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Sample records for 221fr 213bi 209ti

  1. Radioimmunotherapy of infection with 213Bi-labeled antibodies

    Dadachova, Ekaterina

    2008-01-01

    Bismuth-213 (213Bi) (physical half-life 46 min) is a beta-emitter (97%) and an alpha-emitter (3%) which decays to short lived alpha-emitter Polonium-213 and could therefore be used as an in vivo generator of alpha particles with the energy of around 8 MeV. 213Bi has been successfully used during the last decade in both clinical and pre-clinical work for radioimmunotherapy (RIT) of cancer with 213Bi-labeled monoclonal antibodies (mAbs). RIT has been proposed as a novel techonology for treatmen...

  2. Radioimmunotherapy of micrometastases in lung with vascular targeted213Bi

    Kennel, S. J.; Boll, R.; Stabin, M; Schuller, H M; Mirzadeh, S

    1999-01-01

    A model system has been used to test the efficacy of vascular targeting of α-particle emitter213Bi for therapy of small, ‘artificial’ metastases in mouse lung. Specific monoclonal antibody (mAb) 201B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of t...

  3. An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation

    A method for construction and operation of an 225Ac/213Bi generator capable of producing 25-100 mCi of 213Bi suitable for clinical antibody labeling is described. The generator has been designed to have an effective lifetime of several weeks, producing up to six therapeutic doses of radionuclide per day. To date, 57 clinical doses have been prepared and injected into patients using the described 213Bi generator. Factors such as radiation damage, radioprotection, iodide eluate chemistry, radiolabeling chemistry and radionuclidic purity are addressed

  4. Long-Term Toxicity of 213Bi-Labelled BSA in Mice.

    Laëtitia Dorso

    Full Text Available Short-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 (213Bi. Toxicity is greatly influenced not only by the pharmacokinetics and binding specificity of the vector but also by non-specific irradiation due to the circulating radiopharmaceutical in the blood. To assess this, an acute and chronic toxicity study was carried out in mice injected with 213Bi-labelled Bovine Serum Albumin (213Bi-BSA as an example of a long-term circulating vector.Biodistribution of 213Bi-BSA and 125I-BSA were compared in order to evaluate 213Bi uptake by healthy organs. The doses to organs for injected 213Bi-BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of 213Bi-BSA and monitored for 385 days. Plasma parameters, including alanine aminotransferase (ALT, aspartate aminotransferase (AST, blood urea nitrogen (BUN and creatinine, were measured and blood cell counts (white blood cells, platelets and red blood cells were performed. Mouse organs were examined histologically at different time points.Haematological toxicity was transient and non-limiting for all evaluated injected activities. At the highest injected activity (11.1 MBq, mice died from liver and kidney failure (median survival of 189 days. This liver toxicity was identified by an increase in both ALT and AST and by histological examination. Mice injected with 7.4 MBq of 213Bi-BSA (median survival of 324 days had an increase in plasma BUN and creatinine due to impaired kidney function, confirmed by histological examination. Injection of 3.7 MBq of 213Bi-BSA was safe, with no plasma enzyme modifications or histological abnormalities.Haematological toxicity was not limiting in this study. Liver failure was observed at the highest injected activity (11.1 MBq, consistent with liver damage observed in human clinical trials. Intermediate injected activity (7.4 MBq should be used with caution because of

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

    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.

  6. Preclinical safety studies of 213BI labeled PA12 for targeted alpha therapy of cancer

    Full text: The urokinase plasminogen activator (uPA) system is involved in cancer growth and metastasis. The plasminogen activator inhibitor type 2 (PAI2) and uPA can form a stable complex, which is bound to the cell surface uPA receptor (uPAR). We labeled PAI2 with 213Bi to form the alpha conjugate. This conjugate targets uPA/uPAR and has been found to have promising therapeutic properties for breast, prostate and pancreatic cancer. This paper reports studies of the acute and delayed toxicity in mice; the effect of lysine renal protection; pharmacokinetics; a comparison of CHX-A-DTPA and cDTPA chelators, and in vivo 213Bi-PAI2 stability by Ca-DTPA challenge. Pharmacokinetics of 213Bi-PAI2 in nude mice demonstrated that the kidneys were the critical organs for retention of Bismuth in the chelate complex. The CHX-A-DTPA and cDTPA immunoconjugates were found to have similar percent I D/kg in the kidney, with no significant retention of Bi evident in other organs such as liver, heart, lung, and spleen. Ca-DTPA chelators significantly reduced the renal 213Bi accumulation at 15 minutes, not for 30 and 120 minutes, indicating high in vivo stability of 213Bi-PAI2 and the need for pre-injection purification of conjugates. The acute toxicity limit by weight loss was more than 450 MBq/kg. Mild to moderate, patchy tubular necrosis was observed accompanied by slight urea increase. Radiation nephritis was the source of lethal delayed toxicity arising at 20 - 30 weeks post-treatment, for which the maximum tolerance dose was 110 MBq/kg. Kidney uptake was not significantly decreased by lysine at 185 MBq/kg, nor was there any change in delayed toxicity

  7. {sup 177}Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to {sup 213}Bi-immunotherapy, but causes toxicity not observed with {sup 213}Bi

    Seidl, Christof; Zoeckler, Christine; Beck, Roswitha; Senekowitsch-Schmidtke, Reingard [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Quintanilla-Martinez, Leticia [Universitaetsklinikum Tuebingen, Institute for Pathology, Tuebingen (Germany); Bruchertseifer, Frank [Institute for Transuranium Elements, European Commission, Joint Research Centre, Karlsruhe (Germany)

    2011-02-15

    {sup 213}Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the {beta}-emitter {sup 177}Lu has proven to be beneficial in targeted therapy, {sup 177}Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of {sup 213}Bi-d9MAb. Nude mice were inoculated intraperitoneally with HSC45-M2 gastric cancer cells expressing d9-E-cadherin and were treated intraperitoneally 1 or 8 days later with different activities of specific {sup 177}Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific {sup 177}Lu-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of {sup 177}Lu-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically. Treatment with {sup 177}Lu-immunoconjugates (1.85, 7.4, 14.8 MBq) significantly prolonged survival. As expected, treatment on day 1 after tumour cell inoculation was more effective than treatment on day 8, and specific {sup 177}Lu-d9MAb conjugates were superior to nonspecific {sup 177}Lu-d8MAb. Treatment with 7.4 MBq of {sup 177}Lu-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of {sup 177}Lu-d9MAb was not free of toxic side effects. In some animals lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen but were not observed after treatment with {sup 213}Bi-d9MAb at comparable therapeutic efficacy. The therapeutic efficacy of {sup 177}Lu-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with {sup 213}Bi-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis. (orig.)

  8. 177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi

    213Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the β-emitter 177Lu has proven to be beneficial in targeted therapy, 177Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of 213Bi-d9MAb. Nude mice were inoculated intraperitoneally with HSC45-M2 gastric cancer cells expressing d9-E-cadherin and were treated intraperitoneally 1 or 8 days later with different activities of specific 177Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific 177Lu-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of 177Lu-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically. Treatment with 177Lu-immunoconjugates (1.85, 7.4, 14.8 MBq) significantly prolonged survival. As expected, treatment on day 1 after tumour cell inoculation was more effective than treatment on day 8, and specific 177Lu-d9MAb conjugates were superior to nonspecific 177Lu-d8MAb. Treatment with 7.4 MBq of 177Lu-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of 177Lu-d9MAb was not free of toxic side effects. In some animals lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen but were not observed after treatment with 213Bi-d9MAb at comparable therapeutic efficacy. The therapeutic efficacy of 177Lu-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with 213Bi-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis. (orig.)

  9. On the ^{221}Rn \\to ^{221}Fr Decay Scheme

    Gromov, K Ya; Norseev, Yu V; Samatov, Zh K; Sergienko, V A; Fominykh, V I; Chumin, V G

    2002-01-01

    The results of investigating the ^{221}Rn beta^{-}-decay and the ^{225}Ac alpha-decay are compared. It is shown that ^{221}Fr levels at 145.9 and 393.2 keV are excited at the ^{221}Rn decay. Intensities and reduced probabilities of the beta^{-}-decay to the ^{221}Fr levels are determined. A conclusion is drawn that the parity of the ^{221}Rn ground state is positive.

  10. Radioimmunotherapy of fungal infection with 213-Bi- and 188-Re-labeled antibody

    Aim: Radioimmunotherapy (RIT) is a therapeutic modality that utilizes monoclonal antibodies (mAb) radiolabeled with therapeutic radioisotopes to selectively deliver lethal doses of radiation to cells. We hypothesized that 18B7 mAb (murine IgG1), specific for Cryptoccocus neoformans (CN) polysaccharide capsule, may be used to deliver fungicidal doses of radioisotopes to the sites of CN infection in vitro and in vivo. Materials and Methods: 18B7 mAb was radiolabeled with either the beta-emitter 188-Rhenium (188Re) or with the alpha-emitter 213-Bismuth (213Bi). The biodistribution of radiolabeled 18B7 was measured in BALB/c mice with and without intratracheal CN infection. For in vitro killing assays 105 CN cells/well were treated with 0-3.2 μCi 213Bi-18B7 (3 h incubation), 32 μCi 188Re-18B7 (48 h incubation) or with radiolabeled IgG1 MOPC21 as a control and minimal inhibitory concentrations (MIC) were determined. To compare the activity of radiolabeled mAb's against CN infection with an established antifungal drug, we evaluated the susceptibility of CN strain to Amphoterecin B. In vivo therapy of CN was conducted in groups of 10 A/JCr mice infected intravenously with 105 CN cells 24 h prior to treatment with 50-200 μCi 213Bi- or 188Re-18B7, 213Bi- or 188Re-MOPC21, unlabeled 18B7 or saline. Student's t test for unpaired data was used to analyze in vitro data, and log-rank test - for animal survival data. Results: MAb 18B7 preserved its immunoreactivity post-labeling and delivered 10% ID/g to the lungs of the CN-infected BALB/c mice in 24 h after injection. Two-log reduction in colony forming units (CFU) was achieved in treatment of CN with 213Bi-18B7 and 188Re-18B7, which compared favorably with Amphoterecin B. MIC's were determined to be 0.4 μCi/1.5 mg and 4 μCi/1.25 mg mAb for 213Bi-18B7 and 188Re-18B7, respectively. The fungicidal activity of irrelevant mAb 213Bi-or 188Re-MOPC21 was negligible (P213Bi-18B7 and of 100 μCi 188Re-18B7 significantly (P<0

  11. Radioimmunotherapy Using Vascular Targeted 213Bi: The Role of TNF-Alpha in the Development of Pulmonary Fibrosis

    Davis, I.A.; Kennel, S.J.

    1998-10-14

    A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to CHX-b-DTPA, successfully delivers chelated 213Bi, an {alpha}-particle emitter, (213Bi-201B) rapidly to lungvascular endothelium. When injected at doses of l MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors and others had extended life-spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor-alpha (TNF-{alpha}), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events which culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (Enbrel{trademark}) as inhibitors of TNF-{alpha}, were unsuccessful. Additionally, mice genetically deficient for TNF-{alpha} production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor bearing BALB/c mice receiving Enbrel{trademark} or mice genetically deficient in TNF-{alpha} production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that, in normal mice, while TNF-{alpha} may induce an inflammatory response following {alpha}-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.

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

    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

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

    Radioimmunotherapy with α-particle-emitting nuclides, such as213Bi, 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 213Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of 213Bi-d9MAb targeting d9-E-cadherin and 213Bi-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 213Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of α-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213Bi-d9MAb compared with unspecific 213Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound 213Bi-immunoconjugates per cell exceeded 2 x 104, most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by 213Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. 213Bi-immunoconjugates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells. (orig.)

  14. Experimental therapy of disseminated B-Cell lymphoma xenografts with 213Bi-labeled anti-CD74

    A 213Bi-labeled antibody to CD74 was evaluated as a therapeutic agent for B-cell lymphoma. The α-particle emission, with a half-life of 46 min, is appropriate for therapy of micrometastases. The labeled Ab retained full immunoreactivity, and was potent at single-cell kill of the Raji B-lymphoma cell line. Approximately 30 decays of cell-bound 213Bi was required for a cell kill of 99%, and dosimetry calculations suggested that the cGy dose delivered was sufficient to produce the level of toxicity observed. A non-reactive control Ab, labeled similarly, also produced toxicity, due to decays occurring in the medium, but was approximately 3-fold less potent than the reactive Ab. In a SCID mouse xenograft micrometastatic model, Ab injection at day 2 or day 5 after tumor inoculation resulted in strong, specific suppression of tumor growth, with some apparent cures

  15. 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

    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

  16. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial

    Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting 90Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of 90Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide 213Bi with a mean tissue range of 81 μm may have a more favourable toxicity profile. Therefore, we evaluated locally injected 213Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality. In a pilot study, we included five patients with critically located gliomas (WHO grades II-IV). After diagnosis by biopsy, 213Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated. Targeted radiopeptide therapy using 213Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. 213Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection. This study provides proof of concept that targeted local radiotherapy using 213Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis. (orig.)

  17. 213Bi-anti-EGFR radioimmunoconjugates and X-ray irradiation trigger different cell death pathways in squamous cell carcinoma cells

    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

  18. 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

    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.)

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

    Targeted therapy with α-particle emitting radionuclides is a promising new option in cancer therapy. Stable conjugates of the vascular tumour-homing peptide F3 with the α-emitter 213Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined 213Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either 213Bi-DTPA-F3 or paclitaxel both in vitro and in vivo. Cytotoxicity of treatment with 213Bi-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 213Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either 213Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with 213Bi-DTPA-F3 (1.85 MBq) and paclitaxel (120 μg) 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 213Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either 213Bi-DTPA-F3 or paclitaxel alone. Combined treatment with 213Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application. (orig.)

  20. {sup 213}Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Boll, R.; Murphy, K. [Oak Ridge National Laboratory, Oak Ridge, TN (United States)

    2014-11-15

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as {sup 90}Y/{sup 177}Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with {sup 213}Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with {sup 90}Y/{sup 177}Lu-DOTATOC were treated with an intraarterial infusion of {sup 213}Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of {sup 213}Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and {sup 68}Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of {sup 213}Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  1. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as 90Y/177Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with 213Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC were treated with an intraarterial infusion of 213Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of 213Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and 68Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of 213Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  2. Somatostatin-receptor-targeted {alpha}-emitting {sup 213}Bi is therapeutically more effective than {beta}{sup -}-emitting {sup 177}Lu in human pancreatic adenocarcinoma cells

    Nayak, Tapan K. [Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-0001 (United States); Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131 (United States); Norenberg, Jeffrey P. [Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-0001 (United States)]. E-mail: jpnoren@unm.edu; Anderson, Tamara L. [Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-0001 (United States); Prossnitz, Eric R. [Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, NM 87131 (United States); Stabin, Michael G. [Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN 37232 (United States); Atcher, Robert W. [Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-0001 (United States); Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States)

    2007-02-15

    Introduction: Advance clinical cancer therapy studies of patients treated with somatostatin receptor (sstr)-targeted [DOTA{sup 0}-Tyr{sup 3}]octreotide (DOTATOC) labeled with low-linear-energy-transfer (LET) {beta}{sup -}-emitters have shown overall response rates in the range of 15-33%. In order to improve outcomes, we sought to compare the therapeutic effectiveness of sstr-targeted high-LET {alpha}-emitting {sup 213}Bi to that of low-LET {beta}{sup -}-emitting {sup 177}Lu by determining relative biological effectiveness (RBE) using the external {gamma}-beam of {sup 137}Cs as reference radiation. Methods: Sstr-expressing human pancreatic adenocarcinoma Capan-2 cells and A549 control cells were used for this study. The effects of different radiation doses of {sup 213}Bi and {sup 177}Lu labeled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and sstr-targeted DOTATOC were investigated with a clonogenic cell survival assay. Apoptosis was measured using the Cell Death Detection ELISA{sup PLUS} 10x kit. Results: Using equimolar DOTATOC treatment with concurrent irradiation with a {sup 137}Cs source as reference radiation, the calculated RBE of [{sup 213}Bi]DOTATOC was 3.4, as compared to 1.0 for [{sup 177}Lu]DOTATOC. As measured in terms of absorbance units, [{sup 213}Bi]DOTATOC caused a 2.3-fold-greater release of apoptosis-specific mononucleosomes and oligonucleosomes than [{sup 177}Lu]DOTATOC at the final treatment time of 96 h (P<.001) in sstr-expressing Capan-2 cells. Conclusions: In conclusion, at the same absorbed dose, [{sup 213}Bi]DOTATOC is therapeutically more effective in decreasing survival than is [{sup 177}Lu]DOTATOC in human pancreatic adenocarcinoma cells due to its comparatively higher RBE.

  3. Preclinical evaluation of NETA-based bifunctional ligand for radioimmunotherapy applications using 212Bi and 213Bi: Radiolabeling, serum stability, and biodistribution and tumor uptake studies

    Introduction: Despite the great potential of targeted α-radioimmunotherapy (RIT) as demonstrated by pre-clinical and clinical trials, limited progress has been made on the improvement of chelation chemistry for 212Bi and 213Bi. A new bifunctional ligand 3p-C-NETA was evaluated for targeted α RIT using 212Bi and 213Bi. Methods: Radiolabeling of 3p-C-NETA with 205/6Bi, a surrogate of 212Bi and 213Bi, was evaluated at pH 5.5 and room temperature. In vitro stability of the 205/6Bi-3p-C-NETA-trastuzumab conjugate was evaluated using human serum (pH 7, 37 °C). Immunoreactivity and specific activity of the 205/6Bi-3p-C-NETA-trastuzumab conjugate were measured. An in vivo biodistribution study was performed to evaluate the in vivo stability and tumor targeting properties of the 205/6Bi-3p-C-NETA-trastuzumab conjugate in athymic mice bearing subcutaneous LS174T tumor xenografts. Result: The 3p-C-NETA-trastuzumab conjugate was extremely rapid in complexing with 205/6Bi, and the corresponding 205/6Bi-3p-C-NETA-trastuzumab was stable in human serum. 205/6Bi-3p-C-NETA-trastuzumab was prepared with a high specific activity and retained immunoreactivity. 205/6Bi-3p-C-NETA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low normal organ and high tumor uptake. Conclusion: The results of the in vitro and in vivo studies indicate that 3p-C-NETA is a promising chelator for RIT applications using 212Bi and 213Bi. Further detailed in vivo evaluations of 3p-C-NETA for targeted α RIT are warranted

  4. Non-invasive visualisation of the development of peritoneal carcinomatosis and tumour regression after 213Bi-radioimmunotherapy using bioluminescence imaging

    Non-invasive imaging of tumour development remains a challenge, especially for tumours in the intraperitoneal cavity. Therefore, the aim of this study was the visualisation of both the development of peritoneal carcinomatosis and tumour regression after radioimmunotherapy with tumour-specific 213Bi-Immunoconjugates, via in vivo bioluminescence imaging of firefly luciferase-transfected cells. Human diffuse-type gastric cancer cells expressing mutant d9-E-cadherin were stably transfected with firefly luciferase (HSC45-M2-luc). For bioluminescence imaging, nude mice were inoculated intraperitoneally with 1 x 107 HSC45-M2-luc cells. On days 4 and 8 after tumour cell inoculation, imaging was performed following D-luciferin injection using a cooled CCD camera with an image intensifier unit. For therapy, mice were injected with 2.7 MBq 213Bi-d9MAb targeting d9-E-cadherin on day 8 after tumour cell inoculation. Bioluminescence images were taken every 4 days to monitor tumour development. After i.p. inoculation of HSC45-M2-luc cells into nude mice, development as well as localisation of peritoneal carcinomatosis could be visualised using bioluminescence imaging. Following 213Bi-d9MAb therapy on day 8 after intraperitoneal inoculation of HSC45-M2-luc cells, small tumour nodules were totally eliminated and larger nodules showed a clear reduction in size on day 12 after tumour cell inoculation. Subsequently a recurrence of tumour mass was observed, starting from the remaining tumour spots. By measuring the mean grey level intensity, tumour development over time could be demonstrated. Non-invasive bioluminescence imaging permits visualisation of the development of peritoneal carcinomatosis, localisation of tumour in the intraperitoneal cavity and evaluation of therapeutic success after 213Bi-d9MAb treatment. (orig.)

  5. A=225 implantation for $^{221}$Fr source for TRIUMF atom trap

    The FrPNC Collaboration is mounting an atom trap for parity violation experiments and precision spectroscopy on francium atoms at TRIUMF's ISAC facility. We would like to use ISOLDE's capability of simultaneously implanting A=225 (while another experiment runs online) to make a long-lived source feeding $^{221}$Fr for tests of the trap. $^{225}$Ra $\\beta$-decays to $^{225}$Ac, which then $\\alpha$-decays, producing 100 keV $^{221}$Fr t$_{1/2}$= 4.8 minute recoils. The implanted A=225 source would be shipped to TRIUMF, where it would be held for several minutes at a time a few mm from the same yttrium foil that normally receives the ISAC beam. SRIM calculations imply that 20% of the $^{221}$Fr will be implanted in a 1 cm diameter spot on the yttrium. Then the yttrium foil is moved to the trap and heated to release the Fr atoms, just as in normal ISAC online operation. A test implantation will be done at 10$^{7}$/sec production for 1 day, testing whether carbon cracking on the implantation foil in the mass separ...

  6. Targeted alpha-radionuclide therapy of functionally critically located gliomas with {sup 213}Bi-DOTA-[Thi{sup 8},Met(O{sub 2}){sup 11}]-substance P: a pilot trial

    Cordier, D.; Merlo, A. [University Hospitals, Division of Neurosurgery, Basel (Switzerland); Forrer, F.; Good, S.; Mueller-Brand, J. [University Hospitals, Institute of Nuclear Medicine, Basel (Switzerland); Bruchertseifer, F.; Morgenstern, A.; Apostolidis, C. [Institute for Transuranium Elements, European Commission, Joint Research Centre, Karlsruhe (Germany); Maecke, H. [University Hospitals, Institute of Nuclear Medicine, Basel (Switzerland); University Hospital Basel, Nuclear Medicine and Radiological Chemistry, Basel (Switzerland); Reubi, J.C. [University of Berne, Institute of Pathology, Berne (Switzerland)

    2010-07-15

    Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting {sup 90}Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of {sup 90}Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide {sup 213}Bi with a mean tissue range of 81 {mu}m may have a more favourable toxicity profile. Therefore, we evaluated locally injected {sup 213}Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality. In a pilot study, we included five patients with critically located gliomas (WHO grades II-IV). After diagnosis by biopsy, {sup 213}Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated. Targeted radiopeptide therapy using {sup 213}Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. {sup 213}Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection. This study provides proof of concept that targeted local radiotherapy using {sup 213}Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis. (orig.)

  7. Investigation of $\\alpha$-decay rates of $^{221}$Fr, $^{224}$Ra and $^{226}$Ra in different environments

    2007-01-01

    It has recently been suggested, and indicated experimentally, that $\\alpha$- decay half-lives are modified by solid state effects in the surrounding environment. We propose here to measure with high accuracy the $\\alpha$-decay half-life of $^{221}$Fr, $^{224}$Ra and $^{226}$Ra in insulators and metals. Furthermore we plan to investigate the temperature dependency of the half-life in these materials (room temperature, 4 K and 10 mK).

  8. In vitro evaluation of {sup 213}Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage

    Vandenbulcke, Katia; Lahorte, Christophe; Slegers, Guido [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Gent (Belgium); De Vos, Filip; Dierckx, Rudi A. [Division of Nuclear Medicine, Ghent University Hospital (Belgium); Offner, Fritz [Department of Hematology, Ghent University Hospital (Belgium); Philippe, Jan [Department of Clinical Chemistry, Ghent University Hospital (Belgium); Apostolidis, Christos; Molinet, Roger; Nikula, Tuomo K. [European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe (Germany); Bacher, Klaus; De Gelder, Virginie; Vral, Anne; Thierens, Hubert [Department of Anatomy, Embryology, Histology and Medical Physics, Ghent University (Belgium)

    2003-10-01

    External source radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. {sup 213}Bi was eluted from a {sup 225}Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A''-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to {sup 213}Bi conjugated to CD20 antibody or after external {sup 60}Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated {sup 213}Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by {sup 213}Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, {sup 213}Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high

  9. In vitro evaluation of 213Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage

    External source radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. 213Bi was eluted from a 225Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A''-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to 213Bi conjugated to CD20 antibody or after external 60Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated 213Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by 213Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, 213Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high-LET targeted alpha particle exposure killed B-CLL cells

  10. The investigation of the decay of the deformed 167Yb, 164Tm, 225Ac, 221Fr nuclei. Beta-spectrograph with positional-sensitive detector

    The decay of the deformed 167Yb, 164Tm, 225Ac,221Fr nuclei is investigated in this work. For 167Yb and 164Tm decays the specters of the conversion electrons were measured. 32 γ-transitions were found for 167 Yb decay, 6 of which were found for the first time. The multipolarities for 9 γ-transitions were found. For 164Tm decay 23 new γ-transitions were found. The theoretical investigations of the collective states in the nucleus were carried out. Octupole-rotatory line with k=1- was found in the measurement of conversion electrons specters of the short-life nuclei. Device' nonlinearity was 0,04%. Resolution was Δβρ/βρ 0,11%. Effective light yield was 1-2 %. The decay of 225Ac and 221Fr nuclei were investigated. The investigations of α-γ -coincidence, α-γ - rays were carried out. 24 new γ -transitions for 225Ac and 13 ones for 221Fr were found. The new levels and their intensities were defined more precisely. Intensity balance calculations were carried out and the full populations of the nuclear levels were calculated. (author). 3 tabs.; 10 figs

  11. Retention studies of recoiling daughter nuclides of 225Ac in polymer vesicles

    Alpha radionuclide therapy is steadily gaining importance and a large number of pre-clinical and clinical studies have been carried out. However, due to the recoil effects the daughter recoil atoms, most of which are alpha emitters as well, receive energies that are much higher than the energies of chemical bonds resulting in decoupling of the radionuclide from common targeting agents. Here, we demonstrate that polymer vesicles (i.e. polymersomes) can retain recoiling daughter nuclei based on an experimental study examining the retention of 221Fr and 213Bi when encapsulating 225Ac. - Highlights: • First reported loading of 213Bi and 225Ac in polymer vesicles (i.e. polymersomes). • Encapsulating 225Ac in polymersomes results in up to 69 % recoil retention of 221Fr. • Encapsulating 225Ac in polymersomes results in up to 53 % recoil retention of 213Bi

  12. Retention studies of recoiling daughter nuclides of 225Ac in polymer vesicles.

    Wang, G; de Kruijff, R M; Rol, A; Thijssen, L; Mendes, E; Morgenstern, A; Bruchertseifer, F; Stuart, M C A; Wolterbeek, H T; Denkova, A G

    2014-02-01

    Alpha radionuclide therapy is steadily gaining importance and a large number of pre-clinical and clinical studies have been carried out. However, due to the recoil effects the daughter recoil atoms, most of which are alpha emitters as well, receive energies that are much higher than the energies of chemical bonds resulting in decoupling of the radionuclide from common targeting agents. Here, we demonstrate that polymer vesicles (i.e. polymersomes) can retain recoiling daughter nuclei based on an experimental study examining the retention of (221)Fr and (213)Bi when encapsulating (225)Ac. PMID:24374072

  13. Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

    Introduction: Targeted alpha therapy (TAT) has the potential for killing micro-metastases with minimum collateral damage to surrounding healthy tissue. In-vivo generator radionuclides, such as223Ra, 225Ra, and 225Ac, are of special interest for radiotherapeutic applications as they emit multiple α-particles during their decay. Utilizing appropriate carriers capable of retaining both the parent radioisotope as well as daughter products is important for the effective delivery of the radioisotope to the tumor site while mitigating global in vivo radiotoxicity. In this work, LaPO4 core and core + 2 shells nanoparticles (NPs) (NPs with 2 layers of cold LaPO4 deposited on the core surfaces) were synthesized containing either 223Ra or225Ra/225Ac, and the retention of the parents and daughters within the NPs in vitro was investigated. Methods: Core LaPO4 NPs were synthesized in aqueous solution by reacting 1 equivalent of La(NO3)3, along with few microcuries of either 223Ra or 225Ra/225Ac, with 1 equivalent of sodium tripolyphosphate (TPP) under moderate heating and purified by membrane dialysis. Core-shell NPs were also synthesized with one (core + 1 shell) and two (core + 2 shells) cold LaPO4 layers deposited onto the radioactive cores. The NPs were then characterized by transmission electron microscopy (TEM) and powder x-ray diffraction (XRD). Identification and quantification of radioactive parents and daughters released from the NPs in vitro were investigated using gamma-ray spectroscopy. Results: XRD and TEM analysis revealed that the NPs crystallized in the rhabdophane phase with mean diameters of 3.4 and 6.3 nm for core and core + 2 shells, respectively. The core LaPO4 NPs retained up to 88% of 223Ra over 35 days. However, in the core + 2 shells NPs, the retention of 223Ra and its daughter, 211Pb, was improved to > 99.9% over 27 days. Additionally, the retention of 225Ra/225Ac parents was > 99.98% and ~ 80% for the 221Fr and 213Bi daughters over 35 days for the

  14. Dependence of the half-life of 221Fr on the implantation environment

    Olaizola, B.; Fraile, L.M.; Riisager, Karsten; Correia, J.G.; Fynbo, Hans Otto Uldall; Jeppesen, Henrik; Johnston, K.; Kirsebom, Oliver Sølund; Skovbo, Katrine; Thomsen, Lotte Ansgaard

    The possible dependence of the half-life of 221Fr on the solid-state environment has been investigated by the simultaneous measurement of implanted 221Fr ions in an insulator (Si) and a metallic substrate (Au) at the ISOLDE facility at CERN. Our results indicate that, if existing, the difference ...

  15. Präklinische Untersuchungen zur Radiopeptidtherapie der Peritonealkarzinose mit Alpha-Strahlern

    Drecoll, Enken Maren Susanna

    2016-01-01

    Das Tumor Homing Peptids F3 wurde stabil an den α-Emitter 213Bi gebunden und seine zytotoxische Wirkung auf Karzinomzellen in vitro und in vivo untersucht. Hierbei konnte nachgewiesen werden, dass 213Bi-DTPA-(F3)2 in den Zellkern von Karzinomzellen internalisiert wird. Mäuse mit intraperitonealen Xenograft-Tumoren wurden mit 11,1 MBq 213Bi-DTPA-(F3)2 behandelt. In einer Tumorpräventionsstudie konnte die Überlebenszeit der Tiere um über 80 % gesteigert werden, in einer Tumorreduktionsstudie um...

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

    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

  17. Radioimmunotherapy with engineered antibody fragments

    Authors have developed and begun evaluating radiometal-chelated (213Bi) engineered antibody fragments as radioimmunotherapy agents that target the HER2/neu (c-erbB-2) antigen. The diabody format was found to have 40-fold greater affinity for HER2/neu and to be associated with significantly greater tumor localization than is achieved with scFv molecule. It is shown that short-lived isotopes like 213Bi would be most effective when used in conjunction with antibodies that targeted diffuse malignancies (leukemia or lymphoma) or when used for very rapid pretargeted radioimmunotherapy application in which the radioisotope is conjugated to a very small ligand

  18. Conventional and Pretargeted Radioimmunotherapy Using Bismuth-213 to Target and Treat Non-Hodgkin Lymphomas Expressing CD20: A Preclinical Model toward Optimal Consolidation Therapy to Eradicate Minimal Residual Disease

    Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease (MRD) because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (213Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)4SA fusion protein (FP), followed by a dendrimeric clearing agent and (213Bi)DOTA-biotin. After 90 min, tumor uptake for 1F5(scFv)4SA was 16.5 ± 7.0 % injected dose per gram (ID/g) compared with 2.3 ± 0.9 % ID/g for the control FP. Mice treated with anti-CD20 PRIT and 600 (micro)Ci (213Bi)DOTA-biotin exhibited marked tumor growth delays compared to controls (mean tumor volume 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared to 23 days for the control FP (p 213Bi-labeled anti-CD20 PRIT.

  19. Evaluation of complexing properties of chelating agents for the bismuth-213

    The bismuth-213 is an alpha- and beta-emitting radioelement of very short physical half-life (45 min) obtained by means of a (225Ac-213Bi) generator. Given its radiotoxicity, this element presents an interest in radioimmunotherapy (RIT). At present, the DTPA derivatives alone are used in radiolabelling of antibodies for RIT. This study presents the complexing properties of other chelates potentially usable to this goal. Four original chelating agents were synthesized in order to choose the families giving the best results in complexing the 213Bi: the tri-ethylene-tetra-amino-hexa-carboxylic acid (HETA), the 1, 4, 7, 10-tetra-aza-cyclo-dodecane-1, 4, 7, 10-tetraacetic- 1- Gly-L-p-nitro Phe-amide (DOTA-pept), the 1, 4, 8, 11-tetrakis [(S)-2 hydroxy-propyl]-1, 4, 8, 11-tetra-aza-cyclo-tetra-decane (THEOH), and the ethylenediamine di-acetate di-acetamide-bis-thiophenol (EDTA-TH). Given the physical characteristics of 213Bi and the goal of our research, the studies of complexation were conducted by C.C.M. on silica, in highly diluted solution, with fixed chelates-213Bi incubation time (15 min), and variable temperature and concentrations. Analysis of the results have been done by means of a phosphor-imager by measuring the number of pixels associated to every chromatographic spot. The obtained results show that the poly-aza poly-carboxylic derivatives and poly-aza di-thio dicarboxylic derivatives are the only able ones to complex rapidly and quantitatively the 213Bi

  20. Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody

    Schwartz, J; O' Donoghue, J A; Humm, J L [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Jaggi, J S [Bristol-Myers Squibb, Plainsboro, NJ (United States); Ruan, S; Larson, S M [Nuclear Medicine Service Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); McDevitt, M; Scheinberg, D A, E-mail: schwarj1@mskcc.org [Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065 (United States)

    2011-02-07

    Clinical therapeutic studies using {sup 225}Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of {sup 225}Ac. The purpose of this study was to determine the amount of {sup 225}Ac and non-equilibrium progeny in the mouse kidney after the injection of {sup 225}Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with {sup 225}Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess {sup 213}Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess {sup 213}Bi reaching the kidney ({gamma}-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq{sup -1}, of which 0.46 (SD 0.16) Gy kBq{sup -1} (i.e. 60%) was due to non-equilibrium excess {sup 213}Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess {sup 213}Bi (0.31 (SD 0.11) Gy kBq{sup -1}) represented {approx}46% of the total. For the medulla the dose contribution from excess {sup 213}Bi (0.81 (SD 0.28) Gy kBq{sup -1}) was {approx}80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq{sup -1} following administration of {sup 225}Ac-huM195 with non-equilibrium excess {sup 213}Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the

  1. Single-dose anti-CD138 radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment of multiple myeloma in a preclinical model

    Fichou, Nolwenn; Gouard, Sébastien; Maurel, Catherine; Barbet, Jacques; Ferrer, Ludovic; Morgenstern, Alfred; Bruchertseifer, Frank; Faivre-Chauvet, Alain; Bigot-Corbel, Edith; Davodeau, François; Gaschet, Joëlle; Chérel, Michel

    2015-01-01

    Objectives Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to 213Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic eff...

  2. Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide

    Frampas, Eric; Maurel, Catherine; Remaud-Le Saec, Patricia; Mauxion, Thibault; Faivre-Chauvet, Alain; Davodeau, Francois; Bardies, Manuel; Barbet, Jacques [Universite de Nantes, Inserm, UMR 892, Centre de Recherche en Cancerologie Nantes-Angers (CRCNA), Nantes (France); Goldenberg, David M. [Immunomedics, Inc., Morris Plains, NJ (United States); Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, NJ (United States)

    2011-12-15

    We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses. LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for {sup 131}I, {sup 177}Lu, {sup 90}Y, {sup 211}At, and {sup 213}Bi using realistic specific activities. Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached {proportional_to}9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), {sup 211}At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. {sup 90}Y and {sup 213}Bi would also deliver high absorbed doses to tumor (18.6 for {sup 90}Y and 26.5 Gy for {sup 213}Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity. Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially {sup 211}At, with kidneys being the dose-limiting organ. {sup 177}Lu and {sup 131}I should be considered for repeated injections. (orig.)

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

    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.

  4. Reactor production of Thorium-229.

    Hogle, Susan; Boll, Rose Ann; Murphy, Karen; Denton, David; Owens, Allison; Haverlock, Tamara J; Garland, Marc; Mirzadeh, Saed

    2016-08-01

    Limited availability of (229)Th for clinical applications of (213)Bi necessitates investigation of alternative production routes. In reactor production, (229)Th is produced from neutron transmutation of (226)Ra, (228)Ra, (227)Ac and (228)Th. Irradiations of (226)Ra, (228)Ra, and (227)Ac targets at the Oak Ridge National Laboratory High Flux Isotope Reactor result in yields of (229)Th at 26 days of 74.0±7.4MBq/g, 260±10MBq/g, and 1200±50MBq/g, respectively. Intermediate radionuclide yields and cross sections are also studied. PMID:27163437

  5. Bifunctional chelating agents for targeted α-particle radiotherapy

    An α-emitting radionuclide is proposed as a better choice for application in radiotherapy of either leukemias or lymphomas due to very high cytotoxicity, short emission path length, and immediate energy deposition minimizing collateral cytotoxicity. Metallic α-emitters that have been studied are 212Bi and 213Bi. Bifunctional derivatives of diethylenetriamine pentaacetic acid (DTPA) were found to form Bi(III) complexes that were labile in vivo. Pre-clinical experiments confirmed both the stability of the CHX-DTPA ligands for the Bi(III) isotopes and the therapeutic applicability of these α-emitting isotopes

  6. High-resolution laser spectroscopy with the Collinear Resonance Ionisation Spectroscopy (CRIS) experiment at CERN-ISOLDE

    Cocolios, T. E.; de Groote, R. P.; Billowes, J.; Bissell, M. L.; Budinčević, I.; Day Goodacre, T.; Farooq-Smith, G. J.; Fedosseev, V. N.; Flanagan, K. T.; Franchoo, S.; Garcia Ruiz, R. F.; Gins, W.; Heylen, H.; Kron, T.; Li, R.; Lynch, K. M.; Marsh, B. A.; Neyens, G.; Rossel, R. E.; Rothe, S.; Smith, A. J.; Stroke, H. H.; Wendt, K. D. A.; Wilkins, S. G.; Yang, X.

    2016-06-01

    The Collinear Resonance Ionisation Spectroscopy (CRIS) experiment at CERN has achieved high-resolution resonance ionisation laser spectroscopy with a full width at half maximum linewidth of 20(1) MHz for 219,221 Fr, and has measured isotopes as short lived as 5 ms with 214 Fr. This development allows for greater precision in the study of hyperfine structures and isotope shifts, as well as a higher selectivity of single-isotope, even single-isomer, beams. These achievements are linked with the development of a new laser laboratory and new data-acquisition systems.

  7. Single-dose anti-CD138 radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment of multiple myeloma in a preclinical model

    Nolwenn eFichou

    2015-11-01

    Full Text Available Objectives: Radioimmunotherapy (RIT has emerged as a potential treatment option for multiple myeloma (MM. In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to 213Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with 213Bi for α-RIT or 177Lu for β-RIT.Methods: A new monoclonal anti-CD138 antibody, 9E7.4, was generated by immunizing a rat with a murine CD138-derived peptide. Antibody specificity was validated by flow cytometry, biodistribution and α-RIT studies. Then, a β-RIT dose-escalation assay with the 177Lu-radiolabeled 9E7.4 mAb was performed in KalwRij C57/BL6 mice 10 days after i.v. engraftment with 5T33 MM cells. Animal survival and toxicological parameters were assessed to define the optimal activity.Results: α-RIT performed with 3.7 MBq of 213Bi-labeled 9E7.4 anti-CD138 mAb increased median survival to 80 days compared to 37 days for the untreated control and effected cure in 45% of animals. β-RIT performed with 18.5 MBq of 177Lu-labeled 9E7.4 mAb was well tolerated and significantly increased mouse survival (54 versus 37 days in the control group; however, no mice were cured with this treatment.Conclusion: This study revealed the advantages of α-RIT in the treatment of MM in a preclinical model where β-RIT shows almost no efficacy.

  8. New method for large scale production of medically applicable Actinium-225 and Radium-223

    Alpha-emitters (211At, 212Bi, 213Bi, 223Ra, 225Ac) are promising for targeted radiotherapy of cancer. Only two alpha decays near a cell membrane result in 50% death of cancer cell and only a single decay inside the cell is required for this. 225Ac may be used either directly or as a mother radionuclide in 213Bi isotope generator. Production of 225Ac is provided by three main suppliers - Institute for Transuranium Elements in Germany, Oak Ridge National Laboratory in USA and Institute of Physics and Power Engineering in Obninsk, Russia. The current worldwide production of 225Ac is approximately 1.7 Ci per year that corresponds to only 100-200 patients that could be treated annually. The common approach for 225Ac production is separation from mother 229Th or irradiation of 226Ra with protons in a cyclotron. Both the methods have some practical limitations to be applied routinely. 225Ac can be also produced by irradiation of natural thorium with medium energy protons . Cumulative cross sections of 225Ac, 227Ac, 227Th, 228Th formations have been obtained recently. Thorium targets (1-9 g) were irradiated by 114-91 MeV proton beam (1-50 μA) at INR linear accelerator. After dissolution in 8 M HNO3 + 0.004 M HF thorium was removed by double LLX by HDEHP in toluene (1:1). Ac and REE were pre-concentrated and separated from Ra and most fission products by DGA-Resin (Triskem). After washing out by 0.01 M HNO3 Ac was separated from REE by TRU Resin (Triskem) in 3 M HNO3 media. About 6 mCi 225Ac were separated in hot cell with chemical yield 85%. The method may be upscaled for production of Ci amounts of the radionuclide. The main impurity is 227Ac (0.1% at the EOB) but it does not hinder 225Ac from being used for medical 225Ac/213Bi generators. (author)

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

    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

  10. Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

    Dadachova, Ekaterina; Nakouzi, Antonio; Bryan, Ruth A.; Casadevall, Arturo

    2003-09-01

    There is an urgent need for new antimicrobial therapies to combat drug resistance, new pathogens, and the relative inefficacy of current therapy in compromised hosts. Ionizing radiation can kill microorganisms quickly and efficiently, but this modality has not been exploited as a therapeutic antimicrobial strategy. We have developed methods to target ionizing radiation to a fungal cell by labeling a specific mAb with the therapeutic radioisotopes Rhenium-188 and Bismuth-213. Radiolabeled antibody killed cells of human pathogenic fungus Cryptococcus neoformans in vitro, thus converting an antibody with no inherent antifungal activity into a microbicidal molecule. Administration of radiolabeled antibody to mice with C. neoformans infection delivered 213Bi and 188Re to the sites of infection, reduced their organ fungal burden, and significantly prolonged their survival without apparent toxicity. This study establishes the principle that targeted radiation can be used for the therapy of an infectious disease, and suggests that it may have wide applicability as an antimicrobial strategy.

  11. Antitumor Immunity Induced after α Irradiation

    Jean-Baptiste Gorin

    2014-04-01

    Full Text Available Radioimmunotherapy (RIT is a therapeutic modality that allows delivering of ionizing radiation directly to targeted cancer cells. Conventional RIT uses β-emitting radioisotopes, but recently, a growing interest has emerged for the clinical development of α particles. α emitters are ideal for killing isolated or small clusters of tumor cells, thanks to their specific characteristics (high linear energy transfer and short path in the tissue, and their effect is less dependent on dose rate, tissue oxygenation, or cell cycle status than γ and X rays. Several studies have been performed to describe α emitter radiobiology and cell death mechanisms induced after α irradiation. But so far, no investigation has been undertaken to analyze the impact of α particles on the immune system, when several studies have shown that external irradiation, using γ and X rays, can foster an antitumor immune response. Therefore, we decided to evaluate the immunogenicity of murine adenocarcinoma MC-38 after bismuth-213 (213Bi irradiation using a vaccination approach. In vivo studies performed in immunocompetent C57Bl/6 mice induced a protective antitumor response that is mediated by tumor-specific T cells. The molecular mechanisms potentially involved in the activation of adaptative immunity were also investigated by in vitro studies. We observed that 213Bi-treated MC-38 cells release “danger signals” and activate dendritic cells. Our results demonstrate that α irradiation can stimulate adaptive immunity, elicits an efficient antitumor protection, and therefore is an immunogenic cell death inducer, which provides an attractive complement to its direct cytolytic effect on tumor cells.

  12. Hyperfine anomalies in Fr: boundaries of the spherical single particle model

    Zhang, J; Aubin, S; Behr, J A; Gomez, E; Gwinner, G; Orozco, L A; Pearson, M R; Sprouse, G D

    2015-01-01

    We have measured the hyperfine splitting of the $7P_{1/2}$ state at the 100 ppm level in Fr isotopes ($^{206g,206m, 207, 209, 213, 221}$Fr) near the closed neutron shell ($N$ = 126 in $^{213}$Fr). The measurements in five isotopes and a nuclear isomeric state of francium, combined with previous determinations of the $7S_{1/2}$ splittings, reveal the spatial distribution of the nuclear magnetization, i.e. the Bohr-Weisskopf effect. We compare our results with a simple shell model consisting of unpaired single valence nucleons orbiting a spherical nucleus, and find good agreement over a range of neutron-deficient isotopes ($^{207-213}$Fr). Also, we find near-constant proton anomalies for several even-$ N$ isotopes. This identifies a set of Fr isotopes whose nuclear structure can be understood well enough for the extraction of weak interaction parameters from parity non-conservation studies.

  13. Emission Channeling Studies of the Lattice Site of Oversized Alkali Atoms Implanted in Metals

    2002-01-01

    % IS340 \\\\ \\\\ As alkali atoms have the largest atomic radius of all elements, the determination of their lattice configuration following implantation into metals forms a critical test for the various models predicting the lattice site of implanted impurity atoms. The site determination of these large atoms will especially be a crucial check for the most recent model that relates the substitutional fraction of oversized elements to their solution enthalpy. Recent exploratory $^{213}$Fr and $^{221}$Fr $\\alpha$-emission channeling experiments at ISOLDE-CERN and hyperfine interaction measurements on Fr implanted in Fe gave an indication for anomalously large substitutional fractions. To investigate further the behaviour of Fr and other alkali atoms like Cs and Rb thoroughly, more on-line emission channeling experiments are needed. We propose a number of shifts for each element, where the temperature of the implanted metals will be varied between 50$^\\circ$ and 700$^\\circ$~K. Temperature dependent measurements wi...

  14. Melanin-targeting antibody as a potential agent for radioimmunotherapy of melanoma

    Aim: Melanoma is a cancer of increasing incidence for which new methods of treatment and imaging are urgently needed. Currently there is no effective therapy for metastatic melanoma as this tumor is resistant to radiation and chemotherapy. The majority of human melanomas are pigmented with melanin. Here we investigated the possibility of using a melanin-binding antibody (mAb 6D2) which was originally developed against fungal melanin as a delivery vehicle for RIT of pigmented melanoma. Materials and Methods: MAb 6D2 (IgM type) was generated from hybridomas obtained from mice immunized with melanin isolated from Cryptococcus neoformans. The mAb was radiolabeled with 213Bi or 111In via bifunctional chelator CHXA'' and with 188Re - via 'direct labeling'. The immunoreactivity of radiolabeled 6D2 mAb towards fungal melanin was tested by immunofluorescence. Cell binding of 213Bi-6D2, 188Re-6D2 and irrelevant IgM 12A1 was evaluated by incubating 2 μg/mL mAb with 0.23-2 x 106 human slightly pigmented melanoma cells SK-28-MEL (whole or lysed) which were grown with or without 110 μM L-tyrosine to promote melanin formation. In vivo binding of 111In-6D2 was studied by scintigraphic imaging in nude mice injected IP with 2.8 x 106 SK-28-MEL cells 24 h before 111In-6D2; biodistribution of 188Re-6D2 was performed in nude mice bearing SK-28-MEL xenografted tumors. Results: The immunoreactivity of radiolabeled 6D2 mAb to melanin was demonstrated by immunofluorescence. Cell binding of 213Bi-6D2 and 188Re-6D2 was higher for the melanoma cells grown with 110 μM L-tyrosine suggesting melanin-specific binding. There was no significant difference (P>0.05) in binding to the whole or lysed cells which may be due to reactivity with melanin or precursors found on the cell surface. In mice injected IP with SK-28-MEL cells there was more retention of 111In-6D2 in intraperitoneal cavity compared to irrelevant 111In-IgM and control animals with no tumor cells. The biodistribution of 188Re-6D2 m

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

    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

  16. Comparative analysis of multiple myeloma treatment by CD138 antigen targeting with bismuth-213 and Melphalan chemotherapy

    Introduction: Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a MM model. In order to define where alpha-RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha-RIT using a [213Bi]-anti-mCD138 antibody in a syngeneic MM mouse model. Methods: C57BL/KaLwRij mice were grafted with 1 × 106 5T33 murine MM cells. Luciferase transfected 5T33 cells were used for in vivo localization. The first step of the study was to assess the dose-response of Melphalan 21 days after engraftment. The second step consisted in therapeutic combination: Melphalan followed by RIT at day 22 or day 25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone, RIT alone at day 22 or day 25 (3.7 MBq of [213Bi]-anti-CD138) and Melphalan combined with alpha-RIT. Results: Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with Melphalan alone, only the 200 μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25 days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, and results in increased leukocyte and red blood cell toxicity. Conclusions: Alpha-RIT seems to be a good alternative to Melphalan. Association of these two treatments provides no benefit. The perspectives of this work would be to evaluate RIT impact on the regimens incorporating the novel agents bortezomide, thalidomide and lenalidomide

  17. TRASH TO TREASURE: CONVERTING COLD WAR LEGACY WASTE INTO WEAPONS AGAINST CANCER

    Nicholas, R.G.; Lacy, N.H.; Butz, T.R.; Brandon, N.E.

    2004-10-06

    As part of its commitment to clean up Cold War legacy sites, the U.S. Department of Energy (DOE) has initiated an exciting and unique project to dispose of its inventory of uranium-233 (233U) stored at Oak Ridge National Laboratory (ORNL), and extract isotopes that show great promise in the treatment of deadly cancers. In addition to increasing the supply of potentially useful medical isotopes, the project will rid DOE of a nuclear concern and cut surveillance and security costs. For more than 30 years, DOE's ORNL has stored over 1,200 containers of fissile 233U, originally produced for several defense-related projects, including a pilot study that looked at using 233U as a commercial reactor fuel. This uranium, designated as special nuclear material, requires expensive security, safety, and environmental controls. It has been stored at an ORNL facility, Building 3019A, that dates back to the Manhattan Project. Down-blending the material to a safer form, rather than continuing to store it, will eliminate a $15 million a year financial liability for the DOE and increase the supply of medical isotopes by 5,700 percent. During the down-blending process, thorium-229 (229Th) will be extracted. The thorium will then be used to extract actinium-225 (225Ac), which will ultimately supply its progeny, bismuth-213 (213Bi), for on-going cancer research. The research includes Phase II clinical trials for the treatment of acute myelogenous leukemia at Sloan-Kettering Memorial Cancer Center in New York, as well as other serious cancers of the lungs, pancreas, and kidneys using a technique known as alpha-particle radioimmunotherapy. Alpha-particle radioimmunotherapy is based on the emission of alpha particles by radionuclides. 213Bi is attached to a monoclonal antibody that targets specific cells. The bismuth then delivers a high-powered but short-range radiation dose, effectively killing the cancerous cells but sparing the surrounding tissue. Production of the actinium and

  18. TRASH TO TREASURE: CONVERTING COLD WAR LEGACY WASTE INTO WEAPONS AGAINST CANCER

    As part of its commitment to clean up Cold War legacy sites, the U.S. Department of Energy (DOE) has initiated an exciting and unique project to dispose of its inventory of uranium-233 (233U) stored at Oak Ridge National Laboratory (ORNL), and extract isotopes that show great promise in the treatment of deadly cancers. In addition to increasing the supply of potentially useful medical isotopes, the project will rid DOE of a nuclear concern and cut surveillance and security costs. For more than 30 years, DOE's ORNL has stored over 1,200 containers of fissile 233U, originally produced for several defense-related projects, including a pilot study that looked at using 233U as a commercial reactor fuel. This uranium, designated as special nuclear material, requires expensive security, safety, and environmental controls. It has been stored at an ORNL facility, Building 3019A, that dates back to the Manhattan Project. Down-blending the material to a safer form, rather than continuing to store it, will eliminate a $15 million a year financial liability for the DOE and increase the supply of medical isotopes by 5,700 percent. During the down-blending process, thorium-229 (229Th) will be extracted. The thorium will then be used to extract actinium-225 (225Ac), which will ultimately supply its progeny, bismuth-213 (213Bi), for on-going cancer research. The research includes Phase II clinical trials for the treatment of acute myelogenous leukemia at Sloan-Kettering Memorial Cancer Center in New York, as well as other serious cancers of the lungs, pancreas, and kidneys using a technique known as alpha-particle radioimmunotherapy. Alpha-particle radioimmunotherapy is based on the emission of alpha particles by radionuclides. 213Bi is attached to a monoclonal antibody that targets specific cells. The bismuth then delivers a high-powered but short-range radiation dose, effectively killing the cancerous cells but sparing the surrounding tissue. Production of the actinium and

  19. Laser Spectroscopy of Neutron Rich Bismuth Isotopes

    2002-01-01

    %IS344 :\\\\ \\\\ The aim of the experiment is to measure the optical isotope shifts and hyperfine structures of bismuth isotopes across the N=126 shell closure in order to extract the change in mean square charge radii ($\\delta\\langle r^{2}\\rangle$) and static moments. These include the first isotones of lead to be measured directly above the shell closure and will provide new information on the systematics of the kink ($\\delta\\langle r^{2}\\rangle)$ seen in the lead isotopic chain. After two very successful runs the programme has been extended to include the neutron deficient isotopes below $^{201}$Bi to study the systematics across the $i_{13/2}$ neutron sub-shell closure at N=118.\\\\ \\\\ During the initial 2 runs (9 shifts) the isotope shifts and hyperfine structures of three new isotopes, $ ^{210,212,213}$Bi and the 9$^{-}$ isomer of $^{210}$Bi have been measured. The accuracy of the previous measurements of $^{205,206,208}$Bi have been greatly improved. The samples of $ ^{208,210,210^{m}}$Bi were prepared by c...

  20. Monte Carlo nanodosimetry of alpha particle passages through the capillary endothelial nucleus application to systemic Targeted Alpha Therapy

    Full text: The biological effects of Targeted Alpha Therapy are strongly affected by the heterogeneous specific energy delivered to tumor cells. For systemic Targeted Alpha Therapy, all blood vessels inevitably received a background radiation from non-targeted decays with the blood circulation. The Geant4 Monte Carlo code was adapted to simulate the spatial non-uniform distribution of the alpha emitting radioisotope sources 213Bi, 212Bi and 211At. A cylindrical annulus was taken as a geometrical model to approximate the capillary. The endothelial cell nucleus was set to be an ellipsoid filled with liquid water to simulate nanometric target volumes at unit density. The Geant4 Low Energy physics model, based on the Livermore approach, was selected to model the particle interactions with the material in the experimental setup. The threshold of production of secondary particles was 7 eV. We validated the program with published results using spheroid cell geometry. The specific energy deposited in a capillary endothelial cell nucleus per radioactive decay and the capillary endothelial cell survival rates were calculated for the source constrained in the capillary lumen or the source binding to the surface antigen on the perivascular cancer cells. The measurement of nanodosimetric event size spectra based on simulated nanodosimetric data is presented. The value and limitations of this approach are discussed. (author)

  1. The biokinetics of alpha-particle emitting radiopharmaceuticals

    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.)

  2. The biokinetics of alpha-particle emitting radiopharmaceuticals

    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.)

  3. Alpha-emitting radioisotopes production for radioimmunotherapy

    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.

  4. [Neuroendocrine tumors: Peptide receptors radionuclide therapy (PRRT)].

    Papamichail, Dimitris G; Exadaktylou, Paraskevi E; Chatzipavlidou, Vasiliki D

    2016-01-01

    Neuroendocrine tumors (neuroendocrine tumors-NET) are a heterogeneous group of neoplasms with a common embryological origin and diverse biological behavior, derived from cells of the neuroendocrine system, the system APUD (amine precursor uptake and decarboxylation). They are characterized by overexpression of all five somatostatin receptors (SSTR1-SSTR5), particularly type 2 (SST2). Surgical resection of the tumor is the treatment option, with a possibility of complete remission in patients with limited disease. Somatostatin analogs (octreotide and lanreotide) are the treatment of choice in patients with residual disease, particularly when it comes to NET non-pancreatic origin. Systemic chemotherapy is administered primarily to patients with poorly differentiated carcinomas. PRRT treatment is recommended in case of non-responsiveness of the disease. The ideal candidates for PRRT are patients with unresectable disease of high and intermediate differentiation. Somatostatine analogs radiolabelled with Indium-111 ((111)In), Yttrium-90 ((90)Y), Lutetium-177 ((177)Lu) and Bismuth-213 ((213)Bi), are selectively concentrated in the tumor cells, causing maximum tissue damage to tumors and with fewer effects on healthy tissue and the immune system. In the current review, it was demonstrated that patients with unresectable grade 1 or 2 disease showed increased PFS (progression free survival) and OS (overall survival), while quality of life was improved after PRRT treatment as compared to somatostatin analogs, chemotherapy and other targeted therapies. PMID:27035909

  5. Meson-Exchange Enhancement of First-Forbidden $\\beta$-Transitions in the Lead Region

    Delaure, B J P; Severijns, N

    2002-01-01

    Both on-line and off-line low temperature nuclear orientation is used to measure the $\\beta$-asymmetry parameter for the first-forbidden g.s. $\\rightarrow$~g.s. $\\beta$-transitions of $^{205}$Hg, $^{207,209}$Tl, $^{209}$Pb and $^{213}$Bi. From this, the ratio of the rank-zero and the rank-one strengths in these decays can be deduced, with the rank of a $\\beta$-transition being defined as the total angular momentum of the lepton system. Combining this result with the experimental ${ft}$-values yields for the first time a purely experimental determination of the rank-zero contribution in these $\\Delta$ J = 0 first-forbidden transitions. This provides an independent check of the large enhancement (of about 100% over the impulse approximation) of the rank-zero matrix element of $\\gamma_{5} $, caused by meson exchange currents (MEC), which was recently obtained from a comparison of calculated first-forbidden $\\beta$-decay rates with experimentally observed values for nuclei in the lead region (A = 205-212). Measur...

  6. A compact automated radionuclide separation system for nuclear medical applications

    We have constructed an instrument for the rapid chromatographic separation of clinically useful quantities of radionuclides for use in diagnostic or therapeutic nuclear medicine. The modular system consists of a laptop computer controller and driver software, an interface module, and a separation module comprising a high speed syringe pump, multiport valves, and miniature chromatographic columns. The small size (13 x 13 x 25 cm) of the separation module simplifies shielding and the remote computer controlled operation minimises radiation exposure to personnel. This instrument is well suited for use in radionuclide generators as separations can be performed rapidly (about 5 min) with decontamination factors of 106 achieved by using recent advances in resin-based separation methods. Separation columns can be selected for the purification of 90Y, 212/213Bi, or 186/188Re for radiotherapy or 99mTc, 201Tl, 18F, or 111In for diagnostic imaging. Experiments describing the separation of 212Bi from 224Ra and its daughters in nitric acid media by extraction chromatography will be discussed, as will μCi to mCi-scale separations of other therapeutic radionuclides

  7. A rapid sample changer system for studying fission shape isomers through the electron-capture-delayed fission process

    A new sample changer system has been designed to rapidly transport activity from a heavy element production target chamber at the Lawrence Berkeley National Laboratory 88-Inch Cyclotron to a fission, α-particle, X-ray, and γ-ray detection site. This changer was specifically designed to help study the nuclear structure of isotopes involved in electron-capture-delayed fission decay with half-lives greater than 30 s. The system integrates a rotating wheel and a cycling piston to transport samples from the end of a gas transport capillary line to the detection site. The overall efficiency of the sample changer system was determined by running off-line experiments to determine the activity collection site efficiency and the detector efficiencies. Under the most favorable conditions, we calculated a relative He-KCl gas transport and collection efficiency of around 70%. Efficiencies were calculated by comparing the yield of 221Fr (half-life=4.8 min) at the sample changer collection site to the activity collected directly on a piece of glass filter paper

  8. Activity determination of 229Th by means of liquid scintillation counting

    Liquid scintillation measurements of 229Th in radioactive equilibrium with its progenies were carried out. The counting efficiency was determined by means of a free parameter model. The measurements were made in a custom-built triple-to-double coincidence ratio (TDCR) system. In addition, a new portable mini-TDCR system with three channel photomultipliers and two commercial counters were tested. The decay of the short-lived 213Po requires great care, since it often occurs during the dead time of the counter systems. Also the rather short-lived 217At may decay during the dead time caused by 221Fr decay events. The overall counting efficiency of the TDCR system of PTB was found to be about 700% (depending on the degree of chemical quenching) and the relative standard uncertainty of the activity concentration was found to be about 0.23%. The determined activity concentration was compared with the outcome of alpha spectrometry under defined solid angle and excellent agreement was found. The TDCR efficiency calculations can be easily adapted to activity determinations of 225Ra or 225Ac in equilibrium with their progenies. - Highlights: • The activity of a 229Th solution was determined by means of TDCR measurements. • The relative standard uncertainty was found to be 0.23%. • A new portable mini-TDCR system was successfully tested. • Results are in good agreement with the outcome from alpha spectrometry

  9. Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy

    Huang, Chen-Yu; Oborn, Bradley M.; Guatelli, Susanna; Allen, Barry J. [Centre for Experimental Radiation Oncology, St. George Clinical School, University of New South Wales, Kogarah, New South Wales 2217 (Australia); Illawarra Cancer Care Centre, Wollongong, New South Wales 2522, Australia and Centre for Medical Radiation Physics, University of Wollongong, New South Wales 2522 (Australia); Centre for Medical Radiation Physics, University of Wollongong, New South Wales 2522 (Australia); Centre for Experimental Radiation Oncology, St. George Clinical School, University of New South Wales, Kogarah, New South Wales 2217 (Australia)

    2012-03-15

    Purpose: Metastatic melanoma lesions experienced marked regression after systemic targeted alpha therapy in a phase 1 clinical trial. This unexpected response was ascribed to tumor antivascular alpha therapy (TAVAT), in which effective tumor regression is achieved by killing endothelial cells (ECs) in tumor capillaries and, thus, depriving cancer cells of nutrition and oxygen. The purpose of this paper is to quantitatively analyze the therapeutic efficacy and safety of TAVAT by building up the testing Monte Carlo microdosimetric models. Methods: Geant4 was adapted to simulate the spatial nonuniform distribution of the alpha emitter {sup 213}Bi. The intraluminal model was designed to simulate the background dose to normal tissue capillary ECs from the nontargeted activity in the blood. The perivascular model calculates the EC dose from the activity bound to the perivascular cancer cells. The key parameters are the probability of an alpha particle traversing an EC nucleus, the energy deposition, the lineal energy transfer, and the specific energy. These results were then applied to interpret the clinical trial. Cell survival rate and therapeutic gain were determined. Results: The specific energy for an alpha particle hitting an EC nucleus in the intraluminal and perivascular models is 0.35 and 0.37 Gy, respectively. As the average probability of traversal in these models is 2.7% and 1.1%, the mean specific energy per decay drops to 1.0 cGy and 0.4 cGy, which demonstrates that the source distribution has a significant impact on the dose. Using the melanoma clinical trial activity of 25 mCi, the dose to tumor EC nucleus is found to be 3.2 Gy and to a normal capillary EC nucleus to be 1.8 cGy. These data give a maximum therapeutic gain of about 180 and validate the TAVAT concept. Conclusions: TAVAT can deliver a cytotoxic dose to tumor capillaries without being toxic to normal tissue capillaries.

  10. Targeted alpha anticancer therapies: update and future prospects

    Allen BJ

    2014-11-01

    Full Text Available Barry J Allen,1,2 Chen-Yu Huang,3 Raymond A Clarke2 1Faculty of Physics, University of Sydney, Sydney, NSW, Australia; 2Faculty of Medicine, Ingham Institute, University of Western Sydney, Liverpool, NSW, Australia; 3Central Clinical School, University of Sydney, Sydney, NSW, AustraliaAbstract: Targeted alpha therapy (TAT is an emerging option for local and systemic cancer treatment. Preclinical research and clinical trials show that alpha-emitting radionuclides can kill targeted cancer cells while sparing normal cells, thus reducing toxicity. 223RaCl2 (Xofigo® is the first alpha emitting radioisotope to gain registration in the US for palliative therapy of prostate cancer bone metastases by indirect physiological targeting. The alpha emitting radioisotopes 211At, 213Bi, 225Ac and 227Th are being used to label targeting vectors such as monoclonal antibodies for specific cancer therapy indications. In this review, safety and tolerance aspects are considered with respect to microdosimetry, specific energy, Monte Carlo model calculations, biodosimetry, equivalent dose and mutagenesis. The clinical efficacy of TAT for solid tumors may also be enhanced by its capacity for tumor anti-vascular (TAVAT effects. This review emphasizes key aspects of TAT research with respect to the PAI2-uPAR complex and the monoclonal antibodies bevacizumab, C595 and J591. Clinical trial outcomes are reviewed for neuroendocrine tumors, leukemia, glioma, melanoma, non-Hodgkins lymphoma, and prostate bone metastases. Recommendations and future directions are proposed.Keywords: biodosimetry, microdosimetry, mutagenesis, PAI2, bevacizumab, C595, J591, tumors, cancer, metastases

  11. Preclinical testing of radiopharmaceuticals for novel applications in HIV, bacterial and fungal infectious diseases

    Antibiotics, antifungal and antiviral medications have traditionally been used in the management of infections. Due to widespread emergence of resistance to antimicrobial medications, and their side effects, there is a growing need for alternative approaches for management of such conditions. Antibiotic resistant bacterial pathogens are on the rise. A cure has not been achieved for viral infections like AIDS, while fungal and parasitic infections are constant threats to the health of general public. The incidence of opportunistic infections in immunocompromised individuals like HIV patients, patients receiving high dose steroids, chemotherapy patients, and organ transplant recipients is on the rise. Radioimmunotherapy (RIT) has the potential to be a suitable and viable therapeutic modality in the arena of infection management. Provided the target-associated antigen is expressed by the target cells and minimally or not expressed by other tissues, selective targeting of radiation to target sites can be theoretically accomplished with relative sparing normal tissues from radiation exposure. In our laboratory we successfully demonstrated the effectiveness of RIT for treating infectious diseases. We targeted murine cryptococcosis with a mAb to the Cryptococcus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 (213Bi) or Rhenium-188 (188Re). We subsequently extended the applicability of RIT for treating bacterial and viral infections. One of the advantages of using RIT to treat infections as opposed to cancer is that, in contrast to tumor cells, cells expressing microbial antigens are antigenically very different from host tissues and thus provide the potential for exquisite specificity and low cross-reactivity. Ever increasing incidence of infectious pathologies, exhaustion of antimicrobial possibilities and rising drug resistance calls for use of alternative and novel therapeutic options and we believe RIT is the need of the hour to combat these

  12. Effects of radiation type and delivery mode on a radioresistant eukaryote Cryptococcus neoformans

    Introduction: Most research on radioresistant fungi, particularly on human pathogens such as Cryptococcus neoformans, involves sparsely-ionizing radiation. Consequently, fungal responses to densely-ionizing radiation, which can be harnessed to treat life-threatening fungal infections, remain incompletely understood. Methods: We addressed this issue by quantifying and comparing the effects of densely-ionizing α-particles (delivered either by external beam or by 213Bi-labeled monoclonal antibodies), and sparsely-ionizing 137Cs γ-rays, on Cryptococus neoformans. Results: The best-fit linear-quadratic parameters for clonogenic survival were the following: α = 0.24 × 10−2 Gy−1 for γ-rays and 1.07 × 10−2 Gy−1 for external-beam α-particles, and β = 1.44 × 10−5 Gy−2 for both radiation types. Fungal cell killing by radiolabeled antibodies was consistent with predictions based on the α-particle dose to the cell nucleus and the linear-quadratic parameters for external-beam α-particles. The estimated RBE (for α-particles vs. γ-rays) at low doses was 4.47 for the initial portion of the α-particle track, and 7.66 for the Bragg peak. Non-radiological antibody effects accounted for up to 23% of cell death. Conclusions: These results quantify the degree of C. neoformans resistance to densely-ionizing radiations, and show how this resistance can be overcome with fungus-specific radiolabeled antibodies

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

    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.

  14. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes (211At, 213Bi, 223Ra and 225Ac) and 6 beta emitters (32P, 33P, 67Cu, 90Y, 131I and 177Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development

  15. 232Th(d,4n)230Pa cross-section measurements at ARRONAX facility for the production of 230U

    Introduction: 226Th (T1/2 = 31 min) is a promising therapeutic radionuclide since results, published in 2009, showed that it induces leukemia cells death and activates apoptosis pathways with higher efficiencies than 213Bi. 226Th can be obtained via the 230U α decay. This study focuses on the 230U production using the 232Th(d,4n)230Pa(β−)230U reaction. Methods: Experimental cross sections for deuteron-induced reactions on 232Th were measured from 30 down to 19 MeV using the stacked-foil technique with beams provided by the ARRONAX cyclotron. After irradiation, all foils (targets as well as monitors) were measured using a high-purity germanium detector. Results: Our new 230Pa cross-section values, as well as those of 232Pa and 233Pa contaminants created during the irradiation, were compared with previous measurements and with results given by the TALYS code. Experimentally, same trends were observed with slight differences in orders of magnitude mainly due to the nuclear data change. Improvements are ongoing about the TALYS code to better reproduce the data for deuteron-induced reactions on 232Th. Conclusions: Using our cross-section data points from the 232Th(d,4n)230Pa reaction, we have calculated the thick-target yield of 230U, in Bq/μA·h. This value allows now to a full comparison between the different production routes, showing that the proton routes must be preferred

  16. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    Huang, C.Y. [University of Sydney, Camperdown, NSW (Australia); Guatelli, S [University of Wollongong, Wollongong, NSW (Australia); Oborn, B [Illawarra Cancer Care Centre, Wollongong, NSW (Australia); Allen, B [University of Western Sydney, Liverpool, NSW (Australia)

    2014-06-01

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes ({sup 211}At, {sup 213}Bi, {sup 223}Ra and {sup 225}Ac) and 6 beta emitters ({sup 32}P, {sup 33}P, {sup 67}Cu, {sup 90}Y, {sup 131}I and {sup 177}Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.

  17. Clinical review on RIT

    Full text of publication follows. Radioimmunotherapy (RIT) has been in use for more than 20 years and has progressed significantly with the discovery of new molecular targets, the development of new stable chelates, the humanization of monoclonal antibodies (MAbs), and the use of pre-targeting techniques. Today, 2 products targeting the CD20 antigen are approved in the treatment of B lymphoma: 131-tositumomab (Bexxar) and 90Y-ibritumomab tiuxetan (Zevalin). RIT can be applied in clinical practice for patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy in front-line treatment in FL patients. Hematological toxicity is the major side effect of RIT and depends on bone marrow involvement and prior treatment. High-dose treatment, RIT as consolidation, RIT in first-line treatment, fractionated RIT and use of new humanized MAbs, in particular targeting CD22, showed promising results in B lymphoma. Targeting of antigens other than CD20 appears particularly interesting in the context of consolidation therapy after rituximab-based therapy. In other hemopathies, such as multiple myeloma (MM), RIT efficacy has been suggested in preclinical studies. Syndecan-1 is expressed in all MM and preclinical studies showed promising results using 213Bi-labeled anti-CD138. In solid tumors, more resistant to radiations and less accessible to large molecules such as MAbs, clinical efficacy remains limited. However, RIT used in minimal or small-size metastatic disease has shown promising clinical efficacy. Pre-targeting approaches have shown potential in increasing the therapeutic index of radiolabeled antibodies. Recently, a phase II clinical trial showed efficacy of anti-CEA pre targeted 131I-RIT in 42 progressive medullary thyroid carcinoma patients. Disease control according RECIST criteria (objective response + stabilization) was observed in 32 patients (76.2%), including one durable CR of at least 40 months and 31 durable

  18. Production of Endohedral Fullerenes by Ion Implantation

    Diener, M.D.; Alford, J. M.; Mirzadeh, S.

    2007-05-31

    The empty interior cavity of fullerenes has long been touted for containment of radionuclides during in vivo transport, during radioimmunotherapy (RIT) and radioimaging for example. As the chemistry required to open a hole in fullerene is complex and exceedingly unlikely to occur in vivo, and conformational stability of the fullerene cage is absolute, atoms trapped within fullerenes can only be released during extremely energetic events. Encapsulating radionuclides in fullerenes could therefore potentially eliminate undesired toxicity resulting from leakage and catabolism of radionuclides administered with other techniques. At the start of this project however, methods for production of transition metal and p-electron metal endohedral fullerenes were completely unknown, and only one method for production of endohedral radiofullerenes was known. They therefore investigated three different methods for the production of therapeutically useful endohedral metallofullerenes: (1) implantation of ions using the high intensity ion beam at the Oak Ridge National Laboratory (ORNL) Surface Modification and Characterization Research Center (SMAC) and fullerenes as the target; (2) implantation of ions using the recoil energy following alpha decay; and (3) implantation of ions using the recoil energy following neutron capture, using ORNL's High Flux Isotope Reactor (HFIR) as a thermal neutron source. While they were unable to obtain evidence of successful implantation using the ion beam at SMAC, recoil following alpha decay and neutron capture were both found to be economically viable methods for the production of therapeutically useful radiofullerenes. In this report, the procedures for preparing fullerenes containing the isotopes {sup 212}Pb, {sup 212}Bi, {sup 213}Bi, and {sup 177}Lu are described. None of these endohedral fullerenes had ever previously been prepared, and all of these radioisotopes are actively under investigation for RIT. Additionally, the chemistry for

  19. Radionuclide therapy in Russia: Experience, problems, and perspectives

    effective, accessible and safe in future. At present the main work is to create tungsten-rhenium stationary generator of high activity, which can be used in large medical centers or other institutions to prepare and transport radiopharmaceuticals to radiological clinics. Russia has big stores of alpha-radioactive isotopes and the technology of isolating thorium-229 from uranium-233 is being worked out. The construction of 229Th/225Ac industrial generator and 225Ac/213Bi medical generator is under process. Biological and clinical trials of radiopharmaceuticals labeled with alpha-radioactive radionuclides are planned. Subsequent development in nuclear medicine in Russia is not only the research and introduction of new effective radiopharmaceuticals in clinical practice but also to improve the radio diagnostic equipment used in medical institutions and participation in international clinical/research trials. (author)

  20. Hurdles for a Broader Use of 211At and for the Synthesis of 211At-Labelled Radiopharmaceuticals at High Activities for Clinical Use

    One of the key impediments to the use of 211At is the very well known deleterious effect of high radiation fields caused by its alpha particles on the synthesis of 211At-labelled radiopharmaceuticals. This is problematic because radiolysis-mediated effects can produce diminishing efficiency of electrophilic astatination reactions due to increasing deposition of radiation dose with increasing activities and with the passage of the time. Astatine-211 has chemical properties that permit complex labelling strategies and a longer half-life than 213Bi that makes it more suitable when the targeting molecule does not gain immediate access to the tumour cells. The first clinical evaluation was published in 2001 [2] in patients with brain tumour. Although this study circumvents many of the challenges to entering clinical studies with 211At and many obstacles had to be surmounted before clinical studies could be initiated, several problems were encountered in maintaining efficient labelling with escalating radiation dose of α-particle even with fresh 211At elution [3]. Astatine-211 also has an additional hurdle to overcome before to its clinical application in labelled radiopharmaceuticals related with its production and distribution. Among the potential group of promising α- emitter it is the only one produced by cyclotrons, but due to the scarcity of cyclotrons equipped with 25−30 MeV α-particle beams, it will of necessity be utilized in distant locations from the site of production. It presents a major chemical challenge because the diminishing efficiency of electrophilic astatination reactions with the passage of the time is well known, a problem likely related to the radiolysis produced by the high LET (linear energy transfer) meaning that large amounts of energy are deposited in a highly localized manner. This problem has been most comprehensively investigated to understand and evaluate the role of the radiolysis effects of astatine alpha particles in the synthesis

  1. Developments in theranostic agents - some highlights of COST TD1004

    Full text of publication follows. The COST Action TD1004 Theragnostics Imaging and Therapy: an Action to Develop Novel Nano-sized Systems for Imaging-Guided Drug Delivery started in October 2011 within the Chemistry and Molecular Sciences and Technologies domain committee. The main objective of the Action is to increase the knowledge of imaging-guided drug delivery procedures and to apply this knowledge to the development of theranostic agents through an interdisciplinary approach that involves chemists, biologists, imaging and pharmaceutical technologists. This Action consists of five complementary Working Groups: (WG1) Imaging reporters for theranostic agents, (WG2) Nano-carriers for theranostic agents, (WG3) Preparation and selection of targeting vectors, (WG4) Theranostic agents responsive to endogenous and external stimuli, (WG5) Set-up of preclinical theranostic protocols. Investigations devoted to the design, synthesis, physico-chemical characterization and testing of imaging reporters tailored for theranostic applications are carried out. Interesting results have been obtained for the different imaging modalities addressing sensitivity (MRI), efficient tracers' labelling (PET, SPECT, radiotherapy), multiplex detection (Optical Imaging). Some results appear particularly worth to be noted: novel chelator system for Sc radionuclides and for MRI, macrocyclic ligands containing bis(phosphonate) side arm(s) yielding excellent systems for the coordination of Ga-68, applications of this and other PET isotopes (e.g. 64Cu, 95Nb) for 'theranostic' applications (with 90Y, 177Lu or 223,225Ra, 225Ac, 212Pb, 213Bi) using peptides, affibodies, antibodies as well as various nano-carriers. In the MRI field, where the sensitivity is the key-issue, it has been shown that innovative systems, based on Gd, may allow the in vivo visualization of cellular targeting and may serve as multimodal probes. The results from the research activities carried out in the COST

  2. Targeted alpha therapy for cancer

    Allen, Barry J.; Raja, Chand; Rizvi, Syed; Li, Yong; Tsui, Wendy; Zhang, David; Song, Emma; Qu, Chang Fa; Kearsley, John; Graham, Peter; Thompson, John

    2004-08-01

    Targeted alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukaemia, colorectal, breast and prostate cancers, and by a phase 1 trial of intralesional TAT for melanoma. The alpha-emitting radioisotope used is Bi-213, which is eluted from the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (e.g. plasminogen activator inhibitor-2 PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukaemia (WM60), colorectal (C30.6), breast (PAI2, herceptin), ovarian (PAI2, herceptin, C595), prostate (PAI2, J591) and pancreatic (PAI2, C595) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. The 213Bi-9.2.27 AC is injected into secondary skin melanomas in stage 4 patients in a dose escalation study to determine the effective tolerance dose, and to measure kinematics to obtain the equivalent dose to organs. In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than non-specific ACs, specific beta emitting conjugates or free isotopes. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress advanced sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Intralesional doses up to 450 µCi in human

  3. Targeted Alpha Therapy Approach to the Management of Pancreatic Cancer

    Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope 213Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC). Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (∼100 μm diameter), causing apoptosis in some 70–90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of micro

  4. Nuclear medicine - the condition and prospects

    admissibly small volumes owing to what many patients with diseases of a thyroid gland are unreasonably exposed to surgical treatment. It is necessary to note that now also new technologies in radiotherapy with use marked an alpha and beta irradiation actively take root. As an example it is possible to result use an alpha - radiating radionuclides, such as 213Bi, 90Y, 186Re and of some others which in a combination to antibodies or marked peptides allow to receive more high levels of an irradiation on some orders above in the field of localization of malignant tumors, than in bodies round the organism. Much to our regret, these medical preparations practically in the country also are not used. Global practice shows what the therapeutic effect is achieved at the minimal influence of an irradiation on healthy bodies. Necessity of outstripping development of diagnostic methods, including development of the new technologies based on use high-sensitivity detectors of the equipment which considerably will allow to increase resolution of radiodiagnostic techniques are quite clear, that in turn will enable to apply insignificant shares of activity or in stable isotopes to wider using the of diagnostic procedures. A little bit better a situation with diagnostic RP for research of internal bodies, at that that the material base of many branches radionuclides diagnostics leaves to wish the best owing to what many divisions may not carry out highly technological researches

  5. Environmental Assessment for the U-233 Disposition, Medical Isotope Production, and Building 3019 Complex Shutdown at the Oak Ridge National Laboratory

    The purpose of the proposed action evaluated in this environmental assessment (EA) is the processing of uranium-233 (233U) stored at the Oak Ridge National Laboratory (ORNL) and other small quantities of similar material currently stored at other U. S. Department of Energy (DOE) sites in order to render it suitable for safe, long-term, economical storage. The 233U is stored within Bldg. 3019A, which is part of the Bldg. 3019 Complex. The location of the Bldg. 3019 Complex is shown on Fig. 1.1. Additionally, the proposed action would increase the availability of medical isotopes needed for research and treatment and place the Bldg. 3019 Complex in safe and stable shutdown for transfer to the DOE program for decontamination and decommissioning (D and D). DOE has determined that there is no programmatic use for the 233U currently in storage at ORNL other than as a possible source of medical isotopes. Since 233U is a special nuclear material, continued long-term storage of the ORNL inventory in its current configuration represents a significant financial liability for DOE. Continued long-term storage in Bldg. 3019A would require major capital upgrades and retrofits to critical facility systems that have deteriorated due to aging or that may not meet current standards. Storing the material in its current form requires significant annual operating expenses to meet the material-handling requirements and to provide protection against nuclear criticality accidents or theft of the material. The ORNL inventory of 233U represents most of the readily available source of thorium-229 (229Th) in the Western Hemisphere. Actinum-225 (225Ac) and its daughter product, bismuth-213 (213Bi), are isotopes in the decay chain of 233U/229Th that are showing significant promise for ongoing cancer research, including clinical trials for treatment of acute myelogenous leukemia. These isotopes are also being explored for treatment of other cancers of the lungs, pancreas, and kidneys. Figure 1

  6. Production and radiochemical separation of 203Pb radioisotope for nuclear medicine

    Complete text of publication follows. The heavy metal pollution due to their industrial production, waste repository or accident as the cyanide spill in river Tisza in 2002, increase the scientific interest for using an ideal trace isotope for monitoring these type of events. The lead is one of the most toxic and commonly used heavy metal, its poisoning is often deadly because very difficult to recognize and identify. The neuro-scientific study of biodegradation effect of lead could be an impressive scientific field of application of 203Pb radioisotope. However the targeted radionuclide therapy especially the α-emitting radioisotope therapy is also strongly interested to find an ideal tracer for the 213Bi and 212Pb therapy. Therefore the 203Pb is a potential radioisotope for this role due to its radiation behaviour and as heavy metal element. The 203Tl(p,n) 203Pb nuclear reaction was chosen for the production. The irradiation was done at the compact cyclotron of Atomki with proton beam 14.5 MeV energy and beam current of 7 μAs. The thickness of the target material was 840 μm, the irradiation time was 3 hours and the produced activity was 40 MBq at EOB. It corresponds to 1.87 MBq/μAh physical yield of the reaction which correlating with the cross section curve. A new technique was developed for target preparation. The metal Tl was pressed into a copper backing and covered with a HAWAR foil with thickness of 11 μm. The covering foil saved the surface of the Tl from the oxidation and also transferred the dissipating heat to the cooling He gas. The back side of the target was cooled with pressured cold water. The irradiated Tl target was pressed out from the copper backing, which had only the thickness of 0.2 mm. Then the Thallium was dissolved in nitric acid. The excess acid was evaporated slowly. The nitrate form was transferred to chloride form by 8 mol/dm 3 HCl and the Thallium was kept in 3+ oxidation stage by hydrogen peroxide. The separation was carried out

  7. Comparative analysis of CD138 antigen targeting for the treatment of multiple myeloma with bismuth-213 and Melphalan chemotherapy

    Full text of publication follows. Aim: multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow, with the presence of a monoclonal immunoglobulin in serum and/or urine and development of osteolytic bone lesions in human. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a multiple myeloma model and seems particularly suited for disseminated tumour cells or small clusters of tumour cells. CD138 (Syndecan-1) is found mainly in epithelial cells, but has been shown to be expressed by most myeloma cells, both in human and in mouse. In order to define where alpha RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha RIT using a bismuth-213-labelled anti-mouse CD138 rat antibody in a syngeneic mouse MM model. Material and Methods: C57BL/KaLwRij mice were grafted with 106 5T33 cells (murine myeloma cells). Luciferase transfected 5T33 were used for in vivo localization of the cells during the course of disease. The first step of the study was to assess the dose-response of Melphalan (100, 200 et 300 μg/mouse), 21 days after engraftment. The second step consisted in therapeutic association: Melphalan followed by RIT at d22 et d25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone (200 μg), RIT alone at d22 and d25 (3.7 MBq of 213Bi-anti-CD138) and Melphalan combined with alpha RIT. Results: fifty percent of untreated mice died by d64 after MM engraftment. In mice treated with Melphalan alone, only the 200 μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at d22 after tumour engraftment. However, the therapeutic window seems to be narrow, indeed no effect was observed with

  8. Redefining the relative biological effectiveness (RBE) in the context of the EQDX formalism

    Full text of publication follows. Objective: the relative biological effectiveness (RBE) of high-LET radiation (alpha-particles, e.g.) is defined as the ratio of the absorbed dose of a reference radiation (usually external beam) to a test radiation absorbed dose for a same biological endpoint, often a surviving fraction of cells. However, as it is currently defined, the RBE is dependent on the dosimetric end point as well as the dose values and is therefore limited in its utility, as a range of experimental values are often reported and it is unclear which value should be used in which context. We propose adoption of a quantity, called the RBE2, which relates the high-LET absorbed dose to 2-Gy fraction megavoltage external beam equivalents. Method: recently, the ICRU has promulgated the use of the equi-effective dose EQDX for bio-effect modeling of radiation responses. EQDX is defined as the total absorbed dose delivered by the external beam reference treatment plan of fraction size X that leads to the same biological effect as a test treatment plan. It was proposed that 2-Gy fractions of megavoltage X-rays should be the reference. Therefore, within this context relating the high-LET absorbed dose, not to a single fraction of external beam or β-emitter radiation, but to 2-Gy fraction external beam equivalent is a logical step, and more readily understood. We propose to call this new ratio RBE2, in keeping with the EQDX naming convention. Furthermore, for high-LET radiations typically used in nuclear medicine, α-particles and Auger electrons, the RBE2 value is dose-independent. The theoretical framework for the proposed new formalism is presented as is the application to two tumor cell lines. Results: the radiobiological parameters are obtained by fitting the curves to dose-response data from α-particle (213Bi) and β-particle (137Cs) radiation to two cell lines: a murine breast cancer cell line, NT2.5 and a human breast cancer cell line, MDA-MB-231. From these

  9. Track 8: health and radiological applications. Isotopes and radiation: general. 3. Extraction of 229Th from 233U for Medical Research Applications

    The use of 213Bi as an alpha emitter is being explored by the medical research community for treatment of a variety of cancers. An example is the protocol for the treatment of acute myeloid leukemia developed by Memorial Sloan-Kettering Cancer Center. The humanized antibody HuM195 is used to target a surface protein on the cancer cell. Bismuth is linked to the antibody with a chelating agent. Because of the high linear energy transfer and short range of the emitted alpha particle, there is a high probability of killing the targeted cell without exposing other parts of the body to a large dose of radiation. Bismuth-213 is extracted as the decay product of 225Ac, which in turn is extracted as a decay product of 229Th. A limited supply of 229Th, itself a product of the decay of 233U, has been separated by Oak Ridge National Laboratory (ORNL). About 95 mCi was separated from waste materials remaining from the processing of 233U in the 1970's. An additional 15 mCi was separated directly from 233U in 1998. In June 2000, the secretary of energy announced a program to separate additional thorium to support Phase II human trials at Sloan-Kettering and growing research programs at other institutions. This paper describes a project that will extract an additional 70 mCi of 229Th from a 3.3-kg batch of 233U sent to ORNL by Mound Laboratories in 1996. This project requires a process and location that would support the sustained extraction of thorium from 233U. The flow-sheet used for the initial processing of uranium was adopted, with several modifications. The 233U is currently stored in the ORNL Radiochemical Development Facility (RDF). The adjacent Radioactive Materials Analytical Laboratory (RMAL) was selected as the processing site because of the availability of both trained radiochemical staff and the type of hot cells suitable for processing uranium with increasingly high levels of 232U. Decay products from this isotope, especially 208Tl, add to the dose associated with

  10. Software for the on-off-line A-A-T coincidence experiment with use of semiconductor detector of nuclear radiation

    or 8192 channels (off-5). Program of the accumulation spectra coincidences of the type A-A-T in mode (in list mode), i.e. formation of 3-dimensional matrixes of the coincidences. (conexe, co-on-wd, on-separ, online3, on-co-pi, recoilt, coin-buf, coin-tim, off-stab) . Program for the diagnostics of the equipment. Program of the long-term storage of single spectra with ensuring the stabilizations on the reference peaks in spectra (07-11-tm, 07-11-bf, 11-07-tm, 11-07-bf) . Program for the sorting of the coincidence spectra (p132sort, p231sort, s123sort, sum-a-g, sum-g-a, sum-g-g). Tools software (kl19-n16, 8k-to-4k, bin-dat, sum-4k, sum-8k, sub-4k, sub-8k, compr-4k, compr-8k, multi-4k, multi-8k). Program of the preliminary and final visualization of the measured results (pict-vec, surfsort, pol-3, z-pol-c). Program of the transformations of the accumulated information in type suitable for the following analysis and quantitative processing. The descriptions of the programs, block diagrams, necessary explanations upon their using are presented. In application, in view of significant volume, listings of some programs are given only. The equipment, program of management and control of experiment are used for study of the structure of the exited states of nuclei at decay of 213Bi, 209Tl [4], 221Rn [5]. The methods to determination of the absolute activity of the radioactive sources, absolute efficiency of detectors of γ-radiations and intensities weak cross-over γ-transitions [6]. (author)