS)

    With the recent development of Direct Thoron Progeny Sensors (DTPS), it is possible to measure directly the time integrated progeny concentrations. Earlier methods of measuring progeny concentration focused on measuring the thoron gas concentration and assigning the progeny concentration using the equilibrium factor. But, in the case of thoron, the equilibrium factor is not well defined, and moreover the concentration of thoron also varies with distance from the source. In fact, large variations in the thoron concentrations are expected near and away from walls making it almost impossible to estimate a representative concentration from one point measurements. So, it is extremely essential to measure the progeny concentration directly and in this regard, DTPS provide a convenient passive technique for time integrated measurements. DTPSs are absorber (aluminized mylar of 50 μm thickness) mounted LR-115 type nuclear track detectors which selectively detect only the 8.78 MeV alpha particles emitted from 212Po atoms which are formed from the radioactive decay of 212Pb and 212Bi atoms deposited on the absorber surface. These sensors are designed to yield the time averaged equilibrium equivalent thoron concentration (EETC) and not the gas concentration. The sensitivity factor of DTPS is expressed as the track density registered for 1 day exposure to an environment containing 1 Bqm-3 of EETC, and was found to be 0.94 Tr cm-2 d-1/EETC (Bqm-3). The progeny of thoron are the isotopes of Polonium, Bismuth and Lead. In the indoor environment these progeny are found in unattached state (particle diameter 1-5 nm) and attached state (100-1000 nm). The progeny 212Pb, which has got the longest half-life of 10.6 hours, is mostly found in attached state. In typical indoor conditions, the unattached fraction is of the order of 2%. Therefore it is a general concept that the 212Pb will be uniformly distributed in the room. Of course there are some contradictory reports like Katase et al

  2. Cell death triggered by alpha-emitting {sup 213}Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Seidl, Christof; Schroeck, Hedwig; Seidenschwang, Sabine; Beck, Roswitha; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Schmid, Ernst [National Research Center for Environment and Health, Institute of Radiation Biology, GSF, Neuherberg (Germany); Abend, Michael [German Armed Forces, Institute of Radiobiology, Munich (Germany); Becker, Karl-Friedrich [Technische Universitaet Muenchen, Institute of Pathology, Munich (Germany); National Research Center for Environment and Health, Institute of Pathology, GSF, Neuherberg (Germany); National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany); Apostolidis, Christos; Nikula, Tuomo K. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Kremmer, Elisabeth [National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany)

    2005-03-01

    Radioimmunotherapy with {alpha}-particle-emitting nuclides, such as{sup 213}Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by {sup 213}Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of {sup 213}Bi-d9MAb targeting d9-E-cadherin and {sup 213}Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as {sup 213}Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and {sup 213}Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with {sup 213}Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of {alpha}-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific {sup 213}Bi-d9MAb compared with unspecific {sup 213}Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound {sup 213}Bi-immunoconjugates per cell exceeded 2 x 10{sup 4}, most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by {sup 213}Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. {sup 213}Bi-immunoconjugates seem

  3. On the analytic estimation of radioactive contamination from degraded alphas

    International Nuclear Information System (INIS)

    The high energy spectrum of alpha particles emitted from a single isotope uniformly contaminating a bulk solid has a flat energy spectrum with a high end cutoff energy equal to the maximal alpha kinetic energy (Tα) of the decay. In this flat region of the spectrum, we show the surface rate rb (Bq keV−1cm−2) arising from a bulk alpha contamination ρb (Bq cm−3) from a single isotope is given by rb =ρb Δ R/ 4 Δ E , where Δ E = E1−E2>0  is the energy interval considered (keV) in the flat region of the spectrum and Δ R = R2−R1, where R2 (R1) is the amount of the bulk material (cm) necessary to degrade the energy of the alpha from Tα to E2 (E1). We compare our calculation to a rate measurement of alphas from 147Sm, (15.32 ± 0.03% of Sm(nat) and half life of (1.06 ± 0.01)× 1011 yr [1]), and find good agreement, with the ratio between prediction to measurement of 100.2%± 1.6% (stat)± 2.1% (sys). We derive the condition for the flat spectrum, and also calculate the relationship between the decay rate measured at the surface for a [near] surface contamination with an exponential dependence on depth and a second case of an alpha source with a thin overcoat. While there is excellent agreement between our implementation of the sophisticated Monte Carlo program SRIM [2] and our intuitive model in all cases, both fail to describe the measured energy distribution of a 148Gd alpha source with a thin (∼200μg cm−2) Au overcoat. We discuss possible origins of the disagreement and suggest avenues for future study

  4. [Research programs in radiotherapy]. DOE final report, 1996

    International Nuclear Information System (INIS)

    Results which have not yet been published in detail are reported here on the following associated studies: Progress in the area of macrocyclic chelates for targeted therapy; Progress in biologic activation with radioimmunoconjugate therapy: Association of molecular receptor increase and tumor response in ChL6/L6 protocol patients; Progress in genetically engineered Lym-1 single chain molecules; Progress in analysis of molecular genetic coded messages to enhance tumor response; Progress on development and validation of planar imaging for therapy planning systems; Progress in development of a 3-D treatment planning system using SPECT; Progress in development of methods to evaluate enhancement of tumor penetration in a murine model; and Progress in clinical applications

  5. Preparation of a Lysine based DTPA derivative and its Immuno conjugate for RIT

    Energy Technology Data Exchange (ETDEWEB)

    Lee, So-Young; Pyun, Mi-Sun; Hong, Young-Don; Choi, Sun-Ju [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2007-10-15

    Radioimmunotherapy (RIT) has beneficiary effect of both immunotherapy and radiotherapy in cancer treatment. Those are the effect on predominant tumoricidal potency induced by radiation and intensified tumor cell targeting by antibody of radioimmunoconjugate. For conjugation of radioisotope with antibody for RIT the introduction of proper BFCA (bifunctional chelating agent) is very important. The most widely used BFCA is a diethylene triamine penta acetic acid (DTPA), However, it is known to form less stable conjugation due to competitive conjugation between radioisotope and antibody. In present study, to overcome the unstable chelation we synthesized the lysine based DTPA derivative. Furthermore, we prepared even more stable conjugate with human IgG using this DTPA derivative by its active isothiocyanate, demonstrated a stability of the immunoconjugate.

  6. [Research programs in radiotherapy]. DOE final report, 1996

    Energy Technology Data Exchange (ETDEWEB)

    DeNardo, S.J.

    1996-12-31

    Results which have not yet been published in detail are reported here on the following associated studies: Progress in the area of macrocyclic chelates for targeted therapy; Progress in biologic activation with radioimmunoconjugate therapy: Association of molecular receptor increase and tumor response in ChL6/L6 protocol patients; Progress in genetically engineered Lym-1 single chain molecules; Progress in analysis of molecular genetic coded messages to enhance tumor response; Progress on development and validation of planar imaging for therapy planning systems; Progress in development of a 3-D treatment planning system using SPECT; Progress in development of methods to evaluate enhancement of tumor penetration in a murine model; and Progress in clinical applications.

  7. Development of 177Lu-DOTA-anti-CD20 for radioimmunotherapy

    International Nuclear Information System (INIS)

    Rituximab was successively labeled with 177Lu-lutetium chloride. 177Lu chloride was obtained by thermal neutron flux (4 x 1013 n cm-2 s-1) of natural Lu2O3 sample with a specific activity of 2.6-3 GBq/mg. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 deg C using DOTA, N-hydroxy succinimide (NHS) in CH2Cl2. DOTA-rituximab was obtained by the addition of 1 mL of a rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH 7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 deg C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 deg C in 24 h. Radio-thin layer chromatography showed an overall radiochemical purity of >98% at optimized conditions (specific activity = 444 MBq/mg, labeling efficacy; 82%). The final isotonic 177Lu-DOTA-rituximab complex was checked by gel electrophoresis for structure integrity control. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rats were carried out to determine complex distribution of the radioimmunoconjugate up to 168 h. The biodistribution data were in accordance with other antiCD20 radioimmunoconjugates already reported. (author)

  8. Development of anti-CD30 radioimmunoconstructs (RICs) for treatment of Hodgkin's lymphoma. Studies with cell lines and animal studies

    International Nuclear Information System (INIS)

    Objectives: comparison of the binding affinity to a CD30-positive Hodgkin lymphoma (HL) cell line and biodistribution in HL bearing mice of new anti-CD30 radioimmunoconjugates (RICs) of varying structure and labelling nuclides. Methods: The antibodies Ki-4 and 5F11 were radioiodinated by the chloramine T method or labelled with 111In via p-NCS-Benzyl-DOTA. In addition, the Ki-4-dimer was investigated in the iodinated form. The RICs were analyzed for retained immunoreactivity by immunochromatography. In-vitro binding studies were performed on CD30-positive L540 cell lines. For in-vivo biodistribution studies, SCID mice bearing human HL xenografts were injected with the various radio-immunoconjugates. After 24 h, activities in the organs and tumour were measured for all 5 RICs. Tumour-free animals were studied in the same way with 131I-Ki-4 24 h p. i. The three RICs with the highest tumour/background ratios 24 h p.i. (131I-Ki-4, 131I-5F11, 111In-bz-DOTA-Ki-4) were analysed further at 48 h and 72 h. Results: all the RICs were successfully labelled with high specific activities (28-47 TBq/mmol) and sufficient radiochemical yields (> 80%). Scatchard plot analysis proved high tumour affinity (KD = 20-220 nmol/l). In-vivo tumour accumulation in % of injected dose per g tissue (% ID/g) lay between 2.6 (131I-5F11) and 12.3 % ID/g (131I-Ki-4) with permanently high background in blood. Tumour/blood-ratios of all RICs were below one at all time points. Conclusions: in-vitro tumour cell affinities of all RICs were promising. However, in-vivo biokinetics tested in the mouse model did not meet expectations. This highlights the importance of developing and testing further new anti-CD30 conjugates. (orig.)

  9. Proposal for translational analysis and development of clinical radiolabeled immunoglobulin therapy

    International Nuclear Information System (INIS)

    Background and purpose: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies. Material and methods: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin. Results: We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies. Conclusions: We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents

  10. Preparation and quality control and biodistribution studies of [90Y]-DOTA-cetuximab for radioimmunotherapy

    International Nuclear Information System (INIS)

    Yttrium-90 is a useful radionuclide for radioimmunotherapy (RIT) and the anti-epidermal growth factor receptor (anti-EGFR) antibody cetuximab is clinicsally approved for the treatment of EGFR-expressing metastatic colorectal cancer and advanced head and neck cancer. Thus in this work radiolabeling of monoclonal anti-EGFR with 90Y for radioimmunotherapy (RIT) is targeted. Cetuximab was successively labeled with [90Y] chloride (74 MBq) 2 mCi after conjugation with macrocyclics bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid mono-(N-hydroxysuccinimidyl) ester (DOTA-NHS), purified and concentrated by centrifugation using an Amicon Ultra-15 filter (Millipore, MWCo, 30000). 90Y chloride was obtained by 90Sr/90Y generator. Radiolabeling was completed in 2 h by the addition of DOTA-cetuximab conjugate at 42 °C. The stability of radiolabeled was studied in human serum. Biodistribution studies in normal rats were carried out to determine the radioimmunoconjugate distribution up to 96 h. Radiochemical purity of 92 % (using ITLC) was obtained for final radioimmunoconjugate (Specific activity = 0.55 GBq/mg). Stability of radiolabeled protein in presence of human serum was tested at 37 °C for up to 24 h. Biodistribution studies demonstrated the highest ID/g % in the blood (2.62 ± 0.005 at 24 h) and the liver (2.19 ± 0.001). This study demonstrated that 90Y-DOTA-cetuximab is a potential compound for the treatment of EGFR-expressing cancers. (author)

  11. Production of Actinium-225 via High Energy Proton Induced Spallation of Thorium-232

    International Nuclear Information System (INIS)

    The science of cancer research is currently expanding its use of alpha particle emitting radioisotopes. Coupled with the discovery and proliferation of molecular species that seek out and attach to tumors, new therapy and diagnostics are being developed to enhance the treatment of cancer and other diseases. This latest technology is commonly referred to as Alpha Immunotherapy (AIT). Actinium-225/Bismuth-213 is a parent/daughter alpha-emitting radioisotope pair that is highly sought after because of the potential for treating numerous diseases and its ability to be chemically compatible with many known and widely used carrier molecules (such as monoclonal antibodies and proteins/peptides). Unfortunately, the worldwide supply of actinium-225 is limited to about 1,000mCi annually and most of that is currently spoken for, thus limiting the ability of this radioisotope pair to enter into research and subsequently clinical trials. The route proposed herein utilizes high energy protons to produce actinium-225 via spallation of a thorium-232 target. As part of previous R and D efforts carried out at Argonne National Laboratory recently in support of the proposed US FRIB facility, it was shown that a very effective production mechanism for actinium-225 is spallation of thorium-232 by high energy proton beams. The base-line simulation for the production rate of actinium-225 by this reaction mechanism is 8E12 atoms per second at 200 MeV proton beam energy with 50 g/cm2 thorium target and 100 kW beam power. An irradiation of one actinium-225 half-life (10 days) produces ∼100 Ci of actinium-225. For a given beam current the reaction cross section increases slightly with energy to about 400 MeV and then decreases slightly for beam energies in the several GeV regime. The object of this effort is to refine the simulations at proton beam energies of 400 MeV and above up to about 8 GeV. Once completed, the simulations will be experimentally verified using 400 MeV and 8 GeV protons

  12. Production of Actinium-225 via High Energy Proton Induced Spallation of Thorium-232

    Energy Technology Data Exchange (ETDEWEB)

    Harvey, James T.; Nolen, Jerry; Vandergrift, George; Gomes, Itacil; Kroc, Tom; Horwitz, Phil; McAlister, Dan; Bowers, Del; Sullivan, Vivian; Greene, John

    2011-12-30

    The science of cancer research is currently expanding its use of alpha particle emitting radioisotopes. Coupled with the discovery and proliferation of molecular species that seek out and attach to tumors, new therapy and diagnostics are being developed to enhance the treatment of cancer and other diseases. This latest technology is commonly referred to as Alpha Immunotherapy (AIT). Actinium-225/Bismuth-213 is a parent/daughter alpha-emitting radioisotope pair that is highly sought after because of the potential for treating numerous diseases and its ability to be chemically compatible with many known and widely used carrier molecules (such as monoclonal antibodies and proteins/peptides). Unfortunately, the worldwide supply of actinium-225 is limited to about 1,000mCi annually and most of that is currently spoken for, thus limiting the ability of this radioisotope pair to enter into research and subsequently clinical trials. The route proposed herein utilizes high energy protons to produce actinium-225 via spallation of a thorium-232 target. As part of previous R and D efforts carried out at Argonne National Laboratory recently in support of the proposed US FRIB facility, it was shown that a very effective production mechanism for actinium-225 is spallation of thorium-232 by high energy proton beams. The base-line simulation for the production rate of actinium-225 by this reaction mechanism is 8E12 atoms per second at 200 MeV proton beam energy with 50 g/cm2 thorium target and 100 kW beam power. An irradiation of one actinium-225 half-life (10 days) produces {approx}100 Ci of actinium-225. For a given beam current the reaction cross section increases slightly with energy to about 400 MeV and then decreases slightly for beam energies in the several GeV regime. The object of this effort is to refine the simulations at proton beam energies of 400 MeV and above up to about 8 GeV. Once completed, the simulations will be experimentally verified using 400 MeV and 8 Ge

  13. From academy to industry

    International Nuclear Information System (INIS)

    Full text of publication follows. Clinical efficacy of radioimmunotherapy (RIT) has been clearly documented in the consolidation situation, such as first line treatment of indolent Non Hodgkin Lymphoma after induction chemotherapy [1] or after salvage resection of liver metastases from colon carcinoma [2], when tumor targets have a small, preferably microscopic, size. In this favorable situation RIT, which is a targeted therapy with toxicity limited to hematological toxicity, has a great potential and could be competitive with chemotherapy in particular for solid tumors. Such potential has been recently demonstrated in prostate cancer [3]. A lot of academic preclinical studies have been performed using multiple antibodies and antibody formats labeled with varied beta-emitting and more recently alpha particle-emitting radionuclides. With regard to other targeted therapies, the efficacy of RIT has been fully recognized and academic preclinical studies have been extended to a lot of clinical phase I/II studies but a limited number of phase II studies. Paradoxically, despite quite encouraging results, the number of industrially implemented phase III studies has been limited to the fingers of one hand illustrating a gap between academy and industry. For the last ten years only 2 ARCs (Antibody Radio Conjugates) (Zevalin and Bexxar) have been approved. The reasons for such a gap are complex and multiple but they could be summarized in one word: Money. The cost for a phase III study, enrolling hundreds of patients, exceeds the financial capabilities of most radiopharmaceutical companies and, up to now, Big Pharmas did not dare to invest in this field of RIT in part because they are not familiar with the use of radionuclides and prefer to develop ADCs (Antibody Drug Conjugates) even if they are generally more toxic and no more efficient than ARCs. For the future of RIT it is crucial to succeed in convincing Big Pharmas to invest in this field of ARCs. For this purpose it

  14. Cuban Monoclonal Antibodies for Radioimmunodiagnosis and Radioimmunotherapy of Cancer Diseases

    International Nuclear Information System (INIS)

    The Centre of Molecular Immunology produces monoclonal antibodies for treating cancer diseases. We are mainly focus on two target systems; one is the epidermal growth factor receptor (EGF-R) because there is a tremendous relationship between the EGF/EGF-R system and several human tumours such as lung, head and neck, ovarian breast and brain cancers; the second one is the ganglioside system, the relevance of certain gangliosides in tumour growth and metastatic dissemination has been well documented, GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues. Nimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) that was obtained by complementarity-determining regions grafting of a murine mAb (ior egf/r3) to a human framework having remarkable antiproliferative, pro-apoptotic, and antiangiogenic effects. A Phase I clinical trial was performed to evaluate the toxicity and clinical effect of an intracavitary (intracerebral) administration of a single dose of nimotuzumab (h-R3) labelled with increasing doses of 188Re. All patients bearing astrocytomas grade III/IV should be treated previously with conventional therapies and have an EGF-R overexpression in the tumour, demonstrated by immunohistochemical study. Maximal tolerated dose was 3 mg of the h-R3 labelled with 10 mCi of 188Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5% of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas. GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues according to immunohistochemical studies, using either polyclonal or monoclonal antibodies. But both immunohistochemical and biochemical methods have strongly suggested its over-expression in human breast and colon

  15. Imaging cancer using PET - the effect of the bifunctional chelator on the biodistribution of a {sup 64}Cu-labeled antibody

    Energy Technology Data Exchange (ETDEWEB)

    Dearling, Jason L.J., E-mail: jason.dearling@childrens.harvard.ed [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States); Voss, Stephan D. [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States); Dunning, Patricia; Snay, Erin [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Fahey, Frederic [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States); Smith, Suzanne V. [Australian National Science and Technology Organisation (ANSTO), New Illawarra Road, PMB1, Menai, New South Wales 2234 (Australia); Huston, James S. [EMD Serono Research Center, 45A Middlesex Turnpike, Billerica, MA 01821-3936 (United States); Boston Biomedical Research Institute, Watertown, MA 02472-2899 (United States); Meares, Claude F. [Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616-5295 (United States); Treves, S. Ted; Packard, Alan B. [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States)

    2011-01-15

    Introduction: Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodynamic stability of the {sup 64}Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with {sup 64}Cu using these chelators in tumor-bearing mice. Methods: The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH{sub 2}-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N, N', N'', N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH{sub 2}-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N, N', N', N''-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1, 8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with {sup 64}Cu and injected into mice bearing subcutaneous human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomography images acquired at 1, 24 and 48 hours post-injection, and at 48 hours post-injection a full ex vivo biodistribution study was carried out. Results: The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [{sup 64}Cu]ch14.18-p-NH{sub 2}-Bn-NOTA was 4.74 {+-} 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [{sup 64}Cu]ch14.18-SarAr was 8.06 {+-} 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. Conclusions: The results of this

  16. Development of anti-CD30 radioimmunoconstructs (RICs) for treatment of Hodgkin's lymphoma. Studies with cell lines and animal studies

    Energy Technology Data Exchange (ETDEWEB)

    Dietlein, M.; Boerner, S.M.; Fischer, T.; Zimmermanns, B.; Kobe, C.; Schicha, H.; Schomaecker, K. [Dept. of Nuclear Medicine, Univ. of Cologne (Germany); Hansen, H.; Schnell, R.; Tawadros, S.; Engert, A.; Staak, O.; Pogge von Strandmann, E. [Dept. of Internal Medicine I, Univ. of Cologne (Germany)

    2010-07-01

    Objectives: comparison of the binding affinity to a CD30-positive Hodgkin lymphoma (HL) cell line and biodistribution in HL bearing mice of new anti-CD30 radioimmunoconjugates (RICs) of varying structure and labelling nuclides. Methods: The antibodies Ki-4 and 5F11 were radioiodinated by the chloramine T method or labelled with {sup 111}In via p-NCS-Benzyl-DOTA. In addition, the Ki-4-dimer was investigated in the iodinated form. The RICs were analyzed for retained immunoreactivity by immunochromatography. In-vitro binding studies were performed on CD30-positive L540 cell lines. For in-vivo biodistribution studies, SCID mice bearing human HL xenografts were injected with the various radio-immunoconjugates. After 24 h, activities in the organs and tumour were measured for all 5 RICs. Tumour-free animals were studied in the same way with {sup 131}I-Ki-4 24 h p. i. The three RICs with the highest tumour/background ratios 24 h p.i. ({sup 131}I-Ki-4, {sup 131}I-5F11, {sup 111}In-bz-DOTA-Ki-4) were analysed further at 48 h and 72 h. Results: all the RICs were successfully labelled with high specific activities (28-47 TBq/mmol) and sufficient radiochemical yields (> 80%). Scatchard plot analysis proved high tumour affinity (K{sub D} = 20-220 nmol/l). In-vivo tumour accumulation in % of injected dose per g tissue (% ID/g) lay between 2.6 ({sup 131}I-5F11) and 12.3 % ID/g ({sup 131}I-Ki-4) with permanently high background in blood. Tumour/blood-ratios of all RICs were below one at all time points. Conclusions: in-vitro tumour cell affinities of all RICs were promising. However, in-vivo biokinetics tested in the mouse model did not meet expectations. This highlights the importance of developing and testing further new anti-CD30 conjugates. (orig.)

  17. Imaging cancer using PET - the effect of the bifunctional chelator on the biodistribution of a 64Cu-labeled antibody

    International Nuclear Information System (INIS)

    Introduction: Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodynamic stability of the 64Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with 64Cu using these chelators in tumor-bearing mice. Methods: The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH2-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N, N', N'', N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH2-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N, N', N', N''-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1, 8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with 64Cu and injected into mice bearing subcutaneous human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomography images acquired at 1, 24 and 48 hours post-injection, and at 48 hours post-injection a full ex vivo biodistribution study was carried out. Results: The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p 64Cu]ch14.18-p-NH2-Bn-NOTA was 4.74 ± 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [64Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. Conclusions: The results of this study indicate that differences in the thermodynamic stability of these chelator-Cu(II) complexes were not associated with significant differences in uptake of the tracer by the tumor

  18. Optimized preparation and preliminary evaluation of [64Cu]-DOTA-trastuzumab for targeting ErbB2/Neu expression

    International Nuclear Information System (INIS)

    Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. Trastuzumab is a monoclonal antibody that binds with high affinity to HER2/neu, which is over expressed on breast and other tumors. Developing new tracers for the detection of this cancer is of great interest. In this study, trastuzumab was successively labeled with [64Cu]CuCl2 after conjugation with DOTA-NHS-ester. The conjugate was purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-trastuzumab was labeled with 64Cu produced by 68Zn(p,αn)64Cu nuclear reaction (30 MeV protons at 180 μA). Radiochemical purity, integrity of protein after radiolabeling and immunoreactivity of radiolabeled mAb trastuzumab with HER2/neu antigen and SkBr3 cell line were performed by RIA. In vitro stability of radiolabeled mAb in human serum was determined by thin layer chromatography. In vitro internalization studies were performed with the SkBr3 cell line and the tissue biodistribution of the 64Cu-DOTA-trastuzumab was evaluated in wild-type rat (90 ± 5.5 μCi, 2, 6, 12, 24 h p.i.). The radioimmunoconjugate was prepared with a radiochemical purity of higher than 96 ± 0.5 % (ITLC) and specific activity as high as 5.3 μCi/μg. The average number of chelators per antibody for the conjugate used in this study was 5.8/1. The sample was showed to have similar patterns of migration in the gel electrophoresis. The 64Cu-DOTA-trastuzumab showed high immunoreactivity towards HER2/neu antigen and SkBr3 cell line. In vitro stability of the labeled product was found to be more than 94 % in PBS and 82 ± 0.5 % in human serum over 48 h. In vitro internalization studies of the 64Cu-DOTA-trastuzumab showed that up to 11.5 % of the radioimmunoconjugate internalized after 10 h. The accumulation of the radiolabeled mAb in liver, skin, intestine, lung, spleen

  19. Monte Carlo Simulations of Necrotic Cell Targeted Alpha Therapy

    International Nuclear Information System (INIS)

    Full text: Hypoxic tumour cells are radioresistant and are significant contributors to the locoregional recurrences and distant metastases that mark treatment failure. Due to restricted circulatory supply, hypoxic tumor cells frequently become necrotic and thus necrotic areas often lie near hypoxic tumour areas. In this study we investigate the feasibility of binding an alpha-emitting conjugate to necrotic cells located in the proximity of hypoxic, viable tumour cells. Monte Carlo radiation transport simulations were performed to investigate the dose distribution resulting from the thorium 227 (Th227) decay chain in a representative tumour geometry. The Geant4 software toolkit was used to simulate the decay and interactions of the Th227 decay chain. The distribution of Th227 was based on a study by Thomlinson and Gray of human lung cancer histological samples (Thomlinson RH, Gray LH. Br J Cancer 1955; 9:539). The normalized dose distribution obtained with Geant4 from a cylindrical Th227 source in water is illustrated in Fig. I. The relative contribution of the different decay channels is displayed, together with a profile through the centre of the accumulated dose map. The results support the hypothesis that significant α-particle doses will be deposited in the hypoxic tumor tissue immediately surrounding the necrotic core (where the majority of Th227 will be located). As an internal a-particle generator, the Th227-radioimmunoconjugate shows potential as an efficient hypoxic tumour sterilizer.

  20. Monte Carlo simulations of dose distributions with necrotic tumor targeted radioimmunotherapy

    International Nuclear Information System (INIS)

    Radio-resistant hypoxic tumor cells are significant contributors to the locoregional recurrences and distant metastases that mark failure of radiotherapy. Due to restricted tissue oxygenation, chronically hypoxic tumor cells frequently become necrotic and thus there is often an association between chronically hypoxic and necrotic tumor regions. This simulation study is the first in a series to determine the feasibility of hypoxic cell killing after first targeting adjacent areas of necrosis with either an α- or β-emitting radioimmunoconjugate. - Highlights: • A representative necrotic tumor geometry was created in the Geant4 Monte Carlo toolkit. • Custom designed particle tracking was performed allowing for separation of deposited doses from different decay particles. • Post-processing of the data included relative biological effectiveness of the different decay particles and effects of cell oxygenation. • Physical and equivalent doses resulting from 177Lu and 212Pb were compared by means of dose maps and dose profiles. • 212Pb appears to be a promising isotope for necrotic tumor targeted α-therapy and will be pursued in future in vivo studies

  1. Preparation, quality control and biodistribution studies of [67Ga]-DOTA-anti-CD20

    International Nuclear Information System (INIS)

    Rituximab was successively labeled with [67Ga]-gallium chloride. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 C using DOTA, N-hydroxy succinimide (NHS) in CH2Cl2. DOTA-Rituximab was obtained by the addition of 1 mL of a Rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH=7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 C in 3 h. Radio-thin layer chromatography showed an overall radiochemical purity of 90%-95% at optimized conditions (specific activity = 30 GBq/mg, labeling efficacy; 82%). The final isotonic 67Ga-DOTA-rituximab complex was checked by gel electrophoresis for radiolysis. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rat model performed to determine complex distribution of the radioimmunoconjugate up to 28 h. (orig.)

  2. Preclinical evaluation of copper-67 labelled anti-MUC1 mucin antibody C595 for therapeutic use in bladder cancer

    International Nuclear Information System (INIS)

    Transitional cell carcinoma of the bladder is the fifth commonest cause of death from cancer in men in the United Kingdom. Most patients present early with superficial disease, though with current treatment up to 20% progress to invasive disease, which has a poor prognosis. Better local treatments are required to limit this tumour progression. The ease of access to the bladder via a catheter provides the ideal opportunity for antibody (Ab) targeted therapy. We have previously shown that indium-111 labelled anti-MUC1 mucin Ab C595 selectively localises to bladder tumours after intravesical administration. We have selected copper-67 as an alternative radiolabel with suitable physical characteristics for radioimmunotherapy. This communication demonstrates that C595 can be reproducibly labelled with 67Cu and that the radioimmunoconjugate is both stable and maintains high immunoreactivity. Pilot studies on cystectomy specimens in a novel ex vivo system and in one patient confirmed the ability of this conjugate to localise to tumour after intravesical administration. On the basis of these studies we are now in a position to study the intravesical administration of 67Cu-labelled C595 in patients with bladder cancer with a view to a therapeutic trial. (orig.). With 4 figs., 1 tab

  3. {sup 177}Lu-labeled-VG76e monoclonal antibody in tumor angiogenesis: a comparative study using DOTA and DTPA chelating systems

    Energy Technology Data Exchange (ETDEWEB)

    Fani, M.; Psimadas, D. [Inst. of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research ' ' Demokritos' ' , Athens (Greece); Biomedica Life Sciences S.A., Athens (Greece); Bouziotis, P.; Gourni, E.; Varvarigou, A.D. [Inst. of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research ' ' Demokritos' ' , Athens (Greece); Harris, A.L. [Weatherall Inst. of Molecular Medicine, Cancer Research U.K., Univ. of Oxford (United Kingdom); Loudos, G. [Biomedical Simulations and Imaging Lab., National Technical Univ. of Athens (Greece); Maecke, H.R. [Div. of Radiological Chemistry, Univ. Hospital Basel (Switzerland)

    2007-07-01

    Vascular endothelial growth factor (VEGF) is one of the molecules which regulate angiogenesis, a phenomenon observed in many diseases, including cancer. VG76e, an anti-VEGF monoclonal antibody, was labeled with {sup 177}Lu via p-SCN-Bz-DOTA and CHX-A''-DTPA chelating systems, in order to investigate its possible therapeutic use. Labeling was performed by a 30 min incubation of {sup 177}LuCl{sub 3} and each immunoconjugate, at 37 C. Radiochemical analysis showed the formation of a single radioactive species, at a yield higher than 98%, for both immunoconjugates. Kits have been formulated for both VG76e-DOTA and VG76e-DTPA. Stability studies, in the presence of a competitor excess, showed that both radiolabeled species remained sufficiently stable (95%) for at least 48 h. Biodistribution results in normal mice were similar for both radioimmunoconjugates, with no significant bone uptake. Gamma camera images of tumor-bearing mice showed satisfactory visualization of the tumor 24 h p.i., while a higher uptake was observed at 48 h p.i. Our findings indicate that both the bifunctional chelating agents p-SCN-Bz-DOTA and CHX-A''-DTPA can be used for the labeling of VG76e with {sup 177}Lu, with high labeling yield and stability. Their in vivo behaviour in normal and tumor-bearing mice looks promising and they can be successfully used for tumor imaging studies. (orig.)

  4. PET imaging of osteosarcoma in dogs using a fluorine-18-labeled monoclonal antibody fab fragment

    International Nuclear Information System (INIS)

    Four dogs with histologically confirmed osteogenic sarcoma were studied with PET following intravenous injection of the 18F-labeled Fab fragment of TP-3, a monoclonal antibody specific for human and canine osteosarcomas. The antibody fragment was labeled using the N-succinimidyl (8-(4'-(18F)fluorobenzyl)amino)suberate acylation agent. Blood clearance of activity was biphasic in all dogs but half-times were variable (T1/2β = 2-13 hr). Catabolism of labeled Fab was reflected by the decrease in protein-associated activity in serum from more than 90% at 1 min to 60%-80% at 4 hr. PET images demonstrated increased accumulation of 18F at the primary tumor site relative to normal contralateral bone in one dog as early as 15 min after injection. Biopsies obtained after euthanasia indicated higher uptake at the edges of the tumor as observed on the PET scans. Tumor uptake was 1-3 x 10-3% injected dose/g, a level similar to that reported for other Fab fragments in human tumors. In the three dogs with metastatic disease, early PET images reflected activity in the blood pool but later uptake was observed in suspected metastatic sites. These results, although preliminary, suggest that PET imaging of 18F-labeled antibody fragments is feasible and that dogs with spontaneous tumors could be a valuable model for preclinical research with radioimmunoconjugates. 34 refs., 6 figs., 2 tabs

  5. Use of 99mTc-MAG3-biocytin in Avidin/Biotin based Three Step Targeting

    International Nuclear Information System (INIS)

    A general point of concern in clinical radioimmunoscintigraphy(RIS) and radioimmunotherapy(RIT) studies is the long residence time of radioimmunoconjugates in the bloodstream, resulting in limited sensitivity and specificity in RIS and in myelotoxicity in RIT. A solution to this problem might be the use of so-called pretargeting strategies. The concept of pretargeting is based on the separation, in time, of antibody localization and radionuclide targeting. Several ligand-receptor systems have been evaluated of which the biotin-(strept)avidin system is the most widely studied. The attractiveness of this system lies in the very high affinity of avidin and streptavidin for biotin. The 3E8 antibody was produced from humanized anti- TAG-72 monoclonal antibody (AKA) by amino acid change in 95-99 residues of heavy chain complementary determinant regions (HCDRs) 3 using phage displayed library technology.In this study, we are investigating the feasibility of pretargeting strategy using biontinylated 3E8, avidin and 99mTc-MAG3-biocytin in LS174T tumor bearing mice model. We prepare biotinylated 3E8 antibody conjugates, perform radiolabeling and in vitro targeting of 99mTc-MAG3-biocytin and evaluate tumor pretargeting in tumor bearing nude mice model

  6. Preparation, biodistribution, and dosimetry of 188Re-Labeled MoAb ior cea1 and its f(ab')2 fragments by avidin-biotin strategy

    International Nuclear Information System (INIS)

    The biotinylated monoclonal antibody (MoAb) ior cea1 and its F(ab')2 fragments were labeled with Re-188 by combination of avidin-biotin strategy. 188Re-MoAb, 188Re-MoAb-biotin, 188Re-F(ab')2, and 188Re-F(ab')2-biotin preparations were produced for these studies with specific activities of 1.30±0.18 GBq/mg and from instant freeze-dried kit formulations using ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) as a weak competing ligand. There were no significant differences (p>0.05) between the biodistribution in mice of biotinylated and unbiotinylated 188Re-labeled immunoconjugates. When avidin was injected as a chase after injection of 188Re-MoAb-biotin or 188Re-F(ab')2-biotin, the blood radioactivity level decreased approximately 75% (cumulated activity) and the effective dose decreased almost 25% with respect to that of the radioimmunoconjugates in which the chase effect was not used. Our results suggest that 188Re-labeled biotinylated MoAb ior cea1 and its F(ab')2 fragments prepared by this method are stable complexes in vivo

  7. Immunotherapy of non-Hodgkin's lymphoma with hLL2 (epratuzumab, an anti-CD22 monoclonal antibody) and Hu1D10 (apolizumab).

    Science.gov (United States)

    Leonard, John P; Link, Brian K

    2002-02-01

    Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA]) and radiolabeled forms, as well as radioimmunoconjugates targeting other antigens, has resulted in the exploration of alternative targets for immunotherapeutic strategies in lymphoma. We report on the rationale for and initial efforts in the development of two unlabeled, humanized monoclonal antibodies directed against molecules commonly expressed in B-cell malignancies. hLL2 (epratuzumab; Immunomedics, Inc, Morris Plains, NJ) binds to the CD22 antigen, while Hu1D10 (apolizumab; Protein Design Labs, Inc, Fremont, CA) reacts with a polymorphism on the HLA-DR beta chain. Preclinical studies and early clinical evaluations suggest that these agents have a potential role as novel therapeutic targets for lymphoma with acceptable toxicity profiles. Further efforts will explore optimal clinical settings for their use, as well as define treatment regimens either as single agents or in combination with chemotherapy or other biologics. PMID:11842393

  8. Pursuing nuclear energy with no nuclear contamination - from neutron flux reactor to deuteron flux reactor

    International Nuclear Information System (INIS)

    : (1) Selective Resonant tunneling model has predicted 3-deuteron fusion which has been found in experiments [6, 7] as well. The reasonable inference is the neutrino emission from the metal hydrides. The feasibility of detection of this neutrino is discussed based on the information from the KamLAND neutrino detector in Japan. (2) Nano-meter technique should be used to increase the deuterium flux through the palladium surface. (3) Gas-discharge tube in combination with optical monochrometer would be the suitable experiment at the current funding level. (4) Negative feed-back should be used to solve the problem of the reproducibility; then, based on the deuteron flux a self-sustaining reactor would be feasible. References [1]. Xing Z. Li, Jian Tian, Ming Y. Mei and Chong X. Li, 'Sub-barrier Fusion and Selective Resonant Tunneling,' Phys. Rev., C 61, 024610 (2000) [2]. Xing Z. Li, Bin Liu, Si Chen, Qing Ming Wei, and Heinrich Hora, 'Fusion cross-sections for inertial fusion energy,' Laser and Particle Beam, 22,469 (2004) [3]. G. Fralick , et al., 'Results of an Attempt to Measure Increased Rates of the Reaction D +D--- 3He + n in a Nonelectrochemical Cold Fusion Experiment,' NASA Technical Memorandum 102430 (1989) [4]. Xing Z. Li, et al., 'Correlation between abnormal deuterium flux and heat flow in a D/Pd system,' J. Phys. D: Appl. Phys. 36 3095-3097, (2003) [5]. Y. Iwamura, et al., 'Elemental Analysis of Pd Complexes: Effects of D2 gas permeation, 'Jpn. J. Appl. Phys., 41 4642 (2002) [6]. J. Kasagi, et al., 'Energetic Protons and Alpha Particles Emitted in 150-keV Deuteron Bombardment on Deuterated Ti,' J. Phys. Soc. Japan, 64 (3), 778 (1995) [7]. A. Takahashi, et al., 'Anomalous enhancement of three-body deuteron fusion in titanium deuteride with low-energy D+ beam implantation,' Fusion Technol., 34, 256 (1998)

  9. Design Techniques for Power-Aware Combinational Logic SER Mitigation

    Science.gov (United States)

    Mahatme, Nihaar N.

    The history of modern semiconductor devices and circuits suggests that technologists have been able to maintain scaling at the rate predicted by Moore's Law [Moor-65]. With improved performance, speed and lower area, technology scaling has also exacerbated reliability issues such as soft errors. Soft errors are transient errors that occur in microelectronic circuits due to ionizing radiation particle strikes on reverse biased semiconductor junctions. These radiation induced errors at the terrestrial-level are caused due to radiation particle strikes by (1) alpha particles emitted as decay products of packing material (2) cosmic rays that produce energetic protons and neutrons, and (3) thermal neutrons [Dodd-03], [Srou-88] and more recently muons and electrons [Ma-79] [Nara-08] [Siew-10] [King-10]. In the space environment radiation induced errors are a much bigger threat and are mainly caused by cosmic heavy-ions, protons etc. The effects of radiation exposure on circuits and measures to protect against them have been studied extensively for the past 40 years, especially for parts operating in space. Radiation particle strikes can affect memory as well as combinational logic. Typically when these particles strike semiconductor junctions of transistors that are part of feedback structures such as SRAM memory cells or flip-flops, it can lead to an inversion of the cell content. Such a failure is formally called a bit-flip or single-event upset (SEU). When such particles strike sensitive junctions part of combinational logic gates they produce transient voltage spikes or glitches called single-event transients (SETs) that could be latched by receiving flip-flops. As the circuits are clocked faster, there are more number of clocking edges which increases the likelihood of latching these transients. In older technology generations the probability of errors in flip-flops due to SETs being latched was much lower compared to direct strikes on flip-flops or SRAMs leading to

  10. Studies on the optimization of leukemia and non-Hodgkin lymphoma therapies using opioids, chemotherapy and radioimmunotherapy

    International Nuclear Information System (INIS)

    Despite complex treatment schedules for cancer, the occurrence of resistances and relapses is a major concern in oncology. Hence, novel treatment options are needed. In this thesis, different approaches using radioimmunotherapy and the opioid D,L-methadone alone or in combination with doxorubicin were analyzed regarding their cytotoxic potential and the triggered signalling pathways in sensitive and resistant leukaemia and non-Hodgkin lymphoma (NHL). The radioimmunoconjugates [Bi-213]anti-CD33 and [Bi-213]anti-CD20 for treatment of acute myeloid leukaemia (AML) or NHL, respectively, were applied exemplary for the use of targeted alpha-therapies (TAT). Depending on the analyzed cell lines, the used activity concentrations and specific activities (MBq/μg antibody) apoptosis was induced abrogating radio- and chemo-cross-resistances specifically. The cell death was caspase-dependent activating the mitochondrial pathway and was executed by downregulation of the anti-apoptotic proteins XIAP and Bcl-xL. D,L-Methadone induces apoptosis in vitro and in vivo in opioid-receptor (OR) expressing cells depending on the OR density and the used concentrations. Resistances could be overcome and proliferation was inhibited. In combination with doxorubicin, a synergistic effect regarding cytotoxicity in ex vivo patient cells and cell lines was observed. This effect depends on the increase of doxorubicin uptake co-administering D,L-methadone whereas doxorubicin enhances OR expression. The activation of OR leads to the downregulation of cAMP playing a pivotal role in apoptosis induction. In vivo, the therapeutic potential of D,L-methadone alone or in combination with doxorubicin could be proven as mice transplanted with human T-ALL-cells could be identified as tumour free. In summary, these studies show that TAT using [Bi-213]anti-CD33 and [Bi-213]anti-CD20 as well as the opioid D,L-methadone harbour the potential to optimize conventional treatment modalities for leukaemia and NHL.

  11. Alpha radioimmunotherapy of multiple myeloma: study of feasibility of ex vivo medullary purge

    International Nuclear Information System (INIS)

    The efficiency of the radioimmunotherapy (RIT) using beta emitters has been clinically proved in treatments of refractory forms of lymphoma. The alpha-emitting radioelements of short half-life are also good potential candidates for RIT, applicable to tumor targets accessible rapidly to the molecules of the radio-immuno-conjugates of size compatible with the short range of alpha particles (50 to 80 μm). The goal of this study is to demonstrate the feasibility of such an approach on a model of myeloma multiply targeted by specific antibodies (B-B4) coupled to bismuth-213 with a chelating agent (benzyl-DTPA). The efficiency of the alpha RIT was evaluated in vitro by means of different techniques analyzing the cellular mortality (the method of limited dilution), the effects on DNA (the testing of micro-nuclei), the analysis of radio-induced apoptosis (the test with acridine orange) and finally the study of non-specific irradiation on population of cells of hematopoietic system un-recognized by the B-B4 benzyl-DTPA) immuno-conjugate. The first results have shown besides the technical feasibility of the project a strong dose dependent cellular mortality with a survival falling rapidly from 28% to around 1 o/oo for a single doubling of the dose from 14.8 kBq / 105 cells (0.4 μCi) to 29.6 kBq/105 cells (0.8 μCi). The cellular mortality was total at 300 kBq/105 cells (8 μCi). The cells in an apoptosis state were evidenced at rates up to 40% for a dose of 7.4 kBq/105 cells (0.2 μ Ci). New experiments will permit confirming these first results and determining the irradiation range having in view a utilization in protocols of purging of the myeloma cells on pockets obtained after plasmaphereses

  12. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

    Science.gov (United States)

    Ray, Geoffrey L.; Baidoo, Kwamena E.; Keller, Lanea M. M.; Albert, Paul S.; Brechbiel, Martin W.; Milenic, Diane E.

    2011-01-01

    Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administeringescalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease. PMID:22229017

  13. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

    Directory of Open Access Journals (Sweden)

    Diane E. Milenic

    2011-12-01

    Full Text Available Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave, and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h and 31.70 ± 16.20 (72 h, respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease.

  14. Studies on the optimization of leukemia and non-Hodgkin lymphoma therapies using opioids, chemotherapy and radioimmunotherapy; Studien zur Optimierung von Leukaemie- und non-Hodgkin-Lymphom-Therapien durch den Einsatz von Opioiden, Chemotherapeutika und Radioimmuntherapien

    Energy Technology Data Exchange (ETDEWEB)

    Roscher, Mareike

    2013-05-24

    Despite complex treatment schedules for cancer, the occurrence of resistances and relapses is a major concern in oncology. Hence, novel treatment options are needed. In this thesis, different approaches using radioimmunotherapy and the opioid D,L-methadone alone or in combination with doxorubicin were analyzed regarding their cytotoxic potential and the triggered signalling pathways in sensitive and resistant leukaemia and non-Hodgkin lymphoma (NHL). The radioimmunoconjugates [Bi-213]anti-CD33 and [Bi-213]anti-CD20 for treatment of acute myeloid leukaemia (AML) or NHL, respectively, were applied exemplary for the use of targeted alpha-therapies (TAT). Depending on the analyzed cell lines, the used activity concentrations and specific activities (MBq/μg antibody) apoptosis was induced abrogating radio- and chemo-cross-resistances specifically. The cell death was caspase-dependent activating the mitochondrial pathway and was executed by downregulation of the anti-apoptotic proteins XIAP and Bcl-xL. D,L-Methadone induces apoptosis in vitro and in vivo in opioid-receptor (OR) expressing cells depending on the OR density and the used concentrations. Resistances could be overcome and proliferation was inhibited. In combination with doxorubicin, a synergistic effect regarding cytotoxicity in ex vivo patient cells and cell lines was observed. This effect depends on the increase of doxorubicin uptake co-administering D,L-methadone whereas doxorubicin enhances OR expression. The activation of OR leads to the downregulation of cAMP playing a pivotal role in apoptosis induction. In vivo, the therapeutic potential of D,L-methadone alone or in combination with doxorubicin could be proven as mice transplanted with human T-ALL-cells could be identified as tumour free. In summary, these studies show that TAT using [Bi-213]anti-CD33 and [Bi-213]anti-CD20 as well as the opioid D,L-methadone harbour the potential to optimize conventional treatment modalities for leukaemia and NHL.

  15. Preparation and quality control of radiometal-DOTARituximab

    International Nuclear Information System (INIS)

    In this work Rituximab has been labeled by Ga-67 using a new one-step method for in-situ preparation of macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTANHS). DOTA-NHS was prepared at 25 deg. C using DOTA, Nhydroxy succinimide (NHS) in CH Cl in one step. DOTA- 2 2 Rituximab was obtained by the addition of 1 ml of a Rituximab pharmaceutical solution (5 mg/ml, in phosphate buffer, pH=7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 deg. C with continuous mild stirring for 15 hours. Radiolabeling was performed at 37 deg. C in 3 hrs using Ga-67 Chlorides or Cu-64 Acetate. Thin layer radiochromatography demonstrated an overall radiochemical purity of 90-95% at optimized conditions (specific activity =30 GBq/mg, labeling efficacy= 82%). The final isotonic radio-metal-DOTA-Rituximab complex was checked by gel electrophoresis for radiolysis. TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary bio-distribution studies of the Ga-67 immunoconjugate in normal rat model performed to determine complex distribution of the radioimmunoconjugate up to 28hrs by imaging and organ counting after sacrificing the rats. In this study a facile method for incorporation of metal chelating moiety into peptides and antibody structure is presented. (author)

  16. Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90-DOTA-peptide in tumor-bearing mice

    International Nuclear Information System (INIS)

    A bifunctional chelating agent, DOTA-Gly3-L-(p-isothiocyanato)-phenylalanine amide (DOTA-peptide-NCS), was studied in nude mice bearing human breast cancer xenografts (HBT 3477) to determine its potential for radioimmunoconjugate therapy. Indium-111 and yttrium-90 were attached to an anti-adenocarcinoma chimeric L6 (ChL6) monoclonal antibody (MAb) after pre-chelation to the DOTA-peptide-NCS and the desired neutral radiochelates were obtained by purification. The unique characteristic of the DOTA-peptide-NCS to form neutral complexes with trivalent metals was utilized to separate the resulting 111In and 90Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The paramacokinetics of 111In- and 90Y-DOTA-peptide-ChL6 were obtained for 5 days after injection in nude mice bearing HBT 3477 xenographs. The results were compared with the pharmacokinetics of 125I-ChL6 obtained in the same mouse model. The whole-body clearance of 125I-ChL6, 90Y-and 111In-DOTA-peptide-ChL6 was monoexponential with biologic half-times of 92, 104 and 160 hr, respectively. Blood clearances of the three radiopharmaceuticals were biphasic. The radiometal immunoconjugates had greater tumor uptake and slower clearances. Indium-111- and 90Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pre-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake in enhanced and a favorable therapeutic index is achieved using these agents. 29 refs., 7 figs., 2 tabs

  17. Preparation and quality control of 177Lu-DOTA-Rituximab for radioimmunotherapy of relapsed and refractory B-cell NHL patients

    International Nuclear Information System (INIS)

    Full text of publication follows. Background: the prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumor-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumor cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immuno-conjugate of Rituximab and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab was desalted with sodium bi-carbonate (0.1 M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in-vitro stability and pyrogenicity were studied. Immunoreactivity of 177Lu-DOTA-Rituximab was assessed using RAMOS cells. The radio-immuno-conjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: an average of 4.02 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single Rituximab antibody. The radiochemical purity of the labelled antibody was >95 % with preserved affinity for CD20 antigen. The final preparation was stable up to ∼120 hours when tested under different conditions. Bacterial endotoxin level in the sample was less than the permissible levels(<0.2 EU/ml). A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Conclusion: a favorable radiochemical purity, stability and biodistribution of the radiolabelled immuno-conjugate indicated that 177Lu-DOTA-antiCD20 antibody-Rituximab might be a promising therapeutic agent for the treatment of relapsed and refractory Non Hodgkin's Lymphoma. (authors)

  18. Preparation and in vivo evaluation of a novel stabilized linker for 211At labeling of protein

    International Nuclear Information System (INIS)

    Significant improvement of in vivo stability of 211At-labeled radioimmunoconjugates achieved upon employment of a recently reported new linker, succinimidyl N-2-(4-[211At]astatophenethyl)succinamate (SAPS), prompted additional studies of its chemistry. The 211At radiolabeling of succinimidyl N-2-(4-tributylstannylphenethyl)succinamate (1) was noted to decline after storage at -15oC for greater than 6 months. Compound 1 was found to degrade via a ring closure reaction with the formation of N-2-(4-tributylstannylphenethyl)succinimide (3), and a modified procedure for the preparation of 1 was developed. The N-methyl structural analog of 1, succinimidyl N-2-(4-tributylstannylphenethyl)-N-methyl succinamate (SPEMS), was synthesized to investigate the possibility of improving the stability of reagent-protein linkage chemistry. Radiolabeling of SPEMS with 211At generates succinimidyl N-2-(4-[211At]astatophenethyl)-N-methyl succinamate (Methyl-SAPS), with yields being consistent for greater than 1 year. Radiolabelings of 1 and SPEMS with 125I generated succinimidyl N-2-(4-[125I]iodophenethyl)succinamate (SIPS) and succinimidyl N-2-(4-[125I]iodophenethyl)-N-methyl succinamate (Methyl-SIPS), respectively, and showed no decline in yields. Methyl-SAPS, SAPS, Methyl-SIPS and SIPS were conjugated to Herceptin for a comparative assessment in LS-174T xenograft-bearing mice. The conjugates of Herceptin with Methyl-SAPS or Methyl-SIPS demonstrated immunoreactivity equivalent to if not superior to the SAPS and SIPS paired analogs. The in vivo studies also revealed that the N-methyl modification resulted in a superior statinated product

  19. Nature of the bifunctional chelating agent used for radioimmunotherapy with yttrium-88 monoclonal antibodies: critical factors in determining in vivo survival and organ toxicity

    International Nuclear Information System (INIS)

    One factor that is critical to the potential effectiveness of radioimmunotherapy is the design of radiometal-chelated antibodies that will be stable in vivo. Stability in vivo depends on the condition that both the chelate linkage and radiolabeling procedures not alter antibody specificity and biodistribution. In addition, synthesis and selection of the chelating agent is critical for each radiometal in order to prevent inappropriate release of the radiometal in vivo. In the present study, we compare the in vivo stability of seven radioimmunoconjugates that use different polyaminocarboxylate chelating agents to complex yttrium-88 to the mouse anti-human interleukin-2 receptor monoclonal antibody, anti-Tac. Chelate linkage and radiolabeling procedures did not alter the immunospecificity of anti-Tac. In order to assess whether yttrium was inappropriately released from the chelate-coupled antibody in vivo, iodine-131-labeled and yttrium-88 chelate-coupled antibodies were simultaneously administered to the same animals to correlate the decline in yttrium and radioiodinated antibody activity. The four stable yttrium-88 chelate-coupled antibodies studied displayed similar iodine-131 and yttrium-88 activity, indicating minimal elution of yttrium-88 from the complex. In contrast, the unstable yttrium-88 chelate-coupled antibodies had serum yttrium-88 activities that declined much more rapidly than their iodine-131 activities, suggesting loss of the radiolabel yttrium-88 from the chelate. Furthermore, high rates of yttrium-88 elution correlated with deposition in bone. Four chelating agents emerged as promising immunotherapeutic reagents: isothiocyanate benzyl DTPA and its derivatives 1B3M, MX, and 1M3B

  20. Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells

    International Nuclear Information System (INIS)

    Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-xL, a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies. (orig.)

  1. Preparation and preclinical evaluation of 177Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors

    International Nuclear Information System (INIS)

    Objectives: Nimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) which recognizes the external domain of the epidermal growth factor receptor (EGFR) with high specificity. It was demonstrated that h-R3 has a unique clinical profile for immunotherapy of adult gliomas and pediatric pontine gliomas. The aim of this work was to evaluate the conjugate 177Lu-h-R3 as a potential radioimmunoconjugate for radioimmunotherapy (RIT) of tumors overexpressing EGFR. Methods: h-R3 was modified with the macrocylcic ligand S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) and the acyclic ligand S-2-(4-Isothiocyanatobenzyl)-diethylenetriamine pentaacetic acid (p-SCN-Bn-DTPA); the immunoconjugates were labeled with no-carried added 177Lu. Specificity and affinity were tested using radioimmunoassays in a cell line overexpressing EGFR. Biodistribution in mice, healthy or bearing A431 epithelial carcinoma xenografts, was performed for 11 days. Tumor uptake, the influence of the nature of the chelate and the way of administration were studied. Absorbed dose in tumor and selected organs was calculated using the OLINDA/EXM software; the data from the animals was extrapolated to humans. Results: 177Lu-h-R3 conjugates were obtained with specific activity up to 915 MBq/mg without significant loss of immunoreactivity. The binding of 177Lu-h-R3 conjugates to A431 cells showed to be EGFR specific, and the affinity was similar to native h-R3. Tumor uptake reached a maximum value of 22.4±3.1 %ID/g at 72 h and remained ∼20% ID/g over 1 week. Locoregional application showed better tumor/nontumor ratios than intravenous application. Conclusions: 177Lu-h-R3 should be considered for further evaluations as a potential radiopharmaceutical for RIT of tumors overexpressing EGFR.

  2. Analysis of patient survival in a phase 1 trial of systemic targeted alpha therapy for metastatic melanoma

    International Nuclear Information System (INIS)

    Full text: Survival results are analysed from a Phase I study of Systemic Targeted Alpha Therapy for patients with metastatic melanoma. The effect of key parameters such as melanoma inhibitory activity protein, age, sex, injected dose, lactate dehydrogenase (LDH), metastatic disease stage and treatment dose are examined. Following intravenous administration of the alpha immunoconjugate, 213Bi-cDTPA-9,2,27, patients were monitored for response and toxicity over subsequent days, weeks and months, Responses were measured by physical examination, computed tomography scan and blood sampling, including MIA and LDH. Responses were assessed using CT at 8 weeks, In addition to the above tools, toxicity was monitored by blood pathology, urine analysis and glomerular filtration rate and human anti-mouse antibody response, Thirty eight patients with stage IV melanoma or in transit metastasis were treated with activities in the range 55-925 MBq, No adverse events of any type or level were observed, so the maximum tolerance dose was not achieved. An objective partial response rate of 10% was observed, with 40% stable disease at 8 weeks and a median survival of 8,9 months. Survival analysis showed MIA, disease stage, LDH and treatment effect to be significant prognostic indicators for survival. The favourable clinical characteristic identified in this study will be important in stratification for future clinical trials of metastatic melanoma patients. The lack of significant effect of dose on survival suggests a confounding factor, namely the variable tumour capillary permeability that alters the delivery and efficacy of the radio-immunoconjugate to the melanoma cells in the perivascular space.

  3. Validation of analytical method to calculate the concentration of conjugated monoclonal antibody; Validacao de metodo analitico para calculo de concentracao de anticorpo monoclonal conjugado

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    Alcarde, Lais F.; Massicano, Adriana V.F.; Oliveira, Ricardo S.; Araujo, Elaine B. de, E-mail: lais_alcarde@hotmail.com [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2013-07-01

    The objective of this study was to develop a quantitative analytical method using high performance liquid chromatography (HPLC) to determine the antibody concentration in conjunction with bifunctional chelator. Assays were performed using a high performance liquid chromatograph, and the following conditions were used: flow rate of 1 mL / min, 15 min run time, 0.2 M sodium phosphate buffer pH 7.0 as the mobile phase and column of molecular exclusion BioSep SEC S-3000 (300 x 7.8 mm, 5 μM - Phenomenex). The calibration curve was obtained with AcM diluted in 0.2 M sodium phosphate buffer pH 7.0 by serial dilution, yielding the concentrations: 400 μg/mL, 200 μg/mL, 100 μg/mL, 50 μg/mL, 25 μg/mL and 12.5 μg/mL. From the calibration curve calculated the equation of the line and with it the concentration of the immunoconjugate. To ensure the validity of the method accuracy and precision studies were conducted. The accuracy test consisted in the evaluation of 3 samples of known concentration, being this test performed with low concentrations (50 μg/mL), medium (100 μg/mL) and high (200 μg/mL). The precision test consisted of 3 consecutive measurements of one sample of known concentration, subject to the conditions set forth above for the other tests. The correlation coefficient of the standard curve was greater than 97%, the accuracy was satisfactory at low concentrations as well as accuracy. The method was validated by showing it for the accurate and precise determination of the concentration of the immunoconjugate. Furthermore, this assay was found to be extremely important, because using the correct mass of the protein, the radiochemical purity of the radioimmunoconjugate was above 95% in all studies.

  4. Fractionated therapy of HER2-expressing breast and ovarian cancer xenografts in mice with targeted alpha emitting 227Th-DOTA-p-benzyl-trastuzumab.

    Directory of Open Access Journals (Sweden)

    Helen Heyerdahl

    Full Text Available BACKGROUND: The aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate (227Th-DOTA-p-benzyl-trastuzumab. METHODOLOGY/PRINCIPAL FINDINGS: Nude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg (227Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4-5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01 and survival with tumor diameter less than 16 mm was prolonged (p<0.05 in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4-5 days interval groups (p<0.001 and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05. Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4-5 days interval groups (p<0.05. No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05 for SKOV-3 animals and in 2 weeks interval group compared with the 4-5 days interval groups (p<0.05 for SKBR-3 animals. CONCLUSIONS/SIGNIFICANCE: The same concentration of radioactivity split into several fractions may improve toxicity of (227Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose

  5. Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

    International Nuclear Information System (INIS)

    Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2±2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4±5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia. (orig.)

  6. 6th Annual European Antibody Congress 2010: November 29-December 1, 2010, Geneva, Switzerland.

    Science.gov (United States)

    Beck, Alain; Wurch, Thierry; Reichert, Janice M

    2011-01-01

    The 6th European Antibody Congress (EAC), organized by Terrapinn Ltd., was held in Geneva, Switzerland, which was also the location of the 4th and 5th EAC. As was the case in 2008 and 2009, the EAC was again the largest antibody congress held in Europe, drawing nearly 250 delegates in 2010. Numerous pharmaceutical and biopharmaceutical companies active in the field of therapeutic antibody development were represented, as were start-up and academic organizations and representatives from the US Food and Drug Administration FDA. The global trends in antibody research and development were discussed, including success stories of recent marketing authorizations of golimumab (Simponi®) and canakinumab (Ilaris®) by Johnson & Johnson and Novartis, respectively, updates on antibodies in late clinical development (obinutuzumab/GA101, farletuzumab/MORAb-003 and itolizumab/T1 h, by Glycart/Roche, Morphotek and Biocon, respectively) and success rates for this fast-expanding class of therapeutics (Tufts Center for the Study of Drug Development). Case studies covering clinical progress of girentuximab (Wilex), evaluation of panobacumab (Kenta Biotech), characterization of therapeutic antibody candidates by protein microarrays (Protagen), antibody-drug conjugates (sanofi-aventis, ImmunoGen, Seattle Genetics, Wyeth/Pfizer), radio-immunoconjugates (Bayer Schering Pharma, Université de Nantes) and new scaffolds (Ablynx, AdAlta, Domantis/GlaxoSmithKline, Fresenius, Molecular Partners, Pieris, Scil Proteins, Pfizer, University of Zurich) were presented. Major antibody structural improvements were showcased, including the latest selection engineering of the best isotypes (Abbott, Pfizer, Pierre Fabre), hinge domain (Pierre Fabre), dual antibodies (Abbott), IgG-like bispecific antibodies (Biogen Idec), antibody epitope mapping case studies (Eli Lilly), insights in FcγRII receptor (University of Cambridge), as well as novel tools for antibody fragmentation (Genovis). Improvements of

  7. HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts.

    Directory of Open Access Journals (Sweden)

    Tapan K Nayak

    Full Text Available Malignant mesothelioma (MM, a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression is observed in the majority of MM cases. In this study, the utility of HER1-targeted chimeric IgG(1, cetuximab, and a human IgG(2, panitumumab, radiolabeled with (86Y, were evaluated for PET imaging to detect MM non-invasively in vivo, and to select an antibody candidate for radioimmunotherapy (RIT.Radioimmunoconjugates (RICs of cetuximab and panitumumab were prepared by conjugation with CHX-A''-DTPA followed by radiolabeling with (86Y. The HER1 expression of NCI-H226, NCI-H2052, NCI-H2452 and MSTO-211H human mesothelioma cells was characterized by flow cytometry. In vivo biodistribution, pharmacokinetic analysis, and PET imaging were performed in tumor bearing athymic mice.In vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1 mg, demonstrating that uptake in the tumor was receptor specific. Significant differences were observed in the in vivo characteristics of the RICs. The blood clearance T(½α of (86Y-cetuximab (0.9-1.1 h was faster than (86Y-panitumumab (2.6-3.1 h. Also, the tumor area under the curve (AUC to liver AUC ratios of (86Y-panitumumab were 1.5 to 2.5 times greater than (86Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver.This study demonstrates the more favorable HER1-targeting characteristics of (86Y-panitumumab than (86Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging. Due to lower liver uptake, panitumumab based immunoconjugates may fare better in therapy than corresponding cetuximab based

  8. Targeted alpha-therapy using [Bi-213]anti-CD20 as novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells

    Science.gov (United States)

    Roscher, Mareike; Hormann, Inis; Leib, Oliver; Marx, Sebastian; Moreno, Josue; Miltner, Erich; Friesen, Claudia

    2013-01-01

    Radioimmunotherapy (RIT) is an emerging treatment option for non-Hodgkin lymphoma (NHL) producing higher overall response and complete remission rates compared with unlabelled antibodies. However, the majority of patients treated with conventional or myeloablative doses of radiolabelled antibodies relapse. The development of RIT with alpha-emitters is attractive for a variety of cancers because of the high linear energy transfer (LET) and short path length of alpha-radiation in human tissue, allowing higher tumour cell kill and lower toxicity to healthy tissues. In this study, we investigated the molecular effects of the alpha-emitter Bi-213 labelled to anti-CD20 antibodies ([Bi-213]anti-CD20) on cell cycle and cell death in sensitive and radio-/chemoresistant NHL cells. [Bi-213]anti-CD20 induced apoptosis, activated caspase-3, caspase-2 and caspase-9 and cleaved PARP specifically in CD20-expressing sensitive as well as in chemoresistant, beta-radiation resistant and gamma-radiation resistant NHL cells. CD20 negative cells were not affected by [Bi-213]anti-CD20 and unspecific antibodies labelled with Bi-213 could not kill NHL cells. Breaking radio-/chemoresistance in NHL cells using [Bi-213]anti-CD20 depends on caspase activation as demonstrated by complete inhibition of [Bi-213]anti-CD20-induced apoptosis with zVAD.fmk, a specific inhibitor of caspases activation. This suggests that deficient activation of caspases was reversed in radioresistant NHL cells using [Bi-213]anti-CD20. Activation of mitochondria, resulting in caspase-9 activation was restored and downregulation of Bcl-xL and XIAP, death-inhibiting proteins, was found after [Bi-213]anti-CD20 treatment in radio-/chemosensitive and radio-/chemoresistant NHL cells. [Bi-213]anti-CD20 seems to be a promising radioimmunoconjugate to improve therapeutic success by breaking radio- and chemoresistance selectively in CD20-expressing NHL cells via re-activating apoptotic pathways through reversing deficient

  9. Evaluation of 177Lu-DOTA-labeled aglycosylated monoclonal anti-L1-CAM antibody chCE7: influence of the number of chelators on the in vitro and in vivo properties

    International Nuclear Information System (INIS)

    Introduction: In this study, we optimized the 1,4,7,10-tetraazacyclododecane-N-N'-N''-N''''-tetraacetic acid (DOTA) chelator-to-antibody (c/a) ratio for the aglycosylated variant of the anti-L1-CAM antibody chCE7 (chCE7agl), providing high specific activity and low liver uptake in 177Lu-labeled form. Methods: chCE7agl was substituted with increasing molar excess of DOTA-NCS. The number of chelators coupled to the antibody and the binding affinities to target tumor cells (IC5 values) of the resulting immunoconjugates were determined. The different immunoconjugates were labeled with 177Lu; specific activity was measured, and metabolic stability was analyzed in human plasma. The effect of different c/a ratios on blood clearance and liver uptake was tested in nude mice. Changes of the protein backbone structure were analyzed by circular dichroism spectroscopy. Results: chCE7agl was substituted with 7, 12 or 15 DOTA ligands. The IC5 concentrations displacing radioiodinated chCE7 antibody increased with the number of chelators (1.5-fold with 7 ligands, 2.5-fold with 12 ligands and a 5-fold increase with 15 ligands). The highest specific activity for 177Lu-DOTA-chCE7agl was obtained with a c/a ratio of 12 (106 MBq/mg). Radioimmunoconjugates were stable in human plasma for at least 24 h. Blood clearance and liver uptake were measured after 24 h (c/a ratios of 12 and 15) or 48 h (c/a ratio of 7). The liver-to-blood ratios were 0.35±0.14 (7 ligands), 0.77±0.19 (12 ligands) and 17.85±3.44 (15 ligands). Conclusions: DOTA-chCE7agl conjugates with a c/a ratio of 12 combined high specific activity with good in vitro and in vivo properties. The rapid elimination rate from the blood and the high uptake in the liver of chCE7agl substituted with 15 DOTA ligands were found not to be due to conformational changes of the antibody backbone structure

  10. Radioimmunotherapy and Autologous Stem-Cell Transplantation in the Treatment of B-Cell Non-Hodgkin Lymphoma.

    Science.gov (United States)

    Shimoni, Avichai; Zwas, Shifra Tzila

    2016-03-01

    High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is the standard therapy for patients with chemosensitive-relapsed or chemosensitive-refractory aggressive lymphoma. The use of rituximab, an anti-CD20 monoclonal antibody, has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates. However, despite this progress a significant proportion of patients are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches. Novel approaches are needed for these high-risk patients, especially in the rituximab era. Radioimmunotherapy (RIT) is a form of targeted therapy using the parent monoclonal antibody to deliver radiation emitted by a conjugated radioisotope, to the vicinity of antigen-positive tissues. Two radioimmunoconjugates--yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) have been in clinical use. There are multiple studies demonstrating the safety and efficacy of both agents in both indolent and aggressive lymphoma. Radiolabeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. RIT targets radiation to disease sites while limiting exposure of uninvolved critical organs, thus it can safely replace total-body irradiation during conditioning for ASCT. The major toxicity and limiting factor in RIT is myelotoxicity that is easily reversed by stem-cell rescue. RIT can be combined at standard doses with high-dose chemotherapy or can be given in escalated doses either alone or with high-dose chemotherapy before ASCT. Several phase II studies have shown the safety and potential efficacy of both agents using these approaches. A small randomized study comparing standard-dose Zevalin with combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) high-dose chemotherapy and BEAM alone suggested a

  11. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Gruenberg, Juergen; Lindenblatt, Dennis; Cohrs, Susan; Fischer, Eliane [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); Dorrer, Holger [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); Zhernosekov, Konstantin [ITG Isotope Technologies Garching GmbH, Garching (Germany); Koester, Ulli [Institut Laue-Langevin, Grenoble (France); Tuerler, Andreas [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); University of Bern, Department of Chemistry and Biochemistry, Berne (Switzerland); Schibli, Roger [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

    2014-10-15

    The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with {sup 67}Cu- and {sup 177}Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide {sup 177}Lu and the potential alternative {sup 161}Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched {sup 160}Gd targets. {sup 161}Tb and {sup 177}Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of {sup 177}Lu- and {sup 161}Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. {sup 177}Lu- and {sup 161}Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. {sup 161}Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the {sup 177}Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the {sup 161}Tb-DOTA-chCE7 than the {sup 177}Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM {sup 161}Tb RIT is more effective compared to {sup 177}Lu RIT in ovarian cancer xenografts

  12. The role of alpha therapy for local and systemic treatment of cancer

    International Nuclear Information System (INIS)

    Major problems in the management of cancer relate to the inability to control some primary lesions, e.g. glioblastoma multiforme (GBM), and the inability to deal with metastatic cancer arising from malignant cancers such as melanoma, breast and other cancers. Binary alpha therapy using neutron capture in boron-10 offers the potential for improved prognosis for high grade brain tumours such as GBM and melanoma metastases to the brain. Metastatic cancer proceeds through a number of quite separate stages in the development of lethal disease, i e. cells in transit, preangiogenic lesions, subclinical and clinical lesions. Early stages offer the potential for control if targeted alpha therapy is applied. However, the dose must be localised to the cancer cell and this requirement rules out beta-emitting radionuclides, which are more suited for clinical lesions. Alpha-emitting radionuclides are the most appropriate toxins, as their efficacy depends on the linear energy transfer (LET) and range of the alpha particles. After matching the cancer stage, radiolabel and carrier, we find that 149Tb is the radionuclide of choice for systemic therapy in all aspects except production. The production of 149Tb in μCi (kBq) quantities has been achieved using the heavy ion reaction at the ANU tandem accelerator at Canberra and in multi-mCi (MBq) quantities using the spallation reaction in combination with on-line isotope separation technology of ISOLDE at CERN. Terbium is ideally suited for chelation to monoclonal antibodies to produce stable radio-immunoconjugates (RIC). Astatine-211 is a halide and has potential for the elimination of early stage melanoma metastases as At-MTB. However, the availability of the alpha generators 228Th-212Bi and 225Ac-213Bi facilitates the use of Bi-RIC in clinical trials for acute myeloid leukaemia and cystic glioma. Alpha therapy has the potential to control refractory cancers when treated at the minimum residual disease stage. Pre-clinical and

  13. Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical

    International Nuclear Information System (INIS)

    111In-DTPA-anti-γH2AX-Tat, which combines an anti-γH2AX antibody with a cell-penetrating peptide, Tat, and the Auger electron-emitting radioisotope, 111In, targets the DNA damage signalling protein, γH2AX, and has potential as a probe for imaging DNA damage in vivo. The goal of this study was to investigate whether 111In-DTPA-anti-γH2AX-Tat labelled to high specific activity (6 MBq/μg) can amplify treatment-related DNA damage for therapeutic gain. Methods: MDA-MB-468 and MDA-MB-231/H2N (231-H2N) breast cancer cells were incubated with 111In-DTPA-anti-γH2AX-Tat (3 MBq, 6 MBq/μg) or a control radioimmunoconjugate, 111In-DTPA-mIgG-Tat, and exposed to IR or bleomycin. DNA damage was studied by counting γH2AX foci and by neutral comet assay. Cytotoxicity was evaluated using clonogenic assays. 111In-DTPA-anti-γH2AX-Tat was administered intravenously to 231-H2N-xenograft-bearing Balb/c nu/nu mice in tumor growth inhibition studies. Results: The number of γH2AX foci was greater after exposure of cells to IR (10 Gy) plus 111In-DTPA-anti-γH2AX-Tat compared to IR alone (20.6 ± 2.5 versus 10.4 ± 2.3 foci/cell; P 111In-DTPA-anti-γH2AX-Tat resulted in a reduced surviving fraction in cells co-treated with IR (4 Gy) versus IR alone (5.2% ± 0.9% versus 47.8% ± 2.8%; P 111In-DTPA-anti-γH2AX-Tat resulted in a lower SF compared to bleomycin alone. The combination of a single exposure to IR (10 Gy) plus 111In-DTPA-anti-γH2AX-Tat significantly decreased the growth rate of 231-H2N xenografts in vivo compared to either 111In-DTPA-anti-γH2AX-Tat or IR alone (− 0.002 ± 0.004 versus 0.036 ± 0.011 and 0.031 ± 0.014 mm3/day, respectively, P 111In-DTPA-anti-γH2AX-Tat amplifies anticancer treatment-related DNA damage in vitro and has a potent anti-tumor effect when combined with IR in vivo.

  14. Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

    Science.gov (United States)

    DeNardo, Sally J.; Kukis, David L.; Kroger, Linda A.; O’Donnell, Robert T.; Lamborn, Kathleen R.; Miers, Laird A.; DeNardo, David G.; Meares, Claude F.; DeNardo, Gerald L.

    1997-01-01

    Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90Y-labeled DOTA-peptide-ChL6 (90Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N",N‴-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24–72 hours before 90Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy. PMID:9108094

  15. Optimization of a Pretargeted Strategy for the PET Imaging of Colorectal Carcinoma via the Modulation of Radioligand Pharmacokinetics.

    Science.gov (United States)

    Zeglis, Brian M; Brand, Christian; Abdel-Atti, Dalya; Carnazza, Kathryn E; Cook, Brendon E; Carlin, Sean; Reiner, Thomas; Lewis, Jason S

    2015-10-01

    increases in tumor-to-blood activity concentration ratios. This new strategy offers dosimetric benefits as well, yielding a total effective dose of 0.041 rem/mCi, far below the doses produced by directly labeled (64)Cu-NOTA-huA33 (0.133 rem/mCi) and (89)Zr-DFO-huA33 (1.54 rem/mCi). Ultimately, this pretargeted PET imaging strategy boasts a dramatically improved pharmacokinetic profile compared to our first generation system and is capable of clearly delineating tumor tissue with high image contrast at only a fraction of the radiation dose created by directly labeled radioimmunoconjugates. PMID:26287993

  16. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

    International Nuclear Information System (INIS)

    The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with 67Cu- and 177Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide 177Lu and the potential alternative 161Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched 160Gd targets. 161Tb and 177Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of 177Lu- and 161Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. 177Lu- and 161Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. 161Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the 177Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the 161Tb-DOTA-chCE7 than the 177Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM 161Tb RIT is more effective compared to 177Lu RIT in ovarian cancer xenografts. These results suggest that 161Tb is a promising candidate for future clinical applications in

  17. Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Reske, S.N.; Buchmann, I.; Seitz, U.; Glatting, G.; Neumaier, B.; Kotzerke, J.; Buck, A. [Ulm Univ. (Germany). Abt. Nuklearmedizin; Bunjes, D.; Doehner, H. [Abteilung Innere Medizin III, Haematologie und Onkologie, Universitaetsklinikum Ulm (Germany); Martin, H.; Bergmann, L. [Klinik fuer Haematologie und Onkologie, Johann-Wolfgang-Goethe Universitaet Frankfurt (Germany)

    2001-07-01

    Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates ({sup 188}Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2{+-}2.1 (range 6.9-15.8) GBq {sup 188}Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4{+-}5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking {sup 188}Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia. (orig.)

  18. Improved iodine radiolabels for monoclonal antibody therapy.

    Science.gov (United States)

    Stein, Rhona; Govindan, Serengulam V; Mattes, M Jules; Chen, Susan; Reed, Linda; Newsome, Guy; McBride, Bill J; Griffiths, Gary L; Hansen, Hans J; Goldenberg, David M

    2003-01-01

    A major disadvantage of (131)iodine (I)-labeled monoclonal antibodies (MAbs) for radioimmunotherapy has been the rapid diffusion of iodotyrosine from target cells after internalization and catabolism of the radioiodinated MAbs. We recently reported that a radioiodinated, diethylenetriaminepentaacetic acid-appended peptide, designated immunomedics' residualizing peptide 1 (IMP-R1), was a residualizing iodine label that overcame many of the limitations that had impeded the development of residualizing iodine for clinical use. To determine the factors governing the therapeutic index of the labeled MAb, as well as the factors required for production of radioiodinated MAb in high yield and with high specific activity, variations in the peptide structure of IMP-R1 were evaluated. A series of radioiodinated, diethylenetriaminepentaacetic acid-appended peptide moieties (IMP-R1 through IMP-R8) that differed in overall hydrophilicity and charge were compared. Radioiodinations of the peptides followed by conjugations to disulfide-reduced RS7 (an anti-epithelial glycoprotein-1 MAb) furnished radioimmunoconjugates in good overall incorporations, with immunoreactivities comparable to that of directly radioiodinated RS7. Specific activities of up to 8 mCi/mg and yields > 80% have been achieved. In vitro processing experiments showed marked increases in radioiodine retention with all of the adducts; radioiodine retention at 45 h was up to 86% greater in cells than with directly iodinated RS7. Each of the (125)I-peptide-RS7 conjugates was compared with (131)I-RS7 (labeled by the chloramine-T method) in paired-label biodistribution studies in nude mice bearing human lung tumor xenografts. All of the residualizing substrates exhibited significantly enhanced retention in tumor in comparison to directly radioiodinated RS7, but the nontarget uptakes differed significantly among the residualizing labels. The best labels were IMP-R4 and IMP-R8, showing superior tumor-to-non-tumor ratios

  19. Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation

    International Nuclear Information System (INIS)

    Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. 90Y, 188Re and 131I are the most frequently used β--particles. Of these, 90Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate 90Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The 90Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow 90Y-anti-CD45-mAb YAML568 are 6.4 ± 1.2 (bone marrow), 3.9 ± 1.4 (liver) and 1.1 ± 0.4 (kidneys). CD45 is expressed also on the extramedullar clonogenic myeloma progenitor cell that circulates in the peripheral blood. Thus, the conditioning of patients with

  20. Preclinical 89Zr Immuno-PET of High-Grade Serous Ovarian Cancer and Lymph Node Metastasis

    Science.gov (United States)

    Sharma, Sai Kiran; Sevak, Kuntal K.; Monette, Sebastien; Carlin, Sean D.; Knight, James C.; Wuest, Frank R.; Sala, Evis; Zeglis, Brian M.; Lewis, Jason S.

    2016-01-01

    The elevation of cancer antigen 125 (CA125) levels in the serum of asymptomatic patients precedes the radiologic detection of high-grade serous ovarian cancer by at least 2 mo and the final clinical diagnosis by 5 mo. PET imaging of CA125 expression by ovarian cancer cells may enhance the evaluation of the extent of disease and provide a roadmap to surgery as well as detect recurrence and metastases. Methods 89Zr-labeled mAb-B43.13 was synthesized to target CA125 and evaluated via PET imaging and biodistribution studies in mice bearing OVCAR3 human ovarian adenocarcinoma xenografts. Ex vivo analysis of tumors and lymph nodes was performed via autoradiography, histopathology, and immunohistochemistry. Results PET imaging using 89Zr-DFO-mAb-B43.13 (DFO is desferrioxamine) clearly delineated CA125-positive OVCAR3 xenografts as early as 24 h after the administration of the radioimmunoconjugate. Biodistribution studies revealed accretion of 89Zr-DFO-mAb-B43.13 in the OVCAR3 tumors, ultimately reaching 22.3 ± 6.3 percentage injected dose per gram (%ID/g) at 72 h after injection. Most interestingly, activity concentrations greater than 50 %ID/g were observed in the ipsilateral lymph nodes of the xenograft-bearingmice. Histopathologic analysis of the immuno-PET–positive lymph nodes revealed the presence of grossly metastasized ovarian cancer cells within the lymphoid tissues. In control experiments, only low-level, non-specific uptake of 89Zr-labeled isotype IgG was observed in OVCAR3 tumors; similarly, low-activity concentrations of 89Zr-DFO-mAb-B43.13 accumulated in CA125-negative SKOV3 tumors. Conclusion Immuno-PET with 89Zr-labeled mAb-B43.13 is a potential strategy for the noninvasive delineation of extent of disease and may add value in treatment planning and treatment monitoring of high-grade serous ovarian cancer. PMID:26837339

  1. Development of a novel long-lived immunoPET tracer for monitoring lymphoma therapy in a humanized transgenic mouse model.

    Science.gov (United States)

    Natarajan, Arutselvan; Habte, Frezghi; Gambhir, Sanjiv S

    2012-06-20

    radioimmunoconjugate lots were stable up to 5 days in serum in vitro. The present study showed that (89)Zr is well-suited for mAbs to image cancer over an extended period of time (up to 5 days). PMID:22621257

  2. Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation; Myeloablative Radioimmuntherapien zur Konditionierung bei Patienten mit AML, MDS und multiplem Myelom vor Stammzelltransplantation

    Energy Technology Data Exchange (ETDEWEB)

    Buchmann, I. [Abt. fuer Nuklearmedizin, Universitaetsklinik Heidelberg (Germany)

    2008-06-15

    Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. {sup 90}Y, {sup 188}Re and {sup 131}I are the most frequently used {beta}{sup -}-particles. Of these, {sup 90}Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate {sup 90}Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The {sup 90}Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow < 25%. The specific doses (Gy/GBq) are 10.2 {+-} 1.8 (bone marrow), 2.7 {+-} 2 (liver) and < 1 (kidneys). In contrast, radiolabeled anti-CD33- and anti-CD45-antibodies bind to both, most of white blood cells and

  3. Enhancing target/nontarget ratios in radioimmunotherapy: nonspecific human gammaglobulin versus other modalities

    International Nuclear Information System (INIS)

    Full text: The central problem in using radiobioconjugates in therapy is maximising the target/nontarget ratios. Unlike radioimmunoscintigraphy where temporal subtraction of early and late images or clinical context interpretation can be used, radioimmunotherapy and dosimetry demand the highest ratios for the safe use of such radiobioconjugates: frying the tumour without frying the patient. Simultaneously efforts to obtain greater biological specificity are underway in solid tumour therapy comparable to targeting the idiotypes of B cell tumours, and both peptides and newer antibodies are being explored. For increasing tumour localization pre-targetting using either the avidin/biotin approach or bispecific antibodies looking at a chelate in addition to a tumour antigen is being extensively researched. An alternative approach is to reduce nonspecific uptake particularly in the reticuloendothelial system especially the large mass of the liver. Degalactosylation of the antibodies to reduce affinity of the Fc fragment to galactosyl receptors in the liver, or using designer antibody constructs devoid of the Fc fragment: Fab, Fab 2, Fab 3, Fab n or scFv based constructs has been attempted. An inexpensive approach that we have conceived and used is the use of nonspecific human gammaglobulin prior to radioimmunoconjugate administration. This has been done utilizing commercially available inexpensive 16.5 gms% human immunoglobulin preparations(BHARGLOB)rather than the highly expensive IVIG such as Sandoglobulin used in autoimmune disease therapy Aims: To devise optimal schedules for using nonspecific human gammaglobulin for reducing nontarget uptake. Methods: Prior to clinical studies several different large molecular weight agents were evaluated in experimental animals bearing human tumour xenografts, including dextran,hetastarch and gammaglobulin.Gammaglobulin was chosen as the most convenient to administer. In clinical studies various schedules were tried giving Bharglob

  4. Metal ion cage complexes as imaging agents for cancer cells

    International Nuclear Information System (INIS)

    hunching). Radiotoxic effects were monitored at predetermined time points (2 days, 1, 2, 3, 4 weeks, 2, 3, 4, 5 and 6 months). Indicators for the endpoint of the study were body weight loss > 20 %, rapid weight loss of > 10 % overnight, ulceration of tumour, limitation of normal behaviour (e.g. ability to feed or drink) and tumour size > 10 x 10 mm (UK Cancer Council). A significant extension of mouse life was achieved with doses of greater than 20 MBq (from 25 to 46 days for 30 MBq) with no major radiotoxic effects. Complexation of copper by SarAr is extremely fast making the production of 64Cu-SarArB-72.3 immunoconjugate attractive for kit formulation and applicable for use in Nuclear Medicine Departments. Biological studies show the radioimmunoconjugate is stable in vivo and able to induce a therapeutic effect in tumour bearing animals. The shorter half life of 64Cu and the MIRDOSE calculations support the potential of 64Cu for use in treatment on an outpatient basis

  5. Pharmacokinetics and extracorporeal adsorption treatment (ECAT) to reduce circulating blood radioactivity after i.v. administration of humanized biotinylated MAB 111In-MN14 in rats

    International Nuclear Information System (INIS)

    The results of radioimmunotherapy of disseminated solid tumors are still disappointing and hence new strategies are needed. ECAT is a new method for tumor radioimmunotargeting to reduce activity in radiosensitive organs by removing excess of radiolabeled MAb from blood. It was previously developed and experimentally evaluated by us using mouse MAb L6 and HMFG1as well as chimeric BR96. The aim of the study was not only to estimate the influence of biotinylation on pharmacokinetics and biodistribution of humanized MAb 111In-MN14, but also to validate the capacity of subsequent ECAT in terms of reduction of activity in whole body, blood and in various organs after i.v. administration of 111In-hMN14-DOTA-biotin in rats. These results could also be transferred to the pre-targeting strategy based on the biotin-avidin reaction. Methods: hMN14 recognizes the carcinoembryonic antigen expressed on most tumor cells from human colorectal, pancreatic, lung, breast, and ovarian carcinomas. 93 rats were used in the study. After radiolabeling, 111In-hMN14-DOTA was biotinylated in order to enable antibodies to be absorbed on the MITRA-avidin-agarose column (Mitra Medical Technology Ltd, Lund, Sweden). NHS-biotin or Sulfo-NHS-biotin were used for the biotinylation of hMN14. ECAT was explored from un-separated blood in 8 rats. Blood volumes were passed through an adsorption column close to theoretical clearance during 2.5h. WB counts and blood activity were monitored. At dissections, performed immediately after ECAT completion, organs and tissues of interest were removed and measured for activity content. Results: TLC analysis of 111In-hMN14-DOTA-biotin showed a radiochemical purity of > 87% for NHS-biotin and >95% for the sulfo-NHS-biotin reagent. HPLC size exclusion analysis showed no aggregation or fragmentation of the radioimmunoconjugate irrespective of the amount of sulfo-NHS-biotin ratio/mg MAb. Increasing or extensive signs of aggregation were registered already at a low