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Sample records for 177lu 51cr 153sm

  1. Determination of human absorbed dose of cocktail of 153Sm/177Lu-EDTMP, based on biodistribution data in rats

    The aim of this work was to estimate the absorbed dose due to compositional radiopharmaceutical of 153Sm/177Lu-EDTMP in human organs based on biodistribution data of rats by using OLINDA/EXM software. The absorbed dose was determined by the Radiation Dose Assessment Resource (RADAR) formulation after calculating cumulated activities in each organ. The results show that the organs that received the highest absorbed dose were the bone surface and red marrow (1.51 and 7.99 mGy/ MBq for 153Sm, and 1.98 and 10.76 mGy/MBq for 177Lu, respectively). According to the results, using of cocktail of 153Sm/177Lu-EDTMP has considerable characteristics as compared to 153Sm-EDTMP and 177Lu-EDTMP alone. (author)

  2. Organ doses from hepatic radioembolization with 90Y, 153Sm, 166Ho and 177Lu: A Monte Carlo simulation study using Geant4

    Hashikin, N. A. A.; Yeong, C. H.; Guatelli, S.; Abdullah, B. J. J.; Ng, K. H.; Malaroda, A.; Rosenfeld, A. B.; Perkins, A. C.

    2016-03-01

    90Y-radioembolization is a palliative treatment for liver cancer. 90Y decays via beta emission, making imaging difficult due to absence of gamma radiation. Since post-procedure imaging is crucial, several theranostic radionuclides have been explored as alternatives. However, exposures to gamma radiation throughout the treatment caused concern for the organs near the liver. Geant4 Monte Carlo simulation using MIRD Pamphlet 5 reference phantom was carried out. A spherical tumour with 4.3cm radius was modelled within the liver. 1.82GBq of 90Y sources were isotropically distributed within the tumour, with no extrahepatic shunting. The simulation was repeated with 153Sm, 166Ho and 177Lu. The estimated tumour doses for all radionuclides were 262.9Gy. Tumour dose equivalent to 1.82GBq 90Y can be achieved with 8.32, 5.83, and 4.44GBq for 153Sm, 166Ho and 177Lu, respectively. Normal liver doses by the other radionuclides were lower than 90Y, hence beneficial for normal tissue sparing. The organ doses from 153Sm and 177Lu were relatively higher due to higher gamma energy, but were still well below 1Gy. 166Ho, 177Lu and 153Sm offer useful gamma emission for post-procedure imaging. They show potential as 90Y substitutes, delivering comparable tumour doses, lower normal liver doses and other organs doses far below the tolerance limit.

  3. A comparative study of preliminary dosimetry for human based on distribution data in rats with 111In, 90Y, 153Sm, and 177Lu labeled rituximab

    Radfar Edalat

    2012-01-01

    Full Text Available Radio immunotherapy is one of the most important and effective therapies for B-cell non Hoddgkin’s lymphoma treatment. Today, anti CD-20 antibodies labeled with beta emitter radionuclides are used in radio immunotherapy. Various radionuclides for labeling anti CD-20 antibodies have been studied and developed for the treatment and diagnosis of malignancies. This paper describes the preparation, bio-distribution and absorbed dose rate of 111In, 90Y, 177Lu, and 153Sm labeled anti CD-20 antibodies (rituximab in human organs, after injection to rats. The macro cyclic bifunctional chelating agent, N-succinimidyl-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA-NHS for conjugation to antibody, was used to prepare DOTA-rituximab. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. Radio-labeling was performed at 40 °C for 24 hours. After the quality control studies, the final radioactive solution was injected intravenously into rats through their tail vein. The tissue uptakes of each injection were measured. Then we calculated S values for 177Lu and 153Sm by using specific absorbed fractions and data used in the manner of radio-labeled analysis and dosimetry for humans. The absorbed dose rate of each organ was calculated in the specific time by medical internal radiation dose method with linear approximation in the activity measurements.

  4. Dosimetric evaluation of 153Sm-EDTMP, 177Lu-EDTMP and 166Ho-EDTMP for systemic radiation therapy: Influence of type and energy of radiation and half-life of radionuclides

    In radiopharmaceutical therapy, delivered doses to critical organs must be below a certain threshold therefore internal radiation dosimetry of radiopharmaceuticals is essential. Advantages and disadvantages of radionuclides with different characteristics were evaluated for selection of appropriate radionuclide. The Monte Carlo MCNPX simulation program was used to obtain radial dose and cumulative dose of 153Sm, 177Lu and 166Ho used in radiotherapy of bone metastases. A cylindrical geometry with constant density materials was supposed for simulation of femur bone. The radius of bone marrow, bone, and surrounding soft tissue was considered 0.6 cm, 1.3 cm and 4 cm, respectively. It was assumed that the radionuclides were uniformly distributed throughout the tumor. “continuous energy spectrum” of beta particle was used instead of mean beta energy. Our simulations show that absorbed dose in target organ (bone) is greater than other organs and 166Ho gives a higher dose to the critical organ of bone marrow than either 153Sm or 177Lu. Absorbed dose versus time demonstrate faster dose delivery for the short half-life radionuclides (153Sm and 166Ho). These results are in good agreement with clinical observations which show a pain relief within 1 week after intravenous administration of 153Sm-EDTMP, whereas it occurs within 2 week in the case of 177Lu-EDTMP. According to the results, combination of different radionuclides with different characteristics such as 153Sm-EDTMP and 177Lu-EDTMP could be more advantageous to patients with painful bone metastasis. - Highlights: • The radial dose and cumulative dose of 153Sm, 177Lu and 166Ho are calculated. • The effect of half-life of the radionuclide on the suitable activity for injection is studied. • Dose delivery is fast for the short half-life radionuclides (153Sm and 166Ho). • The results are in good accordance with clinical observations. • The combination of different radionuclides with different characteristics

  5. Formulation and evaluation of freeze-dried DOTMP kit for the preparation of clinical-scale {sup 177}Lu-DOTMP and {sup 153}Sm-DOTMP at the hospital radiopharmacy

    Das, Tapas; Banerjee, Sharmila [Bhabha Atomic Research Centre, Radiopharmaceuticals Chemistry Section, Mumbai (India); Chakraborty, Sudipta [Bhabha Atomic Research Centre, Isotope Production and Applications Div., Mumbai (India); Sarma, Haladhar D. [Bhabha Atomic Research Centre, Radiation Biology and Health Sciences Div., Mumbai (India)

    2015-07-01

    The objective of the present work is to develop and evaluate freeze-dried DOTMP kit, which could be utilized for the convenient and single-step preparation of clinical-scale {sup 177}Lu-DOTMP and {sup 153}Sm-DOTMP, both of which have shown potential as alternative agents for metastatic bone pain palliation. Freeze-dried DOTMP kits, each comprising a lyophilized mixture of 20 mg DOTMP and 8.75 mg NaOH, were prepared. The kits were used for the preparation of clinical-scale {sup 177}Lu-DOTMP and {sup 153}Sm-DOTMP complexes. The agents were prepared by dissolving the lyophilized powder in 1 mL of normal saline and incubating with {sup 177}LuCl{sub 3} or {sup 153}SmCl{sub 3}, produced in-house, for 15 min at room temperature. Pharmacokinetic behavior and biological distribution of the agents were studied by carrying out biodistribution as well as scintigraphic studies in normal male Wistar rats. Shelf-life of the freeze-dried kits was also ascertained. Clinical-scale {sup 177}Lu-DOTMP and {sup 153}Sm-DOTMP complexes, comprising up to 3.7 GBq (100 mCi) of activity, were prepared with > 99% radiochemical purity using the freeze-dried kits. The complexes exhibited high in vitro stability when stored at room temperature. Biological studies showed selective skeletal accumulation and insignificant uptake of the radiotracers in any of the vital organs/tissue. The non-accumulated activity exhibited primary urinary clearance. The kits had a shelf-life of 2 years when stored at 4 C temperature. Freeze-dried DOTMP kits, suitable for the preparation of clinical-scale {sup 177}Lu-DOTMP and {sup 153}Sm-DOTMP, have been developed and the radiochemical and biological behaviors of the radiolabeled agents have been studied. The use of the kit at the hospital radiopharmacy is expected to make the preparations easy and convenient. This in turn will enable the widespread dissemination of these promising agents towards their application for regular use.

  6. Formulation and evaluation of freeze-dried DOTMP kit for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP at the hospital radiopharmacy

    The objective of the present work is to develop and evaluate freeze-dried DOTMP kit, which could be utilized for the convenient and single-step preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP, both of which have shown potential as alternative agents for metastatic bone pain palliation. Freeze-dried DOTMP kits, each comprising a lyophilized mixture of 20 mg DOTMP and 8.75 mg NaOH, were prepared. The kits were used for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP complexes. The agents were prepared by dissolving the lyophilized powder in 1 mL of normal saline and incubating with 177LuCl3 or 153SmCl3, produced in-house, for 15 min at room temperature. Pharmacokinetic behavior and biological distribution of the agents were studied by carrying out biodistribution as well as scintigraphic studies in normal male Wistar rats. Shelf-life of the freeze-dried kits was also ascertained. Clinical-scale 177Lu-DOTMP and 153Sm-DOTMP complexes, comprising up to 3.7 GBq (100 mCi) of activity, were prepared with > 99% radiochemical purity using the freeze-dried kits. The complexes exhibited high in vitro stability when stored at room temperature. Biological studies showed selective skeletal accumulation and insignificant uptake of the radiotracers in any of the vital organs/tissue. The non-accumulated activity exhibited primary urinary clearance. The kits had a shelf-life of 2 years when stored at 4 C temperature. Freeze-dried DOTMP kits, suitable for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP, have been developed and the radiochemical and biological behaviors of the radiolabeled agents have been studied. The use of the kit at the hospital radiopharmacy is expected to make the preparations easy and convenient. This in turn will enable the widespread dissemination of these promising agents towards their application for regular use.

  7. Optimization of the preparation and quality control of 177Lu based therapeutic radiopharmaceuticals: Facilities available at PINSTECH

    Isotope Production Division (IPD) at Pakistan Institute of Nuclear Science and Technology (PINSTECH) has established centralized facilities for bulk production of radiopharmaceuticals to be supplied to various nuclear medical centers of the country. Here different groups have been established to look after the production of 99mTc generators, production of sodium iodide (131I) solution and other reactor produced radionuclides; radiopharmaceuticals freeze dried in-vivo diagnostic kits, quality control of radiopharmaceuticals and their dispatch. For this purpose different laboratories including two clean laboratories; one for bulk production of freeze dried in-vivo diagnostic kits and other for 99mTc generators were provided by the IAEA under technical cooperation, have been constructed. Organic laboratory has also been created for synthesis of MAG-3, MIBI, DISIDA, HMPAO, ECD etc. Excellent quality control laboratories have also been established for checking every batch in terms of radionuclidic purity, radiochemical purity, sterility, pyrogenicity and biodistribution in animals. Research activities under IAEA coordinated research programmes related to preparation of therapeutic β-particle emitting radionuclides like 177Lu, 166Ho, 153Sm, 186,188Re etc in PARR-I research reactor and their radiopharmaceuticals formulations with HEDP, EDTMP, FHMA, DOTATATE were also carried out. Studies on the optimization of the production of 177Lu radionuclide by irradiating natural/enriched lutetium targets as solid or liquid in PARR-I reactor for different time intervals were carried out. The irradiation data indicate that specific activity of liquids targets (5.5 Ci/mg) is higher than solid targets (4.6 Ci/mg). Studies on the optimization of 177Lu-EDTMP and 177Lu-DOTA-Tyr3-Octreotate complexes were investigated w.r.t. pH, temperature and incubation period to get a complex of high yield (>99%). Radiochemical purity of 177Lu-DOTA-Tyr3-Octreotate was determined by radio TLC technique

  8. Complexes of low energy beta emitters {sup 47}Sc and {sup 177}Lu with zoledronic acid for bone pain therapy

    Majkowska, Agnieszka [Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw (Poland)], E-mail: a.majkowska@ichtj.waw.pl; Neves, Maria; Antunes, Ines [Instituto Tecnologico e Nuclear, Estrada Nacional 10, 2686-953 Sacavem (Portugal); Bilewicz, Aleksander [Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw (Poland)

    2009-01-15

    Targeted radiopharmaceuticals have been mostly developed to visualize and/or treat oncologic diseases. In targeted radiotherapy radionuclide selection is a key issue, because the radionuclide should provide the appropriate radiation absorbed dose, matching the desirable biologic effect, but at the same time it should preclude irradiation of surrounding healthy tissues. Among the last generation of bisphosphonates with cyclic side chains, zoledronic acid is the most potent bisphosphonate, described till now, which inhibits bone resorption. In this paper, we describe the synthesis, properties and hydroxyapatite binding of zoledronic acid labeled with two low energy beta emitters, {sup 47}Sc and {sup 177}Lu. Radiochemicals labeled with low energy electron emitters are preferred, because they deliver both a therapeutic dose to the bone and spare the bone marrow. Hydroxyapatite adsorption experiments have shown that the binding values obtained with complexes of zoledronic acid labeled with {sup 46}Sc and {sup 177}Lu are much higher than those of bisphosphonates labeled with {sup 153}Sm and {sup 166}Ho. Hence, complexes of zoledronic acid with either {sup 46}Sc or {sup 177}Lu seems to be a promising radiopharmaceutical for bone pain therapy.

  9. Absorbed dose assessment of 177Lu-zoledronate and 177Lu-EDTMP for human based on biodistribution data in rats

    Yousefnia, Hassan; Zolghadri, Samaneh; Jalilian, Amir Reza

    2015-01-01

    Over the past few decades, several bone-seeking radiopharmaceuticals including various bisphosphonate ligands and β-emitting radionuclides have been developed for bone pain palliation. Recently, 177Lu was successfully labeled with zoledronic acid (177Lu-ZLD) as a new generation potential bisphosphonate and demonstrated significant accumulation in bone tissue. In this work, the absorbed dose to each organ of human for 177Lu-ZLD and 177Lu-ethylenediaminetetramethylene phosphonic acid (177Lu-EDT...

  10. Production of 177Lu for targeted radionuclide therapy: Available options

    This review provides a comprehensive summary of the production of 177Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of 177Lu having the required quality for preparation of a variety of 177Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of 177Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. While both “direct” and “indirect” reactor production routes offer the possibility for sustainable 177Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. A broad understanding and discussion of the issues associated with 177Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of 177Lu-labeled radiopharmaceuticals, but also help future developments

  11. Preparation and biological assessment of 177Lu-BPAMD as a high potential agent for bone pain palliation therapy. Comparison with 177Lu-EDTMP

    In this study, 177Lu-(4-{[(bis(phosphonomethyl))- carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (177Lu-BPAMD) was successfully prepared. The quality control, partition coefficient, hydroxyapatite binding assay and stability of the complex were determined. For better comparison, biodistribution patterns of 177Lu-BPAMD and 177Lu-EDTMP complexes were compared in same animal model. 177Lu-BPAMD was prepared with high radiochemical purity ([93 %) and specific activity of 534 GBq/mmol at the optimal conditions. Comparative study between 177Lu-BPAMD and 177Lu-EDTMP indicated higher bone uptake and lesser accumulation in the other organs for 177Lu-BPAMD. 177Lu-BPAMD can be considered as a promising agent for bone pain palliation in the near future. (author)

  12. Comparison of [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is preferable for PRRT?

    Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [177Lu-DOTA0,Tyr3]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [177Lu-DOTA0,Tyr3]octreotide (177Lu-DOTATOC) and [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE), to see which peptide should be preferred for PRRT with 177Lu. In the same patients, 3,700 MBq 177Lu-DOTATOC and 3,700 MBq 177Lu-DOTATATE was administered in separate therapy sessions. Amino acids were co-administered. Whole-body scanning was performed on days 1, 4 and 7 post therapy. Blood and urine samples were collected. We calculated residence times for tumours, spleen and kidneys. All patients had longer residence times in spleen, kidneys and tumours after use of 177Lu-DOTATATE (p=0.016 in each case). Comparing 177Lu-DOTATATE with 177Lu-DOTATOC, the mean residence time ratio was 2.1 for tumour, 1.5 for spleen and 1.4 for kidneys. Dose-limiting factors for PRRT are bone marrow and/or kidney dose. Although the residence time for kidneys was longer when using 177Lu-DOTATATE, the mean administered dose to tumours would still be advantageous by a factor of 1.5, assuming a fixed maximum kidney dose is reached. Plasma radioactivity after 177Lu-DOTATATE was comparable to that after 177Lu-DOTATOC. Urinary excretion of radioactivity was comparable during the first 6 h; thereafter there was a significant advantage for 177Lu-DOTATOC. 177Lu-DOTATATE had a longer tumour residence time than 177Lu-DOTATOC. Despite a longer residence time in kidneys after 177Lu-DOTATATE, tumour dose will always be higher. Therefore, we conclude that the better peptide for PRRT is octreotate. (orig.)

  13. Production logistics and possible applications of 177Lu

    Owing to the favourable decay characteristics, 177Lu can be considered as an attractive radionuclides for various therapeutic applications. Different methodologies of its production, their comparative evaluation along with its possible applications have been described. (author)

  14. Biological evaluation of 153Sm and 166Ho complexes with macrocyclic ligands containing acetate pendant arms as potential agents for therapy

    For the development of therapeutic radiopharmaceuticals it is essential to choose the appropriate beta-emitter as well as the carrier biomolecule. Different carrier biomolecules, namely antibodies and peptides, have been linked to different beta-emitters (153Sm, 166Ho and 177Lu) using tetraaza macrocycles as bifunctional chelators. The cavity size of these chelators, the rigidity of the macrocyclic backbone and the nature of the pendant arms seems to play an important role on the thermodynamic stability and kinetic inertness of the radiocomplexes and on their biological behaviour. In our research group we have been exploring the possibility of using tetraazamacrocycles with different cavity size, pendant arms and rigidity for preparing 153Sm and 166Ho complexes useful for therapeutical applications and/or bone pain palliation. In this communication we present the results obtained when we reacted trita and teta with 153Sm and 166Ho. The complexes are formed in good yields (> 98%), are hydrophilic and present an overall negative charges, as well as low plasmatic protein binding. Good in vitro stability in physiological media and human serum was also found for all the complexes. The biodistribution studies in mice are also presented and have shown that 153Sm/166Ho-trita and 166Ho-teta have rapid tissue clearance, comparably to the corresponding dota complexes. In contrast, 153Sm-teta has a significant lower total excretion and a significant liver and muscle uptake. Our results indicate that 153Sm/166Ho-trita form very stable complexes in vivo. However, teta, which has a larger cavity size, forms less stable complexes with the larger ion Sm3+. The biological profile of 153Sm/166Ho-trita is very interesting for the evaluation of these complexes as therapeutical agents when conjugated to biomolecules

  15. Report on the 1. research coordination meeting on 'Development of therapeutic radiopharmaceuticals based on 177Lu for radionuclide therapy'

    from the production site. Patients suffering from breast, lung and prostate cancer develop metastasis in bone in the advanced stage of their diseases and therapeutic radiopharmaceuticals such as 153Sm-EDTMP and 89SrCl2 are used effectively for pain palliation due to skeletal metastases. Despite the fact that the above bone pain palliating agents give good clinical results; their wider use has met with practical difficulties. Though 153Sm can be prepared in adequate quantities in medium flux reactors, its short half life (47 h) is the major disadvantage. It is essential to handle large quantities of activity to compensate for decay losses, during production and delivery of the radiopharmaceutical. In the case of 89Sr, there is very limited capacity for production due to the very low cross section making this product expensive and unaffordable for many patients. It is expected that a 177Lu based bone palliating agent will offer the same clinical efficacy without the disadvantages mentioned above. Currently there is good published data available on the production of 177Lu and the preparation of phosphonates based radiopharmaceuticals which show high bone uptake. 177Lu produced in the low to medium flux research reactors available in the MS can be used for bone pain palliation. High specific activity 177Lu that is prepared in high flux research reactors is needed for radiolabelling antibodies and peptides. These antibodies introduced to patients alone or in conjunction with 90Y products are showing promising results in clinical trials. Large quantities of high specific activity 177Lu can be prepared by irradiating enriched targets in high flux research reactors and hence, in the long term the cost of high specific activity 177Lu should come down to reasonable levels. The wider availability of 177Lu will make it feasible for the production of therapeutic radiopharmaceuticals with lower cost ensuring higher availability in MS. The CRP 'Development of Therapeutic

  16. Production logistics of 177Lu for radionuclide therapy

    Owing to its favourable decay characteristics 177Lu [T1/2=6.71 d, Eβ(max)=497 keV] is an attractive radionuclide for various therapeutic applications. Production of 177Lu using [176Lu (n,γ)177Lu] reaction by thermal neutron bombardment on natural as well as enriched lutetium oxide target is described. In all, ∼4 TBq/g (108 Ci/g) of 177Lu was obtained using natural Lu target after 7 d irradiation at 3x1013 n/cm2/s thermal neutron flux while it was ∼110 TBq/g (3000 Ci/g) of 177Lu when 60.6% enriched 176Lu target was used. In both the cases, radionuclidic purity was ∼100%, only insignificant quantity of 177mLu [T1/2=160.5 d, Eβ(max)=200 keV] could be detected as the radionuclidic impurity. Production logistics using different routes of production is compared. Possible therapeutic applications of 177Lu are discussed and its merits highlighted by comparison with other therapeutic radionuclides

  17. radiolabeling of DOTA-substance P with 177Lu and biodistribution of 177Lu-DOTA-substance P

    The aim of this project is to evaluate the biodistribution of 177Lu-DOTA-SP in normal mice and in PANC-1 tumor bearing nude mice and to pave the way for its potentially medical application. In this study, 177Lu-DOTA-SP was successfully prepared with labeling yield of greater than 90% at optimized conditions and more than 98% of radiochemical purity after C18 Sep-Pak purification. 177Lu-DOTA-SP showed good stability in saline and in 5% serum while it decomposed slowly in 10% serum. Biodistribution studies in normal mice showed high uptake of 177Lu-DOTA-SP in the kidneys, indicating the excretion mainly by renal pathway. In addition, 177Lu-DOTA-SP was washed out from the blood quickly. Bio- distribution of 177Lu-DOTA-SP in PANC-1 tumor bearing mice showed higher uptake in pancreatic tumor than that in normal pancreas, indicating the presence of NK-1 receptors in PANC-1 pancreatic tumor. However, from SPECT image, no radioactivity accumulation was observed in PANC-1 tumor. Further evaluation is needed to confirm its potential application for radiotherapy of pancreatic cancers. (authors)

  18. Preparation and quality control of {sup 153}Sm radiopharmaceuticals

    Swasono, R. Tamat; Widyastuti, W.; Purwadi, B.; Laksmi, I. [Radioisotope Production Center - BATAN, Jakarta (Indonesia)

    1998-10-01

    The paper summarizes the preparation and quality control of {sup 153}Sm-EDTMP and three {sup 153}Sm-radiosynovectomy agents. Natural and enriched Sm{sub 2}O{sub 3} (98.7% {sup 152}Sm) irradiated in RSG-GAS 30 MW reactor yielded pure and high specific activity {sup 153}Sm. Labeling of EDTMP with {sup 153}Sm was carried out by mixing {sup 153}SmCl{sub 3} solution of pH 4.0 to an EDTMP solution at room temperature then pH adjustment to 8. The {sup 153}Sm-EDTMP complex was separated from the free {sup 153}Sm{sup +3} on a Chelex 100 column. Radiochemical purity was determined by thin layer chromatography using Cellulose sheets and pyridine: ethanol: water (1: 2: 4) mixture as solvent. The {sup 153}Sm-EDTMP has been shown to be stable for two weeks. Three particulate preparations of {sup 153}Sm used for the irradiation of chronic synovitis have been studied. They are hydroxyapatite particles, human serum albumin microspheres and ferric hydroxide macroaggregates. The {sup 153}Sm-ferric hydroxide macroaggregates were prepared in a single step by coprecipitation of {sup 153}Sm in the formation of Fe(OH){sub 3}. Preparation of {sup 153}Sm-labelled hydroxyapatite particles and {sup 153}Sm-labelled albumin microspheres were carried out by {sup 153}Sm labelling of previously prepared particles. Radiolabelling efficiency were greater than 95% for hydroxyapatite particles and macroaggregates and was lower than 20% for albumin microspheres. The particle sizes were inspected using an optical microscope with a haemocytometer and micrometric ocular. (author)

  19. Dosimetric Studies in Normal Mice of 177Lu-DOTA-SP and 177Lu-DOTA-His2-MG

    DOTA-Substance-P (SP) and DOTA-minigastrin (His2-MG) labeled with 177Lu could be used in peptide receptor radionuclide therapy (PRRT) for treatment of various tumour species. Biodistribution studies of both radiopharmaceuticals in normal mice were performed at different times. Absorbed doses in mouse organs were estimated and extrapolated to humans. Dosimetric calculations showed that kidneys received the highest dose, for both radiopharmaceuticals. The Maximum Tolerated Activity (MTA) of 177Lu-DOTA-SP that can be administered without kidney toxicity are 414 and 422 MBq/kg for the standard adult man and woman, respectively. In the same way, the MTA of 177Lu-DOTA-His2-MG are 488 and 518 MBq/kg for the standard adult man and woman, respectively. (authors)

  20. Preparation of 177Lu-DTPA-BIS-BIOTIN and biodistribution evaluation in normal mice

    The labeling method for 177Lu-DTPA-BIS-BIOTIN was established, and the biodistribution of 177Lu-DTPA-BIS-BIOTIN in normal mice was carried out as well. Under the optimal experimental condition (DTPA-BIS-BIOTIN 25 μg, pH=4.5 reacting at 80 degree C for 20 min), the labeling yield of 177Lu-DTPA-BIS-BIOTIN is more than 99.0%. 177Lu-DTPA-BIS-BIOTIN shows pretty good in vitro stability. The biodistribution of 177Lu-DTPA-BIS-BIOTIN in normal mice shows a rapid blood clearance. The uptake of 177Lu-DTPA-BIS-BIOTIN is mainly accumulated in liver, spleen and kidney. 177Lu-DTPA-BIS-BIOTIN is excreted by kidney. The results provide the basis for further study on 177Lu-DTPA-BIS-BIOTIN used in pretargeted radioimage and radiotherapy of cancer. (authors)

  1. Preparation and Biodistribution Evaluation in Mice of ~(177)Lu-DOTA-TOC

    2011-01-01

    The study of 177Lu labeled radiopharmaceuticals for cancer therapy is fast emerging as an important part of nuclear medicine. 177Lu-labelling of DOTA derivatized peptide DOTA-TOC (Tyr3-Octreotide) was carried out and biodistribution of 177Lu-DOTA-TOC in normal

  2. Chemical study on the labeling of EDTB with 153Sm

    Objective: According to conjugation characteristic of N, N, N', N'-tetrakis (2-benzymidazolylmethyl)-1, 2-ethanediamine (EDTB) with lipiodol selectively retained within hepatic tumors, in this paper, the labeling of EDTB with therapeutic nuclide 153Sm was first systematically studied by different labeling pathways, to further develop new labeled compounds with 153Sm for the treatment of hepatocellular carcinoma. Methods: A radio-paper chromatography (RPC) was used to determine the purity of the labeled compound with the mixture of pyridine: ethanol: water (1:2:4, V/V) as developer. Using independence variable method, the effect of labeling conditions, such as reaction time, temperature and concentration of EDTB on labeling yield were investigated, and the in vitro stability of 153Sm-EDTB was also demonstrated by RPC. Results: the RPC analysis indicated that Rf value of free 153Sm or 153Sm-EDTB was 0.0-0.1 and 0.6-0.7, respectively. Using acetic acid as reaction medium, in an open nitrogen-pouring labeling system, heated in boiling water bath for not less than 30 min, the labeling yield of 153Sm-EDTB was more than 97% and could remain in 24 hours after preparing the labeled compound at room temperature. Conclusion: The optimum labeling method and conditions were achieved. The in vitro stability of 153Sm-EDTB was good; thereby this provided possibility for further preparation and biological research of potential therapeutic radiopharmaceutical labeled lipiodol with 153Sm via EDTB for liver cancer

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

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

    2013-01-01

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

  4. Biokinetic study of free 177Lu in NIH mice

    Full text: 177Lu has been identified, by the scientific community, as a radionuclide with interesting advantages compared with 90Y and other beta emitters used in nuclear medicine. This paper analyses the free 177Lu biokinetic behavior in NIH male mice from activity measurements performed by the Radiopharmacy Division of CNEA (Comision Nacional de Energia Atomica) in the frame of an IAEA (International Atomic Energy Agency) Coordinated Research Project. The study of experimental data is a previous condition that allows drawing the activity-time curves for organs and to know the biodistribution of 177Lu. The cumulated activity in organs of interest in NIH male mice are calculated and critical organs are identified. The organs selected for analysis in this paper are the liver, kidneys, spleen, stomach, intestine, lungs, skeleton and red marrow. The last one is estimated from the activity measured in blood based on a recognized method published by Sgouros (2000). The results has been extrapolated to human assuming the same biokinetic behaviour as mice being the applicability of the different extrapolation methods also discussed. The direct extrapolation from mice data was the method of election from a radiological protection point of view. The measurement procedures, the data processing, the extrapolation techniques and the analysis performed in this study will contribute as a basis for future research of this group in the area of antibodies and other radiopharmaceutical labeled with 177Lu. The cumulated activity calculated in each organ is relevant because it makes possible to perform the dose assessment through the application of appropriate dose coefficients. It is a necessary step in order to evaluate the toxicity risk that is required in a pre-clinical study. (author)

  5. Method for preparing high specific activity 177Lu

    Mirzadeh, Saed; Du, Miting; Beets, Arnold L.; Knapp, Jr., Furn F.

    2004-04-06

    A method of separating lutetium from a solution containing Lu and Yb, particularly reactor-produced .sup.177 Lu and .sup.177 Yb, includes the steps of: providing a chromatographic separation apparatus containing LN resin; loading the apparatus with a solution containing Lu and Yb; and eluting the apparatus to chromatographically separate the Lu and the Yb in order to produce high-specific-activity .sup.177 Yb.

  6. 153Sm metallic-hydroxide macroaggregates. An improved preparation for radiation synovectomy

    A new type of preparation employing 153Sm metallic-hydroxide macroaggregates (153Sm-MHM) for radiation synovectomy was developed. The radiopharmaceutical was prepared by reacting the aqueous solution of 153SmCl3 with sodium borohydride solution in 0.5N NaOH. Microscopic analysis showed that 153Sm-MHM mean particle size was 4μm (range 1-15 μm) avoiding the formation of fine particles (153Sm-hydroxide macroaggregates preparations (153Sm-HM). Also, suspension properties as sedimentation rate, were better for 153Sm-MHM than for 153Sm-hydroxyapatite and 153Sm-HM. Biological studies in normal rabbits demonstrated high retention into de Knee joint space even at 48 h after administration of 153Sm-MHM (>99%). (author)

  7. Preliminary studies on /sup 177/Lu-labeled pyrophosphate (/sup 177/Lu-pyp) as a potential bone-seeking radiopharmaceutical for bone pain palliation

    /sup 99m/Tc-Sn-PYP (Technetium-99m labeled tin pyrophosphate) has been widely used as a radiopharmaceutical for bone scanning as well as in nuclear cardiology. It is also found in the body in trace amounts. /sup 177/Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents. PYP is an analogue of MDP and MDP has been labeled with /sup 177/Lu. No study on preparing a complex of /sup 177/Lu with PYP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking /sup 177/Lu -PYP (Lutetium-177 labeled Pyrophosphate) radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. Bio evaluation studies with rabbit under gamma-camera after intravenous injection of /sup 177/Lu- PYP complex in rabbit may yield important information to assess its potential for clinical use as a bone- pain palliation agent for the treatment of bone metastases. /sup 177/Lu was produced by irradiating lutetium foil (11 mg) natural target at a flux approx. equal to 1. 1014 n/cm/sup 2//s for 12 h in the swimming pool type reactor. /sup 177/Lu was labeled with PYP by adding nearly 37 MBq (1.0 mCi) of /sup 177/LuCl/sub 3/ to a vial containing 28 mg Na-PYP (Sodium pyrophosphate). The radiochemical purity and labeling efficiencies were determined by paper chromatography with Whatman 3MM paper using Ammonium Hydroxide:Methanol:Water (1:20:20) as mobile phase. Labeling of /sup 177/Lu with PYP was optimized and a labeled sample was subjected to HPLC analysis. To determine the charge on the /sup 177/Lu-PYP complex, radio-electrophoresis was conducted for 1 hour under a voltage of 300 V and 45 mA current using 0.025 M phosphate buffer (pH 6.9). Bio evaluation studies with rabbit under ?-camera were also performed to verify the skeletal uptake. The quality control using paper radio-chromatography has shown>99% radiochemical purity of /sup 177/Lu-PYP complex. Radio-chromatography also

  8. Preparation of bone tumor therapeutic radiopharmaceuticals 153Sm-EDTMP

    Samarium-153-EDTMP (ethylene diamine tetramethylene phosphonate), for its promising biological properties, has been proved as a palliating therapeutic agent for bone tumor in human beings. 153Sm with high radionuclear purity and specific activity of 5.18 GBq (140 mCi)/mg Sm2O3 was prepared by irradiating natural Sm2O3(152Sm, 26.7%) sample, replacing costly enriched samarium oxide target, at a flux of 4 x 1013 n·cm-2·s-1 for 110 h. The yield of 153Sm complexing with EDTMP is greater than 98% at pH 8∼10 in boiling water bath for 30 min, and not significantly decreases within one week after 153Sm-EDTMP complex formation

  9. Study on cellular survival adaptive response induced by low dose irradiation of 153Sm

    The present study engages in determining whether low dose irradiation of 153Sm could cut down the responsiveness of cellular survival to subsequent high dose exposure of 153Sm so as to make an inquiry into approach the protective action of adaptive response by second irradiation of 153Sm. Experimental results indicate that for inductive low dose of radionuclide 153Sm 3.7 kBq/ml irradiated beforehand to cells has obvious resistant effect in succession after high dose irradiation of 153Sm 3.7 x 102 kBq/ml was observed. Cells exposed to low dose irradiation of 153Sm become adapted and therefore the subsequent cellular survival rate induced by high dose of 153Sm is sufficiently higher than high dose of 153Sm merely. It is evident that cellular survival adaptive response could be induced by pure low dose irradiation of 153Sm only

  10. First measurement of 153Sm in the SIR

    In June 1998, the NIST sent to the International Reference System (SIR) a solution of 153Sm standardized in a 4π ionization chamber. As this radionuclide had not previously been measured in the SIR, the resulting equivalent activity Ae,NIST is compared with the value calculated from the efficiency curve of the SIR. However, problems occurred owing to the presence of 154Eu and 156Eu impurities in the solution. The manner in which the final equivalent activity value for this solution of 153Sm has been deduced is described in this report. (authors)

  11. Studies concerning the preparation of the 153Sm complex with EDTMP (ethylenediaminetetra methylenephosphonic acid) and other 153Sm complexes with other phosphonates, at room temperature

    This work presents a study on the preparation of the complexes 153Sm - EDTMP, 153Sm - HEDP, 153Sm - NTMP, 153Sm - DTPMP and 153Sm - HDTMP at room temperature. The preparation of the complex 153Sm - HDTMP, under heating (70 - 72 deg C), was also studied. Several factors affecting the 153Sm - EDTMP complexing yields were studied, due to its importance for use in Nuclear Medicine. These factors were: the molar ratio [ligand] / [metal], the ligand concentration and the incubation time of the mixture ligand-metal. The preparation of this complex, in low molar ratios, was also investigated. A study of the 153Sm - EDTMP concerning the 'in vitro' stability, when this complex was prepared in low radioactive concentrations was performed. A study on the temperature influence on its degradation, when this complex was obtained in higher radioactive concentrations, was also performed. The preparation of the complexes 153Sm - HEDP, 153Sm - NTMP, 153Sm - DTPMP and 153Sm - HDTMP was investigated by preparing the complexes in two situations: high molar ratio and ligand concentration and low molar ratio and ligand concentration. The 'in vitro' stability of each complex, obtained in low radioactive concentration was studied. In the specific case of the complex 153Sm - HDTMP, its biological distribution in mice was performed. All the complexes were investigated by high performance liquid chromatography (HPLC) and its complexing yields were determined by other three chromatographic processes: ionic exchange, thin layer chromatography (TLC - SG) and paper chromatography. The chromatographic processes were performed by association with specific radiochemical techniques. This work also presents a comparative study on the chromatograms obtained by thin layer chromatography (TLC - SG) and paper chromatography, when evaluated by the technique of cutting the strips into pieces and the chromatograms performed directly on a radiochromatography. The shape of the chromatograms and Rf values of 153

  12. Production of {sup 177}Lu for targeted radionuclide therapy: Available options

    Dah, Ashutosh [Isotope Production and Applications Division, Bhabha Atomic Research Centre (BARC), Mumbai (India); Pillai, Maroor Raghavan Ambikalmajan [Molecular Group of Companies. Kerala (India); Knapp, Furn F. Jr. [Medical Isotopes Program, Isotope Dept. Group, Oak Ridge National Laboratory (ORNL), Oak Ridge (United States)

    2015-06-15

    This review provides a comprehensive summary of the production of {sup 177}Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of {sup 177}Lu having the required quality for preparation of a variety of {sup 177}Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of {sup 177}Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. While both “direct” and “indirect” reactor production routes offer the possibility for sustainable {sup 177}Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. A broad understanding and discussion of the issues associated with {sup 177}Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of {sup 177}Lu-labeled radiopharmaceuticals, but also help future developments.

  13. Influence of binding characteristics of 153Sm-complexes to BSA on their bone uptake

    The bone uptake in normal mice and adsorption on bone model materials (hydroxyapatite and type I collagen) of 153Sm-NTMP, 153Sm-HEDTMP, 153Sm-DCTMP, 153Sm-EDTMP, 153Sm-DTPMP and 153Sm-DTPA are compared, and then the binding characteristics of these 153Sm-complexes to bovine serum albumin (BSA) are investigated. It is found that there is a discrepancy between the bone uptake and the adsorption on bone model materials, and that the binding characteristics of these 153Sm-complexes to BSA play an important role in the process of their bone uptake. Also, the binding characteristics are applied to explain the discrepancy successfully

  14. Comparison of [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate and [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotide: which peptide is preferable for PRRT?

    Esser, J.P. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Medisch Spectrum Twente, Department of Nuclear Medicine, Enschede (Netherlands); Krenning, E.P.; Teunissen, J.J.M.; Kooij, P.P.M.; Gameren, A.L.H. van; Bakker, W.H.; Kwekkeboom, D.J. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands)

    2006-11-15

    Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotide ({sup 177}Lu-DOTATOC) and [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate ({sup 177}Lu-DOTATATE), to see which peptide should be preferred for PRRT with {sup 177}Lu. In the same patients, 3,700 MBq {sup 177}Lu-DOTATOC and 3,700 MBq {sup 177}Lu-DOTATATE was administered in separate therapy sessions. Amino acids were co-administered. Whole-body scanning was performed on days 1, 4 and 7 post therapy. Blood and urine samples were collected. We calculated residence times for tumours, spleen and kidneys. All patients had longer residence times in spleen, kidneys and tumours after use of {sup 177}Lu-DOTATATE (p=0.016 in each case). Comparing {sup 177}Lu-DOTATATE with {sup 177}Lu-DOTATOC, the mean residence time ratio was 2.1 for tumour, 1.5 for spleen and 1.4 for kidneys. Dose-limiting factors for PRRT are bone marrow and/or kidney dose. Although the residence time for kidneys was longer when using {sup 177}Lu-DOTATATE, the mean administered dose to tumours would still be advantageous by a factor of 1.5, assuming a fixed maximum kidney dose is reached. Plasma radioactivity after {sup 177}Lu-DOTATATE was comparable to that after {sup 177}Lu-DOTATOC. Urinary excretion of radioactivity was comparable during the first 6 h; thereafter there was a significant advantage for {sup 177}Lu-DOTATOC. {sup 177}Lu-DOTATATE had a longer tumour residence time than {sup 177}Lu-DOTATOC. Despite a longer residence time in kidneys after {sup 177}Lu-DOTATATE, tumour dose will always be higher. Therefore, we conclude that the better peptide for PRRT is octreotate. (orig.)

  15. Photoionization spectroscopy for laser extraction of the radioactive isotope 177Lu

    D'yachkov, A. B.; Firsov, V. A.; Gorkunov, A. A.; Labozin, A. V.; Mironov, S. M.; Panchenko, V. Y.; Semenov, A. N.; Shatalova, G. G.; Tsvetkov, G. O.

    2015-12-01

    The hyperfine structure of the 5 d6 s 2 2D3/2 → 5 d6 s6 p 4F5/2 transition of the radioactive isotope 177Lu has been investigated by laser photoionization spectroscopy. Measured spectra permitted the determination of hyperfine magnetic dipole constants and electric quadrupole constants for ground and excited state as well as the isotope shift of the 177Lu isotope. The data obtained were used to confirm the selective photoionization of 177Lu from a neutron-irradiated sample that initially had a natural isotope composition. A concentration for 177Lu of 50 % was achieved, and the photoionization efficiency was estimated as suitable for technological application.

  16. 177Lu radiochemical separation from 176Yb irradiated in high-flux research reactor SM

    Ytterbium and lutetium behaviour has been studied during electrolysis of aqueous solutions containing their chlorides and alkali metal citrate (Li, Na, K). The conditions providing the efficient extraction of ytterbium macro amounts into a mercury-pool cathode have been determined. Laboratory-scale experiments were performed to elaborate chromatographic procedures for 177Lu purification from ytterbium macro amounts and accompanying impurities including hafnium (177Lu radioactive decay product). The conditions providing the efficient separation of 177Lu from the above-mentioned impurities using cation-exchange (in α-hydroxy isobutyric acid) and extraction-chromatographic (impregnated with di-2-ethylhexyl phosphoric acid teflon powder as stationary phase and nitric or hydrochloric acids as eluant) methods have been found. Isotopically enriched ytterbium preparation (176Yb - 95.15; 174Yb - 2.47 atomic %) was purified from lutetium impurity and samples of the purified starting material were irradiated in the central neutron trap and beryllium reflector channel of the SM reactor. 177Lu was extracted from the irradiated targets by electroreduction of ytterbium on the mercury-pool cathode from lithium citrate solution. Cation exchange and extraction chromatography methods were used for subsequent purification of 177Lu. The radiochemical processing took about 50 hours. The results of analysis obtained by the spectrometry of X-ray and gamma radiation, mass-spectrometry and emission spectroscopy are as follows: Chemical form: 177LuCl3, solution in hydrochloric acid; solvent (HCl) concentration: 0.01 - 0.1 mol/l; 177Lu specific activity: ≥ 20 Ci/mg; 177mLu to 177Lu activity ratio: ≤ 0.02 %; total gamma emitters (Co-58, Co-60, Zn-65, Mn-54, Fe-59, Cr-51) to 177Lu activity ratio: ≤ 0.01 %; total mass of non-radioactive impurities (Cu, Zn, Al, Fe, Pb) to 177Lu activity ratio: ≤ 500 μg/Ci; total alpha emitters to 177Lu activity ratio ≤ 1x10-5 %. (author)

  17. The entrance to bone tumor cells of 153Sm-EDTMP by microautoradiographic tracing

    The dynamic process of 153Sm-EDTMP entering into bone tumor cells and its behavior characteristic in osteosarcoma cells are studied by microautoradiographic tracing. The results show that 153Sm-EDTMP condense on membrane of osteosarcoma cells at first, then infiltrate through cell membrane or phagocytized by osteosarcoma cells and distributed in the form of phagosomes. In apoptotic osteosarcoma cells 153Sm-EDTMP could be observed in the membrane-bounded apoptotic bodies. So, the progression of apoptosis in osteosarcoma cells induced by 153Sm-EDTMP is dependent on the infiltration and phagocytosis of 153Sm-EDTMP through cell membrane

  18. On the preparation of a therapeutic dose of 177Lu-labeled DOTA-TATE using indigenously produced 177Lu in medium flux reactor

    177Lu could be produced with a specific activity of ∼23,000 mCi/mg (850 GBq/mg) by neutron activation using enriched 176Lu (64.3%) target when irradiation was carried out at a thermal neutron flux of 1x1014 n/cm2/s for 21 d. 177Lu-DOTA-TATE could be prepared in high radiochemical yield (∼99%) and adequate stability using the 177Lu produced indigenously. The average level of radionuclidic impurity burden in 177Lu due to 177mLu was found to be 250 nCi of 177mLu/1 mCi of 177Lu (9.25 kBq/37 MBq) at the end of bombardment, which corresponds to 0.025% of the total activity produced. The maximum specific activity achievable via careful optimization of the irradiation parameters was found to be adequate for the preparation of a therapeutic dose of the radiopharmaceutical. The in-house preparation of this agent using 25 μg (17.41 nmole) of DOTA-TATE and indigenously produced 177Lu (0.8 μg, 4.52 nmole), corresponding to peptide/Lu ratio of 3.85 yielded 98.7% complexation. Allowing possibility of decay due to transportation to users, it has been possible to demonstrate that at our end, a single patient dose of 150-200 mCi (5.55-7.40 GBq) can be prepared by using 250-333 μg of DOTA-TATE conjugate. This amount compares well with 177Lu-DOTA-TATE prepared for a typical peptide receptor radionuclide therapy (PRRT) procedure which makes use of 100 μg of the DOTA-TATE conjugate, which incorporates 50 mCi (1.85 GBq) of 177Lu activity, thereby implying that in order to achieve a single patient dose of 150-200 mCi (5.55-7.40 GBq), 300-400 μg of the conjugate needs to be used

  19. 153Sm oxabiphor in complex therapy of metastatic bone tissue

    The article provides a review of literature regarding radionuclide treatment of bone metastases disease in patients with different malignant neoplasms. Retrospective review of radiopharmaceutical application in the treatment of bone distant metastases is given. Advantages and limitations of different radiotracers have been determined. Possibility of application of the most updated, last generation agent, 153Sm, which is according to literature data showed an excellent analgesic properties and minimum side effects has been comprehensively studied

  20. Occupational doses in neuroendocrine tumors by using 177Lu DOTATATE

    This paper investigated the treatment of neuroendocrine tumors (abdominal tumors) using of 177Lu DOTATATE radiopharmaceutical which is a type of treatment presently used in the experimental form in Brazil and, therefore, not contemplated in norms or specific use. This research studied the occupational doses of this treatment and suggested guidelines or rules of procedures viewing the radiological protection of workers involved and the public. The treatment were followed up by using two types of radiation detection, one a scintillator and a Geiger-Muller, and the measurements were performed in a public hospital at Rio de Janeiro and the other in a private hospital at Sao Paulo. It was observed that the equivalent occupational doses can variate from 160 μSv to 450 μSv, in function of operator, of stage of manipulation, and of the administration method, which can be through the use of infusion pump or manual injection. The use of infusion pump is highly recommended and the hospitalization of the patient until the dose rate measured at 1 m does not surpass 20 μSv/h

  1. Development of 177Lu-phytate Complex for Radiosynovectomy

    Hassan Yousefnia

    2013-05-01

    Full Text Available Objective(s: In this work a new possible agent for radiosynovectomy has been targeted for articular pain palliation. Materials and Methods: Lu-177 of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu2O3 sample with thermal neutron flux of 4 × 1013 n.cm-2.s-1. The product was converted into chloride form which was further used for labeling of 177Lu-phytate complex and checked using ITLC (MeOH: H2O: acetic acid, 4: 4: 2, as mobile phase. The complex stability and viscosity were checked in the final solution up to seven days. The prepared complex solution (100 µCi/100 µl was injected intra-articularly to male rat knee joint. Leakage of radioactivity from injection site and its distribution in organs were investigated up to seven days. Results: The complex was successfully prepared with high radiochemical purity (>99.9 %. Approximately, the whole injected dose has remained in injection site seven days after injection. Conclusion: The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology

  2. 153Sm-HM for arthritic knee pain. Estimated dosimetry

    Osteoarthritis is the most common type of arthropathy and after cardiovascular diseases is the most disabling disease in developing countries. The dosimetry for the clinical application of 153-samarium-hydroxymacroaggregates (153Sm-HM) for radiation synovectomy (RSV) and palliative treatment for arthritic pain, as far as we know, has not been reported. The aim of this research was to estimate the radiation dose necessary for synovial ablation and pain palliation with minimum risk to the patient. 153Sm-HM (370 MBq) was administered intra-articularly in a patient with severe knee pain and hindered motility. Regions of interest drawn on sequential, conjugated, anterior and posterior scintigraphy images were used to obtain the respective activity. The data was entered into a knee joint histological-geometric model designed with micrometric dimensions to represent the synovial cell layers. The Monte Carlo code was used to calculate the absorbed dose in each of the 12 model-cells representing the distance from the synovial liquid to the cartilage or bone. The absorbed dose in the synovial cavity was 114 Gy which is sufficient energy for RSV. The treated patient referred little pain and higher motility with no adverse reactions. 153Sm-HM is a potentially valid radiopharmaceutical for RSV, which effectively palliates knee pain.

  3. DOTA-Tyr3-octreotate labelled with 177Lu and 131I. A comparative evaluation

    The chemical structure of somatostatin receptor ligand 1,4,7,10-tetraazacyclododecane- N,N',N',N'''-tetraacetic acid-Tyr3-octreotate (DOTA-Tyr3-TATE), provides the means for radiolabelling with halogen, by electrophilic substitution, to the Tyr3 residue and with metal, by a coordination mechanism, to the DOTA chelator. In this study, the DOTA-Tyr3-TATE was radiolabelled with 177Lu and 131I of high radiochemical purity and specific activity. The in vitro study regarding the competitive and the saturation binding assays were performed using rat brain cortex membrane. The IC50 value was determined as 4.74nM for natLu-DOTA-Tyr3-TATE and the Kd value was 142.8pM for 177Lu-DOTA-Tyr3-TATE. The biodistribution data of 177Lu-DOTA-Tyr3-TATE and DOTA-131I-Tyr3-TATE in HRS1 (hepato-colangiom carcinomas) tumour bearing rats, show that the 177Lu-DOTA-Tyr3-TATE is more stable and has better uptake than DOTA-131I-Tyr3-TATE. Furthermore, the competitive localization index of 177Lu- DOTA-Tyr3-TATE is three times higher than that obtained for DOTA-131I -Tyr3-TATE. The results of work based on comparative experiments suggest that 177Lu-DOTA-Tyr3- TATE could be an effective targeted radiotherapy agent of SSTR tumours. (author)

  4. Uncertainties in measurement of 90Y and 177Lu activities in an ionisation chamber

    Full text of publication follows. Accurate measurement of administered activity is essential in radionuclide therapy. However, this can be difficult to perform using a standard ionisation chamber, particularly with beta emitting radionuclides where measurements are greatly affected by the type of container (e.g. glass vial vs plastic syringe) in which the activity is contained, as well as the shape and volume of the sample. Methods: All measurements were taken with one of two ionisation chambers of the same model (Capintec CRC-15R). Shipments were received from two different suppliers of 90Y (Polatom; Eckert-Ziegler-EZ) and two suppliers of 177Lu (ITG Munich; Advanced Accelerator Applications-AAA). The quantities of 90Y varied from 2.5-7.4 GBq and of 177Lu from 3.3-8.4 GBq. The calibration factors used to make measurements in the glass vials supplied were 62*10 for 90Y and 450*10 for 177Lu. A reference sample of 177Lu was sent to the UK National Physical Laboratory, Teddington, for absolute calibration. Results: Compared to the manufacturer's calibration, the activities received were (88±23%) for Polatom 90Y (n=7), (103±5%) for EZ 90Y (n=56), (94±2%) for ITG 177Lu (n=93) and (112±5%) for AAA 177Lu (n=14). The large variation in measurements on Polatom 90Y was due to one shipment at 36%; without that value the mean was (96±4%) (n=6). With AAA 177Lu there was a step change during the process with the initial shipments reading significantly higher than the later ones: (115±1%) (n=10) vs (105±4%) (n=4). With 90Y a different calibration factor was required for doses drawn into syringes (49*10), whereas with 177Lu the same value could be used; this is presumably due to the contribution of the gamma emissions of 177Lu. Cross calibration with the national metrology institute showed that our measurements were within about 1% of the accepted value for 177Lu. Conclusions: Accurate measurement of beta emitters used in radionuclide therapy requires careful attention

  5. Radiolabeling parameters of {sup 177}Lu-DOTA-RITUXIMAB

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

    2013-07-01

    Cancer treatment using radioimmunotherapy (RIT) has been the focus of much research in the last two decades. In RIT, a radioisotope is coupled to a monoclonal antibody (mAb) to form a tumor-specific target agent to improve the cytocidal effect of the mAbs. RIT allows the systemic delivery of radiation to disease target by mAbs while sparing normal tissues. Rituximab® (Mabthera - Roche) is a chimeric mouse-human monoclonal antibody; it selectively binds with high affinity to the CD20 antigen, a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and in more than 90% of B cell non-Hodgkin's lymphomas (NHL). The conjugation and radiolabeling process involve special conditions of pH and temperature, long processes of manipulation and mixing. All this process can damage the antibody structure and compromise its clinical application. Therefore, these parameters must be largely studied. The aim of this work was to evaluate the best radiolabeling conditions of DOTA-rituximab. Briefly, 10 mg of antibody previously purified by ultrafiltration device was conjugated with DOTA-NHS-ester (Macrocyclics) in 50 fold molar excess. The reaction was conducted for 1 hour in phosphate buffer pH 8.0 and gently mixing at room temperature, remaining for 24 hours under refrigeration. The immunoconjugated was purified by size exclusion column and ultrafiltration device. The radiolabeled parameters studied were: immunoconjugated mass, activity of {sup 177}LuCl{sub 3}, reaction time, temperature and pH. The radiochemical purity of the preparations was determined using analysis by thin layer chromatography (TLC-SG plates). The best studied condition presented radiochemical purity above 95% and the integrity of antibody was preserved. (author)

  6. Aspects of yield and specific activity of (n,γ) produced 177Lu used in targeted radionuclide therapy

    177Lu-labeled receptor avid peptides and monoclonal antibodies have been effectively used in targeted tumor therapy, owing to the ideally suited decay properties and favourable production logistics of 177Lu [T½ = 6.65 days; Eβ(max) = 497 keV (78.6 %); Eγ = 208 keV (11.0 %)]. The specific activity of 177Lu produced by the (n,γ) route is one of the important criteria, which determines the efficacy of 177Lu-labeled receptor-avid biomolecules. The present article highlights that the specific activity of (n,γ) produced 177Lu cannot be calculated by simply dividing the produced activity by the mass of the target irradiated, unlike other (n,γ) produced medical radioisotopes and there is a significant enhancement of specific activity due to the burn up of the Lu target during irradiation, which is an added advantage towards the utilization of 177Lu in receptor specific therapeutic radiopharmaceuticals. (author)

  7. Synthesis and bio-evaluation of nano-hydroxyapatite trapped by 153Sm

    After nanoHA was synthesized, 153Sm-EDTMP-nanoHA and 153Sm-citrate-nanoHA were prepared and proved stable in vitro. ECT images of New Zealand rabbits injected with 153Sm-EDTMP-nanoHA had better contrast, skeletal figure visible, liver and spleen clear. The images of 153Sm-citrate-nanoHA showed a similar results but kidney invisible, which meant 153Sm-citrate-nanoHA showed a similar results but kidney invisible, which meant 153Sm-citrate-nanoHA was mainly excreted through liver and gall. 153Sm-EDTMP-nanoHA's half effective inhibition concentrations to SMMC-7721 and MCF-7 cells were 1.98 g/L and 0.075 g/L respectively and 153Sm-citrate-nanoHA's were 1.89 g/L and 0.094 g/L proportionally. 153Sm-EDTMP-nanoHA and 153Sm-citrate-nanoHA were worthy of a further research because their half effective inhibition concentrations were much lower than ones of the single nanoHA. (authors)

  8. Preparation of 177Lu-DOTA/DTPA-Bz-Cys-RGD dimer and biodistribution evaluation in normal mice

    177Lu-DOTA-Bz-Cys-RGD dimer and 177Lu-DTPA-Bz-Cys-RGD dimer were prepared, and the in vitro and in vivo properties were compared. TLC and HPLC show that the labeling yields of two radiolabeled compounds are more than 95% under optimal conditions (pH=5.0, reacting at 100 degree C for 15-20 min), and the two radiolabeled compounds show pretty good in vitro stability. HPLC analyses and lg P values reveal that lipophilicity of 177Lu-DOTA-Bz-Cys- RGD dimer is higher than 177Lu-DTPA-Bz-Cys-RGD dimer. The uptake of 177Lu-DTPA-Bz-Cys- RGD dimer in other tissues is significantly higher than that of 177Lu-DOTA-Bz-Cys-RGD dimer at 4 h postinjection, except for blood and spleen. The in vivo stability of 177Lu-DOTA-Bz-Cys-RGD dimer is much better than 177Lu-DTPA-Bz-Cys-RGD dimer. Bz-DOTA is an ideal bifunctional chelator for 177Lu labeling of RGD dimer. (authors)

  9. Preparation, QC and biological evaluation of 177Lu-DOTA-Tyr3- Octreotate

    Somatostatin (SS) plays a major role in the physiological regulation of hormones and organs. Radiolabelled somatostatin analogues have been studied for targeted radiotherapy of neuroendocrine tumors and with other malignancies known to bear somatostatin receptor, such as lymphoma, breast cancer, small-cell lung cancer and melanoma. Reactor produced 177Lu is emerging as an important radionuclide for cancer therapy since it decays with half-life of 6.71d by the emission of β- particles with Eβ of 498 keV (78.6), 384 keV (9.1%) and 176 keV (12.2) to stable 177Hf. The 177Lu radionuclide has tissue mean range of 670 μm is considered to be more effective for the treatment of small tumour. High specific activity 177Lu radionuclide (> 8Ci/mg) prepared in our laboratory is considered to be appropriate for labelling peptides. Several experiments for obtaining optimum labelling yield of 177Lu-DOTA-Tyr3-Octreotate under different reaction parameters such pH, incubation time and reaction temperature were performed. Radiochemical purity of 177Lu-DOTA-Tyr3- Octreotate was determined by radio-TLC with C18 plates developed in 70:30 MeOH:10% NH4OAc. Under these conditions 177Lu-DOTA-Tyr3-Octreotate appears at Rf 0.8 while 177Lu-acetate stays at the Rf 0. High labelling yield (>98%) of 177Lu-DOTA-Tyr3-Octreotate was obtained at pH 4.5 at a temperature of 90 deg. C for 30 minutes incubation time. The 177Lu-DOTA-Tyr3-Octreotate was further investigated for stability in acetate/ascorbate buffer and saline at room temperature (12.15 deg. C). The data showed that the labelled complex was stable in buffer and saline medium for a period >24 hours. Animal study of 177Lu-DOTA-Tyr3-Octreotate was performed in ∼200 g male Sprague Dawley rats. Two hundred microlitres of the labelled (80 μCi) were injected into the tail veins of rats and each rat was killed at 1 hour, 2 hours, 6 hours, 12 hours, 24 hours and 72 hours. Countings were performed using Capintec dose calibrator. The

  10. Investigation of 177Lu-folate based radionuclide tumor therapy in combination with pemetrexed

    Full text of publication follows. Aim: The antifolate pemetrexed (PMX) was shown to improve the tissue distribution profile of radio-folates by reducing undesired renal accumulation without affecting uptake in the tumor. We hypothesized that PMX would have a dual role in combination with therapeutic radio-folates as it may protect kidneys from radio-nephrotoxicity and contribute to the anticancer effect as a chemotherapeutic and/or radiosensitizing agent. Therefore, the aim of the study was to investigate the combined application of 177Lu-folate and PMX in vitro an in vivo. Material and Methods: The DOTA-folate conjugate (EC0800, Endocyte Inc.) was labeled with 177Lu at high specific activity. In vitro the effects of 177Lu-EC0800 alone and in combination with PMX was tested with FR-positive KB tumor cells using MTT and clonogenic assays. In vivo, undesired effects of 177Lu-EC0800 (20 MBq/mouse) with/without co-application of PMX were investigated in non-tumor bearing mice over six months. Kidney function was monitored by the determination of renal accumulation of 99mTc-DMSA using SPECT. Therapy studies in KB tumor-bearing mice were performed with 177Lu-EC0800 (20 MBq) combined with subtherapeutic (0.4 mg) and therapeutic amounts (1.6 mg) of PMX. Results: Determination of the combination index revealed a synergistic inhibitory effect of 177Lu-EC0800 and PMX on the viability of both FR-positive cancer cell lines in vitro (CI < 0.8). In vivo application of 20 MBq 177Lu-EC0800 impaired kidney function 6 months as demonstrated by a significantly reduced renal uptake of 99mTc-DMSA and elevated plasma levels of blood urea nitrogen. Pre-injection of subtherapeutic amounts of PMX (0.4 mg) protected kidneys effectively as demonstrated by parameters which were in the same range as those of untreated control animals. Therapy studies revealed a 3-fold more pronounced anticancer effect and 25% increased survival if 177Lu-EC0800 was combined with therapeutic amounts of PMX

  11. The biodistribution and kinetics of the 153Sm labelled avidin, streptavidin and biotin

    Due to the high affinity of biotin to Av or SA. The authors labelled a biotin derivative (DTPA-biotin) with 153Sm and then bound this 153Sm labelled DTPA-biotin to Av or SA. The in vivo kinetics and biodistribution of 153Sm labelled Av, SA and DTPA-biotin were studied in the rat and mice. The results demonstrated that 153Sm-Av cleared from the blood rapidly with high liver and renal uptake; 153Sm-SA cleared from blood slowly with high retention in liver, spleen and kidney, whereas 153Sm metabolize more fast, and excreted mainly through the kidney. Thereby, the biodistribution difference of SA and Av mentioned above provided an experimental basis for the selection of different components of A-V system in pre-targeting radio-immuno imaging and radioimmunotherapy

  12. Improving quantitative dosimetry in (177)Lu-DOTATATE SPECT by energy window-based scatter corrections

    de Nijs, Robin; Lagerburg, Vera; Klausen, Thomas L;

    2014-01-01

    PURPOSE: Patient-specific dosimetry of lutetium-177 ((177)Lu)-DOTATATE treatment in neuroendocrine tumours is important, because uptake differs across patients. Single photon emission computer tomography (SPECT)-based dosimetry requires a conversion factor between the obtained counts and the...... activity, which depends on the collimator type, the utilized energy windows and the applied scatter correction techniques. In this study, energy window subtraction-based scatter correction methods are compared experimentally and quantitatively. MATERIALS AND METHODS: (177)Lu SPECT images of a phantom with...... technique, the measured ratio was close to the real ratio, and the differences between spheres were small. CONCLUSION: For quantitative (177)Lu imaging MEGP collimators are advised. Both energy peaks can be utilized when the ESSE correction technique is applied. The difference between the calculated and the...

  13. Production Ability Of 177Lu From Natural Lutetium Target On The Dalat Nuclear Reactor

    177Lu is presently being considered as a potential radionuclide, for use in in-vivo targeted radiotherapy, owing to its favorable nuclear decay characteristics. This paper presents some research findings on the ability to produce 177Lu on the IVV-9 research reactor with thermal neutron flux of 1.8 x 1013.cm-2.s-1 at the Nuclear Research Institute to produce this radioactive isotope. Our products have specific activity of 17.7 mCi/mg Lu, radionuclide and radiochemical purities more than 99.9% of total radioactivity. Immediate products are used for the initial basic research of labeling capabilities with DOTATATE, and especially studying on the possibility preparing 177Lu-EDTMP used to treat pain palliation caused by bone metastases. (author)

  14. The addition of DTPA to [177Lu-DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity

    Peptide receptor-targeted radionuclide therapy is nowadays also being performed with DOTA-conjugated peptides, such as [DOTA0,Tyr3]octreotate, labelled with radionuclides like 177Lu. The incorporation of 177Lu is typically ≥99.5%; however, since a total patient dose can be as high as 800 mCi, the amount of free 177Lu3+ (= non-DOTA-incorporated) can be substantial. Free 177Lu3+ accumulates in bone with unwanted irradiation of bone marrow as a consequence. 177Lu-DTPA is reported to be stable in serum in vitro, and in vivo it has rapid renal excretion. Transforming free Lu3+ to Lu-DTPA might reroute this fraction from accumulation in bone to renal clearance. We therefore investigated: (a) the biodistribution in rats of 177LuCl3, [177Lu-DOTA0,Tyr3]octreotate and 177Lu-DTPA; (b) the possibilities of complexing the free 177Lu3+ in [177Lu-DOTA0,Tyr3]octreotate to 177Lu-DTPA prior to intravenous injection; and (c) the effects of free 177Lu3+ in [177Lu-DOTA0,Tyr3]octreotate, in the presence and absence of DTPA, on the biodistribution in rats. 177LuCl3 had high skeletal uptake (i.e. 5% ID per gram femur, with localization mainly in the epiphyseal plates) and a 24-h total body retention of 80% injected dose (ID). [177Lu-DOTA0,Tyr3]octreotate had high and specific uptake in somatostatin receptor-positive tissues, and 24-h total body retention of 19% ID. 177Lu-DTPA had rapid renal clearance, and 24-h total body retention of 4% ID. Free 177Lu3+ in [177Lu-DOTA0,Tyr3]octreotate could be complexed to 177Lu-DTPA. Accumulation of 177Lu in femur, blood, liver and spleen showed a dose relation to the amount of free 177Lu3+, while these accumulations could be normalized by the addition of DTPA. After labelling [DOTA0,Tyr3]octreotate with 177Lu the addition of DTPA prior to intravenous administration of [177Lu-DOTA0,Tyr3]octreotate is strongly recommended. (orig.)

  15. Preparation and evaluation of 177Lu-DOTA-Bz-RGD dimer and 177Lu-DOTA-Bz-PEG4-RGD dimer

    177Lu-DOTA-Bz-RGD dimer and 177Lu-DOTA-Bz-PEG4-RGD dimer were pre- pared, and the effect of PEG4 on labeling conditions and in vitro stability as well as pharma-cokinetic properties and biodistribution in normal mice for the radiolebeled compounds was compared. The results of TLC and HPLC show that the labeling yield of two radiolabeled compounds was more than 95% under optimal conditions (pH 4.0 and pH 6.0, respectively, reacting at 100 degree C for 15-20 min). The two radiolabeled compounds show pretty good stability in saline. HPLC analyses and lgPow values revealed that introducing of PEG4 increased the lipophilic character of radiolabeled compounds, but had no significant changes on pharmacokinetic properties and biodistribution in normal mice. (authors)

  16. Development of a therapeutic radiopharmaceutical 177Lu-DOTA- Minigastrin for potential use in PRRT

    The aim of this work is to obtain 177Lu-DOTA-Minigastrin with high radiochemical purity (RP) and the highest specific activity (Ae) as possible, using a locally produced (Nuclear Reactor RA-3, Ezeiza Atomic Center) 177LuCl3 of an intermediate level of Ae (between 6.36 to 17.95 Ci/mg of 176Lu) ) and also to perform in vitro and in vivo stability tests, dose calculation in normal mice and its extrapolation to a human model. (authors)

  17. Preparation and biological evaluation of 177Lu-labeled rituximab for B-lymphoma treatment

    Edalat Radfar; Azim Arbabi; Dariush Sardari

    2010-01-01

    Introduction: 177Lu is a beta emitter with suitable decay mode [T1/2=6.7 d, Eβmax=497 keV, EΥ=112keV (6.4%) & 208 keV (11%)] for using in radio therapy. Various radiolabeled monoclonal antibodies have been developed in treatment. Rituximab is a chimeric mouse-human monoclonal antibody. Rituximab binds with human B-lymphocate-restricted differentiation antigen: CD20. Rituxsimab was used successfully as an anti-CD20 radiolabeled antibody before. Methods: 177Lu was p...

  18. Antitenascin antibody 81C6 armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands

    Introduction: When labeled with iodine-131, the antitenascin monoclonal antibody (mAb) 81C6 has shown promise as a targeted radiotherapeutic in patients with brain tumors. Because of its more favorable γ-ray properties, lutetium-177 might be a better low-energy β-emitter for this type of therapy. Materials and Methods: Chimeric 81C6 (ch81C6) was labeled with 177Lu using the acyclic 1B4M ligand and the macrocyclic ligands NHS-DOTA and MeO-DOTA and evaluated for binding to tenascin. Three paired-label tissue distribution experiments were performed in normal mice receiving one of the 177Lu-labeled immunoconjugates plus 125I-labeled ch81C6 labeled using Iodogen. Paired-label experiments in athymic mice bearing subcutaneous D54 MG human glioma xenografts were done to directly compare the biodistribution of ch81C6-1B4M-177Lu and 125I-labeled ch81C6, and ch81C6-MeO-DOTA-177Lu and 125I-labeled ch81C6. Similar comparisons were done using murine (mu) instead of ch81C6. The primary parameter utilized for evaluation was the 177Lu/125I uptake ratio in each tissue. Results: In the studies performed in normal mice, the NHS-DOTA ligand yielded the highest 177Lu/125I uptake ratios in tissues indicative of loss of label from the chelate; for this reason, only 1B4M and MeO-DOTA were evaluated further. The 177Lu/125I ratio in bone increased gradually with time for the chimeric conjugates; however, there were no significant differences between ch81C6-1B4M-DTPA-177Lu and ch81C6-MeO-DOTA-177Lu. In contrast, mu81C6-1B4M-DTPA-177Lu and mu81C6-MeO-DOTA-177Lu showed a more dramatic increase in the 177Lu/125I ratio in bone - from 2.4±0.3 and 1.7±0.2 at Day 1 to 8.5±1.1 and 4.2±0.5 at Day 7, respectively. Conclusion: With these antitenascin constructs, the nature of the mAb had a profound influence on the relative degree of loss of 177Lu from these immunoconjugates. MeO-DOTA shows promise as a bifunctional chelate for labeling 81C6 mAbs with 177Lu

  19. Tracer level radiochemistry to clinical dose preparation of 177Lu-labeled cyclic RGD peptide dimer

    Aim: Integrin αvβ3 plays a significant role in angiogenesis during tumor growth and metastasis, and is a receptor for the extracellular matrix proteins with the exposed arginine(R)-glycine(G)-aspartic acid(D) tripeptide sequence. The over-expression of integrin αvβ3 during tumor growth and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Considering the advantages of 177Lu for targeted radiotherapy and enhanced tumor targeting capability of cyclic RGD peptide dimer, an attempt has been made to optimize the protocol for the preparation of clinical dose of 177Lu labeled DOTA-E[c(RGDfK)]2 (E = Glutamic acid, f = phenyl alanine, K = lysine) as a potential agent for targeted tumor therapy. Methods: 177Lu was produced by thermal neutron bombardment on enriched Lu2O3 (82% in 176Lu) target at a flux of 1 × 1014 n/cm2.s for 21 d. Therapeutic dose of 177Lu-DOTA-E[c(RGDfK)]2 (7.4 GBq) was prepared by adding the aqueous solution of the ligand and 177LuCl3 to 0.1 M NH4OAC buffer containing gentisic acid and incubating the reaction mixture at 90 °C for 30 min. The yield and radiochemical purity of the complex was determined by HPLC technique. Parameters, such as, ligand-to-metal ratio, pH of the reaction mixture, incubation time and temperature were varied using tracer quantity of 177Lu (37 MBq) in order to arrive at the optimized protocol for the preparation of clinical dose. Biological behavior of the radiotracer prepared was studied in C57/BL6 mice bearing melanoma tumors. Results: 177Lu was produced with a specific activity of 950 ± 50 GBq/mg (25.7 ± 1.4 Ci/mg) and radionuclidic purity of 99.98%. A careful optimization of several parameters showed that 177Lu-DOTA-E[c(RGDfK)]2 could be prepared with adequately high radiochemical purity using a ligand-to-metal ratio ∼ 2. Based on these studies therapeutic dose of the agent with 7.4 GBq of 177Lu was formulated in ∼ 63 GBq/μM specific

  20. Studies on apoptosis in bone tumor cells induced by 153Sm

    ZHU Shou-Peng; XIAO Dong; HAN Xiao-Feng

    2004-01-01

    The apoptosis in human bone tumor cells induced by internal irradiation with 153Sm was studied. The morphological changes in bone tumor cells were observed by electronic and fluorescent microscopy, as well as DNA agarose gel eletrophoresis. DNA chain fragmentation, microautoradiographic tracing and the inhibition rate of proliferation in bone tumor cells exposed to 153Sm with different duration time were examined. It was demonstrated that the bone tumor cells exposed to 153Sm displayed nuclear fragmentation, pyknosis, margination of condensed chromatin, and formation of membrane bounded apoptotic bodies, whereas the percentage of DNA chain fragmentation of bone tumor cells increases in direct proportion to the duration of irradiation with 153Sm, as well as DNA ladder formation in apoptotic cells. Also a marked inhibition effect of proliferation in bone tumor cells after exposure with 153Sm was observed.

  1. Studies on apoptosis in bone tumor cells induced by 153Sm

    The apoptosis in human bone tumor cells induced by internal irradiation with 153Sm was studied. The morphological changes in bone tumor cells were observed by electronic and fluorescent microscopy, as well as DNA agarose gel electrophoresis. DNA chain fragmentation, microautoradiographic tracing and the inhibition rate of proliferation in bone tumor cells exposed to 153Sm with different duration time were examined. It was demonstrated that the bone tumor cells exposed to 153Sm displayed nuclear fragmentation, pyknosis, margination of condensed chromatin, and formation of membrane bounded apoptotic bodies, whereas the percentage of DNA chain fragmentation of bone tumor cells increases in direct proportion to the duration of irradiation with 153Sm, as well as DNA ladder formation in apoptotic cells. Also a marked inhibition effect of proliferation in bone tumor cells after exposure with 153Sm was observed. (authors)

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

    Beckford, Denis R.; Eigner, Sebastian; Eigner-Henke, Kateřina; Lebeda, Ondřej; Melichar, František; Beran, Miloš

    2012-01-01

    Roč. 39, č. 1 (2012), s. 3-13. ISSN 0969-8051 R&D Projects: GA MŠk 2B06165 Institutional research plan: CEZ:AV0Z10480505 Keywords : Radioimmunotherapy * Nimotuzumab * (177)Lu * Monoclonal antibody Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 2.517, year: 2012

  3. Potential renal toxicity bio-markers indicating radiation injury after 177Lu-octreotate treatment

    Full text of publication follows. The kidneys are one of the most exposed non-tumor tissues and regarded as one of the main dose-limiting organs in peptide receptor radionuclide therapy (PRRT). [177Lu-DOTA0, Tyr3]-octreotate (177Lu-octreotate) has shown promising results in the treatment of somatostatin receptor over-expressing neuroendocrine tumors, but optimization is still needed. The ability to give each patient as much 177Lu-octreotate as possible without inducing nephrotoxicity is necessary for an efficient treatment. However, due to large inter-individual differences in uptake and retention in the kidneys, there is a need for efficient methods that can indicate renal injury early. A possible way is to identify bio-markers for high risk of radiation nephrotoxicity. The aim of this study was to investigate the potential of using urinary retinol binding protein (RBP), and blood valinhydantoin (VH) as bio-markers of nephrotoxicity on adult mice after 177Lu-octreotate treatment. BALB/c nude mice (n=6/group) were i.v. injected with 60 MBq or 120 MBq of 177Lu-octreotate. The control group was mock treated with saline. Spot urine samples were collected before injection, and 14, 30, 60 and 90 days after injection. Analysis of RBP4 and creatinine was performed using Mouse RBP4 ELISA kit and Creatinine kit from R/D Systems, respectively. Erythrocytes were separated from whole blood samples collected 90 days after injection, and analysed for VH by LC-MS/MS. The ratio between VH and a volumetric standard was calculated. The RBP/creatinine level increased with time in both groups given 177Lu-octreotate, with earlier and higher response for the 120 MBq group. No clear change in VH level between the different groups was observed. The results show that RBP may be a promising new bio-marker for radiation induced kidney toxicity. The presently used method based on VH was not sensitive enough to be used as kidney toxicity marker. Further studies on mice are ongoing to validate

  4. Preparation and animal imaging of 153Sm-EDTMP as a bone seeking radiopharmaceutical

    Ethylenediamine- tetra methylenephosphonic acid (EDTMP) has widely used chelator for the labeling of bone seeking radiopharmaceuticals complexed with radio metals. 153Sm can be produced by the HANARO reactor at the Korea Atomic Energy Research Institute, Taejon, Korea. 153Sm has favourable radiation characteristics T1/2=46.7 h, β max=0.81 MeV (20%), 0.71 MeV (49%), 0.64 MeV (30%) and γ=103 keV (30%) emission which is suitable for imaging purposes during therapy. We investigated the labeling condition of 153Sm-Emptied and imaging of 153Sm-EDTMP in normal rats. EDTMP 20 mg was solved in 0.1 mL 2 M NaOH. 153SmCl3 was added to EDTMP solution and pH of the reaction mixtures was adjusted to 8 and 12, respectively. Radiochemical purity was determined with paper chromatography. After 30 min. reaction, reaction mixtures were neutralized to pH 7.4 and the stability was estimated upto 120 hrs. Imaging studies of each reaction were performed in normal rats (37 MBq/0.1 mL). The labeling yield of 153Sm-EDTMP was 99%. The stability of pH 8 reaction at 60, 96 and 120 hr was 99%,95%,89% and that of pH 12 at 36, 60, 96, and 120 hr was 99%, 95%, 88%, 66%, respectively. The 153Sm-EDTMP showed constantly higher bone uptake from 2 to 48 hr after injection. 153Sm-EDTMP, labeled at pH 8 reaction condition, has been stably maintained. Image of 153Sm-EDTMP at 2, 24, 48 hr after injection, demonstrate that 153Sm-EDTMP is a good bone seeking radiopharmaceuticals

  5. Safety and feasibility of percutaneous vertebroplasty with radioactive {sup 153}Sm PMMA in an animal model

    Lu Jun [Department of Radiotherapy, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Deng Jinglan, E-mail: dengjinglan@gmail.com [Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Zhao Haitao [Department of Radiology, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Shi Mei [Department of Radiotherapy, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Wang Jing [Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China); Zhao Lina [Department of Radiotherapy, Xijing Hospital, Fourth Military Medical University, 15 West Changle Road, Xi' an 710032, Shaanxi Province (China)

    2011-05-15

    Purpose: We investigated the safety and feasibility of the combination of samarium-153-ethylenediamine tetramethylene phosphonate ({sup 153}Sm-EDTMP)-incorporated bone cement (BC) with percutaneous vertebroplasty (PVP) in dogs. Methods and materials: {sup 153}Sm-EDTMP-incorporated BC was prepared by combining solid {sup 153}Sm-EDTMP and polymethylmethacrylate (PMMA) immediately before PVP. It was then injected into the vertebrae of four healthy mongrel dogs (two males and two females) by PVP under CT guidance. Each dog was subjected to five PVP sessions at a {sup 153}Sm-EDTMP dose of 30-70 mCi. The suppressive effect of local injection of {sup 153}Sm-EDTMP on the hematopoietic system was evaluated through counting of peripheral blood cells. Distribution of {sup 153}Sm-EDTMP-incorporated BC and the status of tissues adjacent to injected vertebrae were evaluated with SPECT, CT and MRI. Histopathology was carried out to assess the influence of PVP on the vertebra and adjacent tissues at the microscopic level. Results: PVP was done successfully, and all dogs exhibited normal behavior and stable physical signs after procedures. {sup 153}Sm-EDTMP-incorporated BC was concentrated mainly in target vertebrae, and the peripheral blood cells remained within normal range. The spinal cord and tissues around BC did not exhibit signs of injury even when the dosage of {sup 153}Sm-EDTMP increased from 30 mCi to 70 mCi. Conclusion: A dose lower than 70 mCi of {sup 153}Sm is safe when it was injected into vertebrae. {sup 153}Sm-EDTMP-incorporated BC did not influence the effect of PVP. This means might strengthen anti-tumor activity locally for vertebra with osseous metastasis without damaging adjacent tissues.

  6. Reducing renal uptake of 9Y- and 177Lu-labeled alpha-melanocyte stimulating hormone peptide analogues

    Objective: The purpose of this study was to improve the tumor-to-kidney uptake ratios of 9Y- and 177Lu-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Re-Cys3,4,1, D-Phe7, Arg11]α-melanocyte stimulating hormone3-13 {DOTA-Re(Arg11)CCMSH} through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. Methods: A new peptide of DOTA-Re(Glu2, Arg11)CCMSH was designed, synthesized and labeled with 9Y and 177Lu. Pharmacokinetics of 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH was determined in B16/F1 murine melanoma-bearing C57 mice. Results: 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH exhibited significantly (P9Y- and 177Lu-DOTA-Re(Arg11)CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The renal uptake values of 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH were 28.16% and 28.81% of those of 9Y- and 177Lu-DOTA-Re(Arg11)CCMSH, respectively, at 4 h postinjection. 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH displayed higher tumor-to-kidney uptake ratios than 9Y- and 177Lu-DOTA-Re(Arg11)CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The tumor-to-kidney uptake ratio of 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH was 2.28 and 1.69 times of 9Y- and 177Lu-DOTA-Re(Arg11)CCMSH, respectively, at 4 h postinjection. The 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH activity accumulation was low in normal organs except for kidney. Conclusions: Coupling a negatively charged amino acid (Glu) to the CCMSH peptide sequence dramatically reduced the renal uptake values and increased the tumor-to-kidney uptake ratios of 9Y- and 177Lu-DOTA-Re(Glu2, Arg11)CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma

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

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

  8. Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate

    Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). All 177Lu-octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. Four hundred seventy-nine patients received a total of 1,693 administrations of 177Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of 177Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. Hormonal crises after 177Lu-octreotate therapy occur in 1% of patients. Generally, 177Lu-octreotate therapy is well tolerated. (orig.)

  9. Cytogenetic analysis of 153 Sm-EDTMP in peripheral lymphocytes from patients with bone cancer metastasis

    The 153 Sm-EDTMP is a radiopharmaceutical used in nuclear medicine with promising results for the relief of metastatic pain. Therefore, there are few knowledge about the effects of 153 Sm-EDTMP at cellular level. The present study was conducted with the aim of evaluating the cytogenetic effects of 153 Sm-EDTMP in peripheral lymphocytes from patients with bone metastasis (with and without previous radio and/or chemotherapy) by the chromosome aberration technique. For that, the blood samples were collected before and one hour after the endovenous administrations of 153 Sm-EDTMP (mean activity of 42.53 ± 5.31 MBq/kg body weight), taking into account the rapid blood clearance. The principal types of structural chromosome aberrations found gaps and breaks, acentric fragments centric rings, double minutes and dicentrics. The statistical analysis showed that the group submitted to previous radio and chemotherapy before153 Sm-EDTMP administration showed significant difference in chromosome aberrations frequency one hour after the treatment. The analysis of the chromosome modal number and the kinetics of cellular cycle showed no statistical difference among the groups, suggesting that the treatment with 153 Sm-EDTMP, did not influence these parameters. The obtained data showed that the therapy with 153 Sm-EDTMP induced a few quantity of cytogenetic damages in peripheral lymphocytes one hour after its administration in patients, although, theoretically, a long term stochastic effect cannot be disregarded. (author)

  10. Optimization of the production, quality control of samarium-153, 153 Sm-EDTMP and biodistribution of 153 Sm-EDTMP in animals for metastatic bone cancer pain palliation

    Samarium-153 has suitable physical properties for metastatic bone cancer pain palliation with 46.7 hr half-life. Not only decays it with multi-energetic B-radiation but also emits a gamma-ray at 103 keV which is suitable for imaging during therapy. The optimization of 153 Sm production, by irradiation 152 Sm2 O3 as a solid and liquid target, is conducted in TRIGA Mark III research reactor. The feasibility to label it with EDTMP, a bone seeking agent, is also studied. The specific activity obtained from liquid target is about 2 times higher than solid target. At least 500 mCi/week can be produced with specific activity about 50 to 70 mCi/mg Sm. EDTMP as Na-EDTMP and Ca-EDTMP is labelled with 153 Sm at various conditions. The radiochemical purity achieved, is greater than 99% (85 mCi of 153 Sm labelled with Na-EDTMP or Ca-EDTMP, molar ratio of Sm:EDTMP 1:10 and 1:100 respectively, pH 7.5-8). The biodistribution in animals of 153 Sm-Na-EDTMP showed similar results as obtained from 153 Sm-Ca-EDTMP but slightly higher uptake in various organs and showed high skeletal uptake up to 32% at 24 hr post injection. The labeled compound obviously undergoes rapid removal, completely clearance into urine within 24 hr. This labeled compound is under clinical trials

  11. Fluorescence microscopic morphology and inhibition rate studies on apoptosis of osteosarcoma cells induced by 153Sm

    The apoptosis of osteosarcoma cells treated with irradiation by 153Sm-EDTMP was studied. The morphological changes in osteosarcoma cells were observed by fluorescence microscopy. It was found that osteosarcoma cells exposed with 153Sm-EDTMP displayed significant nuclear fragmentation and marked pyknosis. With the prolongation of observing period, the membrane bound apoptotic bodies formation was observed. It should be noted, that with the lengthening of irradiation time by 153Sm-EDTMP, the inhibition rate of proliferation of osteosarcoma cells increased progressively

  12. Apoptosis induced by radionuclide 153Sm and expression of relevant genes in three different cancer cells

    To study apoptosis of PC-3, ER-75-30 and A549 cells induced by radionuclide 153Sm and the expression of bcl-2, bax in apoptosis cells, MTT assay was used to detect the anti-tumor effect, light microscope, transmission electron microscope, flow cytometer were used to detect apoptosis, while image analysis was used to detect the expression of bcl-2 and bax. 153Sm showed anti-tumor effect and could induce tumor cell apoptosis. Both bcl-2 and bax played an important role in apoptosis. Different kind of cells had different sensitivity to 153Sm

  13. Urine management after treatment with ''153 Sm-EDTMP (QUADRAMET)

    The main purpose was to establish and to evaluate a new protocol of individualized treatment of patient urine after ''153 Sm-EDTMP injection, with a more efficient management of the wastes. Excreted urine was collected in an appropriate container form which, previous to sealing it, an aliquot of 10 ml was obtained. Experimental half-life (t1/2) of the isotope was then determined by measuring the activity at different times, besides the minimum time necessary for disposing of the radioactive wastes as regular trash. The measured half-life adjusted well to the theoretical value of the isotope. The time of considered storage oscillated between 19 and 26 days, based on the activity excreted by each patient. The main idea is the consideration of the set container-urine as solid waste: the evaluation of the minimum storage time necessary to its elimination is made in terms of legal limitation of specific activity by mass unit. The immediate advantages ares: the elimination of disagreeable scents by the storage of urine, it is not necessary a liquid waste disposal to eliminate it, and a more accurate knowledge of the specific activity at the moment of the elimination (dilution factor is not used). (Author) 10 refs

  14. Stability and Biodistribution of Thiol-Functionalized and (177)Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles.

    Yook, Simmyung; Lu, Yijie; Jeong, Jenny Jooyoung; Cai, Zhongli; Tong, Lemuel; Alwarda, Ramina; Pignol, Jean-Philippe; Winnik, Mitchell A; Reilly, Raymond M

    2016-04-11

    We are studying a novel radiation nanomedicine approach to treatment of breast cancer using 30 nm gold nanoparticles (AuNP) modified with polyethylene glycol (PEG) metal-chelating polymers (MCP) that incorporate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-particle emitter, (177)Lu. Our objective was to compare the stability of AuNP conjugated to MCP via a single thiol [DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a dithiol [DOTA-PEG-lipoic acid (LA)] or multithiol end-group [PEG-pGlu(DOTA)8-LA4] and determine the elimination and biodistribution of these (177)Lu-labeled MCP-AuNP in mice. Stability to aggregation in the presence of thiol-containing dithiothreitol (DTT), l-cysteine or glutathione was assessed and dissociation of (177)Lu-MCP from AuNP in human plasma measured. Elimination of radioactivity from the body of athymic mice and excretion into the urine and feces was measured up to 168 h post-intravenous (i.v.) injection of (177)Lu-MCP-AuNP and normal tissue uptake was determined. ICP-AES was used to quantify Au in the liver and spleen and these were compared to (177)Lu. Our results showed that PEG-pGlu(DOTA)8-LA4-AuNP were more stable to aggregation in vitro than DOTA-PEG-LA-AuNP and both forms of AuNP were more stable to thiol challenge than DOTA-PEG-OPSS-AuNP. PEG-pGlu((177)Lu-DOTA)8-LA4 was the most stable in plasma. Whole body elimination of (177)Lu was most rapid for mice injected with (177)Lu-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated (177)Lu. All (177)Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and (177)Lu in the liver for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP. These differences were not correlated with in vitro stability of the (177)Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pGlu((177)Lu-DOTA)8-LA4 via a multithiol

  15. A novel 177Lu-labeled porphyrin for possible use in targeted tumor therapy

    Introduction: Porphyrin and its derivatives exhibit inherent affinity for localization in tumors. Hence, porphyrin derivatives radiolabeled with suitable therapeutic radionuclides could be envisaged as potential agents for targeted tumor therapy. In this direction, a water-soluble porphyrin derivative, viz., 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin was synthesized in-house and radiolabeled with 177Lu with an aim to prepare an agent for targeted tumor therapy. 177Lu is an attractive radionuclide for the development of targeted radiotherapeutic agents owing to its suitable decay characteristics [T1/2=6.73 d, Eβ(max)=0.49 MeV, Eγ=208 keV (11%)], comparatively longer half-life and ease of production with high specific activity. Methods: 177Lu was produced by irradiation of enriched Lu2O3 (64.3% 176Lu) at a thermal neutron flux of 1x1014 n/cm2.s for 14 d. The porphyrin was coupled to a suitable chelator, namely, p-aminobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid for complexation with 177Lu. The radiolabeling was achieved by incubating 50 μg of the conjugate with 177LuCl3 (200 ng Lu) in acetate buffer (pH ∼5) at 50oC for 1 h. The radiolabeled conjugate was characterized by high-performance liquid chromatography and its biological efficacy was studied in Swiss mice bearing fibrosarcoma tumors. Results: 177Lu was obtained with a specific activity of ∼550 TBq/g and radionuclidic purity of 99.98%. The 177Lu-labeled porphyrin conjugate was obtained with 99% radiochemical purity and it exhibited good in vitro stability. Biodistribution studies revealed good tumor uptake (2.01% IA/g) within 3 h post injection (p.i.) with >94% injected activity exhibiting renal clearance. No significant accumulation of activity was observed in any of the vital organs/tissue. The tumor/blood and tumor/muscle ratios were 2.89 and 16.80, respectively, at 3 h p.i. and further increased till 2 days p.i. up to which the studies continued. Serial

  16. Multi-factor analysis on events related to hematological toxicity in 153Sm-EDTMP palliative therapy for skeletal metastases

    Objective: To investigate the clinical factors related to hematological toxicity induced by intravenous samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) treatment. Methods A total of 206 patients with bony metastases treated with 153Sm-EDTMP were retrospectively analyzed. Logistic regression (SPSS 10.0 for Windows) and correlation analysis were used to evaluate the factors concerned. Results: Age of the patient, number of bone metastatic lesion, chemotherapy before 153Sm-EDTMP therapy, concurrent radiotherapy and repeat-times of 153Sm-EDTMP treatments were found the individual factors related to hematological toxicity. Chemotherapy before 153Sm-EDTMP, concurrent radiotherapy, medication for normal blood counting and repeat-times of 153Sm-EDTMP treatments were the hematological toxicity factors in multi-factor analysis. Conclusion: In 153Sm-EDTMP therapy, several factors were found related to hematological toxicity suggesting more attention be paid to the change of blood cell counting after the palliative therapy. (authors)

  17. Inhibition of proliferation in bone tumor cells after irradiation by 235U, 147Pm, 153Sm

    The inhibition of proliferation in bone tumor cells after simple or mixed irradiation by 235U, 147Pm, 153Sm was studied. Experimental results indicated that proliferation of bone tumor cells was significantly inhibited at 12 h∼24 h after a simple irradiation by 235U (128.4 Bq), 147Pm (7.4 x 105 Bq), and 153Sm (7.4 x 105 Bq) as well as mixed irradiation by 235U + 147Pm (64.2 Bq + 3.7 x 105 Bq), 235U + 153Sm (64.2 Bq + 3.7 x 105 Bq), 147Pm + 153Sm (3.7 x 105 Bq + 3.7 x 105 Bq). The findings show that the inhibition rate with mixed irradiation was more than that with simple irradiation

  18. 177Lu-DOTMP: a viable agent for palliative radiotherapy of painful bone metastasis

    The suitable nuclear decay characteristics [T1/2 = 6.73 d, Eβ(max) = 497 keV, Eγ = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production with adequate specific activity and radionuclidic purity using a moderate flux reactor are important attributes towards 177Lu to be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study describes the preparation of 177Lu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) and its preliminary biological evaluation in animal models with an aim to proposing it as a viable radiopharmaceutical for bone pain palliation. The choice DOTMP as the polyaminophosphonic acid carrier ligand is based on the enhanced thermodynamic stability and kinetic inertness of the metal-ligand complexes with macrocyclic chelators. 177Lu was produced with a specific activity of ∝ 12 GBq/mg (∝ 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu2O3 target at a thermal neutron flux of ∝ 6 x 1013 n/cm2 s for 21 d. 177Lu-DOTMP complex was prepared in high yield and excellent radiochemical purity (> 99%) using DOTMP synthesized and characterized in-house. The complex exhibited excellent in-vitro stability at room temperature. Biodistribution studies in Wistar rats showed rapid skeletal accumulation of the injected activity [(1.60±0.19)% per gram in femur at 3 h post-injection] with fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic studies carried out in normal Wistar rats and New Zealand white rabbits also demonstrated significant accumulation of the agent in skeleton and almost no retention in any other vital organs. (orig.)

  19. Transcriptional response of kidney tissue after 177Lu-octreotate administration in mice

    Introduction: The kidneys are one of the main dose limiting organs in 177Lu-octreotate therapy of neuroendocrine tumors. Therefore, biomarkers for radiation damage would be of great importance in this type of therapy. The purpose of this study was to investigate the absorbed dose dependency on early transcriptional changes in the kidneys from 177Lu-octreotate exposure. Methods: Female Balb/c nude mice were i.v. injected with 1.3, 3.6, 14, 45 or 140 MBq 177Lu-octreotate. The animals were killed 24 h after injection followed by excision of the kidneys. The absorbed dose to the kidneys ranged between 0.13 and 13 Gy. Total RNA was extracted from separated renal tissue samples, and applied to Illumina MouseRef-8 Whole-Genome Expression Beadchips to identify regulated transcripts after irradiation. Nexus Expression 2.0 and Gene Ontology terms were used for data processing and to determine affected biological processes. Results: Distinct transcriptional responses were observed following 177Lu-octreotate administration. A higher number of differentially expressed transcripts were observed in the kidney medulla (480) compared to cortex (281). In addition, 39 transcripts were regulated at all absorbed dose levels in the medulla, compared to 32 in the cortex. Three biological processes in the cortex and five in the medulla were also shared by all absorbed dose levels. Strong association to metabolism was found among the affected processes in both tissues. Furthermore, an association with cellular and developmental processes was prominent in kidney medulla, while transport and immune response were prominent in kidney cortex. Conclusion: Specific biological and dose-dependent responses were observed in both tissues. The number of affected transcripts and biological processes revealed distinct response differences between the absorbed doses delivered to the tissues

  20. In Vivo Measurement and Characterization of a Novel Formulation of [177Lu]-DOTA-Octreotate

    Dale Bailey

    2016-01-01

    Full Text Available Objective(s:Lutetium-177 can be made with high specific activity and with no other isotopes of lutetium present, referred to as “No Carrier Added” (NCA 177Lu. We have radiolabelled DOTA-conjugated peptide DOTA‐(Tyr3‐octreotate with NCA 177Lu (“NCA-LuTATE” and used it in nearly 40 therapeutic administrations for subjects with neuroendocrine tumours or meningiomas. In this paper, we report on our initial studies on aspects of the biodistribution and dosimetry of NCA-LuTATE from gamma camera 2D whole body (WB and quantitative 3D SPECT (qSPECT 177Lu imaging. Methods: Thirteen patients received 39 NCA-LuTATE injections. Extensive WB planar and qSPECT imaging was acquired at approximately 0.5, 4, 24 and 96 h to permit estimates of clearance and radiation dose estimation using MIRD-based methodology (OLINDA-EXM. Results:The average amount of NCA-Lutate administered per cycle was 7839±520 MBq. Bi-exponential modelling of whole body clearance showed half lives for the fast & slow components of t½=2.1±0.6 h and t½=58.1±6.6 h respectively. The average effective dose to kidneys was 3.1±1.0 Gy per cycle. In eight patients completing all treatment cycles the average total dose to kidneys was 11.7±3.6 Gy. Conclusions: We have shown that NCA-LuTATE has an acceptable radiation safety profile and is a suitable alternative to Carrier-Added 177Lu formulations. The fast component of the radiopharmaceutical clearance was closely correlated with baseline renal glomerular filtration rate, and this had an impact on radiation dose to the kidneys. In addition, it has less radioactive waste issues and requires less peptide per treatment.

  1. Long-term toxicity of [177Lu-DOTA0,Tyr3]octreotate in rats

    Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [177Lu-DOTA0,Tyr3]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [177Lu-DOTA0,Tyr3]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2 x 278 MBq groups. Three doses of 185 MBq [177Lu-DOTA0,Tyr3]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469±18, 134±70 and 65±15 μmol/l, respectively; p177Lu-DOTA0,Tyr3]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage. (orig.)

  2. [177Lu]-DOTA0-Tyr3-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma

    Vaidyanathan, Ganesan; Affleck, Donna J.; Zhao, Xiao-Guang; Keir, Stephen T.; Zalutsky, Michael R.

    2010-01-01

    Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [177Lu-DOTA0,Tyr3]octreotate ([177Lu]DOTA-TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate thi...

  3. Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90Y or 177Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [90Y-DOTA]-TOC or [177Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [90Y-DOTA]-TOC and 141 patients underwent 259 cycles of [177Lu-DOTA]-TOC. The median survival after [177Lu-DOTA]-TOC and after [90Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [177Lu-DOTA]-TOC over [90Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [177Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). The present results revealed no difference in median overall survival after [177Lu-DOTA]-TOC and [90Y-DOTA]-TOC. Furthermore, [177Lu-DOTA]-TOC was less haematotoxic than [90Y-DOTA]-TOC. (orig.)

  4. Radiopharmaceuticals based on 177LU for radionuclide therapy. Development of labeling procedures and Quality control methods

    The cancer in Cuba constitutes a fundamental problem of health and it occupies the second place as cause of death. It is known that the use of labeled biomolecules (like monoclonal antibodies-mAb- and peptides) with radioisotopes has become a viable and promissory alternative for the cancer. The monoclonal antibodies production in Cuba for different uses enjoys national and international prestige. Some years ago, the Center of Molecular Immunology (CIM) and the Isotope Center (CENTIS) joined efforts to develop the applications of the Cuban monoclonal antibodies. Different clinical trials have been carried out to explore the possibilities of the radioimmunotherapy in humans using monoclonal antibodies. We have been developed different radiopharmaceuticals based on monoclonal antibodies labeled with β emitters (131I, 188Re and 90Y). Because of 177Lu is one of the isotopes emerging as a clear choice for therapy, we expect that we can develop a 177Lu radiopharmaceutical based on h-R3 monoclonal antibody (Nimotuzumab). DOTA-conjugated monoclonal antibody could be radiolabelled with 177Lu with high yields, however our main focus will be to further optimize radiolabelling conditions to avoid side reactions. Labeling yields using different DOTA derivatives (DOTA-NHS, DOTA-SCN) were higher than 90%. Quality control evaluation was performed by HPLC and ITLC-SG. . (Author)

  5. Targeted radiotherapy with 177 Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    Malignant pancreas tumours induced in athymic mice are a good model for peptide receptor targeted radiotherapy. The objective of this research was to estimate pancreatic tumour absorbed radiation doses after administration of 177Lu-DOTA-TATE in mice as a therapeutic radiopharmaceutical that could be used in humans. AR42J murine pancreas cancer cells expressing somatostatin receptors, were implanted in athymic mice (n=18) to obtain the 177Lu-DOTA-TATE biokinetics and dosimetry. To estimate its therapeutic efficacy 87 MBq were injected in a tail vein of 3 mice and 19 days p.i. there were a partial relapse. There was an epithelial and sarcoma mixed tumour in the kidneys of mouse III. The absorbed dose to tumour, kidney and pancreas was 50.5 ± 7.2 Gy, 17.5 ± 2.5 Gy and 12.6 ± 2.3 Gy respectively. These studies justify further therapeutic and dosimetry estimations to ensure that 177Lu-DOTA-TATE will act as expected in man considering its kidney radiotoxicity. (Author)

  6. 177Lu-DOTA-lanreotide: a novel tracer as a targeted agent for tumor therapy

    177Lu of specific activity ∼100-110 TBq/g and radionuclidic purity of ∼100% was obtained by irradiation of enriched Lu2O3 (60.6% 176Lu) target for 7 days at a thermal neutron flux of 3x1013n/cm2/sec. The 177Lu labeling of a macrocyclic bifunctional chelating agent viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has been extensively studied. Lanreotide, [β-naphthyl-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2] a disulfide-linked cyclic octapeptide and a somatostatin analog, reported to bind with a wide variety of tumors expressing somatostatin receptors, was conjugated with DOTA. The peptide-BFCA conjugate was characterized with the help of high-resolution two-dimensional proton NMR spectroscopy. The 177Lu labeling of the DOTA-lanreotide conjugate has been standardized to give a radiolabeling yield of 85%. The tracer showed specific binding with A-431 human epidermoid carcinoma and IMR-32 human brain neuroblastoma cells

  7. Application of analytic methodologies for image quantification in neuroendocrine tumor therapy with 177Lu-DOTA

    Neuroendocrine tumors have annual incidence of 1 to 2 cases per one hundred thousand inhabitants. The 177Lu-DOTA-octreotate treatments in 3 or 4 cycles has been effective in controlling disease progression and, in some cases, promote tumor remission. To estimate radiation side effects in healthy organs, image quantification techniques have been broadcast for individualized patient dosimetry. In this paper, image data processing methods are presented to allowing comparisons between different image conjugate views, combined with attenuation correction and system sensitivity. Images were acquired 24, 72 and 192 h after administration of 74 GBq of 177Lu-DOTA using a dual-head gamma camera detection system and they were evaluated with ImageJ software. 4 female patients underwent to two cycles of treatment. The kidneys, liver and whole-body regions of interest were separately assessed by 4 techniques for counts method and 12 techniques for pixel intensity method, considering the main photopeak separately and aided by the attenuation correction map and adjacent windows to photopeak energy. The pixel intensity method was combined with mathematical correction for pixels with null value. The results obtained by the two methods were strongly correlated (r>0.9) (p0.05) was found between the treatment cycles. In conclusion, the pixel intensity method is faster and allows macros, minimizing operator error, and may optimize dosimetry in tumor therapies with 177Lu-DOTA-octreotate. (author)

  8. Preparation of 153Sm-citrate-HA for radioactive synovectomy of rheumatoid arthritis

    A new kind of labelled radiopharmaceutical hydroxyapatite (HA) by means of transfer complexing for the treatment of rheumatoid arthritis is described. HA with partials of 2-10 μm is labelled with 153Sm by a citrate transfer ligand. 153Sm-citrate-HA is obtained in high yield and is extremely stable in vitro. The complexing capability of HA is about 5 mg Sm2O3/g HA, the decomposition rates of 153Sm-citrate-HA both in saline of 0.9% and in human plasma (37 +- 0.5 degree C) are less than 2.0% for a period of 3 half lives. Biodistribution studies in rabbits demonstrated long term retention of nearly 99% of injected 153Sm-Citrate-HA in arthritis joint. Extra-articular leakage of radioactivity in both blood and urine accounted for 0.5% of injected dose, and few retained in other major tissues after about 14.8 MBq of 153Sm-Citrate-HA has injected into the left knee joint of normal rabbits. 153Sm-citrate-HA could be potentially useful in radio-synovectomy treatment of rheumatism arthritis

  9. Evaluation of the biological and scanning distribution of hydroxyapatite-153Sm radiotherapeutic agent

    Fixation of 153Sm labeled hydroxyapatite (HA) in the synovial capsule and extra articular localization were evaluated by means of biological distribution tests and gamma scanning studies. These were carried out using HA-153Sm with particle size ranging between 5 and μm, and radiochemical purity above 99%. Animal models used were wistar rats and new zealand rabbits. Rabbits were injected with 7,4 MBq of HA-153Sm while rats received between 1,85 and 92,6 MBq of HA-153Sm. In both cases injection was given in the intra articular area. After injection, scanning images were obtained in rabbits on the 1st, 3rd and 7st day and in rats on the 2nd and 7th day. Biological distribution studies are conducted in the 2 hours to 9 days range in rats and one the 7th day in rabbits. No extra articular localization of HA-153Sm was found in scanning conducted on rabbits by the 1st, 3rd and 7st day after injection, neither on rats by the 2nd and 7th day. Biological distributions for rabbits and rats show localization above 99% in the intra articular area, during the evaluated periods of time. The evaluations of the biological distribution and the scintigraphic images show that fixation of HA-153Sm in the synovial capsule up to the 9th day is very high

  10. Gamma camera calibration and validation for quantitative SPECT imaging with (177)Lu.

    D'Arienzo, M; Cazzato, M; Cozzella, M L; Cox, M; D'Andrea, M; Fazio, A; Fenwick, A; Iaccarino, G; Johansson, L; Strigari, L; Ungania, S; De Felice, P

    2016-06-01

    Over the last years (177)Lu has received considerable attention from the clinical nuclear medicine community thanks to its wide range of applications in molecular radiotherapy, especially in peptide-receptor radionuclide therapy (PRRT). In addition to short-range beta particles, (177)Lu emits low energy gamma radiation of 113keV and 208keV that allows gamma camera quantitative imaging. Despite quantitative cancer imaging in molecular radiotherapy having been proven to be a key instrument for the assessment of therapeutic response, at present no general clinically accepted quantitative imaging protocol exists and absolute quantification studies are usually based on individual initiatives. The aim of this work was to develop and evaluate an approach to gamma camera calibration for absolute quantification in tomographic imaging with (177)Lu. We assessed the gamma camera calibration factors for a Philips IRIX and Philips AXIS gamma camera system using various reference geometries, both in air and in water. Images were corrected for the major effects that contribute to image degradation, i.e. attenuation, scatter and dead- time. We validated our method in non-reference geometry using an anthropomorphic torso phantom provided with the liver cavity uniformly filled with (177)LuCl3. Our results showed that calibration factors depend on the particular reference condition. In general, acquisitions performed with the IRIX gamma camera provided good results at 208keV, with agreement within 5% for all geometries. The use of a Jaszczak 16mL hollow sphere in water provided calibration factors capable of recovering the activity in anthropomorphic geometry within 1% for the 208keV peak, for both gamma cameras. The point source provided the poorest results, most likely because scatter and attenuation correction are not incorporated in the calibration factor. However, for both gamma cameras all geometries provided calibration factors capable of recovering the activity in

  11. Subacute haematotoxicity after PRRT with {sup 177}Lu-DOTA-octreotate: prognostic factors, incidence and course

    Bergsma, Hendrik; Konijnenberg, Mark W.; Kam, Boen L.R.; Teunissen, Jaap J.M.; Kooij, Peter P.; Krenning, Eric P.; Kwekkeboom, Dik J. [Erasmus University Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Herder, Wouter W. de [Erasmus Medical Center, Department of Internal Medicine, Rotterdam (Netherlands); Franssen, Gaston J.H.; Eijck, Casper H.J. van [Erasmus Medical Center, Department of Surgery, Rotterdam (Netherlands)

    2016-03-15

    In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from {sup 131}I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with {sup 177}Lu-DOTA{sup 0}-Tyr{sup 3}-octreotate ({sup 177}Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit. The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined. Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 x 10{sup 9}/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq {sup 177}Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients. The incidence of subacute haematological toxicity after PRRT with {sup 177}Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from {sup 131}I, seems not to be valid for PRRT with {sup 177}Lu-DOTATATE. (orig.)

  12. Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: prognostic factors, incidence and course

    In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from 131I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit. The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined. Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 x 109/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq 177Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients. The incidence of subacute haematological toxicity after PRRT with 177Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from 131I, seems not to be valid for PRRT with 177Lu-DOTATATE. (orig.)

  13. Comparative biodistributions and dosimetry of [177Lu]DOTA-anti-bcl-2-PNA-Tyr3-octreotate and [177Lu]DOTA-Tyr3-octreotate in a mouse model of B-cell lymphoma/leukemia

    Introduction: The B-cell lymphoma/leukemia-2 (bcl-2) proto-oncogene in non-Hodgkin’s lymphoma (NHL) is a dominant inhibitor of apoptosis. We developed a 177Lu-labeled bcl-2 antisense peptide nucleic acid (PNA)–peptide conjugate designed for dual modality NHL therapy, consisting of a radiopharmaceutical capable of simultaneously down-regulating apoptotic resistance and delivering cytotoxic internally emitted radiation. Methods: DOTA-anti-bcl-2-Tyr3-octreotate was synthesized, labeled with 177Lu, and purified using RP-HPLC. The PNA–peptide conjugate was evaluated in Mec-1 NHL-bearing mice and compared to [177Lu]DOTA-Tyr3-octreotate in biodistribution and excretion studies. These data were then used to generate in vivo dosimetry models. Results: The PNA–peptide conjugate was readily prepared and radiolabeled in high yield and radiochemical purity. An in vivo blocking study determined that administration of 50 μg of non-radioactive PNA–peptide was the optimal mass for maximum delivery to the tumor. Based on that result, a dosing regimen of 177Lu-PNA–peptide, for radiologic effect, followed by the optimal mass of non-radioactive compound, for antisense effect, was designed. Using that dosing regimen, biodistribution of the PNA–peptide showed uptake in the tumor with minimal washout over a 4-day period. Uptakes in receptor-positive normal organs were low and displayed nearly complete washout by 24 h. Dosimetry models showed that the tumor absorbed dose of the PNA–peptide conjugate was approximately twice that of the peptide-only conjugate. Conclusions: Biodistribution data showed specific tumor targeting of the 177Lu-labeled PNA–peptide compound with minimal receptor-positive normal tissue uptake when compared to [177Lu]DOTA-Tyr3-octreotate. In vivo dosimetry models predicted a more favorable tumor absorbed dose from [177Lu]DOTA-anti-bcl-2-Tyr3-octreotate

  14. Studies on {sup 177}Lu-labeled methylene diphosphonate as potential bone-seeking radiopharmaceutical for bone pain palliation

    Abbasi, Imtiaz Ahmed, E-mail: imtiaz_abbasi@yahoo.co

    2011-04-15

    Objective: {sup 99m}Tc-MDP (technetium-99{sup m}-labeled methylene diphosphonate) has been widely used as a radiopharmaceutical for bone scintigraphy in cases of metastatic bone disease. {sup 177}Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents. No study on preparing a complex of {sup 177}Lu with MDP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking {sup 177}Lu-MDP (lutetium-177-labeled MDP) radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. Biodistribution studies after intravenous injection of {sup 177}Lu-MDP complex in rats may yield important information to assess its potential for clinical use as a bone pain palliation agent for the treatment of bone metastases. Methods: {sup 177}Lu was produced by irradiating natural Lu{sub 2}O{sub 3} (10 mg) target at a thermal flux {approx}8.0x10{sup 13} n/cm{sup 2} per second for 12 h in the swimming pool-type reactor.{sup 177}Lu was labeled with MDP by adding nearly 37 MBq (1.0 mCi) of {sup 177}LuCl{sub 3} to a vial containing 10 mg MDP. The radiochemical purity and labeling efficiencies were determined by thin layer chromatography. Labeling of {sup 177}Lu with MDP was optimized, and one sample was subjected to high-performance liquid chromatography (HPLC) analysis. Twelve Sprague-Dawley rats were injected with 18.5 MBq (0.5 mCi). {sup 177}Lu-MDP in a volume of 0.1 ml was injected intravenously and then sacrificed at 2 min, 1 h, 2 h and 22 h (three rats at each time point) after injection. Samples of various organs were separated, weighed and measured for radioactivity and expressed as percent uptake of injected dose per gram. Bioevaluation studies with rats under gamma-camera were also performed to verify the results. Results: The quality control using thin layer chromatography has shown >99% radiochemical purity of {sup 177}Lu-MDP complex. Chromatography with Whatman 3

  15. Electron microscopic morphology and DNA chain fragmentation studies on apoptosis in bone tumor cells induced by 153Sm

    Objective: To study the apoptosis and fraction of DNA chain fragmentation in bone tumor cells induced by 153Sm-EDTMP. Methods: Apoptosis in bone tumor cells exposed to different time periods of 153Sm-EDTMP internal irradiation was observed by electron microscopic morphology and DNA chain fragmentation studies. Results: It was demonstrated that the bone tumor cells internally exposed to 153Sm-EDTMP displayed nuclear fragmentation, margination of condensed chromatin, and formation of membrane bounded apoptotic bodies. The study showed that the percentage of DNA chain fragmentation increases in direct proportion to the duration of internal exposure to 153Sm-EDTMP. Conclusion: Apoptosis induced by 153Sm-EDTMP in bone tumor cells was dependent on the time of 153Sm-EDTMP exposure

  16. Cytogenetic effect of 153 Sm-EDTMP in peripheral lymphocytes of patients with metastatic cancer

    The 153Sm-EDTMP is a radiopharmaceutical used in nuclear medicine with promising results for the relief of metastatic pain. Therefore, there are few knowledge about the effects of 153Sm-EDTMP at cellular level. The present study was conduced with the aim of evaluating the cytogenetic effects of 153Sm-EDTMP in peripheral lymphocytes from patients with bone metastasis (with and without previous radio and/or chemotherapy) by the chromosome aberration technique, either in vivo or in vitro. For that, the blood samples were collected before and one hour after the endovenous administration of 153Sm-EDTMP (mean activity of 42.53+/-5.31 MBq/kg body weight), taking into account the rapid blood clearance. The principal types of structural chromosome aberrations found gaps and breaks, acentric fragments centric rings, double minutes and dicentrics. The statistical analysis showed that the group submitted to previous radio and chemotherapy before 153Sm-EDTMP administration showed significant difference in chromosome aberrations frequency one hour after the treatment. The analysis of the chromosome modal number and the kinetics of cellular cycle showed no statistical difference among the groups, suggesting that the treatment with 153Sm-EDTMP, did not influence these parameters. The carrier molecule, EDTMP, did not influence the induction of chromosome aberration. In relation to the in vitro assays, the obtained data of peripheral lymphocytes of healthy donors and patients with no previous treatment exposed to different radioactive concentration of 153Sm-EDTMP (0.046 - 1.110 MBq/mL) were better adjusted by linear regression model (Y=A+BX). The chromosome damage induced by 153Sm-EDTMP observed in vitro was about 2 fold higher than that found in vivo for the group of patients with no previous treatment. The obtained data showed that the therapy with 153Sm-EDTMP induced a few quantity of cytogenetic damages in peripheral lymphocytes on hour after its administration in patients

  17. 177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

    Ada H V Repetto-Llamazares

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

  18. The content of 153Sm-oxabifor in cancer patients blood in the treatment of bone metastasis

    Concentration 153Sm in the blood of patients with bone metastasis after radionuclide therapy was determined. Considerable variation of the content of 153Sm in blood of patients with various primary cancers from 10 to 65 Bq/ml is found. The effective half-life of 153Sm in the blood of patients was estimated at more than 10 days during the course of the therapy in time interval more than 7 days

  19. Kinetics of 153Sm oxabiphor in the blood of cancer patients undergoing complex therapy for bone metastasis

    Concentration 153Sm in the blood of patients with bone metastasis after radionuclide therapy was determined. Considerable variation of the content of 153Sm in blood of patients with various primary cancers from 10 to 65 Bq/ml is found. The effective half-life of 153Sm in the blood of patients was estimated at more than 10 days during the course of the therapy.

  20. Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using90Y or177Lu

    Introduction: Therapeutic potential of β-emitting cytotoxic radionuclides 90Y and 177Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy 90Y and 177Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of 90Y and 177Lu. Methods: 5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c(RGDyK). 177Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice. Result: The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, 90Y or 177Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (> 99%, RT, < 1 min). 90Y- and 177Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with 90Y or 177Lu. 177Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile. Conclusion: The results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of 90Y and 177Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals

  1. Comparative efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibodystreptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTAbiotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in

  2. Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models.

    Sofia H L Frost

    Full Text Available Pretargeted radioimmunotherapy (PRIT is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y and lutetium-177 (177Lu are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma or Granta (mantle cell lymphoma xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-biotin second step reagent.The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq as for 177Lu (0.6 Gy/MBq. More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes.90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma

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

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

  4. DNA damage in blood lymphocytes in patients after {sup 177}Lu peptide receptor radionuclide therapy

    Eberlein, Uta; Bluemel, Christina; Buck, Andreas Konrad; Werner, Rudolf Alexander; Lassmann, Michael [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Nowak, Carina; Scherthan, Harry [Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich (Germany)

    2015-10-15

    The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with {sup 177}Lu-labelled DOTATATE/DOTATOC. The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with {sup 131}I and {sup 177}Lu. The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. Measurements of RIF and the absorbed dose to the blood after systemic administration of {sup 177}Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair. (orig.)

  5. DNA damage in blood lymphocytes in patients after 177Lu peptide receptor radionuclide therapy

    The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with 177Lu-labelled DOTATATE/DOTATOC. The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with 131I and 177Lu. The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. Measurements of RIF and the absorbed dose to the blood after systemic administration of 177Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair. (orig.)

  6. Biological effective doses in 300 patients undergoing therapy with 177Lu-octreotate

    Full text of publication follows. Aim: fractionated therapy with 177Lu-octreotate has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. The main aim of this study was to calculate the biological effective dose (BED) to the kidneys using an individualized dosimetry protocol, and to assess differences in the number of possible treatment cycles based on BED compared to those based on absorbed dose. Methods: a total of 148 female and 152 male patients with neuroendocrine tumors with high somatostatin receptor expression (grade 3 or 4) were included. After infusion of 7.4 GBq of 177Lu-octreotate SPECT/CT images over the abdomen were acquired at 24, 96 and 168 h after infusion. Absorbed dose to kidneys was calculated based on pharmacokinetic data obtained from SPECT/CT. From this the effective half-life of 177Lu-octreotate in the kidneys was estimated, and BED was calculated using the equation described by Barone et al. (1). Results and discussion: for a single treatment cycle of 7.4 GBq, median (1:st-3:rd quartiles) BED was 5.0 Gy (3.9-6.1) in the right kidney and 4.7 Gy (3.7-5.8) in the left kidney. For the same treatment cycle, BED was 9.0% (7.1-11.3) and 8.7% (7.0-10.9) higher than absorbed dose in right and left kidneys, respectively. In patients with high absorbed doses, BED could be more than 20% higher than absorbed dose. Assuming an absorbed dose limit of 23 Gy and a BED limit of 45 Gy to the kidneys, the possible number of treatment cycles was 5.4 (4.5-6.8) based on absorbed dose while using BED increased the number of possible cycles to 9.8 (8.1-12.5). Conclusions: although biological effective dose to the kidneys is higher than absorbed dose, use of BED to estimate the number of possible treatment cycles in 177Lu-octreotate therapy may allow for more treatment cycles than the use of absorbed dose. Refs: 1) Barone, R. et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y

  7. {sup 177}Lu-DOTMP: a viable agent for palliative radiotherapy of painful bone metastasis

    Das, T.; Chakraborty, S.; Banerjee, S. [Radiopharmaceuticals Div., Bhabha Atomic Research Centre, Mumbai (India); Sarma, H.D. [Radiation Biology and Health Sciences Div., Bhabha Atomic Research Centre, Mumbai (India)

    2008-07-01

    The suitable nuclear decay characteristics [T{sub 1/2} = 6.73 d, E{sub {beta}}{sub (max)} = 497 keV, E{sub {gamma}} = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production with adequate specific activity and radionuclidic purity using a moderate flux reactor are important attributes towards {sup 177}Lu to be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study describes the preparation of {sup 177}Lu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) and its preliminary biological evaluation in animal models with an aim to proposing it as a viable radiopharmaceutical for bone pain palliation. The choice DOTMP as the polyaminophosphonic acid carrier ligand is based on the enhanced thermodynamic stability and kinetic inertness of the metal-ligand complexes with macrocyclic chelators. {sup 177}Lu was produced with a specific activity of {proportional_to} 12 GBq/mg ({proportional_to} 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu{sub 2}O{sub 3} target at a thermal neutron flux of {proportional_to} 6 x 10{sup 13} n/cm{sup 2} s for 21 d. {sup 177}Lu-DOTMP complex was prepared in high yield and excellent radiochemical purity (> 99%) using DOTMP synthesized and characterized in-house. The complex exhibited excellent in-vitro stability at room temperature. Biodistribution studies in Wistar rats showed rapid skeletal accumulation of the injected activity [(1.60{+-}0.19)% per gram in femur at 3 h post-injection] with fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic studies carried out in normal Wistar rats and New Zealand white rabbits also demonstrated significant accumulation of the agent in skeleton and almost no retention in any other vital organs. (orig.)

  8. Preparation and quality control of 177Lu-DOTA-anti-CD20 for Radio immunotherapy

    Hassan Yousefnia; Amir Reza Jalilian; Samaneh Zolghadri; Simindokht Shirvani-Arani; Ali Bahrami-Samani; Mohammad Ghannadi-Maragheh

    2010-01-01

    Introduction: The importance of existence and application of radiolabeled anti-CD20 monoclonal antibodies at nonmyeloablative doses in treating B-cell NHL is well recognized throughout the world. In this work, Rituximab was successively labeled with 177Lu-lutetium chloride. Methods: Lu-177 chloride was obtained by thermal neutron flux (4 × 1013 n.cm-2.s-1) of natural Lu2O3 sample with a specific activity of 2.6-3 GBq/mg. The macrocyclic bifunctional chelating agent, N-succinimidyl-1...

  9. Is 161Tb and alternative to 177Lu? In vitro and in vivo comparison using DOTA-Folate conjugates

    Full text of publication follows. Background: The radio-lanthanide 161Tb decays with a half-life of 165.4 h by emission of low energy β- particles and Auger-e- for therapeutic purposes and γ-radiation suitable for SPECT. 161Tb was recently proposed as a potential alternative to 177Lu for targeted radionuclide tumor therapy [Refs.1,2]. The goal of this study was to compare 161Tb and 177Lu using a tumor targeted DOTA-folate conjugate (cm09 [Ref.3]). Methods. 161Tb was produced by a previously published procedure at PSI [Refs.2,3]. 177Lu was obtained from ITG GmbH, Munich, Germany). Radiolabeling of cm09 was carried out by incubation of the reaction mixture at 95 C. degrees for 10 min. In vitro the effects of 161Tb-cm09 and 177Lu-cm09 were tested on folate receptor (FR)-positive KB cells using an MTT viability assay. In vivo the therapeutic effects of 161Tb-cm09 and 177Lu-cm09 (10 MBq, 0.5 nmol) were compared over 7 weeks in KB tumor bearing mice. Results: 161TbCl3 was prepared in an excellent quality and at high radioactivity concentration. Both, 161Tb-cm09 and 177Lu-cm09 were obtained at high purity (> 98%) at a specific activity of > 40 MBq/nmol. In KB tumor cells, 161Tb-cm09 reduced cell viability more effectively than 177Lu-cm09 (161Tb-cm09: IC50 ∼ 0.014 MBq/ml versus 177Lu-cm09: IC50: ∼ 0.063 MBq/ml). In vivo 161Tb-cm09 showed an increased therapeutic efficacy to reduce tumor growth compared to 177Lu-cm09 which was in agreement with an increased absorbed tumor dose (3.3 Gy/MBq for 161Tb-cm09 versus 2.4 Gy/MBq for 177Lu-cm09). Hence an increased average survival time was observed for mice treated with 161Tb-cm09 (54 d) compared to 177Lu-cm09 (35 d). Conclusions. In this study we demonstrated increased therapeutic efficacy of 161Tb-cm09 compared to 177Lu-cm09 to reduce tumor cell growth in vitro and in vivo. Further investigations with other tumor targeting agents will be necessary to draw final conclusions about the future clinical perspectives of 161Tb

  10. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    Frost, Sophia; Frayo, Shani; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Back, Tom; Fisher, Darrell R.; Press, Oliver W.

    2015-03-01

    Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.

  11. Application of single-vial ready-for-use formulation of 111In- or 177Lu-labelled somatostatin analogs

    For the sake of safety it would be desirable to store and transport the ready-for-use liquid formulation (diagnostics and therapeutics) of radiolabelled peptides. The use of ethanol, in combination with a mixture of gentisic- and ascorbic acid, has superior effects on stabilizing radiolabelled somatostatin analogs. As a consequence, 111In- and 177Lu-labelled somatostatin analogs can be stored and transported in a single-vial ready-for-use liquid formulation up to 7 days after radiolabelling. - Highlights: • Optimal quencher combination: ascorbic- and gentisic acid and ethanol. • Used quencher concentrations had no effect on pharmacokinetics. • Purging the reaction mixture with N2 after radiolabelling resulted in 10% higher RCP. • Quencher mixture stabilize 111In- and 177Lu-labelled SS-analogs during 7 days. • Enables to store and transport 111In- and 177Lu-labelled SS-analogs in a single-vial

  12. Uncertainty propagation for SPECT/CT-based renal dosimetry in 177Lu peptide receptor radionuclide therapy

    Gustafsson, Johan; Brolin, Gustav; Cox, Maurice; Ljungberg, Michael; Johansson, Lena; Sjögreen Gleisner, Katarina

    2015-11-01

    A computer model of a patient-specific clinical 177Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of 177Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED. By introducing variabilities in these steps the combined uncertainty in the output quantity is determined. The importance of different sources of uncertainty is assessed by observing the decrease in standard deviation when removing a particular source. The obtained absorbed dose and BED standard deviations are approximately 6% and slightly higher if considering the root mean square error. The most important sources of variability are the compensation for partial volume effects via a recovery coefficient and the gamma-camera calibration via the system sensitivity.

  13. Uncertainty propagation for SPECT/CT-based renal dosimetry in (177)Lu peptide receptor radionuclide therapy.

    Gustafsson, Johan; Brolin, Gustav; Cox, Maurice; Ljungberg, Michael; Johansson, Lena; Gleisner, Katarina Sjögreen

    2015-11-01

    A computer model of a patient-specific clinical (177)Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of (177)Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED. By introducing variabilities in these steps the combined uncertainty in the output quantity is determined. The importance of different sources of uncertainty is assessed by observing the decrease in standard deviation when removing a particular source. The obtained absorbed dose and BED standard deviations are approximately 6% and slightly higher if considering the root mean square error. The most important sources of variability are the compensation for partial volume effects via a recovery coefficient and the gamma-camera calibration via the system sensitivity. PMID:26458139

  14. Reducing Renal Uptake of {sup 177}Lu Labeled CCK Derivative using Basic Amino Acids

    Lee, Soyoung; Lim, Jaecheong; Joh, Eunha [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-05-15

    Radiolabeled peptides have been designed to target the relative receptors overespressed in tumor cells, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), glucagon-like peptide-a receptor (GLP-1R), and cholecystokinin (CCK) receptor. Most of these peptides are eliminated from the body via the kidney and are partly reabsorbed in the proximal tubular cells. However, the high renal uptake of the radiolabeled peptides may lead to renal toxicity. In this study we investigated various amino acid solutions to reduce the renal uptake of {sup 177}Lu-DOTA-CCK derivative. Renal uptake of {sup 177}Lu-DOTA-CCK derivative is effectively reduced by the administration of positively charged amino acids. The administration of 12 mg of L-lysine was as effective in reducing the renal uptake as 6 mg of lysine and 6 mg of arginine combinations. Further studies will be performed to identify the most potent inhibitor of renal reuptake of radiolabeled peptides and minimize the chance of unwanted side effects.

  15. Reducing Renal Uptake of 177Lu Labeled CCK Derivative using Basic Amino Acids

    Radiolabeled peptides have been designed to target the relative receptors overespressed in tumor cells, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), glucagon-like peptide-a receptor (GLP-1R), and cholecystokinin (CCK) receptor. Most of these peptides are eliminated from the body via the kidney and are partly reabsorbed in the proximal tubular cells. However, the high renal uptake of the radiolabeled peptides may lead to renal toxicity. In this study we investigated various amino acid solutions to reduce the renal uptake of 177Lu-DOTA-CCK derivative. Renal uptake of 177Lu-DOTA-CCK derivative is effectively reduced by the administration of positively charged amino acids. The administration of 12 mg of L-lysine was as effective in reducing the renal uptake as 6 mg of lysine and 6 mg of arginine combinations. Further studies will be performed to identify the most potent inhibitor of renal reuptake of radiolabeled peptides and minimize the chance of unwanted side effects

  16. Targeted radiotherapy with 177 Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    Malignant pancreas tumours induced in athymic mice are a good model for targeted radiotherapy. The objective of this research was to estimate pancreatic tumour absorbed radiation doses and to evaluate 177Lu-DOTA-TATE as a therapeutic radiopharmaceutical that could be used in humans. AR42J murine pancreas cancer cells, which over-express somatostatin receptors, were injected in athymic mice and 20 days later the mean tumour size was 3.08 square cm (n=3). A mean of 86.3 MBq 177Lu-DOTA-TATE, was injected in a tail vein and 19 days after therapy the size of the tumours was 0.81 square cm. There was a partial relapse and after 16 days, when sacrificed, the mean tumour size was 8.28 cubic cm. An epithelial and sarcoma mixed tumour in the kidney of one treated mouse was found. The tumour of the control mouse was 8.61 cubic cm when sacrificed 14 days after tumour induction. Radiotherapy estimates to the tumours was 35.9-39.7 Gy and the tumours might have been completely reduced with a second therapy dose. These preliminary studies justify further therapeutic and dosimetry estimations to ensure that Lu-177-DOTA-TATE will act as expected in man, considering kidney radiation. (Author)

  17. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

    In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [177Lu-DOTA0,Tyr3]octreotate. Male Lewis rats were injected with 278 or 555 MBq [177Lu-DOTA0,Tyr3]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of 99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [177Lu-DOTA0,Tyr3]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [177Lu-DOTA0,Tyr3]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of 99mTc-DMSA SPECT scintigrams at 130 days after [177Lu-DOTA0,Tyr3]octreotate therapy correlated well with 1/creatinine (r 2 = 0.772, p 177Lu-DOTA0,Tyr3]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy. (orig.)

  18. Preparation and preliminary studies on 177Lu-labeled hydroxyapatite particles for possible use in the therapy of liver cancer

    Introduction: Intra-arterial administration of particulates labeled with suitable β--emitting radionuclides has emerged as one of the most successful modality for the treatment of primary and metastatic liver cancer. 177Lu [T1/2=6.73 d, Eβ(max)=0.49 MeV, Eγ=208 keV (11%)] could be envisaged as a viable radionuclide for use in liver cancer therapy with wider acceptability owing to its feasibility of production in large-scale and relatively longer half-life providing logistic advantages. Hydroxyapatite (HA) particles of 20-60 μm size range are chosen as the particulate carrier due to its excellent biocompatibility and ease of labeling with lanthanides. Methods: 177Lu was produced by thermal neutron bombardment on enriched Lu target. HA particles of desired size range were synthesized and characterized. Radiolabeling of HA particles was achieved at room temperatures within 30 min. The biological behavior of 177Lu-labeled HA particles prepared under optimized conditions was tested in Wistar rats. Results: 177Lu was produced with a specific activity of 444.2±41.8 GBq/mg and radionuclidic purity of 99.98%. 177Lu-HA was prepared with high radiochemical purity of >99%, and the radiolabeled agent showed excellent in vitro stability. The agent exhibited ∼73% retention of injected activity in liver after 14 days postadministration with insignificant uptake in any other major organ/tissue except skeleton in biodistribution and imaging studies. Conclusion: 177Lu-HA exhibited promising features in radiochemical studies. However, preliminary biodistribution studies in normal Wistar rats exhibited suboptimum liver retention and an undesirable skeletal uptake

  19. Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate

    The radiolanthanide 161Tb (T1/2 = 6.90 days, Eβ-av = 154 keV) was recently proposed as a potential alternative to 177Lu (T1/2 = 6.71 days, Eβ-av = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare 161Tb and 177Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). 161Tb-cm09 and 177Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo 161Tb-cm09 and 177Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using 99mTc-dimercaptosuccinic acid (DMSA). To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for 161Tb-cm09 (IC50 ∝0.014 MBq/ml and ∝2.53 MBq/ml) compared to 177Lu-cm09 (IC50 ∝0.063 MBq/ml and ∝4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies 161Tb-cm09 reduced tumour growth more efficiently than 177Lu-cm09. These findings were in line with the higher absorbed tumour dose for 161Tb-cm09 (3.3 Gy/MBq) compared to 177Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Compared to 177Lu-cm09 we demonstrated equal imaging features for 161Tb-cm09 but an increased therapeutic efficacy for 161Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical

  20. Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of {sup 177}Lu-EDTMP, a potential bone pain palliation agent

    Mathe, Domokos [Department of Applied Radioisotopes and Animal Experimentation, National ' Frederic Joliot-Curie' Institute of Radiobiology and Radiohygiene, H-1221 Budapest (Hungary)], E-mail: mdomokos@hp.osski.hu; Balogh, Lajos; Polyak, Andras; Kiraly, Reka [Department of Applied Radioisotopes and Animal Experimentation, National ' Frederic Joliot-Curie' Institute of Radiobiology and Radiohygiene, H-1221 Budapest (Hungary); Marian, Terez [Institute of Nuclear Medicine, Debrecen University, Debrecen (Hungary); Pawlak, Dariusz [Institute of Atomic Energy, Radioisotope Centre POLATOM, Swierk-Otwock (Poland); Zaknun, John J.; Pillai, Maroor R.A. [International Atomic Energy Agency (IAEA), Vienna (Austria); Janoki, Gyozo A. [Department of Applied Radioisotopes and Animal Experimentation, National ' Frederic Joliot-Curie' Institute of Radiobiology and Radiohygiene, H-1221 Budapest (Hungary)

    2010-02-15

    Introduction: Radionuclide therapy (RNT) is an effective method for bone pain palliation in patients suffering from bone metastasis. Due to the long half-life, easy production and relatively low {beta}- energy, {sup 177}Lu [T{sub 1/2}=6.73 days, E{sub {beta}}{sub max}=497 keV, E{sub {gamma}}=113 keV (6.4%), 208 keV (11%)]-based radiopharmaceuticals offer logistical advantage for wider use. This paper reports the results of a multispecies biodistribution and toxicity studies of {sup 177}Lu-EDTMP to collect preclinical data for starting human clinical trials. Methods: {sup 177}Lu-EDTMP with radiochemical purity greater than 99% was formulated by using a lyophilized kit of EDTMP (35 mg of EDTMP, 5.72 g of CaO and 14.1 mg of NaOH). Biodistribution studies were conducted in mice and rabbits. Small animal imaging was performed using NanoSPECT/CT (Mediso, Ltd., Hungary) and digital autoradiography. Gamma camera imaging was done in rabbits and dogs. Four levels of activity (9.25 through 37 MBq/kg body weight) of {sup 177}Lu-EDTMP were injected in four groups of three dogs each to study the toxicological effects. Results: {sup 177}Lu-EDTMP accumulated almost exclusively in the skeletal system (peak ca. 41% of the injected activity in bone with terminal elimination half-life of 2130 and 1870 h in mice and rabbits, respectively) with a peak uptake during 1-3 h. Excretion of the radiopharmaceutical was through the urinary system. Imaging studies showed that all species (mouse, rat, rabbit and dog) take up the compound in regions of remodeling bone, while kidney retention is not visible after 1 day postinjection (pi). In dogs, the highest applied activity (37 MBq/kg body weight) led to a moderate decrease in platelet concentration (mean, 160 g/L) at 1 week pi with no toxicity. Conclusion: The protracted effective half-life of {sup 177}Lu-EDTMP in bone supports that modifying the EDTMP molecule by introducing {sup 177}Lu does not alter its biological behaviour as a specific bone

  1. Study on the standardization of the radioactivity measurement for 153Sm-EDTMP injection

    The safety and efficacy of the therapeutic radiopharmaceuticals directly depends on its dosage. In order to determine the radioactivity of 153Sm-EDTMP injection accurately, and ensure the safety and efficacy of the 153Sm-EDTMP injection, the standardization for the radioactivity measurement of 153Sm-EDTMP injection with dose calibrators was studied, in which 4π liquid scintillator and 4πβ-γ coincidence method were used to determine the values of radioactivity (the relative expanded uncertainty is less than 3%)for the 153Sm-EDTMP injection standard source with six experimental setups in four laboratories, then the dose calibrators were calibrated with the standard source. The results showed that a the type of dose calibrator,the container and the volume of the sample solution have effects on the results of measurement, but between 3 to 5 mL, the variation of the volume of sample solution has little effect on the results of measurement. At last the measurement conditions were obtained according to the results of the study. (authors)

  2. Uptake of 153Sm-EDTMP in normal, benign and malignant tumor tissue

    Riegel, A

    2001-01-01

    The present study was designed to investigate and compare the uptake of 153Sm-EDTMP (153Samarium-ethylenediaminetetramethylene phosphonate)and 99mTc-DPD (99mTechnetium-dicarboxypropane diphosphonate) into different soft tissue sarcoma cell lines and various tissue specimen in vitro. After 10-120 minutes of incubation at 22 sup o C and 37 sup o C with 153Sm-EDTMP, the uptake kinetics of this tracer in human soft tissue sarcoma cells SW 684 (fibrosarcoma) and SW 1353 (chondrosarcoma) were assessed. The uptake was temperature-dependent and higher into fibrosarcoma than in chondrosarconma. Normal bone tissue samples of rat and human were incubated with 153Sm-EDTMP and 99mTc-DPD. The uptake of 99mTc-DPD was higher than that of 153Sm-EDTMP. Various benign and malignant bone and soft tissue tumors and metastases of different primaries were treated in the same way. The uptake was generally very low, in the metastatic tissue specimen in part possibly due to their osteolytic character.

  3. Fluorescence microscopic and microautoradiographic studies on apoptosis of bone tumor cells induced by 153Sm-EDTMP

    The apoptosis of bone tumor cells treated with internal irradiation by 153Sm-EDTMP was studied. The morphological changes in bone tumor cells were observed by fluorescence microscopic and microautoradiographic observations. It was found that bone tumor cells internally irradiated with 153Sm-EDTMP, displayed significant nuclear fragmentation and marked pyknosis as well as apoptotic bodies formation. The microautoradiographic study showed that 153Sm-EDTMP could permeate through cell membrane and displayed membrane-seeking condensation in tumor cells. Soon afterwards 153Sm-EDTMP could be phagocytized by the tumor cells and distributed in cytoplasm and nucleus in the form of phagosome. With the prolongation of observing time, the membrane-bounded apoptotic bodies was observed. With the lengthening of internal irradiation time by 153Sm-EDTMP, the inhibition rate of proliferation of bone tumor cells increased progressively. (10 refs., 9 figs., 1 tab.)

  4. Hypocalcaemia after treatment with [177Lu-DOTA0,Tyr3]octreotate

    The aim of this study was to explore the possible mechanisms involved in an observed decline in serum calcium levels in patients with a neuroendocrine tumour (NET) treated with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). In 47 patients with NET who were normocalcaemic at baseline, serum calcium, albumin, creatinine, alkaline phosphatase, gamma glutamyl transpeptidase, magnesium, phosphate and 25-hydroxyvitamin D were prospectively analysed at baseline and up to 6 months after treatment. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3, type 1 aminoterminal propeptide of procollagen, bone-specific alkaline phosphatase, carboxyterminal crosslinking telopeptide of bone collagen, collagen type I crosslinked N-telopeptide, and creatinine and calcium in 24-h urine samples, were evaluated at baseline and at 3 and 6 months. Another 153 patients with NET were included in a retrospective study to estimate the occurrence of hypocalcaemia in a larger patient group. In the prospectively included patients, the mean serum calcium level decreased significantly after treatment (2.31 ± 0.01 to 2.26 ± 0.02 mmol/l, p = 0.02). Eight patients (17 %) showed a marked decrease in serum calcium levels with a nadir of ≤2.10 mmol/l. In five patients (11 %), calcium substitution therapy was prescribed. PTH increased significantly (5.9 ± 0.6 to 6.7 ± 0.8 pmol/l, p = 0.02), presumably in response to the decreasing serum calcium levels. 25-Hydroxyvitamin D remained stable after treatment. Creatinine levels increased significantly (73 ± 3 to 77 ± 3 μmol/l, p = 0.01), but not enough to explain the hypocalcaemia. Phosphate levels remained unaffected. In the retrospectively analysed patients, the mean serum calcium level decreased significantly from 2.33 ± 0.01 at baseline to a nadir of 2.24 ± 0.01 mmol/l at 18 months after treatment (p 177Lu-octreotate, resulting in mild hypocalcaemia in about 20 % of patients. We excluded several potential causes of this hypocalcaemia, so the

  5. Hypocalcaemia after treatment with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate

    Vliet, Esther I. van; Kam, Boen L.R.; Teunissen, Jaap J.M.; Krenning, Eric P.; Kwekkeboom, Dik J. [Erasmus MC, University Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Herder, Wouter W. de; Zillikens, M.C.; Peeters, Robin P. [Erasmus MC, University Medical Center, Department of Internal Medicine, Rotterdam (Netherlands); Rijke, Yolanda B. de [Erasmus MC, University Medical Center, Department of Clinical Chemistry, Rotterdam (Netherlands)

    2013-12-15

    The aim of this study was to explore the possible mechanisms involved in an observed decline in serum calcium levels in patients with a neuroendocrine tumour (NET) treated with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate ({sup 177}Lu-octreotate). In 47 patients with NET who were normocalcaemic at baseline, serum calcium, albumin, creatinine, alkaline phosphatase, gamma glutamyl transpeptidase, magnesium, phosphate and 25-hydroxyvitamin D were prospectively analysed at baseline and up to 6 months after treatment. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D{sub 3}, type 1 aminoterminal propeptide of procollagen, bone-specific alkaline phosphatase, carboxyterminal crosslinking telopeptide of bone collagen, collagen type I crosslinked N-telopeptide, and creatinine and calcium in 24-h urine samples, were evaluated at baseline and at 3 and 6 months. Another 153 patients with NET were included in a retrospective study to estimate the occurrence of hypocalcaemia in a larger patient group. In the prospectively included patients, the mean serum calcium level decreased significantly after treatment (2.31 {+-} 0.01 to 2.26 {+-} 0.02 mmol/l, p = 0.02). Eight patients (17 %) showed a marked decrease in serum calcium levels with a nadir of {<=}2.10 mmol/l. In five patients (11 %), calcium substitution therapy was prescribed. PTH increased significantly (5.9 {+-} 0.6 to 6.7 {+-} 0.8 pmol/l, p = 0.02), presumably in response to the decreasing serum calcium levels. 25-Hydroxyvitamin D remained stable after treatment. Creatinine levels increased significantly (73 {+-} 3 to 77 {+-} 3 {mu}mol/l, p = 0.01), but not enough to explain the hypocalcaemia. Phosphate levels remained unaffected. In the retrospectively analysed patients, the mean serum calcium level decreased significantly from 2.33 {+-} 0.01 at baseline to a nadir of 2.24 {+-} 0.01 mmol/l at 18 months after treatment (p < 0.001). Of the 153 patients, 33 (22 %) showed a serum calcium nadir of {<=}2.10 mmol/l, and 11

  6. Evaluation of radiation safety in (177)Lu-PSMA therapy and development of outpatient treatment protocol.

    Demir, Mustafa; Abuqbeitah, Mohammad; Uslu-Beşli, Lebriz; Yıldırım, Özlem; Yeyin, Nami; Çavdar, İffet; Vatankulu, Betül; Gündüz, Hüseyin; Kabasakal, Levent

    2016-06-01

    The aim of this study is to investigate the outpatient treatment protocol and radiation safety of a new-emerging lutetium-177 ((177)Lu) prostate specific membrane antigen (PSMA) therapy. This work analyzed the dose rate of 23 patients treated with 7400 MBq (177)Lu-PSMA at different distances (0, 0.25, 0.50, 1.0 and 2.0 m) and variable time marks (0, 1, 2, 4, 18, 24, 48 and 120 h) after the termination of infusion. Blood samples were withdrawn from 17 patients within the same group at 3, 10, 20, 40, 60 and 90 min and 2, 3, 24 h after termination of infusion. Seven different patients were asked to collect urine for 24 h and a gamma well counter was used for counting samples. Family members were invited to wear an optically stimulated luminescence dosimeter whenever they were in the proximity of the patients up to 4-5 d. The total dose of the medical team including the radiopharmacist, physicist, physician, nurse, and nuclear medicine technologist was estimated by an electronic personnel dosimeter. The finger dose was determined using a ring thermoluminescent dosimeter for the radiopharmacist and nurse. The mean dose rate at 1 m after 4 h and 6 h was 23  ±  6 μSv h(-1) and 15  ±  4 μSv h(-1) respectively. The mean total dose to 23 caregivers was 202.3  ±  42.7 μSv (range: 120-265 μSv). The radiation dose of the nurse and radiopharmacist was 6 and 4 μSv per patient, respectively, whereas the dose of the physicist and physician was 2 μSv. The effective half life of blood distribution and early elimination was 0.4  ±  0.1 h and 5  ±  1 h, respectively. Seven patients excreted a mean of 45% (range: 32%-65%) from the initial activity in 6 h. Our findings demonstrate that (177)Lu-PSMA is a safe treatment modality to be applied as an outpatient protocol, since the dose rate decreases below the determined threshold of  <30 μSv h(-1) after approximately 5 h and degrades to 20 μSv h(-1) after 6

  7. Production and supply of 99Mo, 153Sm radioisotopes for medical applications - societal benefits

    Application of radioisotopes in medicine has led to the evolution of a new branch of medicine called 'Nuclear Medicine' wherein radioisotope products in the form radiopharmaceuticals are used for the diagnosis of diseases, their follow up, detecting recurrence and also in the treatment of certain diseases. Large scale production, processing and supply of number of radioisotopes for medical application has been a feature of our laboratory. 99Mo is an important radionuclide produced in our reactors to obtain 99mTc, the most commonly used diagnostic radionuclide in the preparation of 99mTc-radiopharmaceuticals through 99Mo-99mTc radionuclide generators. 99Mo for the preparation of generators based on solvent extraction technology is produced by irradiation of natural MoO3 target in Dhruva and Cirus reactors. About 1.5 TBq (∼40 Ci) of 99Mo is processed and supplied to Board of Radiation and Isotope Technology (BRIT) every week on Saturdays to meet the requirements of nuclear medicine centres in the country. 153Sm-EDTMP is a ready-to-use radiopharmaceutical approved for the palliative treatment of metastatic bone pain in patients suffering from primary lung, breast and prostate cancers. 153SmCl3, the primary radiochemical for preparation of 153Sm-radiopharmaceutical is produced by neutron activation of natural or enriched Sm2O3 target in our medium flux research reactors. 150 GBq (4Ci) 153Sm is processed and supplied every month to BRIT for radiopharmaceutical production and further supply to nuclear medicine centres. Logistics of regular production of both 99Mo and 153Sm radionuclides, their quality control and the scope for the production of these radiochemicals with high specific activity to meet the increasing demands in the years to come with concomitant health care benefits to the society at large are discussed in this paper. (author)

  8. Preclinical Evaluation of (177)Lu-Nimotuzumab: A Potential Tool for Radioimmunotherapy of Epidermal Growth Factor Receptor-Overexpressing Tumors

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

    2011-01-01

    Roč. 26, č. 3 (2011), s. 287-297. ISSN 1084-9785 R&D Projects: GA MŠk OE08018 Institutional research plan: CEZ:AV0Z10480505 Keywords : EGFR * (177)Lu * monoclonal antibodies * Nimotuzumab Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 1.787, year: 2011

  9. IMPROVED PLANAR KIDNEY ACTIVITY CONCENTRATION ESTIMATE BY THE POSTERIOR VIEW METHOD IN 177LU-DOTATATE TREATMENTS.

    Magnander, Tobias; Svensson, Johanna; Båth, Magnus; Gjertsson, Peter; Bernhardt, Peter

    2016-06-01

    The aims of this study were to determine how different background regions of interest (ROIs) around the kidney represent true background activity in over- and underlying tissues in (177)Lu-DOTA-octreatate ((177)Lu-DOTATATE) treatments and to determine the influence of the background positions on the kidney activity concentration estimates by the conjugate view (ConjV) and posterior view (PostV) methods. The analysis was performed in single-photon emission computed tomography (SPECT) images of 20 patients, acquired 24 h post injection of a (177)Lu-DOTATATE treatment, by a computer algorithm that created planar images from the SPECT data. The ratio between the activity concentration in the background and the true background varied from 0.36 to 2.08 [coefficient of variation (CV) = 25-181 %] and from 0.44 to 1.52 (CV = 16-70 %) for the right and left kidneys, respectively. The activity concentration estimate in the kidneys was most accurate with the PostV method using a background ROI surrounding the whole kidney, and this combination might be an alternative planar method for improved kidney dosimetry in the (177)Lu-DOTATATE treatments. PMID:27012883

  10. 177Lu-DTPA-BIS-BIOTIN Binding of Octreotide-dextran-avidinated PANC-1 Cell Lines in Vitro

    Tyr3-octreotide, dextran-40 and avidin were used to prepare octreotide-dextran-avidin (TOC-Dx40-Av). DTPA-BIS-BIOTIN was labelled with 177Lu. The in vitro somatostatin receptor binding study was carried out by pretargeted method using TOC-Dx40-Av and 177Lu-DTPA-BIS-BIOTIN. The 24 well cell culture plates were prepared with PANC-1 cell monolayer and then incubated with TOC-Dx40-Av. After two washed with PBS, the cells were incubated with different concentration of 177Lu-DTPA-BIS-BIOTIN (48.8 ∼ 391 pmol). Cells uptake was evaluated with γ counter. The results showed that the chemical purity of TOC-Dx40-Av was over 99%. The results also showed that TOC-Dx40-Av remained high receptor binding affinity to somatostatin receptor which indicated that TOC- Dx40-Av could bind to 177Lu-DTPA-BIS-BIOTIN with the molar ratio of 1 : 1 on the cell surface. (authors)

  11. Preparation, Characterization and Stability Test of 177Lu-CTMP as Palliative Agent For Bone Pain Metastases

    177Lu-CTMP is an ideal radiopharmaceutical for palliative agent on bone pain metastases. This radiopharmaceutical was synthesized from cyclic polyaminophosphonic ligand, known as 1,4,8,11-tetraazacycIotetradecane-l, 4,8,11 tetramethylene phosphonic acid (CTMP) and labeled with 177Lu radio nuclide, a beta emitter which has long enough half life (t1/2=6.71 days, E β-max= 497 KeV). The labeling method was modified from Tapas Das Method by changing buffer type. Ammonium carbonate buffer was changed by phosphate buffer. In this research some variables were used. such as mol comparison (Lu:CTMP), pH variation, and reaction temperature. The result, indicated that an optimum condition of 177Lu-ClMP preparation was at mol comparison Lu:CTMP= 1:20, pH=7, and at room temperature. Optimum labeling of 177Lu-CTMP has been tested using paper chromatography, giving 99.4 % of radiochemical purity. From the stability test, it was found that the radiopharmaceutical was stable until 10 days (when it stored in room temperature and 4°C). After 10 days, decreasing of radiochemical purity, was found if stored in room temperature ( below of the required radiochemical purity «95%)). However, when it was stored at 4°C, it was stable until 21 days with a good condition (radiochemical purity >95%). (author)

  12. Tumor response assessment to treatment with [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors: differential response of bone versus soft-tissue lesions.

    Vliet, E.I. van; Hermans, J.J.; Ridder, M.A. de; Teunissen, J.J.; Kam, B.L.; Krijger, R.R. de; Krenning, E.P.; Kwekkeboom, D.J.

    2012-01-01

    We have noted that bone lesions on CT respond differently from soft-tissue lesions to treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). We therefore compared the response of bone lesions with that of soft-tissue lesions to treatment with (177)Lu-octreotate in patients with gast

  13. Anti-EGFRvIII monoclonal antibody armed with {sup 177}Lu: in vivo comparison of macrocyclic and acyclic ligands

    Hens, Marc; Vaidyanathan, Ganesan; Zhao Xiaoguang [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R., E-mail: zalut001@mc.duke.ed [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States)

    2010-10-15

    Introduction: Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its {beta}-emissions, labeling this mAb with {sup 177}Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. Materials and Methods: L8A4 mAb was labeled with {sup 177}Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1, 2-diamine-pentaacetic acid (CHX-A''-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and {alpha}-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.{Delta}EGFR glioma xenografts over a period of 1 to 8 days to directly compare {sup 177}Lu-labeled L8A4 to L8A4 labeled with {sup 125}I using N-succinimidyl 4-guanidinomethyl-3-[{sup 125}I]iodobenzoate ([{sup 125}I]SGMIB). Results: Except with C-DOTA, tumor uptake for the {sup 177}Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for {sup 177}Lu-1B4M-DTPA-L8A4 and, to an even greater extent, {sup 177}Lu-MeO-DOTA-L8A4 were higher than those for [{sup 125}I]SGMIB-L8A4 in most other tissues. Conclusions: Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for {sup 177}Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage

  14. Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands

    Introduction: Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with 177Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. Materials and Methods: L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1, 2-diamine-pentaacetic acid (CHX-A''-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.ΔEGFR glioma xenografts over a period of 1 to 8 days to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). Results: Except with C-DOTA, tumor uptake for the 177Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for 177Lu-1B4M-DTPA-L8A4 and, to an even greater extent, 177Lu-MeO-DOTA-L8A4 were higher than those for [125I]SGMIB-L8A4 in most other tissues. Conclusions: Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for 177Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application.

  15. Treatment of neuroendocrine tumors (NETs) expressing SMT 90Y and 177Lu

    Neuroendocrine tumors (NETs) are a relatively rare and extremely heterogeneous group, essentially characterized by a different metabolism and endocrine histologically pattern. NETs are a challenge for physicians not only for diagnosis but also for early treatment. In addition to this, QT or RT treatments that require a high rate of cell proliferation to be effective, they are not in these tumors as slow growth. The primary treatment of NETs is surgery, either with a curative intent or tumor shrinkage. Peptide Receptors Radiotherapy (RTPR) consists of the administration for therapeutic purposes of Radiolabeled Synthetic Peptides that bind specifically and with high affinity to receptors of tumor cells. The RTPR of TNE with SMT analogues is effective for handling or metastizados inoperable patients. The Conference gives an accurate picture of the treatment of these tumors both 90Y as 177Lu. (author)

  16. Study On Preparation Of 177Lu-EDTMP For Metastatic Bone Pain Palliation Treatment

    Ethylene diamine tetramethylene phosphonate (EDTMP) is one of the most widely used ligands which forms stable complexes with various radionuclides and all the complexes showed high bone uptake in biodistribution studies. EDTMP has a high affinity to skeleton and osteoblastic bone metastases and many EDTMP chelates posses a considerably high stability.This stimulated application of the ligand as the in-vivo carrier of various radionuclides, intended for both therapy and diagnosis of osteoblastic lesions.The present study intends to formulate EDTMP kits, label them with 177Lu, quality control and in-vitro stability studies. This paper presents some research results on the optimal conditions for labeling EDTMP kit with Lu-177 of low specific activity that was produced on the IVV-9 reactor at the Nuclear Research Institute. (author)

  17. Effect of amplified spontaneous emission on selectivity of laser photoionisation of the 177Lu radioisotope

    D'yachkov, A. B.; Gorkunov, A. A.; Labozin, A. V.; Mironov, S. M.; Panchenko, V. Ya; Firsov, V. A.; Tsvetkov, G. O.

    2016-06-01

    A significant deselecting effect of amplified spontaneous emission has been observed in the experiments on selective laser photoionisation of the 177Lu radioisotope according to the scheme 5d6s2 2D3/2 → 5d6s6p 4Fo5/2 (18505 cm-1) → 5d6s7s 4D3/2(37194 cm-1) → autoionisation state (53375 cm-1). The effect is conditioned by involvement of non-target isotopes from the lower metastable level 5d6s2 2D5/2(1994 cm-1) into the ionisation process. Spectral filtering of spontaneous emission has allowed us to significantly increase the selectivity of the photoionisation process of the radioisotope and to attain a selectivity value of 105 when using saturating light intensities.

  18. Preparation and Evaluation of 177Lu Labeled Nitroimidazole Derivative for Targeting Tumor Hypoxia

    Hypoxia has been known be an important physiological parameter for tumor growth and has been reported to be the cause for poor response to chemotherapy. Mechanistically, tumor hypoxia results from an imbalance between oxygen delivery and oxygen consumption. The identification and quantification of tumor hypoxia may predict the out come and may identify patients who might benefit from concomitant radiosensitizing therapy to overcome the hypoxia effect. In nuclear medicine, there is an interesting observation that nitroimidazole derivatives can selectively accumulate in the hypoxic regions, a character of a good radiosensitizer. In this study, we have synthesized a 2-nitroimidazole derivative containing a DOTA chelator by using a solid phase reaction. The nitroimidazole analogue was radiolabeled with 177Lu. Furthermore biodistribution study was performed to evaluate its tissue uptake, in vivo

  19. In vitro characterization of 177Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

    131I- and 90Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin's lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (177Lu or 90Y. Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 105 times excess of diethylenetriaminepentaacetic acid (DTPA, 37 C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m2 body surface 177Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314 mGy. The administration of 177Lu-DOTA-rituximab was tolerated well. Our results show that DOTA-rituximab (4:1) can be labelled with 177Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL. (orig.)

  20. The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA-conjugated receptor-specific peptides labelled with (177) Lu.

    Volková, Marie; Mandíková, Jana; Bárta, Pavel; Navrátilová, Lucie; Lázníčková, Alice; Trejtnar, František

    2015-01-01

    In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low-molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA-minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala-Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite. PMID:26526343

  1. Production, quality control, biodistribution assessment and preliminary dose evaluation of [177Lu]-tetra phenyl porphyrin complex as a possible therapeutic agent

    Samaneh Zolghadri

    2015-06-01

    Full Text Available Due to interesting therapeutic properties of 177Lu and tumor avidity of tetraphenyl porphyrins (TPPs, 177Lu-tetraphenyl porphyrin was developed as a possible therapeutic compound. 177Lu of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu2O3sample with thermal neutron flux of 4 × 1013 n.cm-2.s-1. Tetraphenyl porphyrin was synthetized and labeled with 177Lu. Radiochemical purity of the complex was studied using Instant thin layer chromatography (ITLC method. Stability of the complex was checked in final formulation and human serum for 48 h. The biodistribution of the labeled compound in vital organs of wild-type rats was studied up to 7 d. The absorbed dose of each human organ was calculated by medical internal radiation dose (MIRD method. A detailed comparative pharmacokinetic study was performed for 177Lu cation and [177Lu]-TPP. The complex was prepared with a radiochemical purity: >97±1% and specific activity: 970-1000 MBq/mmol. Biodistribution data and dosimetric results showed that all tissues receive approximately an insignificant absorbed dose due to rapid excretion of the complex through the urinary tract. [177Lu]-TPP can be an interesting tumor targeting agent due to low liver uptake and very low absorbed dose of approximately 0.036 to the total body of human.

  2. Labelling of Dotatate with 177Lu and 131I for diagnosis and targeted therapy: In vitro and In vivo comparative evaluation

    The studies focused on the radiolabelling of DOTA-Tyr3-TATE (DOTATATE) with 177Lu and 131I, on the biological behaviour of 177Lu-DOTATATE and 131IDOTATATE and on comparative evaluation of the results obtained to select an appropriate radiopeptide for potential application in somatostatin receptor radionuclide therapy. The radiopeptides were obtained with high purities and specific activities, but with different stabilities, with the 177Lu-DOTATATE being more stable than the 131IDOTATATE. The results of competition and saturation binding experiments using rat brain cortex membrane homogenates show a high in vitro affinity (IC50: 4.74nM, Kd: 142.8 for 177Lu-DOTATATE; IC50: 1.28nM, Kd: 157.6 for 131I-DOTATATE). The biodistribution of each radiopeptide as well as the competitive biodistribution of 177Lu- DOTATATE and 131I-DOTATATE in rats bearing HRS1 (Hepatom RS1, a hepatocolangiom carcinoma) tumours illustrate that 177Lu-DOTATATE is more stable and shows better tumour uptake than 131I-DOTATATE, and that the competitive localization index of 177Lu-DOTATATE is three times higher than that of 131I-DOTATATE. The flow cytometry measurements of the HRS1 tumour samples from rats treated with multiple doses of 177Lu-DOTATATE in combination with absorbed dose data show decreases of both the tumour cell proliferation index and DNA ploidy. These data indicate that 177Lu- DOTATATE is a good option for application in somatostatin receptor radionuclide therapy. (author)

  3. Electron microscopic observations and DNA chain fragmentation studies on apoptosis in bone tumor cells induced by 153Sm-EDTMP

    The morphological changes observed by electron microscopy indicate that after internal irradiation with 153Sm-EDTMP bone tumor cells displayed feature of apoptosis, such as margination of condensed chromatin, chromatin fragmentation, as well as the membrane bounded apoptotic bodies formation. The quantification analysis of fragmentation DNA for bone tumor cells induced by 153Sm-EDTMP shows that the DNA fragmentation is enhanced with the prolongation of internally irradiated time. These characteristics suggest that 153Sm-EDTMP internal irradiation could induce bone tumor cells to go to apoptosis

  4. 177Lu medical radioisotope separation from Yb-Lu matrix irradiated pass through ion exchanger resin by eluent of α-Hiba and HNO3 solution

    Since a few last year, Lutetium-177 ( 177Lu) have come to be one of lanthanide radioisotopes which is widely used for the purpose of therapy. Radioisotope of 177Lu emit β-radiation with energy of 497 keV ( 78 %) that is ideal for therapeutical treatment of soft-tissue tumor. It also emits γ-radiation energy of 208 keV (12 %) that is suitable for imaging technique. The characteristic of the emitted radiation energies are as well supported by its physical half live of 6.65 days that makes radioisotope 177Lu to be a choice in the field of nuclear medicine. The domestic capability on the production of carrier free 177Lu do not support yet the wide application of 177Lu. This present proposal is arrived to learn and to master the production of carrier free 177Lu based on nuclear reaction of 176Yb(n,γ) 177Yb. The production process method of carrier free 177Lu is involved separation technique of 177Lu from the matrix of post-irradiated natural Yb, will be performed based on column chromatographic separation using stationary phase of ion exchanger. Comparison Lu/Yb in the Yb-Lu bulk solution in fraction the introduction experiment from the A trial to the E trial that he thought between 0.137 s/he 0.0198 almost resemble the radioisotope comparison 177Lu/ 175Yb in the Yb-Lu bulk solution that he thought between 0.157 s/he 0.0211. Meaning that the introduction experiment of the above still cannot separate the species 177Lu radionuclides from solder Lu-Yb irradiated. In two trials of the optimisation is received by results of Lu/Yb comparison respectively of 18.794 and 25,537 respectively in the fraction 43 compared with Lu/Yb comparison in the Yb-Lu bulk solution that is their respective only of 0.0312. This shows the existence of the separation of the species 177Lu radionuclide from the matrix Yb-You irradiated. The condition for the trial of this optimisation must be evaluated further to receive the separation 177Lu radionuclide from the matrix Yb-Lu that is better

  5. Targeted radiotherapy dosimetry of 153Sm hydroxide macroaggregates for radiation synovectomy

    The dosimetry of the recently developed 153Sm hydroxide macroaggregates (153Sm-MH) for radiation synovectomy has been studied as an agent for the treatment of arthritic synovial joint diseases. This pharmaceutical formulation presents optimal properties in terms of particle size (average 4 μm) sedimentation (0.008 cm min-1) and biological behavior. Direct measurements of depth dose distributions for this beta-gamma emitter present a difficult task; therefore, calculations of depth dose profiles are an invaluable tool for investigating the effectiveness of this therapeutic technique. In spite of the importance of these calculations there are only a few studies dealing with the experimental validation of these calculated depth dose distributions. On the present work the Monte Carlo (MCNP4B) calculated beta-gamma depth dose profiles for a liquid 153Sm beta-gamma source used in radiation synovectomy are compared with experimental depth dose distribution obtained using radiochromic dye film dosimetry (GafChromic trade mark sign ). The calculated and experimental depth dose distribution showed a very good agreement (within 5%) on the region where the dose deposition is dominated by the beeta-particle component (first 800 microns depth on tissue equivalent material). The agreement worsens reaching a maximum deviation of 15% at depths close to the maximum range of the beta-particles. Finally the agreement improves for the region where the gamma component accounts for one third of the total absorbed dose (depths>1 mm). The possible contributions to these differences are discussed as well as their relevance for the application of 153Sm for the treatment of rheumatoid arthritis

  6. Treatment status of painful bone metastases with 153Sm-EDTMP

    The typical management of painful bone metastases is radiation therapy and the graduated use of opiate analgesics. As the development of nuclear medicine, bone-seeking radiopharmaceuticals have been utilized in cancer treatment, especially in management painful bone metastases. 153Sm-EDTMP (samarium-153-ethylenediamine tetramethylene phosphonate) offers a good choice of treating method in palliating pain, improving quality of life, decreasing the rate at which new painful sites develop, and decreasing management costs

  7. Labelling of MoAb with 153SmH1ETA: Preliminary results

    A method to label MoAb with Sm-153 using 1,5,9,13-tetraazacyclohexadecane N,N',N'',N''' tetraacetic acid (H4ETA) as a bifunctional chelator was developed. H4ETA and SmH1ETA were synthesized in our laboratory and characterized by IR spectroscopy, TGA (thermogravimetric analysis), SEM (Scattering Electronic Microscopy), EDAX (Elemental Dispersion Analysis by X-rays) and EPR (Electron Paramagnetic Resonance) at 6 K. The 153SmH1ETAMoAb was prepared by a simple incubation of the MoAb ior cea1, and the 153SmH1ETA complex at neutral pH and at room temperature for 24 h. The specific activity of the labelled antibody was 111 MBq/mg (3 mCi/mg). Sm-153(III) is commercially available with specific activities up to 318.2 GBq/mg. Therefore, under the conditions described above 153SmH1ETA labelled MoAb could be obtained with specific activity up to 1.14 GBq/mg (30.7 mCi/mg). (author)

  8. Production and purification of the {sup 161} Tb, {sup 149} Pm, {sup 166} Ho and {sup 177} Lu radioisotopes; Produccion y purificacion de los radioisotopos {sup 161} Tb, {sup 149} Pm, {sup 166} Ho y {sup 177} Lu

    Jaime S, E. [ININ, 52750 La Marquesa, Estado de Mexico (Mexico)

    2007-07-01

    The present thesis work this constituted by four chapters; the theoretical mark is the first of them, in this chapter an introduction it is presented where is showed the characteristics and importance of the study of the lanthanides in nuclear medicine, as well as the theoretical bases of the analytical methods and of characterization used in this work. The second chapter it describes the methodology followed in the experimental part; while the third chapter shows the obtained results in the separation and purification of the radioisotopes: {sup 149} Pm, {sup 161} Tb, {sup 166} Ho, and {sup 177} Lu. In the fourth chapter the obtained conclusions of this study work are presented where it was concluded that it can separate and to purify the radioisotopes: {sup 149} Pm, {sup 161}Tb, {sup 166} Ho and {sup 177} Lu using the column extraction chromatography. (Author)

  9. Fast voxel-level dosimetry for 177Lu labelled peptide treatments

    Hippeläinen, E.; Tenhunen, M.; Sohlberg, A.

    2015-09-01

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for 177Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions. Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by 177Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared. The photon cross-fire dose from the kidney increased the background’s absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  10. Fast voxel-level dosimetry for 177Lu labelled peptide treatments

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for 177Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions.Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by 177Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared.The photon cross-fire dose from the kidney increased the background’s absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  11. Production and first use of 153SmCl3-ion exchange resin capsule formulation for assessing gastrointestinal motility

    We produced an enteric-coated gelatine capsule containing neutron-activated 153Sm-labelled resin beads for use in gastrointestinal motility studies. In vitro test in simulated gastrointestinal environment and in vivo study on volunteers were performed. Scintigraphic images were acquired from ten volunteers over 24 h while blood and urine samples were collected to monitor the presence of 153Sm. All the capsules remained intact in stomach. This proved to be a safe and practical oral capsule formulation for whole gut transit scintigraphy. - Highlights: ► Enteric-coated gelatin capsule containing 153Sm-labelled resin was manufactured. ► In vitro disintegration test ensured targeted release properties of the formulation. ► In vivo volunteers study confirmed safeness and practical use of the formulation. ► 153Sm can be used as an alternative nuclide to 111In in GI transit scintigraphy.

  12. Scintigraphic dynamics valuation of bone metastasis in the course of the treatment of 153Sm-oksabifor

    In the present study we examined the role of bone scan with 99mTc-pyrophosphate treatment planning 153Sm-oksabifor followed by analysis of post-treatment monitoring of cancer patients with bone metastases

  13. Evaluation of the therapeutic efficacy and radiotoxicity of the conjugates 177Lu-DOTA-E-c(RGDfK)2 and 177Lu-DOTA-GGC-AuNP-c[RGDfk(C)] in a murine model and their relationship with the inhibition of the angiogenic factors VEGF and HIF-1α

    Molecular targeting therapy has become a relevant therapeutic strategy for cancer. The principle that peptide receptors can be used successfully for in vivo targeting of human cancers has been proven, and radiolabeled peptides have been demonstrated to be effective in patients with malignant tumors. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been designed to antagonize the function of α(v)β(3) integrin, thereby inhibiting angio genesis. The conjugation of RGD peptides to radiolabeled gold nanoparticles (AuNP) produces biocompatible and stable m ultimeric systems with target-specific molecular recognition. The aim of this research was to evaluate the therapeutic response of 177Lu-AuNP-RGD in athymic mice bearing α(v)β(3)-integrin-positive C6 gliomas and compare with that of 177Lu-AuNP or 177Lu-RGD. The radiation absorbed dose, metabolic activity (SUV, [18F]fluor-deoxy-glucose-micro PET/CT), renal radiotoxicity, renal and tumoral histological characteristics as well as tumoral VEGF and HIF-1? gene expression (by realtime polymerase chain reaction) following treatment with 177Lu-AuNP-RGD, 177Lu-AuNP or 177Lu-RGD were assessed. Of the radiopharmaceuticals evaluated, 177Lu-AuNP-RGD delivered the highest tumor radiation absorbed dose (63.8 ± 7.9 Gy) vs other treatments. These results correlated with the observed therapeutic response, in which 177Lu-AuNP-RGD significantly (p177Lu). There was a low uptake in non-target organs and no induction of renal toxicity. 177Lu-AuNP-RGD demonstrates properties suitable for use as an agent for molecular targeting radiotherapy. (Author)

  14. Formation of medical radioisotopes 111In, 117mSn, 124Sb, and 177Lu in photonuclear reactions

    The possibility of the photonuclear production of radioisotopes 111In, 117mSn, 124Sb, and 177Lu is discussed. Reaction yields were measured by the gamma-activation method. The enriched tin isotopes 112, 118Sn and Te and HfO2 of natural isotopic composition were used as targets. The targets were irradiated at the linear electron accelerator of Alikhanian National Science Laboratory (Yerevan) at the energy of 40 MeV. The experimental results obtained in this way reveal that the yield and purity of radioisotopes 111In and 117mSn are acceptable for their production via photonuclear reactions. Reactions proceeding on targets from Te and HfO2 of natural isotopic composition and leading to the formation of 124Sb and 177Lu have small yields and are hardly appropriate for the photoproduction of these radioisotopes even in the case of enriched targets

  15. {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.)

  16. 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.)

  17. Therapeutic Efficacy with Treatment-related Toxicities of 177Lu-labeled Bombesin Derivative for the Peptide Receptor Radiotherapy

    The gastrin-releasing peptide receptor (GRPR) has been shown to be overexpressed in many human tumours, including breast cancer, prostate cancer, small cell lung cancer, ovarian cancers, endometrial cancers, and gastrointestinal stromal tumors. In particular, GRPR expression is high in 83 % of invasive primary prostatic carcinomas. These results suggest that 177Lu-labeled bombesin derivative has promising characteristics as a novel nuclear medicine, especially for the treatment of GRPR over-expressing prostate tumors

  18. Improvement in the 111In-DTPA-TYR3-octreotide and 177Lu-DOTATYR3- octreotate production

    Recent advances in receptor mediated-tumor imaging have resulted in the development of somatostatin analogues, the biomolecular basis for the clinical use of these compounds in nuclear medicine for diagnostic and peptide receptor radionuclide therapy (PRRT). PRRT is a very good therapeutic option for patients with metastatic neuroendocrine gastroenteropancreatic (GEP) tumour. Clinical studies with different sst-positives tumors proved advantages of [177Lu-DOTA-Tyr3]octreotate (DOTATATE) for therapy. The aim of this work is to establish and validate the labeling, the quality control procedures of DTPA-Tyr3-Octreotide (DTPA-Oct) and DOTA-Tyr3-Octreotate (DOTATATE) labeled with In-111 and Lu-177, respectively, for routine production at Radiopharmacy Directory (DIRF) Brazil. Labeling were performed in a 'glove-box' using 111InCl3 (Nordion) and in hot-cell with 177LuCl3 (IDB-Holland) at pH 4.5; using DTPA-Oct (Pichem) and DOTATATE (IDBHolland) at room temperature and at 82-85 deg C for 30 minutes, respectively. The radiochemical purity was determined by ITLC-SG in 0.1 mol L-1 sodium citrate, pH 5.5 and by Sep-Pak silica cartridge. Sterility was performed by the microbiology procedures and pyrogen tests by the 'in-vitro' Limulus test (LAL). The stability of both radiolabeled peptides was high even 72 hours under refrigeration. The radiochemical purities of the labeled compounds were confirmed by HPLC. Sterility and pyrogen tests were negative in all delivered vials. The efficient procedure to obtain 111In-DTPA-Oct and 177Lu-DOTATATE was confirmed in the first comparative clinical groups. The methods were validated and 46.287 GMBq of 111In-DTPA-Oct and 1,193 GBq of 177Lu-DOTATATE were distributed in 2008, to nuclear medicine services in Brazil. (author)

  19. Therapeutic Efficacy with Treatment-related Toxicities of {sup 177}Lu-labeled Bombesin Derivative for the Peptide Receptor Radiotherapy

    Lim, Jae Cheong; Cho, Eun Ha; Lee, So Young [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-05-15

    The gastrin-releasing peptide receptor (GRPR) has been shown to be overexpressed in many human tumours, including breast cancer, prostate cancer, small cell lung cancer, ovarian cancers, endometrial cancers, and gastrointestinal stromal tumors. In particular, GRPR expression is high in 83 % of invasive primary prostatic carcinomas. These results suggest that {sup 177}Lu-labeled bombesin derivative has promising characteristics as a novel nuclear medicine, especially for the treatment of GRPR over-expressing prostate tumors.

  20. Somatostatin-based radiopeptide therapy with [{sup 177}Lu-DOTA]-TOC versus [{sup 90}Y-DOTA]-TOC in neuroendocrine tumours

    Romer, A.; Seiler, D.; Brunner, P.; Ng, Q.K.T.; Mueller-Brand, J. [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Marincek, N.; Walter, M.A. [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); University Hospital Bern, Institute of Nuclear Medicine, Bern (Switzerland); Koller, M.T. [University Hospital Basel, Basel Institute for Clinical Epidemiology and Biostatistics, Basel (Switzerland); Maecke, H.R. [University Hospital Basel, Division of Radiochemistry, Basel (Switzerland); Rochlitz, C. [University Hospital Basel, Department of Oncology, Basel (Switzerland); Briel, M. [University Hospital Bern, Institute of Nuclear Medicine, Bern (Switzerland); University Hospital Basel, Basel Institute for Clinical Epidemiology and Biostatistics, Basel (Switzerland); McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton (Canada); Schindler, C. [University of Basel, Swiss Tropical and Public Health Institute, Basel (Switzerland)

    2014-02-15

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides {sup 90}Y or {sup 177}Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [{sup 90}Y-DOTA]-TOC or [{sup 177}Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [{sup 90}Y-DOTA]-TOC and 141 patients underwent 259 cycles of [{sup 177}Lu-DOTA]-TOC. The median survival after [{sup 177}Lu-DOTA]-TOC and after [{sup 90}Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [{sup 177}Lu-DOTA]-TOC over [{sup 90}Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [{sup 177}Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). The present results revealed no difference in median overall survival after [{sup 177}Lu-DOTA]-TOC and [{sup 90}Y-DOTA]-TOC. Furthermore, [{sup 177}Lu-DOTA]-TOC was less haematotoxic than [{sup 90}Y-DOTA]-TOC. (orig.)

  1. {sup 177}Lu-DOTATATE therapy in patients with neuroendocrine tumours: 5 years' experience from a tertiary cancer care centre in India

    Danthala, Madhav; Raghavendra Rao, M. [HCG Oncology Hospitals, Bangalore, Karnataka (India); Kallur, K.G.; Prashant, G.R.; Rajkumar, K. [HCG Oncology Hospitals, Department of Nuclear Medicine, Bangalore, Karnataka (India)

    2014-07-15

    The choice of an appropriate treatment option in patients with inoperable or metastatic neuroendocrine tumours (NETs) is limited, and approximately 50 % of patients have advanced NET at diagnosis, and 65 % die within 5 years. Treatment with {sup 177}Lu-DOTATATE ({sup 177}Lu-[DOTA{sup 0},Tyr{sup 3}] octreotate) is a promising new option in the treatment of metastatic NETs. Patients with metastatic NET who underwent {sup 177}Lu-DOTATATE during the period 2009 to 2013 were included in this retrospective study. Follow-up imaging studies including a {sup 68}Ga-DOTANOC PET/CT scan and a posttherapy {sup 177}Lu-DOTATATE scan were compared with baseline imaging to determine response to treatment. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and Cox regression analysis was also done. Ten patients (25 %) had a minimal response, 13 (32.5 %) had a partial response and 9 (22.5 %) had stable disease. Progressive disease was seen in 8 patients (20 %), including 6 patients who died during or after the treatment period. The estimated mean PFS in those who received one or two cycles of {sup 177}Lu-DOTATATE was 8.3 months (95 % CI 6.2 to 10.3 months) compared to an estimated mean PFS of 45.6 months (95 % CI 40.9 to 50.2 months) in those who received more than two cycles of {sup 177}Lu-DOTATATE (log-rank Mantel-Cox Χ {sup 2} = 8.01, p = 0.005). Our study showed that treatment with {sup 177}Lu-DOTATATE should be considered in the management of NETs, considering the limited success of alternative treatment modalities. Treatment response and PFS is determined primarily by the dose delivered and best results are obtained when more than two cycles of {sup 177}Lu-DOTATATE are given, with careful monitoring for possible side effects. (orig.)

  2. Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model

    Orozco, Johnnie J.; Ethan R. Balkin; Gooley, Ted A.; Kenoyer, Aimee; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Hylarides, Mark D.; Shadman, Mazyar; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD4...

  3. Production of glass microspheres comprising 90Y and 177Lu for treating of hepatic tumors with SPECT imaging capabilities

    Our objective was to determine if glass microspheres impregnated with two radionuclides,90Y as source of therapeutic beta emissions and 177Lu as source of diagnostic gamma emissions can be useful for SPECT imaging during or after application of the 90Y microspheres for treating of hepatic tumors. The glass-based microspheres labeled with 89Y and lutetium (YAS (Lu)) or 89Y and ytterbium (YAS (Yb)) were prepared by the sol-gel process where sol droplets directly were formed to gel microspheres. Results of the neutron activation indicate that such a combination of glass, microspheres allow bio-distribution studies by SPECT imaging with high resolution. - Highlights: → A radioactive microsphere composed of glass was impregnated with two radionuclide 90Y and 177Lu. 177Lu is as a dopant for diagnostic gamma emissions. → The glass-based microspheres labeled with 89Y and lutetium (YAS (Lu)) or 89Y and ytterbium (YAS (Yb)) were prepared by the sol-gel process where gel microspheres directly were formed from sol droplets. → After neutron activation, such a combination of glass, allows SPECT imaging so bio-distribution is possible with better resolution.

  4. Biokinetics and dosimetry with 177Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    Rodríguez-Cortés, J.; de Murphy, C. Arteaga; Ferro-Flores, Ge; Pedraza-López, M.; Murphy-Stack, E.

    Malignant pancreatic tumours induced in athymic mice are a good model for peptide receptor targeted radiotherapy. The objective of this research was to determine biokinetic parameters in mice, in order to estimate the induced pancreatic tumour absorbed doses and to evaluate an `in house' 177Lu-DOTA-TATE radiopharmaceutical as part of preclinical studies for targeted therapy in humans. AR42J murine pancreas cancer cells expressing somatostatin receptors, were implanted in athymic mice (nD22) to obtain biokinetic and dosimetric data of 177Lu-DOTA-TATE. The mean tumour uptake 2 h post injection was 14.76±1.9% I.A./g; kidney and pancreas uptake, at the same time, were 7.27±1.1% I.A./g (1.71±0.90%/organ) and 4.20±0.98% I.A./g (0.42±0.03%/organ), respectively. The mean absorbed dose to tumour, kidney and pancreas was 0.58±0.02 Gy/MBq; 0.23±0.01 Gy/MBq and 0.14±0.01 Gy/MBq, respectively. These studies justify further dosimetric estimations to ensure that 177Lu-DOTA-TATE will act as expected in humans.

  5. Targeted radiotherapy with {sup 177} Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    Rodriguez C, J.; Murphy, C.A. de; Pedraza L, M. [Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga No. 15, 14000 Mexico D.F. (Mexico); Ferro F, G. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico); Murphy S, E. [Hospital Santelena, 06000 Mexico D.F. (Mexico)

    2006-07-01

    Malignant pancreas tumours induced in athymic mice are a good model for peptide receptor targeted radiotherapy. The objective of this research was to estimate pancreatic tumour absorbed radiation doses after administration of {sup 177}Lu-DOTA-TATE in mice as a therapeutic radiopharmaceutical that could be used in humans. AR42J murine pancreas cancer cells expressing somatostatin receptors, were implanted in athymic mice (n=18) to obtain the {sup 177}Lu-DOTA-TATE biokinetics and dosimetry. To estimate its therapeutic efficacy 87 MBq were injected in a tail vein of 3 mice and 19 days p.i. there were a partial relapse. There was an epithelial and sarcoma mixed tumour in the kidneys of mouse III. The absorbed dose to tumour, kidney and pancreas was 50.5 {+-} 7.2 Gy, 17.5 {+-} 2.5 Gy and 12.6 {+-} 2.3 Gy respectively. These studies justify further therapeutic and dosimetry estimations to ensure that {sup 177}Lu-DOTA-TATE will act as expected in man considering its kidney radiotoxicity. (Author)

  6. Biokinetic and dosimetric study of a locally produced kit 177Lu-EDTMP for use as a pain palliative agent

    Bone-seeking radiopharmaceuticals like the ethylenediamine tetramethylene phosphonic acid (EDTMP) labeled with β--emitting radioisotopes have demonstrated their efficacy in the palliative treatment of skeletal metastasis. A biokinetic and dosimetric study of 177Lu-EDTMP in NIH mice was performed. The results obtained were extrapolated to human. We estimate the absorbed doses in organs for two models: an adult male and an adult female. 177Lu-EDTMP has a selective uptake in bone, a rapid elimination from blood and negligible uptake in non-skeletal tissues. The estimated dose in bone is between 14.7-15.3 cGy/mCi for men and between 19.6-20.4 cGy/mCi for women. Bone marrow toxicity represents the limiting factor in this kind of therapy, and to avoid exceed the maximum dose it can tolerate (200 cGy), it was found that the maximum safe activity of 177Lu-EDTMP to be injected to male (73.9 kg), corresponds to a value of 1.01 mCi/kg and a value of 1.25 mCi/kg for female (56.9 kg)

  7. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in 177Lu-DOTATATE peptide receptor radionuclide therapy

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with 177Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for 177Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in 177Lu PRRT. (paper)

  8. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in 177Lu-DOTATATE peptide receptor radionuclide therapy

    Brolin, Gustav; Gustafsson, Johan; Ljungberg, Michael; Sjögreen Gleisner, Katarina

    2015-08-01

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with 177Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for 177Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in 177Lu PRRT.

  9. [177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

    Baum, Richard P.; Kluge, Andreas W.; Kulkarni, Harshad; Schorr-Neufing, Ulrike; Niepsch, Karin; Bitterlich, Norman; van Echteld, Cees J.A.

    2016-01-01

    Purpose: To characterise efficacy and safety of 177Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). Patients and methods: Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with 177Lu-DOTATOC were analysed retrospectively. Subjects were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. Results: In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean ± SD) of 16.1 ± 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 ± 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. Conclusion: 177Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with

  10. The challenges of treating paraganglioma patients with {sup 177}Lu-DOTATATE PRRT: Catecholamine crises, tumor lysis syndrome and the need for modification of treatment protocols

    Makis, William; Mccann, Karey; Mcewan, Alexander J. B. [Dept. of Diagnostic Imaging, Cross Cancer Institute, Alberta (China)

    2015-09-15

    A high percentage of paragangliomas express somatostatin receptors that can be utilized for targeted radioisotope therapy. The aim of this study was to describe and discuss the challenges of treating these tumors with {sup 177}Lu-[DOTA0,Tyr3]octreotate (DOTATATE) radioisotope therapy using established protocols. Three paraganglioma patients were treated with 4–5 cycles of {sup 177}Lu-DOTATATE and were evaluated for side effects and response to therapy. Two of the three patients developed severe adverse reactions following their first {sup 177}Lu-DOTATATE treatment. One patient developed a catecholamine crisis and tumor lysis syndrome within hours of treatment, requiring intensive care unit (ICU) support, and another developed a catecholamine crisis 3 days after treatment, requiring hospitalization. The treatment protocols at our institution were subsequently modified by increasing the radioisotope infusion time from 15 to 30 min, as recommended in the literature, to 2–4 h and by reducing the administered dose of {sup 177}Lu-DOTATATE. Subsequent {sup 177}Lu-DOTATATE treatments utilizing the modified protocols were well tolerated, and response to therapy was achieved in all three patients, resulting in significantly improved quality of life. {sup 177}Lu-DOTATATE is an exciting new therapeutic option in the management of paragangliomas; however, current treatment protocols described in the literature may need to be modified by lengthening the infusion time and/or lowering the initial treatment dose to prevent or reduce the severity of adverse reactions.

  11. The challenges of treating paraganglioma patients with 177Lu-DOTATATE PRRT: Catecholamine crises, tumor lysis syndrome and the need for modification of treatment protocols

    A high percentage of paragangliomas express somatostatin receptors that can be utilized for targeted radioisotope therapy. The aim of this study was to describe and discuss the challenges of treating these tumors with 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE) radioisotope therapy using established protocols. Three paraganglioma patients were treated with 4–5 cycles of 177Lu-DOTATATE and were evaluated for side effects and response to therapy. Two of the three patients developed severe adverse reactions following their first 177Lu-DOTATATE treatment. One patient developed a catecholamine crisis and tumor lysis syndrome within hours of treatment, requiring intensive care unit (ICU) support, and another developed a catecholamine crisis 3 days after treatment, requiring hospitalization. The treatment protocols at our institution were subsequently modified by increasing the radioisotope infusion time from 15 to 30 min, as recommended in the literature, to 2–4 h and by reducing the administered dose of 177Lu-DOTATATE. Subsequent 177Lu-DOTATATE treatments utilizing the modified protocols were well tolerated, and response to therapy was achieved in all three patients, resulting in significantly improved quality of life. 177Lu-DOTATATE is an exciting new therapeutic option in the management of paragangliomas; however, current treatment protocols described in the literature may need to be modified by lengthening the infusion time and/or lowering the initial treatment dose to prevent or reduce the severity of adverse reactions

  12. Dosimetry for {sup 177}Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer

    Delker, Andreas; Fendler, Wolfgang Peter; Brunegraf, Anika; Gosewisch, Astrid; Gildehaus, Franz Josef; Bartenstein, Peter; Boening, Guido [Ludwig-Maximilians-University of Munich, Department of Nuclear Medicine, Munich (Germany); Kratochwil, Clemens; Haberkorn, Uwe [Heidelberg University Hospital, Department for Nuclear Medicine, Heidelberg (Germany); Tritschler, Stefan; Stief, Christian Georg [Ludwig-Maximilians-University of Munich, Department of Urology, Munich (Germany); Kopka, Klaus [German Cancer Research Center (dkfz), Division of Radiopharmaceutical Chemistry, Heidelberg (Germany)

    2016-01-15

    Dosimetry is critical to achieve the optimal therapeutic effect of radioligand therapy (RLT) with limited side effects. Our aim was to perform image-based absorbed dose calculation for the new PSMA ligand {sup 177}Lu-DKFZ-PSMA-617 in support of its use for the treatment of metastatic prostate cancer. Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients (mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after administration of 3.6 GBq (range 3.4 to 3.9 GBq) {sup 177}Lu-DKFZ-PSMA-617. Quantitative 3D SPECT OSEM reconstruction was performed with corrections for photon scatter, photon attenuation and detector blurring. A camera-specific calibration factor derived from phantom measurements was used for quantitation. Absorbed doses were calculated for various organs from the images using a combination of linear approximation, exponential fit, and target-specific S values, in accordance with the MIRD scheme. Absorbed doses to bone marrow were estimated from planar and SPECT images and with consideration of the blood sampling method according to the EANM guidelines. The average (± SD) absorbed doses per cycle were 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 5.1 ± 1.8 Gy for the salivary glands (1.4 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq), 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq), and 44 ± 19 mGy for the bone marrow (0.012 Gy/GBq). The organ absorbed doses did not differ significantly between cycles. The critical absorbed dose reported for the kidneys (23 Gy) was not reached in any patient. At 24 h there was increased uptake in the colon with 50 - 70 % overlap to the kidneys on planar images. Absorbed doses for tumour lesions ranged between 1.2 and 47.5 Gy (13.1 Gy/GBq) per cycle. The salivary glands and kidneys showed high, but not critical, absorbed doses after RLT with {sup 177}Lu-DKFZ-PSMA-617. We suggest that {sup 177}Lu-DKFZ-PSMA-617 is suitable for radiotherapy, offering tumour

  13. Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases

    Lam, Marnix G.E.H.; Rijk, Peter P. van [University Medical Center Utrecht, Department of Nuclear Medicine, P.O. Box 85500, Utrecht (Netherlands); Dahmane, Amel; Stevens, Wil H.M. [CIS bio International, Saclay (France); Klerk, John M.H. de [Meander Medical Center, Department of Nuclear Medicine, Amersfoort (Netherlands); Zonnenberg, Bernard A. [UMC Utrecht, Department of Internal Medicine, Utrecht (Netherlands)

    2008-04-15

    {sup 153}Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet {sup registered}) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa {sup registered}) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg {sup 153}Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before {sup 153}Sm-EDTMP treatment. Urine was collected 48 h after injection of {sup 153}Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of {sup 153}Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 {+-} 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 {+-} 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with {sup 153}Sm-EDTMP. Zoledronic acid treatment does not influence {sup 153}Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe. (orig.)

  14. Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases

    153Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet registered) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa registered) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg 153Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before 153Sm-EDTMP treatment. Urine was collected 48 h after injection of 153Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of 153Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 ± 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 ± 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with 153Sm-EDTMP. Zoledronic acid treatment does not influence 153Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe. (orig.)

  15. Evaluation of the therapeutic efficacy and radiotoxicity of the conjugates {sup 177}Lu-DOTA-E-c(RGDfK){sub 2} and {sup 177}Lu-DOTA-GGC-AuNP-c[RGDfk(C)] in a murine model and their relationship with the inhibition of the angiogenic factors VEGF and HIF-1α; Evaluacion de la eficacia terapeutica y radiotoxicidad de los conjugados {sup 177}Lu-DOTA-E-c(RGDfK){sub 2} y {sup 177}Lu-DOTA-GGC-AuNP-c[RGDfK(C)] en un modelo murino y su relacion con la inhibicion de los factores angiogenicos VEGF y HIF-1α

    Vilchis J, A.

    2013-07-01

    Molecular targeting therapy has become a relevant therapeutic strategy for cancer. The principle that peptide receptors can be used successfully for in vivo targeting of human cancers has been proven, and radiolabeled peptides have been demonstrated to be effective in patients with malignant tumors. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been designed to antagonize the function of α(v)β(3) integrin, thereby inhibiting angio genesis. The conjugation of RGD peptides to radiolabeled gold nanoparticles (AuNP) produces biocompatible and stable m ultimeric systems with target-specific molecular recognition. The aim of this research was to evaluate the therapeutic response of {sup 177}Lu-AuNP-RGD in athymic mice bearing α(v)β(3)-integrin-positive C6 gliomas and compare with that of {sup 177}Lu-AuNP or {sup 177}Lu-RGD. The radiation absorbed dose, metabolic activity (SUV, [18F]fluor-deoxy-glucose-micro PET/CT), renal radiotoxicity, renal and tumoral histological characteristics as well as tumoral VEGF and HIF-1? gene expression (by realtime polymerase chain reaction) following treatment with {sup 177}Lu-AuNP-RGD, {sup 177}Lu-AuNP or {sup 177}Lu-RGD were assessed. Of the radiopharmaceuticals evaluated, {sup 177}Lu-AuNP-RGD delivered the highest tumor radiation absorbed dose (63.8 ± 7.9 Gy) vs other treatments. These results correlated with the observed therapeutic response, in which {sup 177}Lu-AuNP-RGD significantly (p<0.05) reduced tumor progression, tumor metabolic activity, intratumoral vessels and VEGF gene expression compared to the other radiopharmaceuticals. This was consequence of high tumor retention and a combination of molecular targeting therapy (m ultimeric RGD system) and radiotherapy ({sup 177}Lu). There was a low uptake in non-target organs and no induction of renal toxicity. {sup 177}Lu-AuNP-RGD demonstrates properties suitable for use as an agent for molecular targeting radiotherapy. (Author)

  16. Study on the synthesis of AMP derivatives for labeling with 153Sm and 166Ho

    This study describes the synthesis method and characterization of AMP-( Aminomethylene phosphonic acid): (PDTMP; BDTMP; DMPDTMP). AMP is synthesized by the condensation of correlative diamine, phosphorous acid and formaldehyde using a modified Mannich reaction in the presence of hydrochloric acid. Recrystallization of the crude product from water yields white crystals of pure legend, and subsequently characterized using 1H-NMR, IR spectroscopy, melting point, crystal picture, element analysis, metal trace analysis. Synthesized AMP, when tagged with therapeutic radio nuclides such as 153Sm and 166Ho are quite good. Complexes with RC purity and labeling efficiency 20 - 98% and above could be prepared by ordinary reaction condition. (author)

  17. Kit preparation of 153Sm-EDTMP and factors affecting radiochemical purity and stability

    A fast kit method was developed for the production of 153Sm-EDTMP in two steps avoiding the use of nitric acid, evaporation and sterilization of the final solution by autoclave. Methods of analysis for the determination of chemical and radiochemical purity in the radiopharmaceutical solution were established. Factors affecting radiochemical purity and stability of the complex as the molar ratio of EDTMP/Sm, concentration of phosphate buffer and neutralization of EDTMP prior kit preparation were also analyzed. The use of this radiopharmaceutical in rabbits and patients showed selective skeletal uptake. (author). 5 refs., 4 figs., 3 tabs

  18. DNA gel electrophoretic and micro-autoradiographic studies on apoptosis in bone tumor cells after exposure to 153Sm-EDTMP

    Objective: To study the characteristics of injury in apoptotic bone tumor cells and behavior of radionuclide 153Sm in tumor cells. Methods: DNA gel electrophoresis and micro-autoradiographic tracing of apoptotic bone tumor cells at different intervals after 153Sm-EDTMP internal irradiation. Results: Bone tumor cells internally irradiated with 153Sm-EDTMP displayed characteristics of DNA ladder formation in apoptotic cells. 153Sm could permeate through tumor cell membrane and be phagocytized by the tumor cells, showing membrane-seeking and membrane-bounded apoptotic bodies condensation. Conclusion: Progression of apoptosis in bone tumor cells induced by 153Sm-EDTMP is dependent on the time elapse of 153Sm internal irradiation

  19. The involvement of selected membrane transport mechanisms in the cellular uptake of 177Lu-labeled bombesin, somatostatin and gastrin analogues

    Introduction: Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. Methods: In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin (177Lu-DOTA-[Tyr3]octreotate, 177Lu-DOTA-[1-Nal3]octreotide), gastrin (177Lu-DOTA-sargastrin) and bombesin (177Lu-DOTA-[Pro1,Tyr4]bombesin, 177Lu-DOTA-[Lys3]bombesin, 177Lu-PCTA-[Lys3]bombesin) analogues were involved in the study. Results: RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed. Conclusion: The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested 177Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process

  20. Primary investigation of dose-effect relationship of 153Sm-EDTMP in treating multiple bone metastases%153Sm-EDTMP治疗多发骨转移瘤的剂量效应关系初步观察

    Wei Fan; Lixin Chen; Xiaowei Liu; Qiang Tang; Shengfang Zhi; Zongyuan Zeng

    2007-01-01

    Objective: To calculate the focus absorption dose of 153Sm-EDTMP with the Monte Carlo (MC) EGS4 method for treatment of bone metastases from nasopharyngeal carcinoma or breast cancer, and investigate the relationship between the focus absorption dose and painkilling effect of 153Sm-EDTMP. Methods: Four patients with multiple bone metastases from nasopharyngeal or breast carcinoma and suffered from grade Ⅳ bone pain were treated with radionuclide internal irradiation of 153Sm-EDTMP. The absorption dose and dose distribution of bone metastases and other targeted organs were calculated with MC EGS4 program based on the time-order SPECT/CT scanning and the measurement of the radioactivity in the urine accumulation. The release of bone pain and the improvement of life quality were observed. Results: Bone pain of the patients was significantly alleviated to grade Ⅱ for 3-4 weeks after internal 153Sm-EDTMP irradiation. The 3-dimensional absorption dose distribution image of bone metastases and targeted organs showed that the dose distribution in bone metastases was not asymmetrical. After injection of 0.65 × 37 MBq/kg 153Sm-EDTMP, the highest absorption dose in bone lesions was about 4.9-5.9 Gy, and the dose in the lesion margin was about 2.0 Gy. Using the highest dose as reference dose point, the relative absorption dose values of bone marrow, vertebra and sex organ near lesions were 0.48-1.1 Gy, 0.51-0.85 Gy, and 0.01-0.14 Gy, respectively. Conclusion: The absorption dose of bone metastases is significantly lower than treatment dose of 30 Gy after single irradiation of 153Sm-EDTMP. The painkilling effect is limited and in accordance with clinical observation.

  1. Monomeric, dimeric and multimeric system of RGD peptides radiolabeled with 177Lu for tumors therapy that expressing αβ integrin s

    The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been reported as high affinity agents for the α(v)β(3) and α(v)β(5) integrin. The aim of this research was to prepare a multimeric system of 177Lu-labeled gold nanoparticles conjugated to c[RGDfK(C)] [cyclo(Arg-Gly-Asp-Phe-Lys(Cys)] peptides and to compare the radiation absorbed dose with that of 177Lu-labeled monomeric and dimeric RGD peptides to α(v)β(3) integrin-positive U87MG tumors in mice, as well as, evaluate the in vitro potential 177Lu-AuNP-c[RGDfK(C)] as a plasmonic photothermal therapy and targeted radiotherapy system in MCF7 breast cancer cells. DOTA-GGC (1,4,7,10-tetraaza cyclododecane-N,N,N-tetraacetic-Gly-Gly-Cys) and c[RGDfK(C)] peptides were synthesized and conjugated to AuNPs by the spontaneous reaction of the thiol groups. Tem, UV-Vis, XP S, Raman and Far-IR spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. To obtain 177Lu-AuNP-c[RGDfK(C)], the 177Lu-DOTA-GGC radio peptide was first prepared and added to a solution of AuNPs followed by c[RGDfK(C)] (25 μL, 5 μM) at 18 grades C for 15 min. 177Lu-DOTA-GGC, 177Lu- DOTA-cRGDfK and 177Lu-DOTA-E-c(RGDfK)2 were prepared by adding 177LuCl3 (370 MBq) to 5 μL (1 mg/ml) of the DOTA derivative diluted with 50 μL of 1 M acetate buffer at ph 5. The mixture was incubated at 90 grades C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. After laser irradiation, the presence of c[RGDfK(C)]-AuNP in cells caused a significant increase in the temperature of the medium (50.5 grades C, compared to 40.3 grades C without AuNPs) resulting in a significant decrease in MCF7 cell viability down to 9 %. After treatment with 177Lu-AuNP-c[RGDfK(C)], the MCF7 cell proliferation was significantly inhibited. Biokinetic

  2. Application of analytic methodologies for image quantification in neuroendocrine tumor therapy with {sup 177}Lu-DOTA

    Kubo, T.T.A.; Oliveira, S.M.V. [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil); Marco, L.; Mamede, M., E-mail: tadeukubo@gmail.com [Instituto Nacional do Cancer, Rio de Janeiro, RJ (Brazil)

    2012-07-01

    Neuroendocrine tumors have annual incidence of 1 to 2 cases per one hundred thousand inhabitants. The {sup 177}Lu-DOTA-octreotate treatments in 3 or 4 cycles has been effective in controlling disease progression and, in some cases, promote tumor remission. To estimate radiation side effects in healthy organs, image quantification techniques have been broadcast for individualized patient dosimetry. In this paper, image data processing methods are presented to allowing comparisons between different image conjugate views, combined with attenuation correction and system sensitivity. Images were acquired 24, 72 and 192 h after administration of 74 GBq of {sup 177}Lu-DOTA using a dual-head gamma camera detection system and they were evaluated with ImageJ software. 4 female patients underwent to two cycles of treatment. The kidneys, liver and whole-body regions of interest were separately assessed by 4 techniques for counts method and 12 techniques for pixel intensity method, considering the main photopeak separately and aided by the attenuation correction map and adjacent windows to photopeak energy. The pixel intensity method was combined with mathematical correction for pixels with null value. The results obtained by the two methods were strongly correlated (r>0.9) (p<0.001). The paired t-test accepted the null hypothesis of compatibility between the two methods (with and without attenuation correction map) (p<0.05), but rejected it when the adjacent windows were combined. No significant tumor reduction (p>0.05) was found between the treatment cycles. In conclusion, the pixel intensity method is faster and allows macros, minimizing operator error, and may optimize dosimetry in tumor therapies with {sup 177}Lu-DOTA-octreotate. (author)

  3. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities

    DOTA-conjugated peptides, such as [DOTA0,Tyr3]octreotide (DOTATOC) and [DOTA0,Tyr3]octreotate (DOTA-tate), can be labelled with radionuclides such as 90Y, 111In and 177Lu. These radiolabelled somatostatin analogues are used for peptide receptor radionuclide therapy (PRRT). Radioligands for PRRT require high specific activities. However, although these radionuclides are produced without addition of carrier, contaminants are introduced during production and as decay products. In this study, parameters influencing the kinetics of labelling of DOTA-peptides were investigated and conditions were optimised to obtain the highest achievable specific activity. The effects of contaminants were systematically investigated, concentration dependently, in a test model mimicking conditions for labelling with minimal molar excess of DOTA-peptides over radionuclide. Kinetics of labelling of DOTA-peptides were optimal at pH 4-4.5; pH 90Y and 177Lu was completed after 20 min at 80 C, while labelling with 111In was completed after 30 min at 100 C. The effects of contaminants were systematically categorised, e.g. Cd2+ is the target and decay product of 111In, and it was found to be a strong competitor with 111In for incorporation in DOTA. In contrast, Zr4+ and Hf4+, decay products of 90Y and 177Lu, respectively, did not interfere with the incorporation of these radionuclides. The following conclusions are drawn: (a) DOTA-peptides can be radiolabelled at high specific activity; (b) reaction kinetics differ for each radionuclide; and (c) reactions can be hampered by contaminants, such as target material and decay products. (orig.)

  4. Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule.

    Tolmachev, Vladimir; Orlova, Anna; Pehrson, Rikard; Galli, Joakim; Baastrup, Barbro; Andersson, Karl; Sandström, Mattias; Rosik, Daniel; Carlsson, Jörgen; Lundqvist, Hans; Wennborg, Anders; Nilsson, Fredrik Y

    2007-03-15

    A radiolabeled anti-HER2 Affibody molecule (Z(HER2:342)) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (approximately 7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z(HER2:342))(2) was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy beta-emitter (177)Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z(HER2:342))(2)] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z(HER2:342))(2). Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) as a candidate for treatment of disseminated tumors with a high level of HER2 expression. PMID:17363599

  5. Phase II study of radiopeptide {sup 177}Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours

    Claringbold, Phillip G. [Fremantle Hospital, Department of Oncology, Fremantle, WA (Australia); Brayshaw, Paul A.; Turner, J.H. [University of Western Australia, Department of Nuclear Medicine, Fremantle Hospital, Fremantle, WA (Australia); Price, Richard A. [Fremantle Hospital, Department of Radiology, Fremantle, WA (Australia)

    2011-02-15

    In this phase II study we investigated the safety and efficacy of combination capecitabine and {sup 177}Lu-octreotate for the treatment of disseminated, progressive, unresectable neuroendocrine tumours (NETs). Enrolled in the study were 33 patients with biopsy-proven NETs, positive {sup 111}In-octreotide scintigraphy and progressive disease measurable by CT/MRI who were to receive four cycles of 7.8 GBq {sup 177}Lu-octreotate 8-weekly, with 14 days of 1,650 mg/m{sup 2} capecitabine per day. Of the 33 patients, 25 completed four cycles. Minimal transient myelosuppression at 3-4 weeks caused grade 3 thrombocytopenia in one patient but no neutropenia. Nephrotoxicity was absent. Critical organ radiation dosimetry provided median estimates of the dose per cycle to the kidneys of 2.4 Gy and to the liver of 4.8 Gy, and showed cumulative doses all below toxic thresholds. Objective response rates (ORR) were 24% partial response (PR), 70% stable disease (SD) and 6% progressive disease. Median progression-free survival and median overall survival had not been reached at a median follow-up of 16 months (range 5-33 months). Survival at 1 and 2 years was 91% (95% CI 75-98%) and 88% (95% CI 71-96%), respectively. The addition of capecitabine radiosensitizing chemotherapy does not increase the minimal toxicity of {sup 177}Lu-octreotate radiopeptide therapy and led to an ORR of 24% PR and 70% minor response or SD in patients with progressive metastatic NETs. Tumour control and stabilization of disease was obtained in 94% of these patients. (orig.)

  6. DNA gel electrophoretic and microaut oradiographic studies on apoptosisin bone tumor cells after exposure with 153Sm-EDTMP

    1999-01-01

    The apoptosis in bone tumor cells is studied after 153Sm-EDTMP irradiation.Fragmented DNA is analyzed by agarose gel electrophoresis.Experimental observations show that 153Sm-EDTMP exposureinduces the internucleosomal DNA damage in bone tumor cells the DNAladder pattern formation in bone tumor cells is shown.At the same time,the microautoradiographic study indicates that 153153Sm-EDTMP could permeate through cell membrane and displays membrane-seeking condensation in bone tumor cells.Soon afterwards 153Sm-EDTMP could be phagocytized by the tumor cells and distributed in cytoplasm as well as nucleus in the form of phagosome.With the prolongation of observing time, the membrane-bounded apoptotic bodies are observed.

  7. Effect of 153Sm-EDTMP on hematopoiesis and vital organs of 93 patients with bone tumor

    In the present study data on blood cell count, serum biochemistry, electrolyte, enzyme and vital organs of 93 patients with bone tumor or metastasis were investigated before and after treatment with 153Sm-EDTMP. The results showed that, 7 days and 30 days after the administration of 153Sm-EDTMP (0.05). Although at 7 days, there was a declination of the granulocyte count, it returned to normal at 30 days (P>0.05). The platelet count was significantly decreased (0.05>P>0.01)at 30 days after the administration of 153Sm-EDTMP. Thirteen patients received 74-185 MBq (2-5 mCi/kg) and their myelo-biopsies at 3 and 18 months showed no sign of acute or chronic toxicosis

  8. Alternative chromatographic processes for no-carrier added 177Lu radioisotope separation. Part 2. The conventional column chromatographic separation combined with HPLC for high purity

    HPLC technique combined with the simple conventional column solid phase extraction (SPE) chromatography using di-(2-ethylhexyl)orthophosphoric acid (HDEHP) impregnated OASIS-HLB sorbent based SPE resins (OASIS-HDEHP ) was developed for the separation of no-carrier added (n.c.a) 177Lu from the bulk quantity of ytterbium target. This combination strategy was based on combining the advantages of the better resolution of HPLC separation of n.c.a 177Lu from the few milligram level Yb target with the high capacity of the OASISHDEHP column for the separation of 177Lu from the bulk Yb target. The production batches of several hundred mCi activity of n.c.a 177Lu radioisotope separated from 50 mg Yb target activated in a nuclear reactor of medium neutron flux (Φ = 5 x 1013 n x cm-2 x s-1) were successfully performed using this combined separation technique. With the target irradiation in a reactor of higher thermal neutron flux or with the parallel run of several separation units, several Ci-s of n.c.a 177Lu can be profitably produced on a commercial production basis. (author)

  9. Report on short-term side effects of treatments with {sup 177}Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours

    Essen, Martijn van; Kam, Boen L.; Kwekkeboom, Dik J. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Krenning, Eric P. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands); Herder, Wouter W. de; Aken, Maarten O. van [Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands)

    2008-04-15

    Treatment with the radiolabelled somatostatin analogue {sup 177}Lu-octreotate results in tumour remission in 47% of patients with gastroenteropancreatic neuroendocrine tumours. Adding capecitabine to {sup 177}Lu-octreotate, as a radio-sensitiser, may enhance these anti-tumour effects. We now present the short-term toxicity profile of this novel combination. Seven patients were treated with 7.4 GBq {sup 177}Lu-octreotate and capecitabine (1650 mg/m{sup 2} per day) for 2 weeks with an intended number of four cycles. Toxicity, and especially haematological and renal parameters, were monitored on a weekly basis for the first two cycles and 4 and 6 weeks after subsequent cycles. None of the patients had hand-foot syndrome. One patient had grade 1 stomatitis occurring after one of four cycles. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia, but none had grade 4 anaemia. One patient had grade 2 thrombocytopenia after the fourth cycle, and one had grade 3 thrombocytopenia. Grade 4 thrombocytopenia did not occur. No significant changes in serum creatinine levels were observed. None of the patients had symptoms of cardiac ischaemia. Treatment with the combination of {sup 177}Lu-octreotate and capecitabine was feasible and safe considering acute and subacute side effects. We therefore started a randomised, controlled clinical trial to compare this combination with {sup 177}Lu-octreotate as single agent with regard to anti-tumour effects and side effects. (orig.)

  10. MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy.

    Ljungberg, Michael; Celler, Anna; Konijnenberg, Mark W; Eckerman, Keith F; Dewaraja, Yuni K; Sjögreen-Gleisner, Katarina; Bolch, Wesley E; Brill, A Bertrand; Fahey, Frederic; Fisher, Darrell R; Hobbs, Robert; Howell, Roger W; Meredith, Ruby F; Sgouros, George; Zanzonico, Pat; Bacher, Klaus; Chiesa, Carlo; Flux, Glenn; Lassmann, Michael; Strigari, Lidia; Walrand, Stephan

    2016-01-01

    The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy. PMID:26471692

  11. Production of medical radioisotope 153Sm in the Tehran Research Reactor (TRR) through theoretical calculations and practical tests

    Highlights: ► Production of 153Sm isotope by neutron activation in a nuclear reactor was studied. ► Optimal parameters for weight and irradiation time were found. ► This study led to an empirical correction factor (kf). ► Kf enhanced the production procedure of the 153Sm radioisotope. ► The results led to nearly 60% decrease in the amount of material used in the production process. - Abstract: The feasibility of producing 2000–3000 mCi 153Sm by irradiation of 152Sm in 5 MW TRR was studied via TRR core simulation. In this study the cross-section of 152Sm (n,γ) 153Sm reaction from ENDF/B library was used. The effective activation cross section for production of 153Sm is obtained using the neutron spectra in different irradiation channel of the core. The activity of the simulated samples is calculated using the obtained fluxes and cross sections. Then samples were prepared and irradiated under different conditions and fluxes. The final production’s specific activity was measured by the standard dose calibrator ISOMED 1010. By comparison of the theoretical calculations and actual measurements, an empirical correction factor (Kf) was obtained, which is helpful in production procedure of the 153Sm radioisotope. The optimal weight of the samples and irradiation time was studied according to the flux calculations based on the location of the sample and saturated activity calculation. In order to test the proposed conditions, samples were prepared and were irradiated under the proposed conditions. According to the compared results with the initial irradiation condition, the new proposed sample which weighed 4 mg of Sm2O3 is acceptable for the labeling, therefore this study led to nearly 60% decrease in the amount of material used in the production process

  12. Sequential radioimmunotherapy with 177Lu- and 211At-labeled monoclonal antibody BR96 in a syngeneic rat colon carcinoma model

    Eriksson, Sophie E; Elgström, Erika; Bäck, Tom;

    2014-01-01

    UNLABELLED: Alpha-particle emitters, such as astatine-211 (211At), are generally considered suitable for the treatment of small cell clusters due to their short path length, while beta-particle emitters, for example, Lutetium-177 (177Lu), have a longer path length and are considered better for...... small, established tumors. A combination of such radionuclides may be successful in regimens of radioimmunotherapy. In this study, rats were treated by sequential administration of first a 177Lu-labeled antibody, followed by a 211At-labeled antibody 25 days later. METHODS: Rats bearing solid colon...... carcinoma tumors were treated with 400 MBq/kg body weight 177Lu-BR96. After 25 days, three groups of animals were given either 5 or 10 MBq/kg body weight of 211At-BR96 simultaneously with or without a blocking agent reducing halogen uptake in normal tissues. Control animals were not given any 211At-BR96...

  13. Targeted radiotherapy with {sup 177} Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    Murphy, M. A de; Pedraza L, M. [Department of Nuclear Medicine, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico D.F. (Mexico); Rodriguez C, J. [Faculty of Medicine, UAEM, Toluca, Estado de Mexico (Mexico); Ferro F, G. [ININ, 52045 Estado de Mexico (Mexico); Murphy S, E. [Hospital Santelena, Mexico D.F. (Mexico)

    2006-07-01

    Malignant pancreas tumours induced in athymic mice are a good model for targeted radiotherapy. The objective of this research was to estimate pancreatic tumour absorbed radiation doses and to evaluate {sup 177}Lu-DOTA-TATE as a therapeutic radiopharmaceutical that could be used in humans. AR42J murine pancreas cancer cells, which over-express somatostatin receptors, were injected in athymic mice and 20 days later the mean tumour size was 3.08 square cm (n=3). A mean of 86.3 MBq {sup 177}Lu-DOTA-TATE, was injected in a tail vein and 19 days after therapy the size of the tumours was 0.81 square cm. There was a partial relapse and after 16 days, when sacrificed, the mean tumour size was 8.28 cubic cm. An epithelial and sarcoma mixed tumour in the kidney of one treated mouse was found. The tumour of the control mouse was 8.61 cubic cm when sacrificed 14 days after tumour induction. Radiotherapy estimates to the tumours was 35.9-39.7 Gy and the tumours might have been completely reduced with a second therapy dose. These preliminary studies justify further therapeutic and dosimetry estimations to ensure that Lu-{sup 177}-DOTA-TATE will act as expected in man, considering kidney radiation. (Author)

  14. Optimization of the preparation of 153Sm - EDTMP using natural samarium targets for clinical use

    153Sm (specific activity 3.7 to 5.55 GBq/mg) was produced by irradiating natural Sm2O3 at a flux of 2.2 x 1013 n x cm-2 x s-1. Ethylenediaminetetramethylenephosphonate (EDTMP) was synthesised according to a reported method. Complexation was carried out by varying experimental parameters such as mole ratios of metal to ligand, pH, time and temperature of reaction to obtain quantitative yields. The radiochemical purity of the complex was assessed by various analytical techniques including HPLC. In vitro ligand exchange studies were undertaken to ensure suitability of the product for therapy. Biodistribution studies were carried out in Wistar rats and adequate bone uptake, retention and rapid clearance from blood stream were observed. (author)

  15. Treatment with tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy

    Seregni, E.; Maccauro, M.; Chiesa, C.; Pascali, C.; Lorenzoni, A.; Bogni, A.; Coliva, A.; Bombardieri, E. [Fondazione IRCCS Istituto Nazionale Tumori, Nuclear Medicine, Milan (Italy); Mariani, L.; Vullo, S.Lo [Fondazione IRCCS Istituto Nazionale Tumori, Statistics and Biometry Unit, Milan (Italy); Mazzaferro, V. [Fondazione IRCCS Istituto Nazionale Tumori, Surgery and Liver Transplantation, Milan (Italy); De Braud, F.; Buzzoni, R. [Fondazione IRCCS Istituto Nazionale Tumori, Medical Oncology, Milan (Italy); Milione, M. [Fondazione IRCCS Istituto Nazionale Tumori, Pathology Department, Milan (Italy)

    2014-02-15

    Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ({sup 90}Y) and a medium-energy beta/gamma emitter ({sup 177}Lu) in patients with metastatic NET refractory to conventional therapy. A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [{sup 177}Lu]DOTA-TATE (5.55 GBq) and [{sup 90}Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [{sup 177}Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Administration of tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment The results of our study indicates that combined [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. (orig.)

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

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

    2011-01-01

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

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

    Diane E. Milenic

    2011-12-01

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

  18. Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy

    Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter (90Y) and a medium-energy beta/gamma emitter (177Lu) in patients with metastatic NET refractory to conventional therapy. A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [177Lu]DOTA-TATE (5.55 GBq) and [90Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [177Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Administration of tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment The results of our study indicates that combined [90Y]DOTA-TATE and [177Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. (orig.)

  19. [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate: comparison with [{sup 111}In-DTPA{sup 0}]octreotide in patients

    Kwekkeboom, D.J.; Bakker, W.H.; Kooij, P.P.M.; De Jong, M. [Dept. of Nuclear Medicine, Univ. Hospital Rotterdam (Netherlands); Konijnenberg, M.W. [Mallinckrodt Medical, Petten (Netherlands); Srinivasan, A.; Erion, J.L.; Schmidt, M.A.; Bugaj, J.L. [Mallinckrodt Medical, St. Louis, MO (United States); Krenning, E.P. [Dept. of Nuclear Medicine, Univ. Hospital Rotterdam (Netherlands); Dept. of Internal Medicine, University Hospital Rotterdam (Netherlands)

    2001-09-01

    The somatostatin analogue [DOTA{sup 0},Tyr{sup 3}]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA{sup 0},Tyr{sup 3}]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate ({sup 177}Lu-octreotate) with [{sup 111}In-DTPA{sup 0}]octreotide ({sup 111}In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after {sup 177}Lu-octreotate expressed as a percentage of the injected dose was comparable with that after {sup 111}In-octreotide. Urinary excretion of radioactivity was significantly lower than after {sup 111}In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of {sup 177}Lu-octreotate, was comparable to that after {sup 111}In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, {sup 177}Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of {sup 177}Lu as compared with {sup 90}Y may be especially important for small tumours. (orig.)

  20. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

    Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

  1. Synthesis, stabilization and formulation of [177Lu]Lu-AMBA, a systemic radiotherapeutic agent for Gastrin Releasing Peptide receptor positive tumors

    A robust formulation was developed for [177Lu]Lu-AMBA (177Lu-DO3A-CH2CO-G-[4-aminobenzoyl]-QWAVGHLM-NH2), a Bombesin-like agonist with high affinity for Gastrin Releasing Peptide (GRP) receptors. During optimization of labeling, the effect of several radiostabilizers was evaluated; a combination of selenomethionine and ascorbic acid showed superiority over other tested radiostabilizers. The resulting two-vial formulation maintains a radiochemical purity (RCP) of >90% for at least 2 days at room temperature. The method of stabilization should be useful for other methionine-containing peptide radiopharmaceuticals in diagnostic and therapeutic applications

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

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

  3. Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with 177Lu: in vitro comparison of acyclic and macrocyclic ligands

    Introduction: The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy β-emitter 177Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. Materials and Methods: L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S) -cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.ΔEGFR glioma cells over 24 h to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of 177Lu to 125I activity retained in U87.ΔEGFR cells. Results: All chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with 177Lu/125I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for 125I was higher than 177Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, 177Lu/125I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates. Conclusions: The nature of the chelate used to

  4. Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49

    Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both β and γ radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs dimer, sc(Fv)2; tetramer, [sc(Fv)2]2 of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv)2 ]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t1/2 α) of 177Lu-labeled [sc(Fv)2 ]2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t1/2 β) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4 ±1.3 and 8.9 ±0.6 for 177Lu-labeled [sc(Fv)2 ]2 and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0 ±0.6 and 8.4 ±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv)2 ]2 was significantly (p <0.005) reduced in the presence of l-lysine. (orig.)

  5. Pharmacokinetics and biodistribution of {sup 177}Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49

    Chauhan, Subhash C.; Jain, Maneesh; Moore, Erik D.; Wittel, Uwe A.; Batra, Surinder K. [University of Nebraska Medical Center, Department of Biochemistry and Molecular Biology, Omaha, NE (United States); Li, Jing; Gwilt, Peter R. [University of Nebraska Medical Center, College of Pharmacy, Omaha, NE (United States); Colcher, David [Beckman Research Institute at City of Hope National Medical Center, Department of Radioimmunotherapy, Duarte, CA (United States)

    2005-03-01

    Lutetium-177 ({sup 177}Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both {beta} and {gamma} radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the {sup 177}Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. Conjugation and labeling conditions of multivalent scFv with {sup 177}Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs dimer, sc(Fv){sub 2}; tetramer, [sc(Fv){sub 2}]{sub 2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with {sup 177}Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of {sup 177}Lu-labeled tetravalent [sc(Fv){sub 2} ]{sub 2} construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. Approximately, 90% of {sup 177}Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t{sub 1/2} {alpha}) of {sup 177}Lu-labeled [sc(Fv){sub 2} ]{sub 2} and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t{sub 1/2} {beta}) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4 {+-}1.3 and 8.9 {+-}0.6 for {sup 177}Lu-labeled [sc(Fv){sub 2} ]{sub 2} and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0 {+-}0.6 and 8.4 {+-}1.2 in the

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

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

    2016-03-15

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

  7. Avidin-biotin system radiolabelling with 153Sm and its experimental study in pre-targeting radioimmunoimaging with anti-CEA McAb

    Objective: To evaluate the usefulness of 153Sm labelled avidin-biotin system in pre-targeting radioimmunoimaging (RII)with anti-CEA McAb. Methods: Chelate DTPA-biotin (DB2) was first radiolabelled with 153Sm and then bound this 153Sm-DB2 to streptavidin (SA). The labelling of McAb with 153Sm was conducted using the bifunctional chelate cyclic DTPA anhydride (cDTPAa). Experimental studies were carried out in nude mice bearing human colon carcinoma. The authors established two- and three-step strategies for avidin-biotin system pre-targeting techniques. In three-step method A, tumor-bearing nude mice were first injected with McAb-biotin followed by cold avidin (Av) 2 days later and then 153Sm-DB2 1 day after. But in three-step method B, one group of mice was injected with McAb-SA followed by cold biotin 2 days later, and 4 h after biotin, by 153Sm-SA. While two-step protocols consisted of the injection of 153Sm-SA 48 h or 96 h after pre-targeting with McAb-bition (method A); and the injection of 153Sm-DB2 48 h after the use of McAb-SA (method B). SPECT imaging was performed and biodistribution was studied at 4, 24, 48 or 72 h after injection of 153Sm labelled compounds. Results: The authors' results showed that: 1) The three-step method A allowed faster blood clearance of the 153Sm-DB2 and yielded higher T/NT ratios (5.76 at 4 h and 12.94 at 24 h). 2) In the two-step method A, a significant accumulation of 153Sm-SA was observed in the tumor of nude mice which were injected 153Sm-SA 2 days after pre-targeting. The uptake in the tumor was also relatively high even in nude mice received 153Sm-SA 4 days after pre-targeting, demonstrating that the McAb-bition was still bound to the tumors and accessible to the 153Sm-SA even after long period of time. 3) Two- and three-step method A could increase the T/NT ratio in RII, shortening the imaging time (24 and 4 h, respectively). Conclusions: Aforementioned studies provide an experimental evidence for the improvement of pre

  8. Preparation of DOTA-TATE and DOTA-NOC freeze-dried kits for formulation of patient doses of 177Lu-labeled agents and their comparison for peptide receptor radionuclide therapy application

    The objective of the present work is to prepare freeze-dried DOTA-TATE and DOTA-NOC kits for the easy and convenient preparation of patient doses of 177Lu-DOTA-TATE and 177Lu-DOTA-NOC, respectively at the hospital radiopharmacy and to compare the radio-peptides with respect to their radiochemical and biological behaviors. Freeze-dried kits of DOTA-TATE and DOTA-NOC, comprising a lyophilized mixture of 200 μg of DOTA-peptide, 80 mg of gentisic acid and 13.9 mg of ammonium acetate were prepared. Therapeutic doses of 177Lu-labeled peptides (up to 200 mCi, 7.4 GBq) were prepared using these kits and 177Lu, produced in-house, with >99 % radiochemical purity and high stability following an easy and convenient protocol. Comparative pharmacokinetic behavior of the radio-peptides was studied by carrying out biodistribution studies in normal Wistar rats which revealed higher retention of activity in several major organs and slower renal clearance for 177Lu-DOTA-NOC compared to that of 177Lu-DOTA-TATE. Preliminary pharmacokinetic studies, carried out in limited number of patients suffering from cancers of neuroendocrine origins, showed lower accumulation of activity in vital organs and faster renal clearance of 177Lu-DOTA-TATE compared to that of 177Lu-DOTA-NOC. (author)

  9. Efficient protocol for the preparation 153Sm-EDTMP injection: an agent for bone pain palliative treatment

    Full text: 153Sm-EDTMP injection is the preferred radiopharmaceutical for the palliative treatment of bone pain due to the excellent clinical efficacy and minimal myelosuppression in comparison to other bone pain palliative radiopharmaceuticals. However owing to short half life of 153Sm (46 h), shelf life of 153Sm-EDTMP injection is limited. This in turn poses a number of logistic and operational problems namely, availability of radioisotope, radiochemical processing time, quality control testing, packing and transportation and administration to patients within a limited time. BRIT has been manufacturing and supplying this radiopharmaceutical since 1999, however during the last 2-3 years there has been a gradual increase in demand. Presently the amount of radioactivity, of 153Sm, has gone up from 1-2 Ci per batch to 4-5 Ci per and it is increasing. Considering increased radioactivity per batch, for the preparation of 153Sm-EDTMP injection, and production procedure with steam sterilization step, there is increased possibility of radiation exposure, thus serious concern for radiation safety from personnel and environmental point of view. In order to reduce this probability in accordance with ALARA principle, the whole production process has been modified. A new modular production protocol has been developed and adopted, suitable for easy operation in the existing production plant, for handling large batches without compromising on the quality parameters of the final product. This paper gives the details of the modified production process, involving the three operation modules. First module comprises of heating the reaction mixture containing ligand EDTMP and the calculated quantities of 153Sm radioactivity. Second module is for on-line sterilization of the product by membrane filtration (0.22μ). Third module is for aseptic dispensing of unidose activity, in multiple pre-sterilized vials and sealing with sterilized combination seals. Using these semi automated

  10. Comparative study on DOTA-derivatized bombesin analog labeled with 90Y and 177Lu: in vitro and in vivo evaluation

    Introduction: The aim of the study was to compare in vitro and in vivo a novel DOTA-chelated bombesin (BN) analog of the amino acid sequence, QRLGNQWAVGHLM-CONH2 (BN[2-14]NH2), labeled with 90Y and 177Lu, for its potential use in targeted radiotherapy of tumors expressing gastrin releasing peptide (GRP) receptors. The same amino acid sequence, but with different chelator, referred as BN1.1 (Gly-Gly-Cys-Aca-QRLGNQWAVGHLM-CONH2), has already been studied and reported; however, the DOTA-chelated one, suitable for labeling with M+3 type radiometals, was not yet described. Methods: The conditions for labeling of DOTA-BN[2-14]NH2 with noncarrier added 90Y and with 177Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide 90Y-DOTA-BN[2-14]NH2 and 177Lu-DOTA-BN[2-14]NH2 of high SA. The stability of the radiolabeled compounds in human serum was evaluated over a period of 24 h. The human prostate cancer cell line PC-3, known to express GRP receptors, was used for in vitro evaluation of radiolabeled peptide affinity to GRP receptors and for assessment of cytotoxicity of both nonlabeled and radiolabeled peptide. Biodistribution accompanied by receptor blocking was studied in normal Swiss mice. Results: 90Y-DOTA-BN[2-14]NH2 and 177Lu-DOTA-BN[2-14]NH2 were obtained with radiochemical yield >98% and high SA (67.3 GBq 90Y/μmol and 33.6 GBq 177Lu/μmol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2-14]NH2 and both natY- and natLu-labeled analogs to GRP receptors were high (IC50=1.78, 1.99, and 1.34 nM, respectively), especially for the natLu-DOTA-BN[2-14]NH2 complex. The cytotoxicity study of DOTA-BN[2-14]NH2 to PC-3 cells revealed an IC50=6300 nM after 72 h of exposition, while the labeled derivatives showed no significant cytotoxic effect. The internalization rate to PC-3 cells was more rapid for 177Lu-labeled peptide (84.87%) than for the 90Y-labeled one (80.79%), while the efflux

  11. Biological distribution of 51Cr-heparin

    The kinetics of heparin in normal Wistar rats using the radioactive tracer 51Cr, has been studied. The labeled and purified 51Cr-heparin was injected into rats intravenously and by intraperitoneal injection. In measuring the radioactivity of organs it was possible to conclude that the tissues rich in mast cells, liver and spleen, were found to take up the greater amounts of heparin. The curve that represents the logarithm of the concentration of heparin versus time is biexponential. The half-lives of the two exponential were determined. The volume of distribution, the rate constant and the renal clearance were determined by the values of the plasma levels and urinary excretions. The biological half-time, the turnover rate and the turnover time were determined by measuring the residual radioactivity of the total body and urinary excretions. With the data obtained from the mentioned experiments a compartmental model was performed in which the plasma is the central compartment for the distribution of the drug, exchanging with another extraplasmatic compartment and finally the drug being stored in reticulo endothelial system cells. (Author)

  12. Renal function affects absorbed dose to the kidneys and haematological toxicity during {sup 177}Lu-DOTATATE treatment

    Svensson, Johanna; Berg, Gertrud [Sahlgrenska University Hospital, Department of Oncology, Goeteborg (Sweden); Waengberg, Bo [Sahlgrenska University Hospital, Department of Surgery, Goeteborg (Sweden); Larsson, Maria [University of Gothenburg, Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, Goeteborg (Sweden); Forssell-Aronsson, Eva; Bernhardt, Peter [University of Gothenburg, Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, Goeteborg (Sweden); Sahlgrenska University Hospital, Department of Medical Physics and Medical Bioengineering, Goeteborg (Sweden)

    2015-05-01

    Peptide receptor radionuclide therapy (PRRT) has become an important treatment option in the management of advanced neuroendocrine tumours. Long-lasting responses are reported for a majority of treated patients, with good tolerability and a favourable impact on quality of life. The treatment is usually limited by the cumulative absorbed dose to the kidneys, where the radiopharmaceutical is reabsorbed and retained, or by evident haematological toxicity. The aim of this study was to evaluate how renal function affects (1) absorbed dose to the kidneys, and (2) the development of haematological toxicity during PRRT treatment. The study included 51 patients with an advanced neuroendocrine tumour who received {sup 177}Lu-DOTATATE treatment during 2006 - 2011 at Sahlgrenska University Hospital in Gothenburg. An average activity of 7.5 GBq (3.5 - 8.2 GBq) was given at intervals of 6 - 8 weeks on one to five occasions. Patient baseline characteristics according to renal and bone marrow function, tumour burden and medical history including prior treatment were recorded. Renal and bone marrow function were then monitored during treatment. Renal dosimetry was performed according to the conjugate view method, and the residence time for the radiopharmaceutical in the whole body was calculated. A significant correlation between inferior renal function before treatment and higher received renal absorbed dose per administered activity was found (p < 0.01). Patients with inferior renal function also experienced a higher grade of haematological toxicity during treatment (p = 0.01). The residence time of {sup 177}Lu in the whole body (range 0.89 - 3.0 days) was correlated with grade of haematological toxicity (p = 0.04) but not with renal absorbed dose (p = 0.53). Patients with inferior renal function were exposed to higher renal absorbed dose per administered activity and developed a higher grade of haematological toxicity during {sup 177}Lu-DOTATATE treatment. The study confirms the

  13. Time- and dose rate-related effects of internal 177Lu exposure on gene expression in mouse kidney tissue

    Introduction: The kidneys are the dose-limiting organs in some radionuclide therapy regimens. However, the biological impact of internal exposure from radionuclides is still not fully understood. The aim of this study was to examine the effects of dose rate and time after i.v. injection of 177LuCl3 on changes in transcriptional patterns in mouse kidney tissue. Methods: To investigate the effect of dose rate, female Balb/c nude mice were i.v. injected with 11, 5.6, 1.6, 0.8, 0.30, and 0 MBq of 177LuCl3, and killed at 3, 6, 24, 48, 168, and 24 hours after injection, respectively. Furthermore, the effect of time after onset of exposure was analysed using mice injected with 0.26, 2.4, and 8.2 MBq of 177LuCl3, and killed at 45, 90, and 140 days after injection. Global transcription patterns of irradiated kidney cortex and medulla were assessed and enriched biological processes were determined from the regulated gene sets using Gene Ontology terms. Results: The average dose rates investigated were 1.6, 0.84, 0.23, 0.11 and 0.028 mGy/min, with an absorbed dose of 0.3 Gy. At 45, 90 and 140 days, the absorbed doses were estimated to 0.3, 3, and 10 Gy. In general, the number of differentially regulated transcripts increased with time after injection, and decreased with absorbed dose for both kidney cortex and medulla. Differentially regulated transcripts were predominantly involved in metabolic and stress response-related processes dependent on dose rate, as well as transcripts associated with metabolic and cellular integrity at later time points. Conclusion: The observed transcriptional response in kidney tissue was diverse due to difference in absorbed dose, dose rate and time after exposure. Nevertheless, several transcripts were significantly regulated in all groups despite differences in exposure parameters, which may indicate potential biomarkers for exposure of kidney tissue

  14. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with {sup 177}Lu-octreotate

    Sabet, Amir; Ezziddin, Khaled; Reichman, Karl; Haslerud, Torjan; Ahmadzadehfar, Hojjat; Biersack, Hans-Juergen; Ezziddin, Samer [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Pape, Ulrich-Frank [Charite, University Medicine Berlin, Campus Virchow Clinic, Department of Hepatology and Gastroenterology, Berlin (Germany); Nagarajah, James [University Hospital, Department of Nuclear Medicine, Essen (Germany)

    2014-03-15

    Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine - allowing only approximate estimates of GFR - the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using {sup 99m}Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with {sup 177}Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by {sup 99m}Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m{sup 2} per year, relative yearly reduction -1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2-10 ml/min/m{sup 2} per year) and 16 patients (22 %) a significant (>10 ml/min/m{sup 2} per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m{sup 2} per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of

  15. Peptide receptor radionuclide therapy with {sup 177}Lu-DOTATATE: the IEO phase I-II study

    Bodei, Lisa; Grana, Chiara M.; Baio, Silvia M.; Lombardo, Dario; Chinol, Marco; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Cremonesi, Marta; Ferrari, Mahila E. [European Institute of Oncology, Division of Medical Physics, Milan (Italy); Fazio, Nicola [European Institute of Oncology, Division of Medical Oncology, Milan (Italy); Iodice, Simona [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Bartolomei, Mirco [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); M. Bufalini Hospital, Division of Nuclear Medicine, Cesena, FC (Italy); Sansovini, Maddalena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Unit of Radiometabolic Medicine, Meldola, FC (Italy)

    2011-12-15

    Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst{sub 2}), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of {sup 177}Lu-DOTATATE in multiple cycles. Fifty-one consecutive patients with unresectable/metastatic sst{sub 2}-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of {sup 177}Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry. No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival. {sup 177}Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles. (orig.)

  16. Monomeric, dimeric and multimeric system of RGD peptides radiolabeled with {sup 177}Lu for tumors therapy that expressing αβ integrin s; Sistema monomerico, dimerico y multimerico de peptidos de RGD radiomarcados con {sup 177}Lu para terapia de tumores que expresan integrinas αβ

    Luna G, M. A.

    2014-07-01

    The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been reported as high affinity agents for the α(v)β(3) and α(v)β(5) integrin. The aim of this research was to prepare a multimeric system of {sup 177}Lu-labeled gold nanoparticles conjugated to c[RGDfK(C)] [cyclo(Arg-Gly-Asp-Phe-Lys(Cys)] peptides and to compare the radiation absorbed dose with that of {sup 177}Lu-labeled monomeric and dimeric RGD peptides to α(v)β(3) integrin-positive U87MG tumors in mice, as well as, evaluate the in vitro potential {sup 177}Lu-AuNP-c[RGDfK(C)] as a plasmonic photothermal therapy and targeted radiotherapy system in MCF7 breast cancer cells. DOTA-GGC (1,4,7,10-tetraaza cyclododecane-N,N,N-tetraacetic-Gly-Gly-Cys) and c[RGDfK(C)] peptides were synthesized and conjugated to AuNPs by the spontaneous reaction of the thiol groups. Tem, UV-Vis, XP S, Raman and Far-IR spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. To obtain {sup 177}Lu-AuNP-c[RGDfK(C)], the {sup 177}Lu-DOTA-GGC radio peptide was first prepared and added to a solution of AuNPs followed by c[RGDfK(C)] (25 μL, 5 μM) at 18 grades C for 15 min. {sup 177}Lu-DOTA-GGC, {sup 177}Lu- DOTA-cRGDfK and {sup 177}Lu-DOTA-E-c(RGDfK){sub 2} were prepared by adding {sup 177}LuCl{sub 3} (370 MBq) to 5 μL (1 mg/ml) of the DOTA derivative diluted with 50 μL of 1 M acetate buffer at ph 5. The mixture was incubated at 90 grades C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. After laser irradiation, the presence of c[RGDfK(C)]-AuNP in cells caused a significant increase in the temperature of the medium (50.5 grades C, compared to 40.3 grades C without AuNPs) resulting in a significant decrease in MCF7 cell viability down to 9 %. After treatment with {sup 177}Lu

  17. Radiolabelled of c-DOTA-RGD and c-DOTA-RGDf with 177Lu and evaluation in vitro and in vivo stability

    Integrin αvβ3 has a critical role in tumor angio genesis and metastasis. Radiolabelled peptides based on the Arg-Gly-Asp (RGD) sequence have been reported as radiopharmaceuticals with high affinity and selectivity for the αvβ3 integrin. The aim of this study was to label c-DOTA-RGD and c-DOTA-RGDf peptides with 177Lu and to evaluate their in vitro and in vivo stability as potential specific therapeutic radiopharmaceuticals. Labelled was carried out by direct reaction of 177LuCl3 with c-DOTA-RGD peptides in 1 M acetate buffer ph 5.5 at 90o C for 30 min. Radiochemical purity and stability studies were realized by reversed phase HPLC and I TLC-Sg analyses in human serum and saline solution. Biological recognition was performed using MCF7 tumor cells (positive αvβ3) and in athymic mice with induced MCF7 tumors. Molecular mechanics and quantum mechanics calculations were performed to explain experimental results associated with the molecular recognition. 177Lu-DOTA-RGD and 177Lu-DOTA-RGDf were obtained with radiochemical purities > 95%, showing adequate in vitro and in vivo stability and specific binding to □v□3 receptors. (Author)

  18. In vitro and in vivo studies in Balb-c and nude mice of a new 177Lu-Bombesin analog developed for prostate tumor diagnosis and treatment

    In this work we describe the radiolabeling with 177Lu and some properties of the novel bombesin analog BBNp6 - DOTA-X-BBN(6-14), where X is a spacer of six aminoacids. Bombesin (BBN) is an analog of human gastrin releasing peptide (GRP) isolated from the skin of the frog Bombina bombina in 1970. Development of radiolabeled BBN derivatives as agents for diagnostic imaging and systemic radiotherapy has increased considerable because of the observation that GRP receptors (GRPr) are over-expressed in a variety of human tumor cells, such as prostate tumor cells. 177Lu-labeled peptides are attractive due to the excellent radiophysical properties and commercial availability of the radiometal. BBNp6 was labeled with high yield after reacting with 92.5 MBq of 177LuCl3 at 90 deg C for 30 minutes and this mixture kept stable for more than 96 hours at 4 deg C and 1 hour in human plasma. In vivo studies showed a multicompartimental distribution model with fast blood clearance, mainly performed by renal pathway. In addition, 177Lu-BBNp6 showed high affinity for PC-3 tumor xenografts, but not for pancreas and intestine (GRP positive tissues), suggesting its specificity and usefulness for prostate tumor treatment. Moreover, scintigraphic images showed that this derivative can also be a tool in this tumor diagnosis. So, BBNp6 is a promising radiopharmaceutical for prostate tumor imaging and treatment. (author)

  19. An approach for conjugation of 177 Lu- DOTA-SCN- Rituximab (BioSim & its evaluation for radioimmunotherapy of relapsed & refractory B-cell non Hodgkins lymphoma patients

    Parul Thakral

    2014-01-01

    Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177 Lu-DOTA-antiCD20 antibody-Rituximab (BioSim in patients of relapsed and refractory non Hodgkin′s lymphoma can be considered.

  20. Comparison of 90Y/177Lu labeled DOTA-Bz-RGD tetramer and DOTA-RGD tetramer

    90Y/177Lu labeled DOTA-Bz-RGD tetramer and DOTA-RGD tetramer were prepared, and the effect of Bz-DOTA and DOTA on labeling conditions and in vitro stability of radiolabeled compounds was compared. The labeling conditions, including reaction pH, reaction temperature and reaction time, were investigated. ITLC and HPLC show that the labeling yields of four radiolabeled compounds are more than 95% under optimal conditions (pH=6.0, reacting at 100 degree C for 15-20 min); the four radiolabeled compounds show pretty good stability in saline and fetal bovine serum. Although introducing of Bz has no effect on labeling conditions and in vitro stability of radiolabeled compounds, it brings a little change on molecule polarity. HPLC analysis and lg P values reveal that introducing of Bz increases the lipophilicity of radiolabeled compounds. (authors)

  1. Effects of therapy with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate on endocrine function

    Teunissen, Jaap J.M.; Kwekkeboom, Dik J. [Erasmus Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Krenning, Eric P. [Erasmus Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Erasmus Medical Center, Department of Internal Medicine, Rotterdam (Netherlands); Jong, Frank H. de; Feelders, Richard A.; Aken, Maarten O. van; Herder, Wouter W. de [Erasmus Medical Center, Department of Internal Medicine, Rotterdam (Netherlands); Rijke, Yolanda B. de [Erasmus Medical Center, Department of Clinical Chemistry, Rotterdam (Netherlands)

    2009-11-15

    Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate ({sup 177}Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 {+-} 16 to 25 {+-} 4 ng/l, p < 0.05) and follicle-stimulating hormone (FSH) levels increased (5.9 {+-} 0.5 to 22.7 {+-} 1.4 IU/l, p < 0.05). These levels returned to near baseline levels. Total testosterone and sex hormone binding globulin (SHBG) levels decreased (15.0 {+-} 0.9 to 10.6 {+-} 1.0 nmol/l, p < 0.05 and 61.8 {+-} 8.7 to 33.2 {+-} 3.7 nmol, p < 0.05), respectively, whereas non-SHBG-bound T did not change. An increase (5.2 {+-} 0.6 to 7.7 {+-} 0.7 IU/l, p < 0.05) of luteinizing hormone (LH) levels was found at 3 months of follow-up returning to baseline levels thereafter. In 21 postmenopausal women, a decrease in levels of FSH (74.4 {+-} 5.6 to 62.4 {+-} 7.7 IU/l, p < 0.05) and LH (26.8 {+-} 2.1 to 21.1 {+-} 3.0 IU/l, p < 0.05) was found. Of 66 patients, 2 developed persistent primary hypothyroidism. Free thyroxine (FT{sub 4}) levels decreased (17.7 {+-} 0.4 to 15.6 {+-} 0.6 pmol/l, p < 0.05), whereas thyroid-stimulating hormone (TSH) and triiodothyronine (T{sub 3}) levels did not change. Reverse triiodothyronine (rT{sub 3}) levels decreased (0.38 {+-} 0.03 to 0.30 {+-} 0.01 nmol/l, p < 0.05). Before and after therapy adrenocorticotropic hormone (ACTH) stimulation tests showed an adequate response of serum cortisol (> 550 nmol/l, n = 18). Five patients developed elevated HbA{sub 1c} levels (> 6.5%). In men {sup 177}Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non

  2. Targeted antisense radiotherapy and dose fractionation using a 177Lu-labeled anti-bcl-2 peptide nucleic acid-peptide conjugate

    Introduction: The overall goal of these studies was to test the hypothesis that simultaneous down-regulation of a tumor survival gene and delivery of internally emitted cytotoxic radiation will be more effective than either treatment modality alone. The objectives were to evaluate the therapeutic efficacy of a 177Lu-labeled anti-bcl-2-PNA-Tyr3-octreotate antisense conjugate in a mouse model bearing human non-Hodgkin’s lymphoma (NHL) tumor xenografts and to optimize targeted antisense radiotherapy by dose fractionation. Methods: In the initial therapy studies, tumor-bearing mice were given saline, nonradioactive DOTA-anti-bcl-2-PNA-Tyr3-octreotate, 177Lu-DOTA-Tyr3-octreotate, 177Lu-DOTA-PNA-peptide alone, or 177Lu-DOTA-PNA-peptide followed by a chase dose of nonradioactive PNA-peptide. The MTD of 177Lu-DOTA-anti-bcl-2-PNA-Tyr3-octreotate was then determined. Subsequently single dose MTD and four weekly fractionated doses were directly compared, followed by histopathologic evaluation. Results: Antisense radiotherapy using 4.44 MBq of the 177Lu-DOTA-PNA-peptide followed by nonradioactive PNA-peptide was significantly more effective than other low dose treatment regimens. A dose of 18.5 MBq of 177Lu-DOTA-PNA-peptide was determined to be the approximate maximum tolerated dose (MTD). The median times to progression to a 1 cm3 tumor volume were 32 and 49 days for single dose MTD and fractionated dose (4 × 4.63 MBq) groups, respectively. Histopathology revealed metastases in the single dose groups, but not in the dose fractionation group. Conclusions: Targeted antisense radiotherapy using 177Lu-DOTA-anti-bcl-2-PNA-Tyr3-octreotate and DOTA-PNA-peptide conjugate effectively inhibited tumor progression in a mouse model of NHL. Furthermore, a dose fractionation regimen had a significant advantage over a single high dose, in terms of tumor growth inhibition and prevention of metastasis. Advances in knowledge and implications for patient care: Down-regulating bcl-2, an anti

  3. Anti-CD45 radioimmunotherapy with 90Y but not 177Lu is effective treatment in a syngeneic murine leukemia model.

    Johnnie J Orozco

    Full Text Available Radioimmunotherapy (RIT for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11 targeted hematologic tissues, as at 24 hours 48.8 ± 21.2 and 156 ± 14.6% injected dose per gram of tissue (% ID/g of 90Y-DOTA-30F11 and 54.2 ± 9.5 and 199 ± 11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model.

  4. 177Lu-EDTMP for palliation of pain from bone metastases in patients with prostate and breast cancer: a phase II study

    The purpose of this study was to evaluate the efficacy and safety of 177Lu-EDTMP for pain palliation in patients with bone metastases from castration-resistant prostate and breast cancer. The secondary objective was to compare low-dose and high-dose 177Lu-EDTMP in bone pain palliation. Included in the study were 44 patients with documented breast carcinoma (12 patients; age 47 ± 13 years) or castration-resistant prostate carcinoma (32 patients; age 66 ± 9 years) and skeletal metastases. Patients were randomized into two equal groups treated with 177Lu-EDTMP intravenously at a dose of 1,295 MBq (group A) or 2,590 MBq (group B). Pain palliation was evaluated using a visual analogue score (VAS), analgesic score (AS) and Karnofsky performance score (KPS) up to 16 weeks. Toxicity was assessed in terms of haematological and renal parameters. The overall response rate (in all 44 patients) was 86 %. Complete, partial and minimal responses were seen in 6 patients (13 %), 21 patients (48 %) and 11 patients (25 %), respectively. A favourable response was seen in 27 patients (84 %) with prostate cancer and in 11 patients (92 %) with breast cancer. There was a progressive decrease in the VAS from baseline up to 4 weeks (p 177Lu-EDTMP was found to be a safe and effective radiopharmaceutical for bone pain palliation in patients with metastatic prostate and breast carcinoma. There were no differences in efficacy or toxicity between patients receiving low-dose and high-dose 177Lu-EDTMP. (orig.)

  5. Synthesis, analysis, purification and biodistribution in an animal model of radiopharmaceutical 177Lu3+ -dotatato for diagnostic and therapeutic use in neuroendocrine tumors

    The aim of this work was to propose rationalization in the synthesis, analysis and purification of radiopharmaceutical 177 Lu3+ - DOTATATO for diagnostic and therapeutic use in neuroendocrine tumors, as well as for evaluation g biodistribution of this radiopharmaceutical an animal-mode. The complexation reaction for the synthesis of radiopharmaceutical was carried out in ammonium acetate buffer 0.5 M, p H 7.0, for 30 minutes at 95 deg C. The radiochemical purity was > 95%, according to analysis by chromatography in ITLC-SG, when using the sodium citrate buffer 0,1 M, p H 5.0, as the mobile phase. The molar-limit ratio 177Lu3+:DOTATATO, in ammonium acetate buffer 0.5 M, p H 7.0, for 30 minutes at 95 deg C, was dependent on the specific activity and origin of the radioisotope, this being 1:3.5 (370 MBq : 26μg) for that from the Oak Ridge National Laboratory /USA, and 1:16 (370 MBq: 11.8 μg) for that from Nuclear Analytical and Medical Services/Holland, when considering a decay of five days from the production date of te radioisotopes. This rationalization in the synthesis of radiopharmaceutical 177Lu3+ - DOTATATO permits high economy in production costs. Chemical studies on the synthesis of radiopharmaceuticals also placed in evidence the interference of 177Hf4+, the decay product of 177Lu3=, as the 177 Lu3= competitor for DOTATATO. Radiopharmaceutical preparation proved to be stable during 24 hours, at an activity rate of 2775 MBq, with the addition of 0.6 mg/mL of gentisic acid and when kept in dry ice. In biodistribution studies on Swiss and Nuce mice, the specificity of radiopharmaceutical for somatostatin positive-receptor tissues, such as the pancreas, stomach, lungs, adrenal glands, kidneys and the cell tumor AR42J was demonstrated. (author)

  6. 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.

  7. Dosimetry of [177Lu]-DO3A-VS-Cys40-Exendin-4 – impact on the feasibility of insulinoma internal radiotherapy

    Velikyan, Irina; Bulenga, Thomas N; Selvaraju, Ramkumar; Lubberink, Mark; Espes, Daniel; Rosenström, Ulrika; Eriksson, Olof

    2015-01-01

    [68Ga]-DO3A-VS-Cys40-Exendin-4 has been shown to be a promising imaging candidate for targeting glucagon like peptide-1 receptor (GLP-1R). In the light of radiotheranostics and personalized medicine the 177Lu-labelled analogue is of paramount interest. In this study we have investigated the organ distribution of [177Lu]-DO3A-VS-Cys40-Exendin-4 in rat and calculated human dosimetry parameters in order to estimate the maximal acceptable administered radioactivity, and thus potential applicability of [177Lu]-DO3A-VS-Cys40-Exendin-4 for internal radiotherapy of insulinomas. Nine male and nine female Lewis rats were injected with [177Lu]-DO3A-VS-Cys40-Exendin-4 for ex vivo organ distribution study at nine time points. The estimation of human organ/total body absorbed and total effective doses was performed using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1). Six more rats (male: n = 3; female: n = 3) were scanned by single photon emission tomography and computed tomography (SPECT-CT). The renal function and potential cell dysfunction were monitored by creatinine ISTAT and glucose levels. The fine uptake structure of kidney and pancreas was investigated by ex vivo autoradiography. Blood clearance and washout from most of the organs was fast. The kidney was the dose-limiting organ with absorbed dose of 5.88 and 6.04 mGy/MBq, respectively for female and male. Pancreatic beta cells demonstrated radioactivity accumulation. Renal function and beta cell function remained unaffected by radiation. The absorbed dose of [177Lu]-DO3A-VS-Cys40-Exendin-4 to kidneys may limit the clinical application of the agent. However, hypothetically, kidney protection and peptidase inhibition may allow reduction of kidney absorbed dose and amplification of tumour absorbed doses. PMID:25973333

  8. 153 SM-EDTMP (Samario como tratamiento del dolor óseo de origen metastático 153 SM-EDTMP (SAMARIO For the treatment of metastatic bone pain

    A. B. de la Calle

    2006-04-01

    Full Text Available Introducción: 153 Sm-EDTMP es un agente radioactivo que puede ser usado para el diagnóstico así como el tratamiento de algunas enfermedades. El objetivo de este estudio es evaluar la eficacia de 153 Sm-EDTMP en el tratamiento del dolor crónico debido a metástasis óseas en el cáncer de próstata. Material y métodos: Se realiza un estudio prospectivo dónde se incluyen siete pacientes con dolor crónico, en relación con metástasis óseas por cáncer prostático, a los que se les administra de forma intravenosa 153 Sm-EDTMP para controlar el dolor. La eficacia de este agente fue evaluada según los cambios obtenidos en la escala visual-analgésica de (EVA, tiempo en el que se alcanzó la respuesta terapéutica, efectos adversos y cambios en el consumo diario de analgésicos. Resultados: 2 de 7 pacientes (28.5% tuvieron remisión completa del dolor, 4 de 7 (37.2% remisión parcial (EVA ≥1 y ≤3 y 1 de 7 (14.3% no mostraron mejoría. La respuesta terapéutica ocurrió a los 10-30 días después de la administración del fármaco en 83.3% de los pacientes, 16.6% requirieron más tiempo. No se observaron efectos adversos mayores; 20% sintieron nauseas, 5% vómitos y 0% toxicidad hematológica. 5 de 7 pacientes (71.4% redujeron el consumo de analgésicos. Conclusiones: 153 Sm-EDTMP es seguro y eficaz para la paliación rápida del dolor ocasionado por metástasis óseas, aunque aún quedan importantes cuestiones que resolver, fundamentalmente sobre los factores que influyen en la respuesta terapéutica a este radiofármaco.Introduction: 153 Sm-EDTMP is a radioactive agent used for both the diagnosis and treatment of some diseases. The aim of this study is to evaluate the efficacy of 153 Sm-EDTMP for the treatment of chronic pain due to bone metastasis in prostate cancer. Material and methods: Prospective study including seven patients suffering chronic pain due to bone metastasis in prostate cancer to whom intravenous 153 Sm-EDTMP for pain

  9. Development of a {sup 186}Re-HEDP formulation and radio pharmacokinetics comparison with {sup 153}Sm-EDTMP; Desarrollo de una formulacion de {sup 186}Re-HEDP y comparacion radiofarmacocinetica con el {sup 153}Sm-EDTMP

    Bribiesca C, A.I

    1998-12-01

    Because of the growing interest in the use of the beta emitters radiopharmaceuticals applied to therapy in different cancer cases, we developed a formulation of {sup 186} Re-HEDP (hydroxy ethylidene diphosphonate) as a pain palliative in osseous metastases. Besides serving like therapeutic agent, together with the {sup 153} Sm-EDTMP (ethylene diamine tetra methylene phosphonate), which has already been synthesized and proved, labels EHDP could be very useful like a diagnostic agent in the pursuit of the illness. The irradiation conditions for Rhenium-186 were established by ORIGIN 2 codes for TRIGA reactors. A pharmaceutical formulation was developed employing a factorial experimental design obtaining a complex with a radiochemical purity over 90 %. The complexes {sup 186} Re-HEDP {sup 153} Sm-EDTMP were intravenous administered in BALB-C mice sacrifying them in several intervals of time in order to determine the cumulated activity in each organ to perform absorbed dose calculation by MIRD methodology (Medical Internal Radiation Dose). Radio pharmacokinetic data demonstrated that both complexes follow a biexponential kinetic of first order behavior. In the case of the {sup 186} Re-HEDP the value of the {alpha} constant was 0.2789 and {beta} 0.0006 with an effective dose of 2.56 (mSv)/MBq , while for the complex {sup 153} Sm-EDTMP the values of {alpha} to and {beta} were 0.9012 and and 0.616 respectively and the effective dose was 0.262 (mSv)/MBq. In conclusion, radiopharmaceutical {sup 153} Sm-EDTMP, showed a greater bone uptake and a minor effective dose, for which it is a better radiopharmaceutical, respect to with the formulation of {sup 186} Re-HEDP. (Author)

  10. Measurement of fission neutron spectrum averaged cross sections of some threshold reactions on europium: small scale production of no-carrier-added 153Sm in a nuclear reactor

    Employing the activation technique in combination with radiochemical separations and high-resolution γ-ray spectroscopy fission neutron spectrum averaged cross sections were measured for several (n, 2n), (n, p) and (n, α) reactions on isotopes of europium. Our measurements constitute the first systematic studies. Of special interest was the investigation of 153Eu(n, p)153Sm reaction for the production of no-carrier-added 153Sm in a nuclear reactor. Using 100% enriched 153Eu target, 97.21 MBq 153Sm per batch can be produced which is, however, not sufficient for medical application. (orig.)

  11. 153Sm -DOTA-phosphine-ruthenium and gold bimetallic complexes as new radio-theranostics

    Full text of publication follows. Since the pioneer discovery of cisplatin for biological applications by Rosenberg in the 1960's [Ref.1] metal complexes have become the most currently investigated and used class of compounds in cancer chemotherapy [Ref.2]. However in most cases, their mechanisms of action are still poorly understood. Imaging drugs aimed at understanding their mechanism of action and studying their pharmacokinetics is thus one of the key challenges of medicinal chemists today. To take up this challenge new DOTA-phosphine compounds were synthesized. It is a versatile tool to image organometallic complexes, and allowed the access to an unprecedented family of theranostics featuring Au and Ru complexes for the therapeutic moiety and 153Sm for the imaging part. The radiolabelling of the ligand was studied and the stability of corresponding complexes was evaluated. Their cytotoxicity was also tested on cancer cells, and their biodistribution was determined in vivo. References: [1] Rosenberg, B.; VanCamp, L.; Krigas, T., Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode, Nature 1965, 205, 698-699; [2] Zhang, C. X.; Lippard, S. J., New metal complexes as potential therapeutics, Curr. Opin. Chem. Biol. 2003, 7, 481-489. (authors)

  12. Incremental value of metabolic radiotherapy of bone metastases with 153Sm-EDTMP in prostate cancer. About 67 cases

    Full text of publication follows. Introduction: painful bone metastases are common in advanced prostate cancer. Samarium-153-ethylenediaminetetra-methylenephosphonic acid (153Sm-EDTMP; Quadramet) is a beta-particles emitter that concentrates in the areas of enhanced osteoblastic activity and used for palliate pain from bone metastases. Our purpose is to evaluate the incremental value of the 153Sm-EDTMP, in patients affected of cancer of the prostate with painful bony metastasis. Methods: 67 patients with metastatic prostate cancer received a single bolus infusion of 153Sm (37 MBq/kg). All patients had painful bone metastases to more than one anatomical region. Bone specific pain, analgesic score, and blood count were evaluated before and after treatment with a receding of 38 months. Results: we observed a positive answer in 85% of the cases; this answer was complete in 35% of the cases. The results gotten after multiple administrations show that the cures could be repeated with results comparable to those of the first cure. The therapeutic efficiency is at least equivalent to those of the other therapeutic means, with nearly non-existent secondary effects. The only toxicity is of hematological order; it is the most often moderate and reversible with a complete recuperation at the end of 8 weeks. Besides, the effect on the pain came with an improvement of the quality of life of the patients treaties. Conclusion: due to its half-life of 46 hours and its beta emissions, a high dose rate of 153Sm can be delivered to regions adjacent to enhanced osteoblastic activity over a short period of time with little residual long term activity being left in the bone marrow. Its administration to patients with prostate cancer suffering from painful bone metastases that enhance on bone scans, offered clinical relevant pain relief with tolerable hematological toxicity and then enjoy a better quality of life. (authors)

  13. Development of a 186Re-HEDP formulation and radio pharmacokinetics comparison with 153Sm-EDTMP

    Because of the growing interest in the use of the beta emitters radiopharmaceuticals applied to therapy in different cancer cases, we developed a formulation of 186 Re-HEDP (hydroxy ethylidene diphosphonate) as a pain palliative in osseous metastases. Besides serving like therapeutic agent, together with the 153 Sm-EDTMP (ethylene diamine tetra methylene phosphonate), which has already been synthesized and proved, labels EHDP could be very useful like a diagnostic agent in the pursuit of the illness. The irradiation conditions for Rhenium-186 were established by ORIGIN 2 codes for TRIGA reactors. A pharmaceutical formulation was developed employing a factorial experimental design obtaining a complex with a radiochemical purity over 90 %. The complexes 186 Re-HEDP 153 Sm-EDTMP were intravenous administered in BALB-C mice sacrifying them in several intervals of time in order to determine the cumulated activity in each organ to perform absorbed dose calculation by MIRD methodology (Medical Internal Radiation Dose). Radio pharmacokinetic data demonstrated that both complexes follow a biexponential kinetic of first order behavior. In the case of the 186 Re-HEDP the value of the α constant was 0.2789 and β 0.0006 with an effective dose of 2.56 (mSv)/MBq , while for the complex 153 Sm-EDTMP the values of α to and β were 0.9012 and and 0.616 respectively and the effective dose was 0.262 (mSv)/MBq. In conclusion, radiopharmaceutical 153 Sm-EDTMP, showed a greater bone uptake and a minor effective dose, for which it is a better radiopharmaceutical, respect to with the formulation of 186 Re-HEDP. (Author)

  14. Evaluation of genotoxic and cytotoxic effects of 153 Sm-EDTMP in peripheral blood lymphocytes of bone metastasis patients

    In this study the cellular damage in peripheral lymphocytes after exposure to 153 Sm-EDTMP (Samarium-153 ethylene-diamine-tetramietylene-phosphonate) was determined using the technique of micronuclei analysis and differential coloration.153 Sm-EDTMP is a radiopharmaceutical used for pain relief in patients with bone metastases. The analysis of the frequency of micronuclei in patient blood samples obtained one hour after endovenous administration of radiopharmaceutical (41 MBq/kg) showed no statistical difference in relation to basal values in binucleated cells. However the analysis of damage distribution in mononucleated cells, showed that the patients without previous radiotherapy treatment presented a significant increase in the frequency of cells with one micronucleus and in those who had taken previous radiotherapy treatment, in cells with two or more micronuclei. The in vitro experiments conducted with the exposition of total blood to three radiation concentrations of 153 Sm-EDTMP (0.370, 0.555 and 1.110 MBq/mL) during one hour showed an increase in the frequency of micronuclei and necrotic and apoptotic cells with increasing radiation dose. Dose-response curves for healthy donors and patients with bone metastasis without previous radiotherapy treatment were constructed. The comparison of the curves showed that patients presented higher radiosensitivity, either micronuclei or dead cell (necrotic or apoptotic) percentages, than healthy donors. (author)

  15. SPECT/CT images in the calculation of absorbed dose ration between radio-synovectomy procedures with 153Sm-HA and 90Y-HA

    Full text of publication follows. Heterogeneity in the intra-articular distribution of hydroxyapatite (HA) labeled with 90Y or 153Sm at radio-synovectomy (RSV) procedures can be detected by using the fusion between transmission (SPECT) and emission (CT) tomographic images. To avoid this heterogeneity, commonly it is preferred to use 90Y over 153Sm assuming that the larger penetration range of the emitted beta particles will make the absorbed dose distribution more uniform. In this study, we evaluated the validity of this assumption by determining the affected area of RSV procedures in human joints treated with 90Y-HA and 153Sm-HA. Using SPECT/CT images of 3 patients treated with 90Y-HA (185 MBq) or 153Sm-HA (740 MBq), a voxel-by-voxel (voxel size=9.06 mm3) analysis was performed to build 3D distribution of 90Y and 153Sm activity. With the 3D image of the activity correlated to the mass of each voxel, provided by CT images via Housfield scale, the absorbed dose was calculated using the generic equation of absorbed dose rate and the average range of beta particles emitted from 90Y and 153Sm. We have chosen the generic dose equation rather than the MIRD model of voxel dosimetry or the Dose-Point Kernel method because the later models do not allow for a voxel mass dependent dose calculation. In addition, there is little information on 153Sm data and voxel sizes in these models. Considering the average energy and the therapeutic range of emitted beta particles we concluded that the dose in each voxel is not affected by the activity of neighboring voxels. Difference in the RSV procedures using 90Y-HA and 153Sm-HA should be just the dose difference per activity injected. Collisional Stopping Power shows us that the relative dose between these two compounds is 4.12:1. With these results we conclude that beta particles emitted from 90Y and 153Sm do not have range enough to reach cold spots found in heterogeneous distributions of radionuclide at RSV. Hence the spatial dose

  16. Clinical benefit of bone-targeted radiometabolic therapy with {sup 153}Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer

    Ricci, Sergio; Pastina, Ilaria; Cianci, Claudia; Orlandini, Cinzia; Chioni, Aldo; Di Donato, Samantha [Hospital, Nuclear Medicine Service-PET Center, Rovigo (Italy); Boni, Giuseppe; Genovesi, Dario; Grosso, Mariano; AlSharif, Abedallatif; Mariani, Giuliano [Univ. of Pisa (Italy). Regional Center of Nuclear Medicine; Chiacchio, Serena [Univ. of Pisa (Italy). Regional Center of Nuclear Medicine; CNR Inst. of Clinical Physiology, Pisa (Italy); Francesca, Francesco [University Hospital, Pisa (Italy). Div. of Urology; Selli, Cesare [Univ. of Pisa (Italy). Section Urology; Rubello, Domenico [Nuclear Medicine Service-PET, Rovigo (Italy)

    2007-07-15

    Bone metastases are responsible for most of the morbidity associated with hormone-refractory prostate cancer (HRPC). {sup 153}Sm-ethylenediaminetetramethylene phosphonate ({sup 153}Sm-EDTMP) has been approved for palliation of painful skeletal metastases. We retrospectively investigated the possible synergistic effect on survival of {sup 153}Sm-EDTMP (given to HRPC patients for bone pain palliation) and chemotherapy. Forty-five HRPC patients were evaluated, with a median age of 71 years. The number of metastatic bone sites was {<=}10 in 25 patients and >10 in 20 patients. Median serum PSA was 224 ng/ml. Bone pain was mild in 6 patients, moderate in 16, severe in 22 and intolerable in 1. Fifteen patients were only treated with {sup 153}Sm-EDTMP (group A), while 30 patients also received chemotherapy (estramustine phosphate or mitoxantrone plus prednisone) at variable times: between 3 and 5 months after {sup 153}Sm-EDTMP (14 patients, group B) or within 1 month after {sup 153}Sm-EDTMP (16 patients, group C). Haematological toxicities observed after either regimen were in general mild, consistent with common observations after either {sup 153}Sm-EDTMP or chemotherapy, and without any additive adverse effects in the patients receiving both {sup 153}Sm-EDTMP and chemotherapy. Bone pain palliation to some degree was induced by {sup 153}Sm-EDTMP in 32/45 patients (71.1%), the proportion of patients with a favourable clinical response being significantly higher in group C than in group A (87.5% vs 53.3%, p = 0.0388). Also in terms of biochemical response (serum PSA levels), patients of group C performed significantly better than patients of group A (p = 0.0235). Overall median survival from the time of administration of {sup 153}Sm-EDTMP was 15 months in the total cohort of 45 patients, and was significantly longer in group C than in either group B (30 months vs 11 months, p = 0.023) or group A (30 months vs 10 months, p = 0.008). The results of this study confirm that

  17. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate

    Rolleman, Edgar J.; Forrer, Flavio; Bernard, Bert; Bijster, Magda; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Vermeij, Marcel [Erasmus MC, Department of Pathology, Rotterdam (Netherlands)

    2007-05-15

    In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Male Lewis rats were injected with 278 or 555 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of {sup 99m}Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of {sup 99m}Tc-DMSA SPECT scintigrams at 130 days after [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate therapy correlated well with 1/creatinine (r {sup 2} = 0.772, p < 0.001). Amifostine and lysine effectively decreased functional renal damage caused by high-dose [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well

  18. Design and optimization of the production process of radiopharmaceutical 177Lu-DOTA-Nal3-Octreotide for the treatment of gastro-entero-pancreatic tumors

    The radiolabel peptides are molecules of interest in nuclear medicine for their therapeutic and diagnostic application in cancer. Among an impressing group of relevant peptides, those similar of the somatostatin, as the Nal3-Octreotide (NOC), have established as potential radiopharmaceuticals when presenting significant affinity for the receptors of this peptide hormone that are over expressed and broadly distributed in tumors of neuroendocrine origin, as the gastro-entero-pancreatic tumors. On the other hand, the Lutetium-177 (177Lu) is an ideal candidate for the peptides radiolabel and has favorable characteristics to be used in radionuclide therapy. The objective of this work was designing, optimizing and to document the production process of the radiopharmaceutical 177Lu-DOTA-Nal3-Octreotide (177Lu-DOTANOC) for the solicitude of its sanitary registration before the Comision Federal contra Riesgos Sanitarios (COFEPRIS). For the optimization of the production process a factorial design of three variables was evaluated with mixed levels (18 combinations), where the dependent variable is the radiochemical purity and the analytic method used to determine this parameter (High Performance Liquid Chromatography) was validated. Later on, by means of the production of 3 lots of the optimized formula of the radiopharmaceutical 177Lu-DOTANOC the production process was validated and the stability long term study to determine the period of useful life was carried out. The following pharmaceutical formulation was adopted as good: 1.85 GBq (0.5μg) of 177Lu, 250 μg of DOTANOC and 150 μL of acetates Buffer 1 M ph 5 in 5 m L of the medium. The analytic method used to determine the radiochemical purity of the formulation satisfied the requirements for the wished analytic application. We can conclude that the 3 validation lots prepared under protocols of Good Production Practices, in the Plant of Radiopharmaceuticals Production of the Instituto Nacional de Investigaciones

  19. Targeted radionuclide therapy with RAFT-RGD radiolabelled with {sup 90}Y or {sup 177}Lu in a mouse model of αvβ3-expressing tumours

    Bozon-Petitprin, A.; Bacot, S.; Ahmadi, M.; Marti-Batlle, D.; Perret, P.; Broisat, A.; Riou, L.M. [INSERM, U1039, Grenoble (France); Universite de Grenoble, UMR-S1039, Grenoble (France); Gauchez, A.S.; Bourre, J.C.; Fagret, D.; Vuillez, J.P. [INSERM, U1039, Grenoble (France); Universite de Grenoble, UMR-S1039, Grenoble (France); CHRU Grenoble, Hopital Michallon, Service de Medecine Nucleaire, Grenoble (France); Claron, M.; Boturyn, D. [CNRS, UMR 5250, Departement de Chimie Moleculaire, Grenoble (France); Ghezzi, Catherine [INSERM, U1039, Grenoble (France); Universite de Grenoble, UMR-S1039, Grenoble (France); INSERM U1039, Radiopharmaceutiques biocliniques, Batiment Jean Roget, Domaine de la Merci, Faculte de Medecine, La Tronche (France)

    2014-08-28

    The αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK]){sub 4} (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β{sup -} emitters in a nude mouse model of αvβ3 integrin-expressing tumours. Biodistribution and SPECT/CT imaging studies were performed after injection of {sup 90}Y-RAFT-RGD or {sup 177}Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with {sup 90}Y-RAFT-RGD or {sup 177}Lu-RAFT-RGD and {sup 90}Y-RAFT-RAD or {sup 177}Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. Injection of 37 MBq of {sup 90}Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of {sup 177}Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of {sup 90}Y-RAFT-RAD or 37 MBq of {sup 177}Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of {sup 90}Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours. {sup 90}Y-RAFT-RGD and {sup 177}Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy. (orig.)

  20. Radiotherapeutic efficacy of 153Sm-CMDTPA-Tyr3-octreotate in tumor-bearing rats

    A number of radiolabeled somatostatin analogs have been evaluated in animal tumor models for radiotherapeutic efficacy. The majority of the agents tested have used either high-energy beta-emitters, such as Y-90 or Re-188, or the Auger electron-emitting radionuclide, In-111. Because a medium-energy beta-emitter might have equivalent efficacy compared to high-energy emitters, and lower toxicity to non-target tissues, we have evaluated the therapeutic potential of the beta-emitting nuclide, Sm-153, chelated to the somatostatin analog, CMDTPA-Tyr3-octreotate. Using an in vitro binding assay, this octreotate derivative was shown to have high affinity for the somatostatin subtype-2 receptor (IC50 = 2.7 nM). Biodistribution studies in CA20948 tumor-bearing Lewis rats demonstrate that the Sm-153 labeled compound has high uptake and retention in tumor tissue (1.7% injected dose/g tissue, 4 hrs post injection) and has rapid overall clearance properties from non-target tissue. Radiotherapy studies were carried out using 153Sm-CMDTPA-Tyr3-octreotate and CA20948 tumor bearing Lewis rats at 7 days post implant. Dose regimens consisting of single and multiple i.v. injections of 5.0 mCi/rat (185 MBq) were employed over a time span of 7 days. Suppression of tumor growth rate was observed in all treated animals compared to untreated controls. Greater inhibition of tumor growth was observed in animals that received multiple doses. These studies indicate that medium-energy beta-emitting isotopes have considerable potential for the treatment of somatostatin receptor-positive tumors

  1. Specific efficacy of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced neuroendocrine tumours of the small intestine

    Increasing evidence supports the value of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours (NET), but there are limited data on its specific efficacy in NET of small intestinal (midgut) origin. This study aims to define the benefit of PRRT with 177Lu-octreotate for this circumscribed entity derived by a uniformly treated patient cohort. A total of 61 consecutive patients with unresectable, advanced small intestinal NET G1-2 stage IV treated with 177Lu-octreotate (4 intended cycles at 3-month intervals, mean activity per cycle 7.9 GBq) were analysed. Sufficient tumour uptake on baseline receptor imaging and either documented tumour progression (n = 46) or uncontrolled symptoms (n = 15) were prerequisites for treatment. Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Assessment of survival was performed using Kaplan-Meier curves and Cox proportional hazards model for uni- and multivariate analyses. Toxicity was assessed according to standardized follow-up laboratory work-up including blood counts, liver and renal function, supplemented with serial 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance measurements. The median follow-up period was 62 months. Reversible haematotoxicity (≥ grade 3) occurred in five patients (8.2 %). No significant nephrotoxicity (≥ grade 3) was observed. Treatment response according to modified SWOG criteria consisted of partial response in 8 (13.1 %), minor response in 19 (31.1 %), stable disease in 29 (47.5 %) and progressive disease in 5 (8.2 %) patients. The disease control rate was 91.8 %. Median progression-free survival (PFS) and overall survival (OS) was 33 [95 % confidence interval (CI) 25-41] and 61 months (95 % CI NA), respectively. Objective response was associated with longer survival (p = 0.005). Independent predictors of shorter PFS were functionality [hazard

  2. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours

    The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with 177Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with 177Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial 99mTc-DTPA clearance measurements. The median follow-up period was 58 months (range 4 - 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 - 42) and 53 months (95 % CI 46 - 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis. Variables linked

  3. Lessons on Tumour Response: Imaging during Therapy with 177Lu-DOTA-octreotate. A Case Report on a Patient with a Large Volume of Poorly Differentiated Neuroendocrine Carcinoma

    Ulrike Garske, Mattias Sandström, Silvia Johansson, Dan Granberg, Hans Lundqvist, Mark Lubberink, Anders Sundin, Barbro Eriksson

    2012-01-01

    Full Text Available Favourable outcomes of peptide receptor radiotherapy (PRRT of neuroendocrine tumours have been reported during the last years. Still, there are uncertainties on the radionuclides to be used, the treatment planning, and the indication in patients with a high proliferation rate.This case report describes a patient with a high tumour burden of poorly differentiated neuroendocrine carcinoma of unknown primary with a proliferation rate in liver metastases up to 50%, undergoing fractionated treatment with 7 cycles of 177Lu-DOTA-octreotate (7.4 GBq each after disease progression on two different chemotherapy regiments. Based on initial staging scintigraphy, somatostatin receptor expression was very high.Longitudinal dosimetry studies during therapy indicated ongoing increases in tumour-to-organ ratios that coincided with an objective response.We conclude that fractionated therapy with 177Lu-DOTA-octreotate should be considered a treatment option also for those patients with large tumours, high proliferation, and high receptor expression.

  4. Direct in vitro and in vivo comparison of {sup 161}Tb and {sup 177}Lu using a tumour-targeting folate conjugate

    Mueller, Cristina; Reber, Josefine; Haller, Stephanie [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); Dorrer, Holger; Tuerler, Andreas [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); University of Bern, Laboratory of Radiochemistry and Environmental Chemistry, Department of Chemistry and Biochemistry, Bern (Switzerland); Bernhardt, Peter [The Sahlgrenska Academy, University of Gothenburg, Department of Radiation Physics, Gothenburg (Sweden); Sahlgrenska University Hospital, Department of Medical Physics and Medical Bioengeneering, Gothenburg (Sweden); Zhernosekov, Konstantin [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); Schibli, Roger [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

    2014-03-15

    The radiolanthanide {sup 161}Tb (T{sub 1/2} = 6.90 days, Eβ{sup -}{sub av} = 154 keV) was recently proposed as a potential alternative to {sup 177}Lu (T{sub 1/2} = 6.71 days, Eβ{sup -}{sub av} = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare {sup 161}Tb and {sup 177}Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). {sup 161}Tb-cm09 and {sup 177}Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo {sup 161}Tb-cm09 and {sup 177}Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using {sup 99m}Tc-dimercaptosuccinic acid (DMSA). To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for {sup 161}Tb-cm09 (IC{sub 50} ∝0.014 MBq/ml and ∝2.53 MBq/ml) compared to {sup 177}Lu-cm09 (IC{sub 50} ∝0.063 MBq/ml and ∝4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies {sup 161}Tb-cm09 reduced tumour growth more efficiently than {sup 177}Lu-cm09. These findings were in line with the higher absorbed tumour dose for {sup 161}Tb-cm09 (3.3 Gy/MBq) compared to {sup 177}Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Compared to {sup 177}Lu-cm09 we demonstrated equal imaging

  5. Ectopic Corticotropin-Producing Neuroendocrine Tumor of the Pancreas Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

    Makis, William; McCann, Karey; Riauka, Terence A; McEwan, Alexander J B

    2016-01-01

    A 57-year-old woman diagnosed with ectopic Cushing syndrome was found to have a 111In-octreotide-avid corticotropin-producing pancreatic neuroendocrine tumor with liver metastases. She was treated with 4 induction and 4 maintenance cycles of 177Lu-DOTATATE, which normalized her serum corticotropin levels and dramatically reduced the size of the pancreatic primary and liver metastases. PMID:26359569

  6. Sci—Thur AM: YIS - 03: irtGPUMCD: a new GPU-calculated dosimetry code for {sup 177}Lu-octreotate radionuclide therapy of neuroendocrine tumors

    Montégiani, Jean-François; Gaudin, Émilie; Després, Philippe [Physics, Engineering Physics and Optics, Université Laval, Quebec City, QC (Canada); Jackson, Price A. [Molecular Imaging and Targeted Therapeutics, Peter MacCallum Cancer Centre, Melbourne, VIC (Australia); Beauregard, Jean-Mathieu [Radiology, Université Laval, Quebec City, QC (Canada)

    2014-08-15

    In peptide receptor radionuclide therapy (PRRT), huge inter-patient variability in absorbed radiation doses per administered activity mandates the utilization of individualized dosimetry to evaluate therapeutic efficacy and toxicity. We created a reliable GPU-calculated dosimetry code (irtGPUMCD) and assessed {sup 177}Lu-octreotate renal dosimetry in eight patients (4 cycles of approximately 7.4 GBq). irtGPUMCD was derived from a brachytherapy dosimetry code (bGPUMCD), which was adapted to {sup 177}Lu PRRT dosimetry. Serial quantitative single-photon emission computed tomography (SPECT) images were obtained from three SPECT/CT acquisitions performed at 4, 24 and 72 hours after {sup 177}Lu-octreotate administration, and registered with non-rigid deformation of CT volumes, to obtain {sup 177}Lu-octreotate 4D quantitative biodistribution. Local energy deposition from the β disintegrations was assumed. Using Monte Carlo gamma photon transportation, irtGPUMCD computed dose rate at each time point. Average kidney absorbed dose was obtained from 1-cm{sup 3} VOI dose rate samples on each cortex, subjected to a biexponential curve fit. Integration of the latter time-dose rate curve yielded the renal absorbed dose. The mean renal dose per administered activity was 0.48 ± 0.13 Gy/GBq (range: 0.30–0.71 Gy/GBq). Comparison to another PRRT dosimetry code (VRAK: Voxelized Registration and Kinetics) showed fair accordance with irtGPUMCD (11.4 ± 6.8 %, range: 3.3–26.2%). These results suggest the possibility to use the irtGPUMCD code in order to personalize administered activity in PRRT. This could allow improving clinical outcomes by maximizing per-cycle tumor doses, without exceeding the tolerable renal dose.

  7. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option?

    Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). A combination treatment using the high-energy 90Y beta emitter for larger lesions and the lower energy 177Lu for smaller lesions has been postulated in the literature.The aim of the study was to evaluate combined 90Y/177Lu-DOTATATE therapy in comparison to 90Y-DOTATATE alone. Fifty patients with disseminated NET were included in the study prospectively and divided into two groups: group A (n = 25) was treated with 90Y-DOTATATE, whereas group B (n = 25) received the 1:1 90Y/177Lu-DOTATATE. The administered activity was based on 3.7 GBq/m2 body surface area in three to five cycles, with amino acid infusion for nephroprotection. The median overall survival time in group A was 26.2 months while in group B median survival was not reached. Overall survival was significantly higher in group B (p = 0.027). Median event-free survival time in group A was 21.4 months and in group B 29.4 months (p > 0.1). At the 12-month follow-up, comparison of group A vs group B showed stable disease (SD) in 13 vs 16 patients, disease regression (RD) in 5 vs 3 patients and disease progression (PD) in 3 vs 4 patients; 4 and 2 patients died, respectively. The 24-month follow-up results were SD in nine vs ten patients, RD in one patient vs none and PD in four patients in both groups; three and four patients died, respectively. Side effects were rare and mild. The results indicate that therapy with tandem radioisotopes (90Y/177Lu-DOTATATE) provides longer overall survival than with a single radioisotope (90Y-DOTATATE) and the safety of both methods is comparable. (orig.)

  8. Preparation and Preliminary Biological Evaluation of {sup 177}Lu-DOTA folate as Potential Folate Receptor Targeting Therapeutic Agent

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

    2008-10-15

    Folic Acid (FA) and FA derivatives are overexpressed on several tumor cells. The cell-membrane folic acid receptors are known to be responsible for the cellular accumulation of FA and FA analogs, such as methotrexate and folic acid. Folate has been characterized to have high affinity for the folate-receptor positive cells and tissues and considered to be useful as diagnostic imaging and therapeutic agent. In 1940s, Folate analogue, aminopterin, was first used for treatment of leukemia and recently, many folate derivatives were tried for cancer-treatment agent as well as visualization of folate receptor. Many researchers tried to conjugate folic acid with macromolecules or low molecular weight chelators through its alpha or gamma carboxylate. However, despite the reduced binding affinity, FAs are still recognized by the folate receptor. Therefore, we focused to develop folate-based radiopharmaceutical that has the potential to be used as a therapeutic agent. We report here the synthesis and the radiolabeling of {sup 177}Lu-DOTA as well as the biodistribution data of our developed compound.

  9. Synthesis and biological evaluation of 177Lu-DOTA-porphyrin conjugate: a potential agent for targeted tumor radiotherapy

    A novel unsymmetrically substituted water soluble porphyrin derivative namely, 5-(p-aminopropylene-oxyphenyl)-10,15,20-tris-(p-carboxymetylene-oxyphenyl) porphyrin was synthesized and coupled with a bifunctional chelating agent, viz. p-NCS-benzyl-DOTA (p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for developing a suitable conjugate for use in targeted tumor therapy. The porphyrin-p-NCS-benzyl-DOTA conjugate was radiolabeled with 177Lu in good radiolabeling yield. Biodistribution studies performed in Swiss mice bearing fibrosarcoma tumors revealed high tumor uptake (5.33±1.11% injected activity per gm of tumor) within 30 min post-injection. The complex exhibited favorable tumor to blood and tumor to muscle ratios at various post-administration time points. Fast clearance of the non-accumulated activity was observed mostly through the renal pathway. Scintigraphic imaging studies performed in Swiss mice bearing fibrosarcoma tumors also exhibited selective accumulation of activity in the tumor.

  10. In-vitro tests of the labeled peptide 177Lu-DOTA-Substance P and evaluation of the dosimetric calculations in the preclinical stage

    Introduction: Substance P (SP) is the main ligand of neurokin type 1 receptors, which are consistently over expressed in malignant gliomas. Method: 177Lu-DOTA-SP was obtained with high radiochemical purity. Biodistribution in normal mice at different times, were done. Absorbed doses were calculated for different mice organs (cGy/μCi). Absorbed doses in human organs were calculated using two different methods, time scaling (A) and data extrapolation (B). Maximum tolerated doses were calculated according to critical organs (mCi/kg). Results: Maximum tolerated dose that can be injected without kidney toxicity is 11,2 mCi/kg (adult man) and 11,4 mCi/kg (adult woman) according to method A and 47,2 mCi/kg, 56,2 mCi/kg, respectively according to method B. Conclusion: So far, 177Lu-DOTA-SP was achieved with a specific activity (S.a) of 0,05 mCi/ μg of peptide. This S.a can be increased using 177LuCl3 of higher specific activity

  11. Alternative chromatographic processes for no-carrier added 177Lu radioisotope separation. Part 1. Multi-column chromatographic process for clinically applicable

    The conventional multi-column solid phase extraction (SPE) chromatography technique using di-(2-ethylhexyl)orthophosphoric acid (HDEHP) impregnated OASIS-HLB sorbent based SPE resins (OASIS-HDEHP) was developed for the separation of no-carrier added (n.c.a) 177Lu from the bulk quantity of ytterbium target. This technique exploited the large variation of lutetium metal ion distribution coefficients in the varying acidity of the HCl solution-OASIS-HDEHP resin systems for the consecutive loading-eluting cycles performed on different columns. The production batches of several hundred mCi n.c.a 177Lu radioisotope separated from 50 mg Yb target activated in a nuclear reactor of medium neutron flux (Φ = 5 x 1013 n x cm-2 x s-1) were successfully performed using the above mentioned separation technique. With the target irradiation in a reactor of thermal neutron flux Φ = 2 x 1014 n x cm-2 x s-1 or the parallel run of several separation units, many Ci-s of n.c.a 177Lu can be profitably produced. The OASIS-HDEHP resin based multi-column SPE chromatography technique makes the separation process simple and economic and offers an automation capability for operation in highly radioactive hazardous environments. (author)

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

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

    2007-07-01

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

  13. Chemical and biological evaluation of {sup 153}Sm and {sup 46/47}Sc complexes of indazolebisphosphonates for targeted radiotherapy

    Neves, Maria, E-mail: mneves@itn.p [Instituto Tecnologico e Nuclear, Sacavem (Portugal); Teixeira, Fatima C.; Antunes, Ines [INETI-Departamento de Tecnologia de Industrias Quimicas, Lisboa (Portugal); Majkowska, Agnieszka [Institute of Nuclear Chemistry and Technology, Warsaw (Poland); Gano, Lurdes [Instituto Tecnologico e Nuclear, Sacavem (Portugal); Santos, Ana Cristina [IBB-Instituto de Biofisica e Biomatematica, Coimbra (Portugal)

    2011-01-15

    Introduction: Novel 1-hydroxy-1,1-bisphosphonates derived from indazole and substituted at the C-3 position were labeled with the radionuclides {sup 46}Sc and {sup 153}Sm. Several parameters such as molar ligand concentration, pH, reaction time and temperature were studied. The radiolabelling yield, reaction kinetics and stability were assessed and radiocomplexes were evaluated by in vitro and in vivo experiments. Methods: The radionuclides {sup 46}Sc and {sup 153}Sm were obtained by neutron irradiation of natural Sc{sub 2}O{sub 3} and enriched {sup 152}Sm{sub 2}O{sub 3} (98.4%) targets at the neutron flux of 3x10{sup 14} n cm{sup -2} s{sup -1}. The radiolabelling yield, reaction kinetics and stability were accomplished by ascending instant thin layer chromatography. The radiocomplexes were submitted to in vitro experiments (hydroxyapatite binding and lipophilicity) and biodistribution studies in animal models. Results: The radionuclides {sup 46}Sc and {sup 153}Sm were produced with specific activities of 100 and 430 MBq mg{sup -1}, respectively. High radiochemical yields were achieved and the hydrophilic radiocomplexes have shown high degree of binding to hydroxyapatite. Biodistribution studies at 1, 3 and 24 h of the 4 radiocomplexes under study, have showed a similar biodistribution profile with a relatively high bone uptake, slow clearance from blood and a very slow rate of total radioactivity excretion from the whole animal body. Conclusion: We have developed a new class of indazolebisphosphonates complexes with radioisotopes of samarium and scandium. All complexes have shown high degree of binding to hydroxyapatite, which could be attributed to the ionized phosphonate groups. The bone uptake and the bone-to-muscle ratios were relatively low.

  14. New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts

    The proposition of uPAR as a potential target in cancer therapy is advanced by its predominant expression at the invasive front of colorectal cancer (CRC) and its value as prognostic biomarker for poor survival in this disease. In this study, we provide the first in vivo proof-of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model. Methods: A DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with 64Cu and 177Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with 177Lu-DOTA-AE105 once a visible tumor had formed. To evaluate the true effect of the targeted radiotherapy, two controls groups were included in this study, one receiving a 177Lu-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel 18F-FLT PET/CT study was performed on day 0, 1, 3 and 6. Dosimetry calculations were based on a biodistribution study, where organs and tissue of interest were collected 0.5, 1.0, 2.0, 4.0 and 24 h post injection of 177Lu-DOTA-AE105. Toxicity was assessed by recording mouse weight and by H and E staining of kidneys in each treatment group. Results: uPAR-positive HT-29 xenograft was clearly visualized by PET/CT imaging using 64Cu-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using 177Lu-DOTA-AE105, where a significant effect on tumor size and the number of uPAR-positive cells in the tumor was found (p 18F-FLT PET/CT imaging study revealed a significant correlation between 18F-FLT tumor uptake and efficacy of the radionuclide therapy. A histological examination of the kidneys from one animal in each treatment group did not reveal any gross abnormalities and the general performance of all treated animals also showed no indications of radioactivity-induced toxicity. Conclusion: These findings document for the

  15. 177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide

    The aim of this retrospective study was to determine whether patients with previous peptide receptor radionuclide therapy using high-activity 111In-pentetreotide can be safely treated with 177Lu-octreotate and whether addition of radiosensitising chemotherapy increases the toxicity of this agent. Records of 27 patients (aged 17-75) who received 69 (median 3 per patient) 177Lu-octreotate administrations, including 29 in conjunction with radiosensitising infusional 5-fluorouracil (5-FU) (n = 27), or capecitabine (n = 2), between October 2005 and July 2007 subsequent to 1-8 prior cycles of 111In-pentetreotide therapy were analysed. Toxicity was assessed during and at 8-12 weeks post-treatment, with further long-term assessments including survival status reviewed till death or study close-out date of 1 November 2009. Reduction in blood counts was most marked following the first dose of 177Lu-octreotate but at early follow-up the only major haematological toxicity was a single case of grade 4 lymphopaenia. Both the presence of bone metastases and the administration of chemotherapy tended to result in greater reduction in blood counts, but these differences did not reach statistical significance. On long-term follow-up, 16 patients (59%) are alive with median overall survival of 36 months (32-44 months from first 177Lu-octreotate therapy). None of the recorded deaths was directly related to treatment toxicity. One patient had late grade 4 anaemia and thrombocytopaenia secondary to bone marrow failure from progressive infiltration by tumour. No other significant long-term haematological toxicities were recorded and no leukaemia was observed. No renal toxicity was observed on serial serum creatinine or radionuclide glomerular filtration rate (GFR) determination on initial or long-term follow-up. 177Lu-octreotate is a safe and well-tolerated therapy for patients who have previously been treated with 111In-pentetreotide and can be safely combined with radiosensitising

  16. {sup 177}Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity {sup 111}In-octreotide

    Hubble, Daniel; Kong, Grace; Michael, Michael; Johnson, Val; Ramdave, Shakher; Hicks, Rodney John [Peter MacCallum Cancer Centre, Centre for Molecular Imaging, East Melbourne, VIC (Australia)

    2010-10-15

    The aim of this retrospective study was to determine whether patients with previous peptide receptor radionuclide therapy using high-activity {sup 111}In-pentetreotide can be safely treated with {sup 177}Lu-octreotate and whether addition of radiosensitising chemotherapy increases the toxicity of this agent. Records of 27 patients (aged 17-75) who received 69 (median 3 per patient) {sup 177}Lu-octreotate administrations, including 29 in conjunction with radiosensitising infusional 5-fluorouracil (5-FU) (n = 27), or capecitabine (n = 2), between October 2005 and July 2007 subsequent to 1-8 prior cycles of {sup 111}In-pentetreotide therapy were analysed. Toxicity was assessed during and at 8-12 weeks post-treatment, with further long-term assessments including survival status reviewed till death or study close-out date of 1 November 2009. Reduction in blood counts was most marked following the first dose of {sup 177}Lu-octreotate but at early follow-up the only major haematological toxicity was a single case of grade 4 lymphopaenia. Both the presence of bone metastases and the administration of chemotherapy tended to result in greater reduction in blood counts, but these differences did not reach statistical significance. On long-term follow-up, 16 patients (59%) are alive with median overall survival of 36 months (32-44 months from first {sup 177}Lu-octreotate therapy). None of the recorded deaths was directly related to treatment toxicity. One patient had late grade 4 anaemia and thrombocytopaenia secondary to bone marrow failure from progressive infiltration by tumour. No other significant long-term haematological toxicities were recorded and no leukaemia was observed. No renal toxicity was observed on serial serum creatinine or radionuclide glomerular filtration rate (GFR) determination on initial or long-term follow-up. {sup 177}Lu-octreotate is a safe and well-tolerated therapy for patients who have previously been treated with {sup 111}In-pentetreotide and can

  17. {sup 177}Lu-EDTMP for palliation of pain from bone metastases in patients with prostate and breast cancer: a phase II study

    Agarwal, Krishan Kant; Singla, Suhas; Arora, Geetanjali; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India)

    2015-01-15

    The purpose of this study was to evaluate the efficacy and safety of {sup 177}Lu-EDTMP for pain palliation in patients with bone metastases from castration-resistant prostate and breast cancer. The secondary objective was to compare low-dose and high-dose {sup 177}Lu-EDTMP in bone pain palliation. Included in the study were 44 patients with documented breast carcinoma (12 patients; age 47 ± 13 years) or castration-resistant prostate carcinoma (32 patients; age 66 ± 9 years) and skeletal metastases. Patients were randomized into two equal groups treated with {sup 177}Lu-EDTMP intravenously at a dose of 1,295 MBq (group A) or 2,590 MBq (group B). Pain palliation was evaluated using a visual analogue score (VAS), analgesic score (AS) and Karnofsky performance score (KPS) up to 16 weeks. Toxicity was assessed in terms of haematological and renal parameters. The overall response rate (in all 44 patients) was 86 %. Complete, partial and minimal responses were seen in 6 patients (13 %), 21 patients (48 %) and 11 patients (25 %), respectively. A favourable response was seen in 27 patients (84 %) with prostate cancer and in 11 patients (92 %) with breast cancer. There was a progressive decrease in the VAS from baseline up to 4 weeks (p < 0.05). Also, AS decreased significantly from 1.8 ± 0.7 to 1.2 ± 0.9 (p < 0.0001). There was an improvement in quality of life of the patients as reflected by an increase in mean KPS from 56 ± 5 to 75 ± 7 (p < 0.0001). The overall response rate in group A was 77 % compared to 95 % in group B (p = 0.188). There was a significant decrease in VAS and AS accompanied by an increase in KPS in both groups. Nonserious haematological toxicity (grade I/II) was observed in 15 patients (34 %) and serious toxicity (grade III/IV) occurred in 10 patients (23 %). There was no statistically significant difference in haematological toxicity between the groups. {sup 177}Lu-EDTMP was found to be a safe and effective radiopharmaceutical for bone pain

  18. 153Sm3+ and 111In3+ DTPA derivatives with high hepatic specificity: in vivo and in vitro studies

    Prata, M. I. M.; Santos, A.C.; Neves, M.; Geraldes, C. F. G. C.; Lima, J. J. P. de

    2002-01-01

    Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L1) and the ligand DTPA(BOM)3 (BOM=benzyloxymethyl) (L2), radiolabelled with 153Sm3+ and 111In3+, were studied as potential hepatospecific gamma scintigraphic agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The complexes of L2 show even greater hepatobiliary specificity than L1, perhaps as a consequence of longer blo...

  19. Tissue distribution and excretion pattern of 51Cr in animals

    To study distribution and excretion pattern of chromium, 51CrCl3 was orally administered in doses of 66.6 μCi to each rat. Lungs, liver and testis accumulated relatively higher radioactivity earlier and this accumulation persisted in liver and testis for 192 hr. The lungs, heart muscles and gall bladder showed a gradual decline after initial uptake whereas in kidney and spleen it continued to increase as a function of time. Uptake of 51Cr per unit weight of the small intestine was greater than the stomach and the large intestine. On an average, 70.15 percent of the orally administered 51Cr was excreted in faeces within 192 hr of dosing. In the second experiment, six male kids weighing 23.87 kg, on an average, were given orally 500 μCi of 51Cr. Kids were maintained on concentrate mixture and green berseem which contained 0.43 ppm and 0.195 ppm chromium, respectively. The balance studies revealed that 94.93 percent of the total 51Cr dose was excreted in the faeces and 1.93 percent in the urine during 7 day period. Net absorption of 51Cr was, however, only 9.0 percent. (auth.)

  20. Synergistic anti-cancer response to chemotherapy and 177Lu-labelled APOMABR radioimmunotherapy in a preclinical model of lung cancer

    Full text of publication follows. Aim: We have identified a murine monoclonal antibody (APOMABR) which targets the La antigen. La is a ribonucleoprotein which is over-expressed in malignancy and is only accessible to antibody binding when tumour cells die, making APOMABR a dead tumour cell-specific marker. We hypothesise that APOMABR radio-labelled with the β-particle emitting radionuclide Lutetium-177 (177Lu) will be an effective anti-tumour treatment in vivo, particular after chemotherapy, as the targeting of radio-labelled APOMABR specifically to dead tumour cells within the tumour tissue will result in the surrounding viable tumour cells being irradiated with a therapeutic dose of β-radiation. Material and Methods: The binding of APOMABR to viable and dead murine Lewis Lung cells (LL2) was examined in vitro by flow cytometry. Subsequently, C57Bl/6 mice bearing syngeneic LL2 tumours were treated with chemotherapy (gemcitabine/cisplatin) and the tumour uptake of biotinylated APOMABR was determined. We then administered escalating activities of 177Lu-labelled APOMABR or a 177Lu-labelled iso-type control antibody either alone or 24 hours after chemotherapy and monitored tumour growth and survival. We also analysed the bio-distribution of 177Lu-labelled APOMABR in LL2 tumour-bearing mice which had or had not been treated with chemotherapy to determine whether the uptake of APOMABR after chemotherapy treatment was tumour-specific. Results: In vitro analysis revealed that APOMABR did not bind viable LL2 cells, but bound with high avidity to cisplatin-treated, dead LL2 cells. Chemotherapy increased tumour cell death in vivo, and was associated with increased tumour uptake of APOMABR compared to LL2 tumour-bearing mice that did not receive chemotherapy. Administration of escalating doses of 177Lu-labelled APOMABR alone to tumour-bearing mice was well tolerated but showed only modest anti-tumour activity which was comparable to the response seen after chemotherapy

  1. Cytotoxic and genotoxic effects caused by {sup 153} Sm-EDTMP, combined with BrdU a thymidine analog; Efecto citotoxico y genotoxico causado por {sup 153} Sm-EDTMP, combinado con BrdU un analogo de timidina

    Morales A, E.; Ferro F, G.; Morales R, P. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

    2006-07-01

    The ablation of the bone marrow previous to the transplant by means of radiation and chemical antineoplastics its affect indiscriminately to the healthy tissues and in particular those that are in proliferation. The objective of this work is to determine the effect of the incorporation from the BrdU to the DNA on the genotoxicity and cytotoxicity of the cells of the bone marrow caused by the radiopharmaceutical {sup 153}Sm-EDTMP. The genotoxicity was determined by the rate of erythrocytes polychromatic micro nucleates (EPC-MN) and the cytotoxicity by the frequency of EPC. Both parameters determined in peripheral blood after the BrdU administration and {sup 153}Sm-EDTMP. The combination of the BrdU and r1 radiopharmaceutical produced a bigger cytotoxicity that the radiation and the BrdU alone; on the other hand it produced a reduction of the EPC-MN produced by the radiation, suggesting that the cytotoxicity didn't allow the expression of the genotoxicity. (Author)

  2. 177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study

    Paganelli, Giovanni; Sansovini, Maddalena; Ambrosetti, Alice; Severi, Stefano; Ianniello, Annarita; Matteucci, Federica [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola, FC (Italy); Monti, Manuela; Scarpi, Emanuela [IRST IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy); Donati, Caterina [IRST IRCCS, Oncology Pharmacy Laboratory, Meldola (Italy); Amadori, Dino [IRST IRCCS, Department of Medical Oncology, Meldola (Italy)

    2014-10-15

    We evaluated the activity and safety profile of {sup 177}Lu-Dotatate peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced, well-differentiated (G1-G2) gastrointestinal neuroendocrine tumors (GI-NETs). Forty-three patients with radiological tumor progression at baseline and a positive Octreoscan registered completed the treatment with Lu-PRRT, resulting in the cumulative activity of 18.5 or 27.8 GBq in five cycles. Total activity was scheduled on the basis of kidney function or bone marrow reserve. Twenty-five (58 %) patients were treated with a ''standard'' Lu-PRRT full dosage (FD) of 25.7 GBq (range 22.2-27.8), while the remaining 18 patients (42 %) who, at enrolment, showed a higher probability of developing kidney or bone marrow toxicity received a reduced dosage (RD) of 18.4 GBq (range 14.4-20.4). According to SWOG criteria, the overall response was complete response (CR) in (7 %) cases and stable disease (SD) in 33 (77 %), with a disease control rate (DCR) of 84 %. Median response duration was 25 months (range 7-50). Median progression-free survival (PFS) was 36 months (95 % CI 24-nr), and median overall survival (OS) has not yet been reached. Remarkably, none of the patients, including those at a higher risk of toxicity, showed side-effects after either dosage of Lu-PRRT. Lu-PRRT was shown to be an effective therapeutic option in our patients with advanced progressive GI-NETs, showing an 84 % DCR (95 % CI 73-95) that lasted for 25 months and a PFS of 36 months. Both activities of 27.8 GBq and 18.5 GBq proved safe and effective in all patients, including those with a higher probability of developing kidney or bone marrow toxicity. (orig.)

  3. 177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study

    We evaluated the activity and safety profile of 177Lu-Dotatate peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced, well-differentiated (G1-G2) gastrointestinal neuroendocrine tumors (GI-NETs). Forty-three patients with radiological tumor progression at baseline and a positive Octreoscan registered completed the treatment with Lu-PRRT, resulting in the cumulative activity of 18.5 or 27.8 GBq in five cycles. Total activity was scheduled on the basis of kidney function or bone marrow reserve. Twenty-five (58 %) patients were treated with a ''standard'' Lu-PRRT full dosage (FD) of 25.7 GBq (range 22.2-27.8), while the remaining 18 patients (42 %) who, at enrolment, showed a higher probability of developing kidney or bone marrow toxicity received a reduced dosage (RD) of 18.4 GBq (range 14.4-20.4). According to SWOG criteria, the overall response was complete response (CR) in (7 %) cases and stable disease (SD) in 33 (77 %), with a disease control rate (DCR) of 84 %. Median response duration was 25 months (range 7-50). Median progression-free survival (PFS) was 36 months (95 % CI 24-nr), and median overall survival (OS) has not yet been reached. Remarkably, none of the patients, including those at a higher risk of toxicity, showed side-effects after either dosage of Lu-PRRT. Lu-PRRT was shown to be an effective therapeutic option in our patients with advanced progressive GI-NETs, showing an 84 % DCR (95 % CI 73-95) that lasted for 25 months and a PFS of 36 months. Both activities of 27.8 GBq and 18.5 GBq proved safe and effective in all patients, including those with a higher probability of developing kidney or bone marrow toxicity. (orig.)

  4. (153)Sm(3+) and (111)In(3+) DTPA derivatives with high hepatic specificity: in vivo and in vitro studies.

    Prata, M I M; Santos, A C; Neves, M; Geraldes, C F G C; de Lima, J J P

    2002-07-25

    Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L(1)) and the ligand DTPA(BOM)(3) (BOM=benzyloxymethyl) (L(2)), radiolabelled with (153)Sm(3+) and (111)In(3+), were studied as potential hepatospecific gamma scintigraphic agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The complexes of L(2) show even greater hepatobiliary specificity than L(1), perhaps as a consequence of longer blood circulation times due to their strong affinity towards HSA. The (153)Sm(3+) chelates are also more hepatospecific than the corresponding (111)In(3+) chelates. The La(3+) and In(3+) chelates of L(1) and L(2) show some structural and dynamic differences in aqueous solution, as studied by (1)H NMR spectroscopy. While only two nona-coordinated isomers were observed for the La(3+) complexes with both ligands, its number is much larger in the In(3+) complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination number. PMID:12121790

  5. Cytotoxic and genotoxic effects caused by 153 Sm-EDTMP, combined with BrdU a thymidine analog

    The ablation of the bone marrow previous to the transplant by means of radiation and chemical antineoplastics its affect indiscriminately to the healthy tissues and in particular those that are in proliferation. The objective of this work is to determine the effect of the incorporation from the BrdU to the DNA on the genotoxicity and cytotoxicity of the cells of the bone marrow caused by the radiopharmaceutical 153Sm-EDTMP. The genotoxicity was determined by the rate of erythrocytes polychromatic micro nucleates (EPC-MN) and the cytotoxicity by the frequency of EPC. Both parameters determined in peripheral blood after the BrdU administration and 153Sm-EDTMP. The combination of the BrdU and r1 radiopharmaceutical produced a bigger cytotoxicity that the radiation and the BrdU alone; on the other hand it produced a reduction of the EPC-MN produced by the radiation, suggesting that the cytotoxicity didn't allow the expression of the genotoxicity. (Author)

  6. Evaluation of 153Sm-EDTMP in non-human primates: prelude to clinical trials in cancer patients

    Full text: We had earlier reported optimisation of parameters for satisfactory formulation of 153Sm-EDTMP using natural samarium (Sm203) irradiated targets validated by satisfactory bio localisation in rats and rabbits. In the present study, we have attempted to further establish the safety and efficacy of the product through animal studies in monkeys as a prelude to clinical studies in cancer patients. Natural Sm203 (3 batches) irradiated in high neutron flux positions in the Dhruva reactor for 7 days was dissolved in hydrochloric acid and complexed with EDTMP (using both a gift sample and in house synthesized product) under conditions earlier standardized by us. The radiochemical purity by paper chromatography over normal saline (98%) and biodistribution study in rats (2.5-3% ID in femurs at 1-120 hp.i.) revealed satisfactory complexation. Monkeys were administered about 1 mCi of 153Sm per kg and imaged up to 72 hours p.i. Rapid clearance from blood, insignificant retention in liver, kidney and other tissues, and good bone uptake were observed even at 2 h p.i. Prolonged good retention in the skeleton was observed up to 120 hours p.i. EDTMP doses of 2.5 mg/mouse were tolerated indicating a safety factor of about 200 in humans. Thus desirable biological features promising good efficacy in cancer patients have been demonstrated warranting clinical evaluation of this product

  7. Using the 154 Sm(p,d) reaction to extend the level scheme of 153 Sm to the continuum region

    Wilson, Emma; Beausang, Cornelius; Humby, Peter; Simon, Anna; Ross, Timothy; Hughes, Richard; Burke, James; Casperson, Robert; Koglin, Johnathon; Ota, Shuya; Allmond, James; McCleskey, Matthew; McCleskey, Ellen; Saastamoinen, Antti; Chyzh, Roman; Gell, Kristen; Tarlow, Tom; Vyas, Gargi; Starlite Collaboration

    2015-04-01

    Following an experiment performed at the Cyclotron Institute of Texas A&M University, the level scheme of 153 Sm is in the process of being extended. A beam of protons accelerated to 25 MeV impinged on an isotopically enriched 154 Sm target, inducing a (p,d) reaction, thereby producing energetically excited 153 Sm reaction products. The resulting γ-rays and deuterons were detected by the STARLiTe array, which consists of six Compton-suppressed HPGe gamma-ray detectors, and a ΔE-E Si telescope for charged particle identification. In the ongoing analysis of these data, the identification of new γ-rays has been possible. The deuteron spectrum will be used to identify high-lying continuum states, and angular momentum transfer values will be assigned using angular distributions and comparison with DWBA calculations. This work was partly supported by the US DofE under Grant Numbers DE-NA0001801, DE-FG02-05ER41379(UofR); DE-AC52-07NTJKTG(LLNL).

  8. Improving the dose-myelotoxicity correlation in radiometabolic therapy of bone metastases with {sup 153}Sm-EDTMP

    Pacilio, Massimiliano; Basile, Chiara [Azienda Ospedaliera San Camillo Forlanini, Rome (Italy). Dept. of Medical Physics; Ventroni, Guido; Mango, Lucio [Azienda Ospedaliera San Camillo Forlanini, Rome (Italy). Dept. of Nuclear Medicine; Ialongo, Pasquale [Azienda Ospedaliera San Camillo Forlanini, Rome (Italy). Dept. of Radiology; Becci, Domenico [University of Rome, Health Physics Postgraduate School, Rome (Italy)

    2014-02-15

    {sup 153}Sm-ethylene diamine tetramethylene phosphonic acid ({sup 153}Sm-EDTMP) is widely used to palliate pain from bone metastases, and is being studied for combination therapy beyond palliation. Conceptually, red marrow (RM) dosimetry allows myelotoxicity to be predicted, but the correlation is poor due to dosimetric uncertainty, individual sensitivity and biological effects from previous treatments. According to EANM guidelines, basic dosimetric procedures have been studied to improve the correlation between dosimetry and myelotoxicity in {sup 153}Sm-EDTMP therapy. RM dosimetry for 33 treatments of bone metastases from breast, prostate and lung tumours was performed prospectively (with {sup 99m}Tc-MDP) and retrospectively, acquiring whole-body scans early and late after injection. The {sup 153}Sm-EDTMP activity was calculated by prospective dosimetry based on measured skeletal uptake and full physical retention, with the RM absorbed dose not exceeding 3.8 Gy. Patient-specific RM mass was evaluated by scaling in terms of body weight (BW), lean body mass (LBM) and trabecular volume (TV) estimated from CT scans of the L2-L4 vertebrae. Correlations with toxicity were determined in a selected subgroup of 27 patients, in which a better correlation between dosimetry and myelotoxicity was expected. Skeletal uptakes of {sup 99m}Tc and {sup 153}Sm (Tc{sub %} and Sm{sub %}) were well correlated. The median Sm{sub %} was higher in prostate cancer (75.3 %) than in lung (60.5 %, p = 0.005) or breast (60.8 %, p = 0.008). PLT and WBC nadirs were not correlated with administered activity, but were weakly correlated with uncorrected RM absorbed doses, and the correlation improved after rescaling in terms of BW, LBM and TV. Most patients showed transient toxicity (grade 1-3), which completely and spontaneously recovered over a few days. Using TV, RM absorbed dose was in the range 2-5 Gy, with a median of 312 cGy for PLT in patients with toxicity and 247 cGy in those with no

  9. Improving the dose-myelotoxicity correlation in radiometabolic therapy of bone metastases with 153Sm-EDTMP

    153Sm-ethylene diamine tetramethylene phosphonic acid (153Sm-EDTMP) is widely used to palliate pain from bone metastases, and is being studied for combination therapy beyond palliation. Conceptually, red marrow (RM) dosimetry allows myelotoxicity to be predicted, but the correlation is poor due to dosimetric uncertainty, individual sensitivity and biological effects from previous treatments. According to EANM guidelines, basic dosimetric procedures have been studied to improve the correlation between dosimetry and myelotoxicity in 153Sm-EDTMP therapy. RM dosimetry for 33 treatments of bone metastases from breast, prostate and lung tumours was performed prospectively (with 99mTc-MDP) and retrospectively, acquiring whole-body scans early and late after injection. The 153Sm-EDTMP activity was calculated by prospective dosimetry based on measured skeletal uptake and full physical retention, with the RM absorbed dose not exceeding 3.8 Gy. Patient-specific RM mass was evaluated by scaling in terms of body weight (BW), lean body mass (LBM) and trabecular volume (TV) estimated from CT scans of the L2-L4 vertebrae. Correlations with toxicity were determined in a selected subgroup of 27 patients, in which a better correlation between dosimetry and myelotoxicity was expected. Skeletal uptakes of 99mTc and 153Sm (Tc% and Sm%) were well correlated. The median Sm% was higher in prostate cancer (75.3 %) than in lung (60.5 %, p = 0.005) or breast (60.8 %, p = 0.008). PLT and WBC nadirs were not correlated with administered activity, but were weakly correlated with uncorrected RM absorbed doses, and the correlation improved after rescaling in terms of BW, LBM and TV. Most patients showed transient toxicity (grade 1-3), which completely and spontaneously recovered over a few days. Using TV, RM absorbed dose was in the range 2-5 Gy, with a median of 312 cGy for PLT in patients with toxicity and 247 cGy in those with no toxicity (p = 0.019), and 312 cGy for WBC in those with toxicity

  10. Design and optimization of the production process of radiopharmaceutical {sup 177}Lu-DOTA-Nal{sup 3}-Octreotide for the treatment of gastro-entero-pancreatic tumors; Diseno y optimizacion del proceso de produccion del radiofarmaco {sup 177}Lu-DOTA-Nal{sup 3}-Octreotido para el tratamiento de tumores gastroenteropancreaticos

    Sanchez G, M. F.

    2013-07-01

    The radiolabel peptides are molecules of interest in nuclear medicine for their therapeutic and diagnostic application in cancer. Among an impressing group of relevant peptides, those similar of the somatostatin, as the Nal{sup 3}-Octreotide (NOC), have established as potential radiopharmaceuticals when presenting significant affinity for the receptors of this peptide hormone that are over expressed and broadly distributed in tumors of neuroendocrine origin, as the gastro-entero-pancreatic tumors. On the other hand, the Lutetium-177 ({sup 177}Lu) is an ideal candidate for the peptides radiolabel and has favorable characteristics to be used in radionuclide therapy. The objective of this work was designing, optimizing and to document the production process of the radiopharmaceutical {sup 177}Lu-DOTA-Nal{sup 3}-Octreotide ({sup 177}Lu-DOTANOC) for the solicitude of its sanitary registration before the Comision Federal contra Riesgos Sanitarios (COFEPRIS). For the optimization of the production process a factorial design of three variables was evaluated with mixed levels (18 combinations), where the dependent variable is the radiochemical purity and the analytic method used to determine this parameter (High Performance Liquid Chromatography) was validated. Later on, by means of the production of 3 lots of the optimized formula of the radiopharmaceutical {sup 177}Lu-DOTANOC the production process was validated and the stability long term study to determine the period of useful life was carried out. The following pharmaceutical formulation was adopted as good: 1.85 GBq (0.5μg) of {sup 177}Lu, 250 μg of DOTANOC and 150 μL of acetates Buffer 1 M ph 5 in 5 m L of the medium. The analytic method used to determine the radiochemical purity of the formulation satisfied the requirements for the wished analytic application. We can conclude that the 3 validation lots prepared under protocols of Good Production Practices, in the Plant of Radiopharmaceuticals Production of the

  11. A clinical trial of 153Sm EDTMP in promotion of bone metastatic cancer pains%153钐改善骨转移癌痛疗效观察

    王新

    2002-01-01

    Objective To evaluate the effect of 153Sm EDTMP in the bone metastatic cancer pains.Methods In treatment group(32 patients with bone metastatic diseases) 153Sm EDTMP were given by infusion for one time.In control group,32 patients received radiotherapy. The radio dose was DT30Gy,5 times per week for 2 weeks.Pain relief was used as criteria of response at the time treatment finished and 6 months later.Results At the time treatment finished,there were statistically differences in pain relief between two groups.Pains relief rate was superior to control group after 6 months (P< 0.05).Conclusion Treatment with 153Sm EDTMP one time can reduce apparently pains caused by bone metastases,which is conveniently used and well tolerated.

  12. Somatostatin receptor expression in the human spleen - Answer to an enigma by ex-vivo and in-vitro autoradiography after 177Lu-DOTA-octreotate administration

    Full text of publication follows. Aim: radiolabelled somatostatin analogues are being used for diagnostic and therapeutic (PRRT) purposes in patients with somatostatin receptor (SSTR) expressing tumours. During PRRT a significant spleen uptake may lead to radiation doses of > 20 Gy. Yet, the threshold dose for spleen radiation induced toxicity is currently unknown. Based on previous 68Ga-DOTATOC PET/CT studies, demonstrating higher uptake in spleen than in splenosis, white pulp (WP) localization of radioactivity was suggested. This hypothesis was investigated in the current pilot study using the longer lived 177Lu-DOTA-octreotate. Methods: a patient diagnosed with neuroendocrine neoplasm of the pancreatic tail (SUVmax on 68Ga-DOTATOC PET/CT 100.4) with liver metastasis (SUV 47.3, normal liver SUV 12.5) and uptake in the spleen (SUV 41.0) received 1 GBq 177Lu-DOTA-octreotate. 2 h after administration whole-body planar scintigraphy and SPECT/CT of the upper abdomen was performed, followed by laparoscopic resection of the pancreatic tumour and splenectomy the next day. After spleen transport from Bad Berka to Rotterdam ex-vivo micro-SPECT of the removed spleen was acquired for 73 min using 2.5 mm diameter pinholes. Spleen fragments (∼10 * 10 * 5 mm) were either snap-frozen in liquid nitrogen or fixed in 10% formalin and paraffin embedded. Ex-vivo autoradiography of 10 μm cryo-sections was performed and serial sections were used for 111In-DOTA-octreotate in-vitro autoradiography after decay of 177Lu. FFPE sections were used for HE- and immunostaining for SSTR2A and cell subsets CD4 (Th-cell), CD8 (Ts-cell), CD20 (B-cell) and CD68 (macrophage). Results: 177Lu-DOTA-octreotate scintigraphy and SPECT/CT demonstrated high uptake in the pancreatic tumor, hepatic metastasis and homogeneously in the normal spleen. High resolution micro-SPECT imaging of the isolated spleen also revealed a relatively homogeneous uptake (calculated rest activity 60 MBq 177Lu). The vast

  13. Some radiation protection problems connected with the use of 186Re-HEDP and 153Sm-EDTMP for palliative therapy of of bone metastases

    The aim of this paper was to assess whether the ambulatory (outpatient) therapy with 186Re-HEDP and 153Sm-EDTMP is possible in the Czech Republic. Physical characteristics, administered activity, biokinetics of radiopharmaceuticals, radiation protection characteristics, irradiation of patients relatives as well as comparison with limits for rhenium-186 and samarium-153 radiopharmaceuticals are given. The outpatient administration of 186Re-HEDP and 153Sm-EDTMP with the subsequent keeping the patient for 6 hours in a department of nuclear medicine appears to be in compliance with regulations proposed in the Czech Republic as well as ICRP Recommendations. (J.K.) 1 tab., 12 refs

  14. Nuclear model calculations on cyclotron production of 51Cr

    51Cr (T1/2 = 27.7 d), which decays via electron capture (100 %) with 320 keV gamma emission (9.8 %), is a radionuclide with still a large application in biological studies. In this work, ALICE/ASH and TALYS nuclear model codes along with some adjustments are used to calculate the excitation functions for proton, deuteron, α-particle and neutron induced on various targets leading to the production of 51Cr radioisotope. The production yields of 51Cr from various reactions are determined using the excitation function calculations and stopping power data. The results are compared with corresponding experimental data and discussed from point of view of feasibility.

  15. Nuclear model calculations on cyclotron production of {sup 51}Cr

    Kakavand, Tayeb [Imam Khomeini International Univ., Qazvin (Iran, Islamic Republic of). Dept. of Physics; Aboudzadeh, Mohammadreza [Nuclear Science and Technology Research Institute/AEOI, Karaj (Iran, Islamic Republic of). Agricultural, Medical and Industrial Research School; Farahani, Zahra; Eslami, Mohammad [Zanjan Univ. (Iran, Islamic Republic of). Dept. of Physics

    2015-12-15

    {sup 51}Cr (T{sub 1/2} = 27.7 d), which decays via electron capture (100 %) with 320 keV gamma emission (9.8 %), is a radionuclide with still a large application in biological studies. In this work, ALICE/ASH and TALYS nuclear model codes along with some adjustments are used to calculate the excitation functions for proton, deuteron, α-particle and neutron induced on various targets leading to the production of {sup 51}Cr radioisotope. The production yields of {sup 51}Cr from various reactions are determined using the excitation function calculations and stopping power data. The results are compared with corresponding experimental data and discussed from point of view of feasibility.

  16. Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model

    Ullrich, Martin; Bergmann, Ralf; Peitzsch, Mirko; Zenker, Erik F.; Cartellieri, Marc; Bachmann, Michael; Ehrhart-Bornstein, Monika; Block, Norman L.; Schally, Andrew V.; Eisenhofer, Graeme; Bornstein, Stefan R.; Pietzsch, Jens; Ziegler, Christian G.

    2016-01-01

    Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors. For metastatic disease, no effective therapy is available. Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [177Lu]Lu-DOTA-(Tyr3)octreotate (DOTATATE) and AN-238. Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models. In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [64Cu]Cu-DOTATATE. Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14. Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [177Lu]Lu-DOTATATE compared to AN-238 and doxorubicin. Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies. This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo. Our findings highlight the therapeutic potential of somatostatin analogs, especially of [177Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs. Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome. PMID:27022413

  17. Thermodynamic evaluation of the stability of the bone-seeking radiopharmaceutical [177Lu]Lu(III)–DOTP under simulated blood plasma conditions

    Highlights: ► Thermodynamic blood plasma model supports in vivo biodistribution of [177Lu]Lu–DOTP. ► Lu3+ remains predominantly complexed (98.1%) with the DOTP under simulated physiological conditions. ► Thermodynamic and kinetic stability [177Lu]Lu–DOTP in blood plasma facilitates selectivity of the proposed radiopharmaceutical for bone. - Abstract: The stability and in vivo robustness of [177Lu]Lu–DOTP as a potential bone-targeting radiopharmaceutical was determined with the aid of thermodynamic blood plasma modeling simulations. Glass electrode potentiometry was employed to measure the stability constants of the complexes of Lu3+ with DOTP. Similarly, the complexes of DOTP with a selection of the important physiological metal ions: Ca2+, Mg2+, and Cu2+ were determined, representing the typical interactions that the ligand would encounter upon administration. This made possible the construction of a blood plasma model of DOTP, aiding in establishing the potential susceptibility of the radiopharmaceutical. The ligand binds predominantly to calcium in vivo, accounting for 59.6% of that initially introduced as a component of the Lu–DOTP complex. Furthermore, due to a preference of the DOTP to bind to Cu2+ it causes mobilization of the ions in blood plasma, and would therefore indicate a deficiency if the ligand is administered at a concentration of 8.5 × 10−5 mol dm−3. The lutetium-ions are preferentially bound to DOTP, with as much as 98.1% of the Lu3+ occupying the ligand under physiological conditions.

  18. The efficacy of {sup 177}Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis

    Kim, Seong-Jang; Pak, Kyoungjune [Pusan National University Hospital, Department of Nuclear Medicine and Biomedical Research Institute, Busan (Korea, Republic of); Koo, Phillip J.; Kwak, Jennifer J.; Chang, Samuel [University of Colorado School of Medicine, Department of Radiology, Aurora, CO (United States)

    2015-12-15

    This study was performed to evaluate the efficacy of {sup 177}Lu-labelled peptide receptor radionuclide therapy (PRRT) in patients with inoperable or metastatic neuroendocrine tumours (NETs). Systematic searches of MEDLINE and EMBASE databases were performed using the keywords of ''neuroendocrine'', ''{sup 177}Lu'' and ''prognosis''. All published studies of neuroendocrine tumours treated with {sup 177}Lu-labelled radiopharmaceuticals and evaluated with either Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 or Southwest Oncology Group (SWOG) criteria or both were included. If there was more than one published study from the same institution, only one report with the information most relevant to this study was included. Each response criteria group was analysed for disease response rates and disease control rates, defined as the percentages of patients with complete response (CR) + partial response (PR), and CR + PR + stable disease (SD), respectively, to a therapeutic intervention in clinical trials of anticancer agents. The pooled proportions are presented with both a fixed-effects model and random-effects model. Six studies with 473 patients (4 in RECIST criteria group with 356 patients, 3 in SWOG criteria group with 375 patients and 1 in both groups) were included. The RECIST criteria group demonstrated disease response rates ranging between 17.6 and 43.8 % with a pooled effect of 29 % [95 % confidence interval (CI) 24-34 %]. Disease control rates ranged from 71.8 to 100 %. The random-effects model showed an average disease control rate of 81 % (95 % CI 71-91 %). The SWOG criteria group demonstrated disease response rates ranging between 7.0 and 36.5 % with a pooled effect of 23 % (95 % CI 11-38 %). Disease control rates ranged from 73.9 to 89.1 %. The random-effects model showed an average disease control rate of 82 % (95 % CI 71-91 %). {sup 177}Lu-labelled PRRT is an effective treatment

  19. Peptide receptor radionuclide therapy with 90Y/177Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours)

    Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT. Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using 90Y/177Lu-labelled peptides after positive confirmation of SSTR expression on 68Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with 68Ga-DOTATOC PET/CT was carried out every 6 months to assess response to treatment. Clinical (symptomatic) response was also assessed. Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUVmax, accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUVmax. The three asymptomatic patients showed no new lesions or symptomatic worsening. PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or distant spread. Though these are

  20. Exposure of personnel and public due to using 153Sm-labelled EDTMP-Quadramet® in nuclear medicine procedures.

    Wrzesień, Małgorzata; Napolska, Katarzyna; Olszewski, Jerzy

    2016-03-01

    The main aim of this study was to highlight the problems of personnel exposure when administering (153)Sm-labelled ethylene diamine tetramethylene phosphonate-Quadramet(®) to patients and especially to evaluate hand exposure of the personnel. The exposure levels of patients' families and the people who takes care of the patients treated by Quadramet(®) were also estimated. Thermoluminescent detectors were used to measure the doses. The doses received during the injection of the Quadramet(®) by the nursing staff have been determined at the level of 1/150 dose limit for the skin. Exposure of members of the patient's family staying 1.5 m away from the patient being treated with Quadramet(®) has been estimated to be 0.40 mGy. PMID:26041475

  1. Experimental cross section for the 152Sm(n, γ)153Sm reaction at 0.0334 eV

    The neutron capture cross section for the 152Sm(n, γ)153Sm reaction at an energy of 0.0334 eV was measured for the first time using monochromatic neutrons of a powder diffractometer at the TRIGA Mark II nuclear reactor at Dhaka, Bangladesh. The 197Au(n, γ)198Au reaction was used to monitor the neutron beam intensity. The radioactivity of the products was determined via high resolution γ-ray spectrometry. The obtained cross section value is 184 ± 22b, which is consistent with both the ENDF/B-VII and TENDL-2012 data libraries. The measured value at 0.0334 eV and the previous data at 0.0536 eV confirm the reliability of the data in the above libraries. (orig.)

  2. The features of kinetics of 153Sm-oksabifor in bone metastases of cancer of different localization

    Provide evaluation of investigation of kinetics of 153Sm-oksabifor in metastases of cancer the results of complex scintigraphic investigations of 26 patients who were treated by radionuclide therapy were analyzed. The angioscintigraphy during 60 seconds, dynamic scintigraphy during 60-90 minutes and whole body scanning after intravenous bolus injection of 4130-4950 MBq of the radiopharmaceutical in sequence were made. Considerable variability of indices of the radiopharmaceutical kinetics was determined. The features of angioscintigrams from bone metastases with intensive accumulation of the radiopharmaceutical are a short descending segment or its absents and passing an ascending segment into plateau or slowly ascending curve, which are determined the radiopharmaceutical fixation in metastases during first passing the bolus through the vessels. Character of the radiopharmaceutical fixation at angioscintigraphy may be a prognostic factor of the efficacy of radionuclide therapy

  3. Exposure of personnel and public due to using 153Sm-labelled EDTMP-QuadrametR in nuclear medicine procedures

    The main aim of this study was to highlight the problems of personnel exposure when administering 153Sm-labelled ethylene diamine tetramethylene phosphonate-QuadrametR to patients and especially to evaluate hand exposure of the personnel. The exposure levels of patients' families and the people who takes care of the patients treated by QuadrametR were also estimated. Thermoluminescent detectors were used to measure the doses. The doses received during the injection of the QuadrametR by the nursing staff have been determined at the level of 1/150 dose limit for the skin. Exposure of members of the patient's family staying 1.5 m away from the patient being treated with QuadrametR has been estimated to be 0.40 mGy. (authors)

  4. 99TC-MDP@153Sm-EDTMP治疗骨转移癌64例报告

    张萌萌; 常淑玲; 王淑芬; 张宗英; 郭忠

    2001-01-01

    @@恶性肿瘤骨转移(也称骨转移癌)导致的剧烈、持续性骨痛,给患者带来难以忍受的痛苦,放疗、化疗对骨转移癌的治疗已经临床证实疗效不明显.笔者应用99TC-MDP(99锝-亚甲基二磷酸盐)、153Sm-EDTMP(153钐-乙二胺四亚甲基磷酸)治疗收到较好疗效.现报道如下. 1资料与方法 1.1病例资料(1)治疗对象:经临床检查、SPECT全身显像诊断的54例恶性肿瘤骨转移患者中,肺癌18例,乳腺癌10例,直肠癌7例,肝癌3例,鼻咽癌2例,其他恶性肿瘤14例.本组执行“完整疗程”;(2)治疗对照组:经临床检查、SPECT全身显像诊断的10例恶性肿瘤骨转移患者中肺癌7例,乳腺癌2例,直肠癌1例. 1.2治疗药物99TC-MDP为中国核动力研究设计院成都同位素研究所提供,153Sm-EDTMP为中国原子能研究院,北京同位素应用研究所提供.

  5. Survival curves study of platelet labelling with 51Cr

    Platelet kinetics and idiopathic thrombocytopenic purpura were researched in the literature. An 'in vitro' platelet labelling with 51Cr procedure in implementation has been evaluated in human beings. Functions used for fitting considered the cases whether the curve was linear or exponential as well as the presence of hematies. (author)

  6. 51Cr diffusion in Zr-Sn alloys

    The 51Cr volume diffusion in Zr-Sn alloys is measured in polycrystals with big grains by the thin-film method. The Sn content in the alloys ranges from 0.39% at to 6.66 % at. In the beta-phase the analysed temperature range is 982 deg C-1240 deg C. The Sn dehances the 51Cr diffusion in beta-Zr, the effect being small but well defined. Assuming the formation of Sn-Cr dimers, the linear dehancement coefficient b and the parameters for the variation of b with temperature were calculated. The parameters Q and Do were calculated for the more diluted alloys and, upon application of the Zener theory for Do, a negative contribution to the activation entropy is found. Three experiments at different temperatures were performed in the alpha-phase. 51Cr diffuses very fast in alpha-Zr-Sn. No definite correlation is found between the 51Cr diffusivity and the increasing Sn concentration, probably due to the anisotropy of the alfa-phase. (M.E.L.)

  7. Peptide labeling using 188Re, 188Re-MAG3 and 153Sm-H1ETA. A comparison on their in vitro lipophilicity

    Lanreotide peptide was labeled with 153Sm-H1ETA and 188Re-MAG3 in order to evaluate whether or not their conjugation to the peptide produce significant differences of the in vitro lipophilicity with respect to the 188Re-lanreotide prepared by the direct labeling method (highly lipophilic). The differences of lipophilicity between the complexes, were evaluated using a reverse phase HPLC system. The measured lipophilicity of 153Sm-H1ETA-lanreotide, 188Re-MAG3-lanreotide and 188Re-lanreotide was taken to be the capacity factor [k' = (tR - t0)/t0 where tR is the retention time and t0 is the dead time] for each of the complexes under identical chromatography conditions. Results showed that the in vitro lipophilicity decreased in the order 188Re-lanreotide (direct labeling), 188Re-MAG3-lanreotide and 153Sm-H1ETA-lanreotide. Since the last one has a capacity factor (k') similar to that of 188Re-MAG3, some renal elimination for 153Sm-H1ETA-lanreotide could be expected, which probably would reduce the unnecessary radiation dose to normal tissues. (author)

  8. Development of {sup 177}Lu-DTPA-SPIO conjugates for potential use as a dual contrast SPECT/MRI imaging agent

    Shanehsazzadeh, Saeed; Yousefnia, Hassan [Nuclear Science and Technology Research Institute (NSTRI), Tehran (Iran, Islamic Republic of); Gruettner, Cordula [Micromod Partikeltechnologie GmbH, Rostock (Germany); and others

    2016-08-01

    This study describes the preparation, biodistribution of {sup 177}Lu-DTPA-SPIO after intravenous injection in rats. The chelator DTPA dianhydride was conjugated to SPIO NPs using a small modification of the well-known cyclic anhydride method. Conjugation was done at a 1:2 (SPIO:ccDTPA) molar ratio. Conjugation reaction was purified with Magnetic assorting column (MACs) using high gradient magnetic field following incubation, the radio labeled conjugate was checked using RTLC method for labeling and purity checked. The RTLC showed that labeling yield was above 99% after purification and the compound have good in-vitro stabilities until 48 h post injection in the presence of human serum. The biodistribution of {sup 177}Lu-DTPA-SPIO in rats showed dramatic uptake in the reticuloendothelial system (RES) and their clearance is so fast in other organs especially in the blood. In conclusion, due to high uptakes of this radiotracer in the liver and spleen and their fast clearance from other tissues, especially in blood, it is suggested that this radiotracer would be suitable for RES studies.

  9. Individualized dosimetry in patients undergoing therapy with {sup 177}Lu-DOTA-D-Phe{sup 1}-Tyr{sup 3}-octreotate

    Sandstroem, Mattias [Uppsala University Hospital, Department of Oncology, Radiology and Clinical Immunology, Division of Medical Physics, Uppsala (Sweden); Uppsala University Hospital, Department of Hospital Physics, Uppsala (Sweden); Garske, Ulrike [Uppsala University Hospital, Department of Medical Sciences, Division of Nuclear Medicine, Uppsala (Sweden); Granberg, Dan [Uppsala University Hospital, Department of Medical Sciences, Division of Endocrine Oncology, Uppsala (Sweden); Sundin, Anders [Karolinska University Hospital, Department of Molecular Medicine and Surgery, Division of Diagnostic Radiology, Stockholm (Sweden); Lundqvist, Hans [Uppsala University, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden)

    2010-02-15

    In recent years, targeted radionuclide therapy with [{sup 177}Lu-DOTA{sup 0}, Tyr{sup 3}]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging. Attenuation-corrected SPECT data were analysed both by using organ-based volumes of interest (VOIs) to obtain the total radioactivity in the organ, and by using small VOIs to measure the tissue radioactivity concentration. During the first treatment session in 24 patients, imaging was performed 1, 24, 96 and 168 h after [{sup 177}Lu-DOTA{sup 0}, Tyr{sup 3}]octreotate infusion. Absorbed doses in non tumour-affected kidney, liver and spleen were calculated and compared for all three methods (planar imaging, SPECT organ VOIs, SPECT small VOIs). Planar and SPECT dosimetry were comparable in areas free of tumours, but due to overlap the planar dosimetry highly overestimated the absorbed dose in organs with tumours. Furthermore, SPECT dosimetry based on small VOIs proved to be more reliable than whole-organ dosimetry. We conclude that SPECT dosimetry based on small VOIs is feasible and more accurate than conventional planar dosimetry, and thus may contribute towards optimising targeted radionuclide therapy. (orig.)

  10. Formation of medical radioisotopes {sup 111}In, {sup 117m}Sn, {sup 124}Sb, and {sup 177}Lu in photonuclear reactions

    Danagulyan, A. S.; Hovhannisyan, G. H., E-mail: hov-gohar@ysu.am; Bakhshiyan, T. M. [Yerevan State University (Armenia); Avagyan, R. H.; Avetisyan, A. E.; Kerobyan, I. A.; Dallakyan, R. K. [A.I. Alikhanian National Science Laboratory (Yerevan Physics Institute) (YerPhI) (Armenia)

    2015-06-15

    The possibility of the photonuclear production of radioisotopes {sup 111}In, {sup 117m}Sn, {sup 124}Sb, and {sup 177}Lu is discussed. Reaction yields were measured by the gamma-activation method. The enriched tin isotopes {sup 112,} {sup 118}Sn and Te and HfO{sub 2} of natural isotopic composition were used as targets. The targets were irradiated at the linear electron accelerator of Alikhanian National Science Laboratory (Yerevan) at the energy of 40 MeV. The experimental results obtained in this way reveal that the yield and purity of radioisotopes {sup 111}In and {sup 117}mSn are acceptable for their production via photonuclear reactions. Reactions proceeding on targets from Te and HfO{sub 2} of natural isotopic composition and leading to the formation of {sup 124}Sb and {sup 177}Lu have small yields and are hardly appropriate for the photoproduction of these radioisotopes even in the case of enriched targets.

  11. Synthesis and evaluation of Lys{sup 1}(α, γ-Folate)Lys{sup 3}({sup 177}Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer

    Aranda L, L.; Ferro F, G.; Azorin V, E.; Ramirez, F. M.; Ocampo G, B.; Santos C, C.; Jimenez M, N. [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico); Issac O, K. [Universidad Autonoma del Estado de Mexico, Facultad de Medicina, 50180 Toluca, Estado de Mexico (Mexico)

    2015-10-15

    Full text: Lutetium-177 labeled hetero bivalent molecules that interact with different targets on tumor cells have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this work was to synthesize Lys{sup 1} (α,γ-Folate)-Lys{sup 3}({sup 177}Lu-DOTA)-Bombesin (1-14) ({sup 177}LuFolate-Bn), as well as to assess its in vitro and in vivo potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (Fr) and gastrin releasing peptide receptors (GRPR). Lys{sup 1} Lys{sup 3} (DOTA)-Bombesin (1-14) was conjugated to the terminal carboxylic group of the folic acid and the product purified by size-exclusion HPLC. Chemical characterization was carried out by UV-vis, Ft-IR spectroscopies and MALDI-TOF mass spectrometry. {sup 177}Lu labeling was performed by reaction of {sup 177}LuCl{sub 3} with the Lys{sup 1} (α,γ-Folate)-Lys{sup 3} (DOTA)-Bombesin (Folate-Bn) conjugate. In vitro binding studies were carried out in T47D breast cancer cells (positive to Fr and GRPR). Biokinetic studies and micro-SPECT/CT images were obtained using athymic mice with T47D induced tumors. Spectroscopic studies and HPLC analyses indicated that the conjugate was obtained with high chemical and radiochemical purity (98 ± 1.3%). T47D-tumors were clearly visible with high contrast at 2 h after radiopharmaceutical administration. The {sup 177}Lu-absorbed dose delivered to tumors was 23.9 ± 2.1 Gy (74 MBq, intravenously administered) {sup 177}Lu-Folate-Bn demonstrated properties suitable as a theranostic radiopharmaceutical for breast tumors expressing Fr s and GRPR s. (Author)

  12. Synthesis and evaluation of Lys1(α, γ-Folate)Lys3(177Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer

    Full text: Lutetium-177 labeled hetero bivalent molecules that interact with different targets on tumor cells have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this work was to synthesize Lys1 (α,γ-Folate)-Lys3(177Lu-DOTA)-Bombesin (1-14) (177LuFolate-Bn), as well as to assess its in vitro and in vivo potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (Fr) and gastrin releasing peptide receptors (GRPR). Lys1 Lys3 (DOTA)-Bombesin (1-14) was conjugated to the terminal carboxylic group of the folic acid and the product purified by size-exclusion HPLC. Chemical characterization was carried out by UV-vis, Ft-IR spectroscopies and MALDI-TOF mass spectrometry. 177Lu labeling was performed by reaction of 177LuCl3 with the Lys1 (α,γ-Folate)-Lys3 (DOTA)-Bombesin (Folate-Bn) conjugate. In vitro binding studies were carried out in T47D breast cancer cells (positive to Fr and GRPR). Biokinetic studies and micro-SPECT/CT images were obtained using athymic mice with T47D induced tumors. Spectroscopic studies and HPLC analyses indicated that the conjugate was obtained with high chemical and radiochemical purity (98 ± 1.3%). T47D-tumors were clearly visible with high contrast at 2 h after radiopharmaceutical administration. The 177Lu-absorbed dose delivered to tumors was 23.9 ± 2.1 Gy (74 MBq, intravenously administered) 177Lu-Folate-Bn demonstrated properties suitable as a theranostic radiopharmaceutical for breast tumors expressing Fr s and GRPR s. (Author)

  13. Radiochemical and biological studies, including in non-human primates, towards indigenous development of 153Sm-EDTMP for metastatic bone pain palliation

    The combination of ease of formulation and superior biological features of 153Sm-EDTMP in terms of safety and efficacy for metastatic bone pain palliation, together with the prospect of better logistics of production, has prompted extensive efforts by many groups world over for its preparation and evaluation. Our efforts have been directed towards exploring the feasibility for formulation of 153Sm-EDTMP suitable for human use by neutron activation in medium flux reactors of the freely available and inexpensive natural samarium oxide target. The emphasis in biological studies was placed on tests in larger animals (monkeys) as a prelude to clinical evaluation. Feasibility to achieve reasonably high specific activity of 300-700 mCi/mg Sm at EOB with natural samarium has been adequately demonstrated. The radioeuropium contamination, estimated by γ-spectrometry to be 153Sm-EDTMP from natural samarium at high radioactive concentrations of 40-50 mCi 153Sm/mL, acceptable biolocalization, as revealed by both biodistribution studies in rats (femur uptake of 2-3% injected dose at 1h p.i. and retention up to 120 h p.i.) and gamma camera images in monkeys and adequate stability have been feasible. Excellent quality bone images of monkeys were recorded showing rapid clearance from blood, visualization of skeleton, clearance from kidneys within 2 hours and retention in skeleton up to 116 hours p.i. No significant activity in other soft tissues was noted. Comparative evaluation of the product prepared from enriched samarium as well as using in-house synthesized EDTMP has, likewise, revealed identical biolocalization features. EDTMP dose tolerance test in mice showed a safety factor of about 100 for a product made from natural samarium at an adult human dose of 50 mCi 153Sm. Feasibility for production, reasonable safety and satisfactory biolocalisation of the indigenous product has been adequately established so as to warrant clinical trials in patients. (author)

  14. Comparison of sequential planar {sup 177}Lu-DOTA-TATE dosimetry scans with {sup 68}Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy

    Sainz-Esteban, Aurora; Carril, Jose Manuel [Hospital Universitario Marques de Valdecilla, Department of Nuclear Medicine, Santander (Spain); Prasad, Vikas; Schuchardt, Christiane; Zachert, Carolin; Baum, Richard P. [Zentralklinik Bad Berka, Department of Nuclear Medicine and Centre for PET/CT, Bad Berka (Germany)

    2012-03-15

    The aim of the study was to compare sequential {sup 177}Lu-DOTA-TATE planar scans ({sup 177}Lu-DOTA-TATE) in patients with metastasized neuroendocrine tumours (NET) acquired during peptide receptor radionuclide therapy (PRRT) for dosimetry purposes with the pre-therapeutic {sup 68}Ga-DOTA-TATE positron emission tomography (PET)/CT ({sup 68}Ga-DOTA-TATE) maximum intensity projection (MIP) images obtained in the same patients concerning the sensitivity of the different methods. A total of 44 patients (59 {+-} 11 years old) with biopsy-proven NET underwent {sup 68}Ga-DOTA-TATE and {sup 177}Lu-DOTA-TATE imaging within 7.9 {+-} 7.5 days between the two examinations. {sup 177}Lu-DOTA-TATE planar images were acquired at 0.5, 2, 24, 48 and 72 h post-injection; lesions were given a score from 0 to 4 depending on the uptake of the radiopharmaceutical (0 being lowest and 4 highest). The number of tumour lesions which were identified on {sup 177}Lu-DOTA-TATE scans (in relation to the acquisition time after injection of the therapeutic dose as well as with regard to the body region) was compared to those detected on {sup 68}Ga-DOTA-TATE studies obtained before PRRT. A total of 318 lesions were detected; 280 (88%) lesions were concordant. Among the discordant lesions, 29 were {sup 68}Ga-DOTA-TATE positive and {sup 177}Lu-DOTA-TATE negative, whereas 9 were {sup 68}Ga-DOTA-TATE negative and {sup 177}Lu-DOTA-TATE positive. The sensitivity, positive predictive value and accuracy for {sup 177}Lu-DOTA-TATE as compared to {sup 68}Ga-DOTA-TATE were 91, 97 and 88%, respectively. Significantly more lesions were seen on the delayed (72 h) {sup 177}Lu-DOTA-TATE images (91%) as compared to the immediate (30 min) images (68%). The highest concordance was observed for bone metastases (97%) and the lowest for head/neck lesions (75%). Concordant lesions (n = 77; mean size 3.8 cm) were significantly larger than discordant lesions (n = 38; mean size 1.6 cm) (p < 0.05). No such significance was

  15. Anisotropic diffusion of 51Cr in Zr-α monocrystals

    The volume diffusion coefficients of the fast-diffusing solute 51Cr were obtained in oriented α-Zr single-crystals, in the directions parallel and perpendicular to the c axis. The dependence of those diffusion coefficients with temperature was also measured between 7500C and 8480C. Single-crystals were grown by thermal cycling through the transformation αβ (8630C). Diffusion coefficients were measured using the 'thin film' method. In some experiments non-gaussian penetration profiles were obtained and this behaviour is analyzed in the Appendix. The diffusion of 51Cr is faster in the c axis direction, with Q sub(//) (1.59 eV) < Q perpendicular to (1.69 eV). The anisotropy factor f sub(a)=D sub(//)/D perpendicular or approx. = 3. This factor, the activation energies and frequency factores are discussed in comparison with other solutes. (Author)

  16. Genotoxic evaluation of [DOTA,Tyr3]octreotate labeled with 131I and 177Lu in human peripheral lymphocytes in vitro by micronucleus assay

    The radiolabeled receptor-binding peptides have being used for cancer diagnosis and therapy. The octreotate, a somatostatin analogue peptide, bound to various tumors expressing sst receptors (thyroid, pancreas, prostrate, melanoma and lymphomas). The amount and the type of receptors for somatostatin influence the tissue uptake. The [DOTA, Tyr3]octreotate has been used because of its high affinity to somatostatin subtype receptors sstr2 and sstr5. The pharmacokinetic study showed that the blood clearance is rapid and only 9% of the intravenous injected activity remains in human blood after one hour. The aim of this study was to evaluate the cytogenetic effect of radiolabeled [DOTA, Tyr3]octreotate in blood cells in vitro, using the cytokinesis-block micronucleus (MN) assay. This technique allows evaluating the mutagenic effects of both endogenous and exogenous agents at chromosome level. Blood samples of healthy donors were collected in heparinized syringes and exposed to different activities of [DOTA, Tyr3]octreotate labeled with with 131I (n=3) and 177Lu (n=3), where radioactive concentration ranged from 600 to 5600 kBq/mL, corresponding to an injected activity of 3.1 to 28.9 GBq in a reference man of 70 kg weight. 131I and 177Lu are beta- and gamma-emitters. After one-hour exposition to radiopharmaceuticals at 37 deg C, the cells were washed with culture medium for removing the non internalised octreotate and cultivated for 72 hours, according to criteria adopted by the IAEA. The results showed a positive correlation between radioactive concentrations (X) and the frequency of binucleated cells with micronuclei (Y) (P131I-DOTA, Tyr3]octreotate was Y = (1.634 ± 0.236) + (0.912 ± 0.137) 10-3 X and for [177Lu-DOTA, Tyr3]octreotate was Y = (1.715 ± 0.342) + (0.743 ± 0.135) 10-3 X. The non labeled molecule, [DOTA, Tyr3]octreotate, has no influence in the induction of cytogenetic damage. The micronucleus assay with rat pancreatic tumor cells (AR42J) that express the

  17. Urine management after treatment with ''153 Sm-EDTMP (QUADRAMET); Gestion de la orina en el tratamiento con ''153 Sm-EDTMP (QUADRAMET)

    Delgado, A.; Diaz, J. P.; Carrasco, J. L.; Jimenez-Hoyuela, J. M.; Rebollo, A. C.; Martinez del Valle, M. D.; Ortega, S. J.

    2004-07-01

    The main purpose was to establish and to evaluate a new protocol of individualized treatment of patient urine after ''153 Sm-EDTMP injection, with a more efficient management of the wastes. Excreted urine was collected in an appropriate container form which, previous to sealing it, an aliquot of 10 ml was obtained. Experimental half-life (t1/2) of the isotope was then determined by measuring the activity at different times, besides the minimum time necessary for disposing of the radioactive wastes as regular trash. The measured half-life adjusted well to the theoretical value of the isotope. The time of considered storage oscillated between 19 and 26 days, based on the activity excreted by each patient. The main idea is the consideration of the set container-urine as solid waste: the evaluation of the minimum storage time necessary to its elimination is made in terms of legal limitation of specific activity by mass unit. The immediate advantages ares: the elimination of disagreeable scents by the storage of urine, it is not necessary a liquid waste disposal to eliminate it, and a more accurate knowledge of the specific activity at the moment of the elimination (dilution factor is not used). (Author) 10 refs.

  18. {sup 177}Lu- labeled MOv18 as compared to {sup 131}I- or {sup 90}Y-labeled MOv18 has the better therapeutic effect in eradication of alpha folate receptor-expressing tumor xenografts

    Zacchetti, Alberto [Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 (Italy); Coliva, Angela [Department of Imaging and Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 (Italy); Luison, Elena [Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 (Italy); Seregni, Ettore; Bombardieri, Emilio [Department of Imaging and Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 (Italy); Giussani, Augusto [Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg (Germany); Figini, Mariangela [Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 (Italy); Canevari, Silvana [Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 (Italy)], E-mail: silvana.canevari@istitutotumori.mi.it

    2009-10-15

    Introduction: The mouse monoclonal antibody MOv18, directed against the {alpha}-isoform of folate receptor (FR), was investigated to identify the optimal radioconjugate for radioimmunotherapy of minimal residual disease in ovarian cancer. Methods: Pharmacokinetics, biodistribution, long-term therapeutic efficacy and toxicity of MOv18, labeled with the beta-emitters {sup 131}I, {sup 90}Y and {sup 177}Lu, were compared in a xenografted mouse model, composed by two cell lines, A431FR and A431MK, differing only for FR expression. Results: A shorter blood clearance and a higher tumor uptake were observed for {sup 90}Y- and {sup 177}Lu- compared to {sup 131}I-MOv18, and a shorter blood pharmacokinetics was recorded in A431FR-bearing animals. At equitoxic maximum tolerable doses, the general irradiation by {sup 131}I- and {sup 90}Y-MOv18 gives rise to strong targeted effects on A431FR and nontargeted effects on A431MK tumors, while {sup 177}Lu-MOv18 was able to eradicate small size tumor masses expressing the antigen of interest exerting only mild non-targeted effects. Conclusion: {sup 177}Lu-MOv18 at the maximal tolerated dose is the immunoradioconjugate with the best therapeutic window in experimental conditions of small tumor volume.

  19. 177Lu- labeled MOv18 as compared to 131I- or 90Y-labeled MOv18 has the better therapeutic effect in eradication of alpha folate receptor-expressing tumor xenografts

    Introduction: The mouse monoclonal antibody MOv18, directed against the α-isoform of folate receptor (FR), was investigated to identify the optimal radioconjugate for radioimmunotherapy of minimal residual disease in ovarian cancer. Methods: Pharmacokinetics, biodistribution, long-term therapeutic efficacy and toxicity of MOv18, labeled with the beta-emitters 131I, 90Y and 177Lu, were compared in a xenografted mouse model, composed by two cell lines, A431FR and A431MK, differing only for FR expression. Results: A shorter blood clearance and a higher tumor uptake were observed for 90Y- and 177Lu- compared to 131I-MOv18, and a shorter blood pharmacokinetics was recorded in A431FR-bearing animals. At equitoxic maximum tolerable doses, the general irradiation by 131I- and 90Y-MOv18 gives rise to strong targeted effects on A431FR and nontargeted effects on A431MK tumors, while 177Lu-MOv18 was able to eradicate small size tumor masses expressing the antigen of interest exerting only mild non-targeted effects. Conclusion: 177Lu-MOv18 at the maximal tolerated dose is the immunoradioconjugate with the best therapeutic window in experimental conditions of small tumor volume.

  20. Enhancement of somatostatin-receptor-targeted 177Lu-[DOTAdeg. C, -Tyr3]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation

    Introduction: Clinical studies of patients treated with somatostatin-receptor (sstr)-targeted [DOTAdeg. C, -Tyr3]-octreotide (DOTATOC) labeled with 177Lu and 9deg. C, Y have shown overall response rates in the range of 9-33%. This study evaluates the potential for combination therapy with gemcitabine in an effort to improve clinical outcomes. Methods: Human pancreatic adenocarcinoma Capan-2, rat pancreatic cancer AR42J and human small cell lung cancer NCI-H69 cells were each treated with 1 μg/ml gemcitabine for 4 days followed by replacement of the medium alone for four additional days. Cell cycle and direct receptor-uptake studies were performed with 177Lu-DOTATOC after the total 8-day treatment as described. Cell viability and apoptosis experiments were performed to study the effects of gemcitabine pretreatment and 177Lu-DOTATOC radionuclide therapy. Parallel control studies were performed with receptor-non-targeted 177Lu-DOTA and DOTATOC. Results: Cells treated with gemcitabine for 4 days showed a down-regulation of sstr expression as determined by 177Lu-DOTATOC uptake. However, after 4 days of additional growth in absence of gemcitabine, the uptake of 177Lu-DOTATOC was 1.5-3 times greater than that of the untreated control cells. In gemcitabine-pretreated Capan-2 cells, 84% of the cell population was in the G2M phase of the cell cycle. Due to sstr up-regulation and cell cycle modulations, synergistic effects of gemcitabine pretreatment were observed in cell viability and apoptosis assays. 177Lu-DOTATOC resulted in two to three times greater apoptosis in gemcitabine-pretreated Capan-2 cells compared to the untreated cells. Conclusion: Gemcitabine pretreatment up-regulates sstr expression and acts as a radiosensitizer through cell cycle modulation. The rational combination of gemcitabine and sstr-targeted radiopharmaceuticals represents a promising chemoradiation therapeutic tool with great potential to improve clinical outcomes and, thus, merits further study

  1. Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor

    Michael Bzorek

    2013-10-01

    Full Text Available Peptide receptor radionuclide therapy (PRRT is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy.

  2. Radiolabelled 153Sm-chelates of glycoconjugates: multivalence and topology effects on the targeting of the asialoglycoprotein receptor

    In this paper we report and discuss the biodistribution studies with Wistar rats of a series of 153Sm(III)-glycoconjugates, based on DO3A and DO2A(cis) scaffolds (DO3A = 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane; DO2A(cis) = 1,4-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). The effects of changing the sugar type (galactose, lactose and glucose), valency (mono and divalent) and topology on the targeting ability of the liver asialoglycoprotein receptor (ASGPR) are evaluated. Divalent glycoconjugates with different topologies were generated by a pendant glycodendrimeric (generation 1) architecture on a DO3A scaffold and by a linear DO2A(cis)-bis derivative. The results show that the galactose conjugates are more target efficient than the lactose analogues, while the glucose conjugates have no liver targeting ability. Divalent galactose conjugates are more efficiently targeted to the liver than the monovalent ones, while the dendrimeric topology of DO3A-Gal2 has higher targeting efficiency than that of the DO2A(cis)-Gal2. (orig.)

  3. Radiolabelled {sup 153}Sm-chelates of glycoconjugates: multivalence and topology effects on the targeting of the asialoglycoprotein receptor

    Torres, S. [Centro de Quimica, Campus de Gualtar, Univ. do Minho, Braga (Portugal); Martins, J.A.; Andre, J.P.; Neves, M. [Inst. Tecnologico e Nuclear, Sacavem (Portugal); Santos, A.C.; Prata, M.I.M. [Servico de Biofisica, IBILI, Univ. de Coimbra (Portugal); Geraldes, C.F.G.C. [Dept. de Bioquimica, Centro de Espectroscopia RMN e Centro de Neurociencias e Biologia Celular, Univ. de Coimbra (Portugal)

    2007-07-01

    In this paper we report and discuss the biodistribution studies with Wistar rats of a series of {sup 153}Sm(III)-glycoconjugates, based on DO3A and DO2A(cis) scaffolds (DO3A = 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane; DO2A(cis) = 1,4-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). The effects of changing the sugar type (galactose, lactose and glucose), valency (mono and divalent) and topology on the targeting ability of the liver asialoglycoprotein receptor (ASGPR) are evaluated. Divalent glycoconjugates with different topologies were generated by a pendant glycodendrimeric (generation 1) architecture on a DO3A scaffold and by a linear DO2A(cis)-bis derivative. The results show that the galactose conjugates are more target efficient than the lactose analogues, while the glucose conjugates have no liver targeting ability. Divalent galactose conjugates are more efficiently targeted to the liver than the monovalent ones, while the dendrimeric topology of DO3A-Gal{sub 2} has higher targeting efficiency than that of the DO2A(cis)-Gal{sub 2}. (orig.)

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

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

  5. Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2: an in vitro/in vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3 human prostate cancer cells

    Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to identify a BBN analogue that can be radiolabeled with 177Lu and maintains high specificity for GRPr positive prostate cancer tumors in vivo. A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a DOTA-BBN (DOTA 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) conjugate with the following general structure: DOTA-X-Q-W-A-V-G-H-L-M-(NH2), where the spacer group, X = ω-NH2(CH2)7COOH (8-Aoc). The BBN-construct was purified by reversed phase-HPLC (RP-HPLC). Electrospray Mass Spectrometry (ES-MS) was used to characterize both metallated and non-metallated BBN-conjugates. The new DOTA-conjugate was metallated with 177Lu(III)Cl3 or non-radioactive Lu(III)Cl3. The 177Lu(III)- and non-radiolabeled Lu(III)-conjugates exhibit the same retention times under identical RP-HPLC conditions. The 177Lu-DOTA-8-Aoc-BBN[7-14]NH2 conjugate was found to exhibit optimal pharmacokinetic properties in CF-1 normal mice. In vitro and in vivo models demonstrated the ability of the 177Lu-DOTA-8-Aoc-BBN[7-14]NH2 conjugate to specifically target GRP receptors expressed on PC-3 human prostate cancer cells

  6. DNA gel electrophoretic and micro-auto-radiographic studies on apoptosis in bone tumor cells after exposure with 153Sm-EDTMP

    The apoptosis in bone tumor cells is studied after 153Sm-EDTMP irradiation. Fragmented DNA is analyzed by agarose gel electrophoresis. Experimental observations show that 153-EDTMP exposure induces the inter-nucleo-somal DNA damage in bone tumor cells. The DNA ladder pattern formation in bone tumor cells is shown. At the same time, the micro-auto-radiographic study indicate that 153Se-EDTMP could permeate through cell membrane and displays membrane-seeking condensation in bone tumor cells. Soon afterwards 153Sm-EDTMP could be phagocytized by the tumor cells and distributed in cytoplasm as well as nucleus in the form of phagosome. With the prolongation of observing time, the membrane-bounded apoptotic bodies are observed

  7. Dosimetric study of radium-223 chloride and 153Sm-EDTMP for treatment of bone metastases using MCNPX code and available experimental data

    Radium-223 chloride is an alpha emitter radiopharmaceutical which recently has been used for treatment of bone metastases. Absorbed and equivalent doses of 223RaCl2 were studied using MCNPX Monte Carlo code in a phantom consisted of bone marrow, bone and soft tissue. 153Sm-EDTMP as a beta emitter was also simulated for comparison with 223RaCl2. Results show that by injection of 100 µCi 223RaCl2 against 70 mCi 153Sm-EDTMP to a 70 kg adult man, equivalent dose of metastatic bone can be increased about six times without significant increase in delivered dose to healthy tissues. These results demonstrated acceptable agreement with experimental data. (author)

  8. The clinical value of treatment with 153Sm-EDTMP-89SrCl2 joint half volume method for bone metastatic carcinoma

    Objective: To explore therapeutic effects and side effects of half quantity 153Sm-EDTMP joint half quantity 89SrCl2 for patients with bone metastatic carcinoma. Methods: 264 patients with extensive bone metastasis were randomly divided into 4 groups. Group Ⅰ: 156 patients were treated with 153Sm-EDTMP, Group Ⅱ: 78 patient were given 89SrCl2, Group Ⅲ: 20 patients accepted the joint half volume therapy, Group Ⅳ (control group): 10 patients were given 4 ml physiological saline. After therapy, all patients were reviewed routine blood test every week in the next 2 months and bone scintigraphy after 36 months. The efficacy of alleviate pain, the time to onset and the duration, myelosuppression were recorded. one-way ANOVA and χ2-test were performed by SAS V8.2. Results: The alleviate pain efficiency of group Ⅰ, Ⅱ, Ⅲ respectively were 79.5% (124/156), 69.2% (54/78), 85% (17/20). No statistical significance among the 3 groups (P>0.05); Significant differences was existed between each group and the control group (P0.05); Group Ⅱ respectively had significant differences with group Ⅰ and Ⅲ (P 0.05); statistical significance existed between group Ⅰ and group Ⅱ, Ⅲ (P 0.05). Conclusion: Half dose 153Sm-EDTMP joint half dose 89SrCl2 therapy can achieve higher efficacy for bone metastatic carcinoma, and fewer side effect of myelosuppression. (authors)

  9. Assessment of canine intestinal permeability, using 51Cr-labeled ethylenediaminetetraacetate

    The 51Cr-labeled EDTA was validated as a suitable permeability probe in dogs for measurement of passive, unmediated diffusion across intestinal mucosa via intercellular pathways. The 51Cr-labeled EDTA was stable in aqueous solution and did not bind to biologic tissue and fluids. After incubation of 51Cr-labeled EDTA in isolated jejunal loops, analytic subcellular fractionation of jejunal mucosa on reorientating sucrose-density gradients was performed, and no association of 51Cr-labeled EDTA with particulate intracellular organelles was detected. Intravenously administered 51Cr-labeled EDTA was rapidly and completely excreted in urine. Intestinal permeability to 51Cr-labeled EDTA after oral administration was assessed in healthy dogs. The percentage of the administered dose of 51Cr-labeled EDTA excreted in the urine in 24 hours ranged from 2.3 to 17.6% (median, 13%)

  10. Erythrokinetics examination using 59Fe and 51Cr isotopes

    The results are discussed of 55 case studies of various hematological diseases in which 59Fe was used as a tracer in studying iron kinetics, simultaneously with 51Cr as a tracer in studying erythrocyte survival and the localization of erythrocyte destruction. The values of iron metabolism are graphically presented, while erythropoiesis data is tabulated. The method was especially beneficial in conditions that could not easily be diagnosed using laboratory techniques. They included osteomyelofibrosis, polycythemia vera, aplastic anemia, and the myelodysplastic syndrome. The method allows quantitative assessment of erythropoiesis, thus facilitating differential diagnosis in clinical practice. (L.O.). 3 figs., 1 tab., 22 refs

  11. Prospective dosimetry with {sup 99m}Tc-MDP in metabolic radiotherapy of bone metastases with {sup 153}Sm-EDTMP

    Bianchi, L.; Marzoli, L. [Azienda Ospedaliera ' ' Ospedale di Circolo di Busto Arsizio' ' , Struttura Complessa di Fisica Sanitaria, Busto Arsizio, Varese (Italy); Baroli, A. [A.O. ' ' Ospedale di Circolo di Busto Arsizio' ' , Struttura Complessa di Medicina Nucleare, Busto Arsizio, Varese (Italy); Verusio, C. [A.O. ' ' Ospedale di Circolo di Busto Arsizio' ' , Struttura Complessa di Oncologia Medica, Saronno, Varese (Italy); Chiesa, C. [Fondazione Istituto Nazionale Tumori Milano, Struttura Complessa di Medicina Nucleare, Milan (Italy); Pozzi, L. [Azienda Ospedaliera ' ' Ospedale di Circolo di Busto Arsizio' ' , Struttura Complessa di Fisica Sanitaria, Busto Arsizio, Varese (Italy)]|[Universita degli Studi di Milano, Scuola di Specializzazione di Fisica Sanitaria, Milan (Italy)

    2009-01-15

    On the basis of the encouraging results achieved in several clinical trials and its proven therapeutic efficacy, {sup 153}Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP) has become widely used to palliate pain from bone metastases. The results reported in the literature have led the product suppliers (QUADRAMET registered, Schering) to suggest administering a fixed activity per kilogram (37 MBq/kg). However, considering the observed extreme inter-patient variability of skeletal uptake of {sup 153}Sm-EDTMP, a real therapy optimization would require the individualization of the activity to be administered on a dosimetric basis. This should be planned taking into account the generally accepted 2-Gy dose constraint to the haematopoietic red marrow, the critical organ in palliative treatments with beta-emitting, bone-seeking radiopharmaceuticals. Seven to 14 days before treatment with {sup 153}Sm-EDTMP, 44 patients underwent {sup 99m}Tc-methylene diphosphonate (MDP) total-body bone scan with two scans (the first within 10 min of injection, the second after 6 h). The percentage bone uptake (Tc{sub %}) was evaluated as the ratio between total counts at 6 h, adjusted for decay, and total counts at the first scan. Tc{sub %} was then compared to Sm{sub %} similarly derived from 10-min and 24-h whole-body scans. Tc{sub %} and Sm{sub %} were compared both with and without Brenner's method for soft tissue uptake. The correlation between Tc{sub %} and Sm{sub %} was R {sup 2} = 0.81 and R {sup 2} = 0.88 with and without soft tissue correction, respectively. The difference between their average values was statistically significant (Sm{sub %} = 64.3 {+-} 15.2, Tc{sub %} = 56.2 {+-} 16.0; p = 0.017) with soft tissue correction, while was not statistically significant (Sm{sub %} = 68.2 {+-} 15.5, Tc{sub %} = 66.9 {+-} 14.0; p = 0.670) without soft tissue correction. The rate of retention of {sup 99m}Tc-MDP in bone provides a reliable estimate of the {sup 153}Sm

  12. 51Cr release and oxidative stress in the lens

    Examination of the opaque areas of human cortical cataracts has shown that a large portion of the opacity could be attributed to the globules found there. We tested models involving globule formation as a result of oxidative damage to rat lens cells in culture and whole chick embryo lenses. When cell monolayers from a lens cell line were exposed to oxidizing conditions they developed globules on the cell surface. The cells were protected from damage by the addition of glutathione and vitamin C. Thirteen-day chick embryo lenses were also incubated in oxidizing conditions and the amount of cellular damage was assessed using a chromium-51 release assay we have developed. After 24 hr the percent 51Cr in the medium increased by an average of 20% as a result of 10 mM hydrogen peroxide treatment. The addition of the 10 mM vitamin C to the hydrogen peroxide significantly reduced the 51Cr leakage to the control level. Light microscopy of sections of the lens showed a breakdown of the equatorial fibre arrangement in the presence of H2O2, while addition of vitamin C restored the fibre organization to almost normal. The findings suggest that oxidative stress is an important step in cataractogenesis and point towards the use of water soluble antioxidants as protective agents

  13. Specific efficacy of peptide receptor radionuclide therapy with {sup 177}Lu-octreotate in advanced neuroendocrine tumours of the small intestine

    Sabet, Amir; Dautzenberg, Kristina; Haslerud, Torjan; Aouf, Anas; Sabet, Amin; Biersack, Hans-Juergen [University Hospital, Department of Nuclear Medicine, Bonn (Germany); Simon, Birgit [University Hospital, Department of Radiology, Bonn (Germany); Mayer, Karin [University Hospital, Department of Internal Medicine and Oncology, Bonn (Germany); Ezziddin, Samer [University Hospital, Department of Nuclear Medicine, Bonn (Germany); Saarland University, Department of Nuclear Medicine, Homburg (Germany)

    2015-07-15

    Increasing evidence supports the value of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours (NET), but there are limited data on its specific efficacy in NET of small intestinal (midgut) origin. This study aims to define the benefit of PRRT with {sup 177}Lu-octreotate for this circumscribed entity derived by a uniformly treated patient cohort. A total of 61 consecutive patients with unresectable, advanced small intestinal NET G1-2 stage IV treated with {sup 177}Lu-octreotate (4 intended cycles at 3-month intervals, mean activity per cycle 7.9 GBq) were analysed. Sufficient tumour uptake on baseline receptor imaging and either documented tumour progression (n = 46) or uncontrolled symptoms (n = 15) were prerequisites for treatment. Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Assessment of survival was performed using Kaplan-Meier curves and Cox proportional hazards model for uni- and multivariate analyses. Toxicity was assessed according to standardized follow-up laboratory work-up including blood counts, liver and renal function, supplemented with serial {sup 99m}Tc-diethylenetriaminepentaacetic acid (DTPA) clearance measurements. The median follow-up period was 62 months. Reversible haematotoxicity (≥ grade 3) occurred in five patients (8.2 %). No significant nephrotoxicity (≥ grade 3) was observed. Treatment response according to modified SWOG criteria consisted of partial response in 8 (13.1 %), minor response in 19 (31.1 %), stable disease in 29 (47.5 %) and progressive disease in 5 (8.2 %) patients. The disease control rate was 91.8 %. Median progression-free survival (PFS) and overall survival (OS) was 33 [95 % confidence interval (CI) 25-41] and 61 months (95 % CI NA), respectively. Objective response was associated with longer survival (p = 0.005). Independent predictors of shorter PFS were

  14. Bone marrow dosimetry in peptide receptor radionuclide therapy with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate

    Forrer, Flavio; Krenning, Eric P.; Kooij, Peter P.; Bernard, Bert F.; Bakker, Willem H.; Teunissen, Jaap J.M.; Jong, Marion de; Kwekkeboom, Dik J. [Erasmus MC Rotterdam, Department of Nuclear Medicine, Rotterdam (Netherlands); Konijnenberg, Mark [Mallinckrodt Medical BV, Research and Development, Petten (Netherlands); Lom, Kirsten van [Erasmus MC Rotterdam, Department of Haematology, Rotterdam (Netherlands); Herder, Wouter W. de [Erasmus MC Rotterdam, Department of Internal Medicine, Rotterdam (Netherlands)

    2009-07-15

    Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called ''remainder of the body'' to the bone marrow. Bone marrow aspirates were drawn in 15 patients after treatment with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found (r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose. (1) After PRRT with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone

  15. Solar neutrino and 51Cr results from SAGE

    The Russian-American solar neutrino Experiment (SAGE) has carried out measurements of the capture rate of solar neutrinos on metallic gallium in a radiochemical experiment at the Baksan Neutrino Observatory during the period January 1990 to December 1994. The measured capture rate on 71Ga is 72+12/-10 (stat) +5/-7 (syst) SNU. This represents only 53-59 % of the predicted Standard Solar Model (SSM) rates. Taken together with the measurements of the other solar neutrino experiments, this deficit would appear to be best interpreted as due to Mikheyev-Smirnov-Wolfenstein neutrino oscillations. A measurement of the production rate of 71Ge by an intense 51Cr source to test the overall operation of the experiment showed the extraction efficiency was 0.95 ± 0.11 (stat) +0.05/-0.08 (syst), indicating that the experiment is operating as expected. (orig.)

  16. Occupational doses in neuroendocrine tumors by using {sup 177}Lu DOTATATE; Doses ocupacionais em tratamento de tumores neuroendocrinos utilizando {sup 17'}7Lu DOTATATE

    Costa, Gustavo Coelho Alves; Sa, Lidia Vasconcellos de, E-mail: gustavo@ird.gov.b, E-mail: lidia@ird.gov.b [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)

    2011-10-26

    This paper investigated the treatment of neuroendocrine tumors (abdominal tumors) using of {sup 177}Lu DOTATATE radiopharmaceutical which is a type of treatment presently used in the experimental form in Brazil and, therefore, not contemplated in norms or specific use. This research studied the occupational doses of this treatment and suggested guidelines or rules of procedures viewing the radiological protection of workers involved and the public. The treatment were followed up by using two types of radiation detection, one a scintillator and a Geiger-Muller, and the measurements were performed in a public hospital at Rio de Janeiro and the other in a private hospital at Sao Paulo. It was observed that the equivalent occupational doses can variate from 160 {mu}Sv to 450 {mu}Sv, in function of operator, of stage of manipulation, and of the administration method, which can be through the use of infusion pump or manual injection. The use of infusion pump is highly recommended and the hospitalization of the patient until the dose rate measured at 1 m does not surpass 20 {mu}Sv/h

  17. Synthesis and biological evaluation of a novel (177)Lu-DOTA-[Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) analogue for melanocortin-1 receptor-positive tumor targeting.

    Lim, Jae Cheong; Hong, Young Don; Kim, Jin Ju; Choi, Sang Mu; Baek, Hye Suk; Choi, Sun-Ju

    2012-10-01

    In this study, a novel α-melanocyte stimulating hormone (α-MSH) analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled [Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) (DOTA-GMSH) for melanocortin-1 receptor (MC-1R) targeting was newly synthesized, radiolabeled with (177)Lu, and in vitro and in vivo characterized. (177)Lu-labeled peptides were prepared with a high radiolabeling yield (>98%), and its Log p value was -2.89. No degradation was observed not only by serum incubation at 37°C for 7 days but also by an HPLC analysis of radioactive metabolites in urine. A cell binding assay revealed that an inhibitory concentration of 50% (IC(50)) of the peptide was 3.80 nM. The tumor-to-blood ratio, which was 14.27 at 2 hours p.i., was increased to 56.37 at 24 hours p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and was rapidly cleared from the blood pool. We, therefore, conclude that (177)Lu-DOTA-GMSH has promising characteristics for application in nuclear medicine, namely for the diagnosis of MC-1R over-expressing tumors. PMID:22831553

  18. In vitro and in vivo evaluation of 177Lu- and 9Y-labeled E. coli heat-stable enterotoxin for specific targeting of uroguanylin receptors on human colon cancers

    The human E. coli heat-stable enterotoxin (STh, amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. Analogs of STh are currently being used as vectors targeting human colon cancers. Previous studies in our laboratory have focused on development of 111Indium-labeled STh analogs for in vivo imaging applications. Here, we extend the scope of this work to include targeting of the therapeutic radionuclides 9Y and 177Lu. The peptide DOTA-F19-STh(1-19) was synthesized using conventional Fmoc-based solid-phase techniques and refolded in dilute aqueous solution. The peptide was purified by RP-HPLC and characterized by MALDI-TOF MS and in vitro receptor binding assay. The DOTA-conjugate was metallated with nonradioactive Lu(III)Cl3 and Y(III)Cl3, and IC5 values of 2.6±0.1 and 4.2±0.9 nM were determined for the Lu- and Y-labeled peptides, respectively. 177Lu(III)Cl3 and 9Y(III)Cl3 labeling yielded tracer preparations that were inseparable by C18 RP-HPLC, indicating that putative differences between Lu-, Y- and In coordination spheres are not observed in the context of labeled STh peptides. In vivo biodistribution studies of the 177Lu-labeled peptide in severe combined immunodeficient (SCID) mice bearing T-84 human cancer tumor xenografts showed rapid clearance from the bloodstream, with >90 %ID in the urine at 1 h pi. Localization of the tracer within tumor xenografts was 1.86±0.91 %ID/g at 1 h pi, a value higher than for all other tissues with the exception of kidney (2.74±0.24 %ID/g). At 24 h pi, >98 %ID was excreted into the urine, and 0.35±0.23 %ID/g remained in tumor, again higher than in all other tissues except kidney (0.91±0.46 %ID/g). Biodistribution results at 24 h pi for the 9Y-labeled peptide mirrored those for the 177Lu analog, in agreement with the

  19. Variations in absorbed doses from 51Cr in investigations with labelled erythrocytes

    In nuclear medicine 51Cr labelled red blood cells are used to determine erythrocyte volume, red cell survival, or the site of red cell destruction. The author examined the variations in adsorbed doses from 51Cr in 77 patients with various diseases in whom erythrokinetic investigations were performed for diagnostic purposes. Autologous erythrocytes were incubated with Na2CrO4 (37 kBq (1.0 uCi) 51Cr/kg body weight) and injected intravenously. 51Cr activity in blood was then followed for 10 weeks. 51Cr activity over liver, spleen, and sacrum and whole-body retention of 51Cr were measured for the same period. A compartmental model was assumed to describe the kinetics of 51Cr tagged to red blood cells. It is a noncirculating linear model with the compartments represented by organs (spleen, liver, bone, residual body) rather than physiological compartments. The computer program SAAM-25 was used to provide the kinetic parameters and the organ retention functions. From the cumulated activities of the source regions, organ doses and effective dose equivalents were calculated according to the MIRD concepts. The highest organ doses were found for spleen, liver, and red marrow. The calculated dose values for 51Cr found in this study confirm only partly the values reported in ICRP Publication 17, but are higher up to a factor of 9 for some organs. 16 references, 1 figure, 3 tables

  20. Random comparison study of the clinical response to 153Sm-EDTMP 1.0 mCi/kg and 1.5 mCi/kg

    Sixty-seven patient with painful bone metastases were randomized to two groups. Group 1 (n=34) received 1.0 mCi/kg of 153Sm-EDTMP and group II (n=33) received 1.5 mCi/kg. All of them met inclusion criteria and there was no significantly difference between the basic conditions of two groups. After receiving 153Sm-EDTMP intravenously, all patients were kept in close follow-up weekly with blood counting, physician visiting and collecting patient's self-filling-in diary including pain score, Karnofsky performance scale and analgesic consumption. The follow-up duration was six weeks. The final overall condition assessed by physician were graded into no change (including worse), slight relief, significant relief and complete relief. Only significant relief and complete relief were considered as effectiveness for pain relief. Haematological toxicity grade was evaluated based on the nadir of WBC ad PLT counts. The results indicated that the higher dosage group had a higher effectiveness rate (75.76%) compared to the lower dosage group (67.65%), but without statistic significance (x2=0.5365, 0.25153Sm-EDTMP could be used for those patients with better haematological function and 1.0 mCi/kg used for those patients with poorer haematological function. (author)

  1. Measurement of 153Sm-EDTMP bone uptake by whole-body scintigraphy and its application to individualized treatment dosimetry of bone metastasis

    To calculate a safe and effective 153Sm-EDTMP therapy dose, a whole-body scintigraphy technique for prospective individual dosimetry was developed and the results were compared with 5 h urine collection method in 20 patients with bone metastases. Anterior and posterior whole-body images were obtained 10 min and 5 h after intravenous injection of 740 MBq 153Sm-EDTMP and the bone uptake value was determined. There is a close correlation between the bone uptake value obtained from the whole-body scintigraphy and 5 h urine collection method (r = 0.93). The radiation absorption dose to red marrow was limited to 1.4 Gy and the administered activity calculated from bone uptake value by whole-body scintigraphy was 1.40-2.27 GBq (mean 1.90 GBq). If the activity was calculated according to the standard body weight of 37 MBq·kg-1, the administered activity would be 1.75-2.41 GBq (mean 2.18), the radiation absorption dose to red marrow would be 1.37-2.27 Gy (mean 1.63 Gy), but at these doses significant myelotoxicity would be anticipated, thus emphasizing the need for individual prospective dosimetry

  2. Uptake studies of environmentally hazardous 51Cr in Mung beans

    Attempt has been made to study the accumulation behaviour of a common plant, Mung bean (Vigna radiata) towards Cr(III) and Cr(VI) to have an insight on the migration and bio-magnification of Cr. For this purpose healthy germinated Mung bean seeds were sown in the sand in the presence of Hoagland's nutrient solution containing measured amount of K251Cr2O7 and 51Cr(NO3)3.9H2O. Growth rate was also studied in the presence and absence of phosphate salts in the medium. It has been found that the transfer of chromium from soil to plant is significantly low (maximum 5% for both Cr(III) and Cr(VI)). Maximum accumulation of Cr occurs in the root with respect to the total chromium accumulation by the plant. Other parts of the Mung bean plant, e.g. cotyledons, shoot and leaves, show negligible accumulation. Therefore, the chance of direct intake of Cr through food as well as through the grazing animals to human body is less. - The chance of bio-magnification of Cr(III) or Cr(VI) to human body via direct or indirect intake of Mung bean is negligible

  3. Outcome of peptide receptor radionuclide therapy with {sup 177}Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours

    Ezziddin, Samer; Khalaf, Feras; Vanezi, Maria; Haslerud, Torjan; Zreiqat, Abdullah Al; Biersack, Hans-Juergen; Sabet, Amir [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Mayer, Karin [University Hospital, Department of Internal Medicine and Oncology, Bonn (Germany); Willinek, Winfried [University Hospital, Department of Radiology, Bonn (Germany)

    2014-05-15

    The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with {sup 177}Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with {sup 177}Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial {sup 99m}Tc-DTPA clearance measurements. The median follow-up period was 58 months (range 4 - 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 - 42) and 53 months (95 % CI 46 - 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis

  4. Feasibility and utility of re-treatment with {sup 177}Lu-DOTATATE in GEP-NENs relapsed after treatment with {sup 90}Y-DOTATOC

    Severi, Stefano; Sansovini, Maddalena; Ianniello, Annarita; Nicolini, Silvia; Caroli, Paola; Paganelli, Giovanni [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine Unit, Meldola, FC (Italy); Bodei, Lisa [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Ibrahim, Toni [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Osteoncology and Rare Tumors Center, Meldola (Italy); Di Iorio, Valentina [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Oncology Pharmacy Laboratory, Meldola (Italy); D' Errico, Vincenzo [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Medical Physics Unit, Meldola (Italy); Monti, Manuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy)

    2015-12-15

    Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 - 3 years. In the present study, we investigated the use of low dosage re-treatment with {sup 177}Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with {sup 90}Y-DOTATOC (Y-PRRT). Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 - 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6 %, median PFS was 22 months (95 % CI 16 months - not reached) compared to 28 months (95 % CI 20 - 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment. (orig.)

  5. Influence of biological assay conditions on stability assessment of radiometal-labelled peptides exemplified using a {sup 177}Lu-DOTA-minigastrin derivative

    Ocak, Meltem [Clinical Department of Nuclear Medicine, Medical University Innsbruck, A-6020, Innsbruck (Austria); Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul University, 34116, Istanbul (Turkey); Helbok, Anna; Guggenberg, Elisabeth von [Clinical Department of Nuclear Medicine, Medical University Innsbruck, A-6020, Innsbruck (Austria); Ozsoy, Y. [Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul University, 34116, Istanbul (Turkey); Kabasakal, Levent [Department of Nuclear Medicine, Cerrahpasa Medical Faculty, 34098, Istanbul (Turkey); Kremser, Leopold [Division of Clinical Biochemistry, Protein Micro-Analysis Facility, Biocenter, Medical University Innsbruck, A-6020, Innsbruck (Austria); Decristoforo, Clemens, E-mail: clemens.decristoforo@uki.a [Clinical Department of Nuclear Medicine, Medical University Innsbruck, A-6020, Innsbruck (Austria)

    2011-02-15

    Introduction: Lack of correlation between in vitro and in vivo stability is a general problem for the development of radiopeptides especially in the case of minigastrin derivatives for therapeutic applications. In this study, we compared the influence of experimental conditions on radiopeptide stability results in vitro using a model Minigastrin (MG) analogue labelled with Lu-177. Additionally, we attempted to characterize the main serum enzymatic cleavage sites by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) analysis. Methods: In vitro stability of a DOTA-minigastrin derivative ({sup 177}Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-NIe-Asp-Phe-NH{sub 2}) was tested in serum, rat tissue homogenates and two different standardised enzymatic mixtures. Quantification of the metabolised radiopeptides at different time intervals was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). Metabolites were characterised by MALDI-TOF-MS. Urine was collected after 15 min p.i. into the mice and compared with in vitro metabolites by RP-HPLC. Results: Faster degradation of the radiopeptide was found in blood in comparison with plasma and serum incubation and in components from rats faster than from human origin. Fast degradation was observed in kidney and liver homogenates as well as in standardised enzymatic mixtures, also revealing variations in the metabolic profile. In urine, no intact peptide was detected already 5 min post injection. MALDI-TOF-MS revealed major cleavage sites at the carboxy terminus of the peptide. Conclusion: Very variable results may be found when different kind of incubation media for testing radiopeptide stabilities is used. Serum incubation studies may overestimate stability; therefore, results should be interpreted with care and combined with alternative in vitro and in vivo investigations.

  6. Rapid blood clearance and lack of long-term renal toxicity of {sup 177}Lu-DOTATATE enables shortening of renoprotective amino acid infusion

    Kashyap, Raghava; Eu, Peter [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne (Australia); Jackson, Price [Peter MacCallum Cancer Centre, Department of Physical Sciences, Melbourne (Australia); Hofman, Michael S.; Hicks, Rodney J. [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne (Australia); The University of Melbourne, Departments of Medicine and Radiology, Melbourne (Australia); Beauregard, Jean-Mathieu [Universite Laval, Department of Radiology, Quebec City (Canada); Zannino, Diana [Peter MacCallum Cancer Centre, Department of Biostatistics and Clinical Trials, Melbourne (Australia)

    2013-12-15

    The aim of the study was to investigate the feasibility of shortening the recommended 4-h renoprotective amino acid infusion in patients receiving peptide receptor chemoradionuclide therapy (PRCRT) using radiosensitizing 5-fluorouracil. We evaluated the clearance of radiopeptide from the blood, long-term nephrotoxicity in patients undergoing PRCRT with the conventional 4-h amino acid infusion and renal uptake in patients receiving an abbreviated infusion. The whole-blood clearance of {sup 177}Lu-DOTA-octreotate (LuTate) was measured in 13 patients receiving PRCRT. A retrospective analysis of short-term and long-term changes in glomerular filtration rate (GFR) in 96 consecutive patients receiving a 4-h infusion was performed. Renal LuTate retention estimated using quantitative SPECT/CT in 22 cycles delivered with a 2.5-h amino acid infusion was compared with that in 72 cycles with the 4-h infusion. LuTate demonstrated biexponential blood clearance with an initial clearance half-time of 21 min. Approximately 88 % of blood activity was cleared within 2 h. With the 4-h protocol, there was no significant change in GFR (1.2 ml/min mean increase from baseline; 95 % CI -6.9 to 4.4 ml/min) and no grade 3 or 4 nephrotoxicity at the end of induction PRCRT. The long-term decline in GFR after a median follow up of 22 months was 2.2 ml/min per year. There was no significant difference in the renal LuTate retention measured in patients receiving a 2.5-h amino acid infusion compared to those who had a 4-h infusion. The greatest renal exposure to circulating radiopeptide occurs in the first 1 - 2 h after injection. This, combined with the safety of LuTate PRCRT, allows consideration of an abbreviated amino acid infusion, increasing patient convenience and reducing human resource allocation. (orig.)

  7. Feasibility and utility of re-treatment with 177Lu-DOTATATE in GEP-NENs relapsed after treatment with 90Y-DOTATOC

    Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 - 3 years. In the present study, we investigated the use of low dosage re-treatment with 177Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with 90Y-DOTATOC (Y-PRRT). Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 - 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6 %, median PFS was 22 months (95 % CI 16 months - not reached) compared to 28 months (95 % CI 20 - 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment. (orig.)

  8. Rapid blood clearance and lack of long-term renal toxicity of 177Lu-DOTATATE enables shortening of renoprotective amino acid infusion

    The aim of the study was to investigate the feasibility of shortening the recommended 4-h renoprotective amino acid infusion in patients receiving peptide receptor chemoradionuclide therapy (PRCRT) using radiosensitizing 5-fluorouracil. We evaluated the clearance of radiopeptide from the blood, long-term nephrotoxicity in patients undergoing PRCRT with the conventional 4-h amino acid infusion and renal uptake in patients receiving an abbreviated infusion. The whole-blood clearance of 177Lu-DOTA-octreotate (LuTate) was measured in 13 patients receiving PRCRT. A retrospective analysis of short-term and long-term changes in glomerular filtration rate (GFR) in 96 consecutive patients receiving a 4-h infusion was performed. Renal LuTate retention estimated using quantitative SPECT/CT in 22 cycles delivered with a 2.5-h amino acid infusion was compared with that in 72 cycles with the 4-h infusion. LuTate demonstrated biexponential blood clearance with an initial clearance half-time of 21 min. Approximately 88 % of blood activity was cleared within 2 h. With the 4-h protocol, there was no significant change in GFR (1.2 ml/min mean increase from baseline; 95 % CI -6.9 to 4.4 ml/min) and no grade 3 or 4 nephrotoxicity at the end of induction PRCRT. The long-term decline in GFR after a median follow up of 22 months was 2.2 ml/min per year. There was no significant difference in the renal LuTate retention measured in patients receiving a 2.5-h amino acid infusion compared to those who had a 4-h infusion. The greatest renal exposure to circulating radiopeptide occurs in the first 1 - 2 h after injection. This, combined with the safety of LuTate PRCRT, allows consideration of an abbreviated amino acid infusion, increasing patient convenience and reducing human resource allocation. (orig.)

  9. Influence of biological assay conditions on stability assessment of radiometal-labelled peptides exemplified using a 177Lu-DOTA-minigastrin derivative

    Introduction: Lack of correlation between in vitro and in vivo stability is a general problem for the development of radiopeptides especially in the case of minigastrin derivatives for therapeutic applications. In this study, we compared the influence of experimental conditions on radiopeptide stability results in vitro using a model Minigastrin (MG) analogue labelled with Lu-177. Additionally, we attempted to characterize the main serum enzymatic cleavage sites by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) analysis. Methods: In vitro stability of a DOTA-minigastrin derivative (177Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-NIe-Asp-Phe-NH2) was tested in serum, rat tissue homogenates and two different standardised enzymatic mixtures. Quantification of the metabolised radiopeptides at different time intervals was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). Metabolites were characterised by MALDI-TOF-MS. Urine was collected after 15 min p.i. into the mice and compared with in vitro metabolites by RP-HPLC. Results: Faster degradation of the radiopeptide was found in blood in comparison with plasma and serum incubation and in components from rats faster than from human origin. Fast degradation was observed in kidney and liver homogenates as well as in standardised enzymatic mixtures, also revealing variations in the metabolic profile. In urine, no intact peptide was detected already 5 min post injection. MALDI-TOF-MS revealed major cleavage sites at the carboxy terminus of the peptide. Conclusion: Very variable results may be found when different kind of incubation media for testing radiopeptide stabilities is used. Serum incubation studies may overestimate stability; therefore, results should be interpreted with care and combined with alternative in vitro and in vivo investigations.

  10. Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra-Articular Administration of 177Lu-Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience

    Shinto, Ajit S.; Kamaleshwaran, K. K.; Chakraborty, Sudipta; Vyshakh, K.; Thirumalaisamy, S. G.; Karthik, S.; Nagaprabhu, V. N.; Vimalnath, K. V.; Das, Tapas; Banerjee, Sharmila

    2015-01-01

    The aim of this study is to assess the effectiveness of Radiosynovectomy (RSV) using 177Lu-labeled hydroxyapatite (177Lu-HA) in the treatment of painful synovitis and recurrent joint effusion of knee joints in rheumatoid arthritis (RA). Ten patients, diagnosed with RA and suffering from chronic painful resistant synovitis of the knee joints were referred for RSV. The joints were treated with 333 ± 46 MBq of 177Lu-HA particles administered intra-articularly. Monitoring of activity distribution was performed by static imaging of knee joint and whole-body gamma imaging. The patients were evaluated clinically before RSV and at 6 months after the treatment by considering the pain improvement from baseline values in terms of a 100-point visual analog scale (VAS), the improvement of knee flexibility and the pain remission during the night. RSV response was classified as poor (VAS organs was visible in the whole-body scan. Static scans of the joint at 1 month revealed complete retention of 177Lu-HA in the joints. All patients showed decreased joint swelling and pains, resulting in increased joint motion after 6 months. The percentage of VAS improvement from baseline values was 79.5 ± 20.0% 6 months after RS and found to be significantly related to patients' age (P = 0.01) and duration of the disease (P = 0.03). Knees with Steinbrocker's Grades 0 and I responded better than those with more advanced changes (Steinbrocker's Grades III and IV) in terms of VAS improvement (75% vs. 45.8%) (P < 0.001). The overall success rate (VAS ≥ 50) was 80%. Remission of pain during the night was achieved in 100%, and knee flexibility was improved in 80%. The changes in the blood pool phase before RSV were 3.2 ± 0.7 and after the therapy 1.4 ± 0.7 (P < 0.001). The J/B ratio was: Before RSV 2.4 ± 0.3; after treatment 1.0 ± 0.2 (P < 0.05). CRP concentration 4 and 24 weeks after the therapy was significantly lower than before treatment. The fibrinogen level was not different before and

  11. A comparative study of 51Cr releasing assay and lymphocyte colony inhibition test for detecting LAK activity

    51Cr releasing assay is widely used for detecting cytotoxicity. The correlation coefficient between 51Cr and traditional cyto-colony inhibition test is 0.9915(p51Cr releasing assay is considered to be much simpler and quicker, also can be recommended to be used in clinical practice

  12. Experimental cross section for the {sup 152}Sm(n, γ){sup 153}Sm reaction at 0.0334 eV

    Uddin, M. Shuza; Datta, Tapash Kumar; Hossain, Syed Mohammod; Zakaria, A.K.M.; Islam, Mohammad Amirul; Naher, Kamrun; Shariff, M. Asad; Yunus, S.M. [Atomic Energy Research Establishment, Dhaka (Bangladesh). Inst. of Nuclear Science and Technology; Afroze, Nasmin [Atomic Energy Research Establishment, Dhaka (Bangladesh). Inst. of Nuclear Science and Technology; Jahangirnagar Univ., Dhaka (Bangladesh). Dept. of Physics; Islam, S.M. Ajharul [Jahangirnagar Univ., Dhaka (Bangladesh). Dept. of Physics

    2014-10-01

    The neutron capture cross section for the {sup 152}Sm(n, γ){sup 153}Sm reaction at an energy of 0.0334 eV was measured for the first time using monochromatic neutrons of a powder diffractometer at the TRIGA Mark II nuclear reactor at Dhaka, Bangladesh. The {sup 197}Au(n, γ){sup 198}Au reaction was used to monitor the neutron beam intensity. The radioactivity of the products was determined via high resolution γ-ray spectrometry. The obtained cross section value is 184 ± 22b, which is consistent with both the ENDF/B-VII and TENDL-2012 data libraries. The measured value at 0.0334 eV and the previous data at 0.0536 eV confirm the reliability of the data in the above libraries. (orig.)

  13. Cross sections of deuteron induced reactions on $^{nat}$Sm for production of the therapeutic radionuclide $^{145}$Sm and $^{153}$Sm

    Tárkányi, F; Takács, S; Ditrói, F; Csikai, J; Ignatyuk, A V

    2014-01-01

    At present, targeted radiotherapy (TR) is acknowledged to have great potential in oncology. A large list of interesting radionuclides is identified, including several radioisotopes of lanthanides, amongst them $^{145}$Sm and $^{153}$Sm. In this work the possibility of their production at a cyclotron was investigated using a deuteron beam and a samarium target. The excitation functions of the $^{nat}$Sm(d,x)$^{145153}$Sm reactions were determined for deuteron energies up to 50 MeV using the stacked-foil technique and high-resolution $\\gamma$-ray spectrometry. The measured cross sections and the contributing reactions were analyzed by comparison with results of the ALICE, EMPIRE and TALYS nuclear reaction codes. A short overview and comparison of possible production routes is given.

  14. Pre-therapeutic dosimetry of normal organs and tissues of {sup 177}Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer

    Kabasakal, Levent; AbuQbeitah, Mohammad; Ayguen, Aslan; Yeyin, Nami [Istanbul University, Department of Nuclear Medicine, Cerrahpasa Medical Faculty, Istanbul (Turkey); Ocak, Meltem [Istanbul University, Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul (Turkey); Demirci, Emre [Sisli Etfal Training and Research Hospital, Department of Nuclear Medicine, Istanbul (Turkey); Toklu, Turkay [Yeditepe University Medical Faculty, Department of Nuclear Medicine, Istanbul (Turkey)

    2015-12-15

    {sup 177}Lu-617-prostate-specific membrane antigen (PSMA) ligand seems to be a promising tracer for radionuclide therapy of progressive prostate cancer. However, there are no published data regarding the radiation dose given to the normal tissues. The aim of the present study was to estimate the pretreatment radiation doses in patients who will undergo radiometabolic therapy using a tracer amount of {sup 177}Lu-labeled PSMA ligand. The study included seven patients with progressive prostate cancer with a mean age of 63.9 ± 3.9 years. All patients had prior PSMA positron emission tomography (PET) imaging and had intense tracer uptake at the lesions. The injected {sup 177}Lu-PSMA-617 activity ranged from 185 to 210 MBq with a mean of 192.6 ± 11.0 MBq. To evaluate bone marrow absorbed dose 2-cc blood samples were withdrawn in short variable times (3, 15, 30, 60, and 180 min and 24, 48, and 120 h) after injection. Whole-body images were obtained at 4, 24, 48, and 120 h post-injection (p.i.). The geometric mean of anterior and posterior counts was determined through region of interest (ROI) analysis. Attenuation correction was applied using PSMA PET/CT images. The OLINDA/EXM dosimetry program was used for curve fitting, residence time calculation, and absorbed dose calculations. The calculated radiation-absorbed doses for each organ showed substantial variation. The highest radiation estimated doses were calculated for parotid glands and kidneys. Calculated radiation-absorbed doses per megabecquerel were 1.17 ± 0.31 mGy for parotid glands and 0.88 ± 0.40 mGy for kidneys. The radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p < 0.05). The calculated radiation dose to bone marrow was 0.03 ± 0.01 mGy/MBq. Our first results suggested that {sup 177}Lu-PSMA-617 therapy seems to be a safe method. The dose-limiting organ seems to be the parotid glands rather than kidneys and bone marrow. The lesion radiation doses are

  15. Pre-therapeutic dosimetry of normal organs and tissues of 177Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer

    177Lu-617-prostate-specific membrane antigen (PSMA) ligand seems to be a promising tracer for radionuclide therapy of progressive prostate cancer. However, there are no published data regarding the radiation dose given to the normal tissues. The aim of the present study was to estimate the pretreatment radiation doses in patients who will undergo radiometabolic therapy using a tracer amount of 177Lu-labeled PSMA ligand. The study included seven patients with progressive prostate cancer with a mean age of 63.9 ± 3.9 years. All patients had prior PSMA positron emission tomography (PET) imaging and had intense tracer uptake at the lesions. The injected 177Lu-PSMA-617 activity ranged from 185 to 210 MBq with a mean of 192.6 ± 11.0 MBq. To evaluate bone marrow absorbed dose 2-cc blood samples were withdrawn in short variable times (3, 15, 30, 60, and 180 min and 24, 48, and 120 h) after injection. Whole-body images were obtained at 4, 24, 48, and 120 h post-injection (p.i.). The geometric mean of anterior and posterior counts was determined through region of interest (ROI) analysis. Attenuation correction was applied using PSMA PET/CT images. The OLINDA/EXM dosimetry program was used for curve fitting, residence time calculation, and absorbed dose calculations. The calculated radiation-absorbed doses for each organ showed substantial variation. The highest radiation estimated doses were calculated for parotid glands and kidneys. Calculated radiation-absorbed doses per megabecquerel were 1.17 ± 0.31 mGy for parotid glands and 0.88 ± 0.40 mGy for kidneys. The radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p < 0.05). The calculated radiation dose to bone marrow was 0.03 ± 0.01 mGy/MBq. Our first results suggested that 177Lu-PSMA-617 therapy seems to be a safe method. The dose-limiting organ seems to be the parotid glands rather than kidneys and bone marrow. The lesion radiation doses are within acceptable

  16. Clinical results of radionuclide therapy of neuroendocrine tumours with {sup 90}Y-DOTATATE and tandem {sup 90}Y/{sup 177}Lu-DOTATATE: which is a better therapy option?

    Kunikowska, Jolanta; Krolicki, Leszek [Medical University of Warsaw, Nuclear Medicine Department, Warsaw (Poland); Hubalewska-Dydejczyk, Alicja; Sowa-Staszczak, Anna [Collegium Medicum Cracow, Cracow (Poland); Mikolajczak, Renata; Pawlak, Dariusz [Institute of Atomic Energy POLATOM, Swierk-Otwock (Poland)

    2011-10-15

    Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). A combination treatment using the high-energy {sup 90}Y beta emitter for larger lesions and the lower energy {sup 177}Lu for smaller lesions has been postulated in the literature.The aim of the study was to evaluate combined {sup 90}Y/{sup 177}Lu-DOTATATE therapy in comparison to {sup 90}Y-DOTATATE alone. Fifty patients with disseminated NET were included in the study prospectively and divided into two groups: group A (n = 25) was treated with {sup 90}Y-DOTATATE, whereas group B (n = 25) received the 1:1 {sup 90}Y/{sup 177}Lu-DOTATATE. The administered activity was based on 3.7 GBq/m{sup 2} body surface area in three to five cycles, with amino acid infusion for nephroprotection. The median overall survival time in group A was 26.2 months while in group B median survival was not reached. Overall survival was significantly higher in group B (p = 0.027). Median event-free survival time in group A was 21.4 months and in group B 29.4 months (p > 0.1). At the 12-month follow-up, comparison of group A vs group B showed stable disease (SD) in 13 vs 16 patients, disease regression (RD) in 5 vs 3 patients and disease progression (PD) in 3 vs 4 patients; 4 and 2 patients died, respectively. The 24-month follow-up results were SD in nine vs ten patients, RD in one patient vs none and PD in four patients in both groups; three and four patients died, respectively. Side effects were rare and mild. The results indicate that therapy with tandem radioisotopes ({sup 90}Y/{sup 177}Lu-DOTATATE) provides longer overall survival than with a single radioisotope ({sup 90}Y-DOTATATE) and the safety of both methods is comparable. (orig.)

  17. Peptide receptor radionuclide therapy with {sup 177}Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and {sup 18}F-FDG PET

    Ianniello, Annarita; Sansovini, Maddalena; Severi, Stefano; Nicolini, Silvia; Caroli, Paola; Paganelli, Giovanni [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Unit, Meldola (Italy); Grana, Chiara Maria [European Institute of Oncology Milan (IEO), Division of Nuclear Medicine, Milan (Italy); Massri, Katrin [Ospedale San Luca, Nuclear Medicine, Department of Radiology, Lucca (Italy); Bongiovanni, Alberto [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Osteoncology and Rare Tumors Center, Meldola (Italy); Antonuzzo, Lorenzo [AOU Careggi, SC Oncologia Medica 1, Firenze (Italy); Di Iorio, Valentina [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Oncology Pharmacy Laboratory, Meldola (Italy); Sarnelli, Anna [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Medical Physics Unit, Meldola (Italy); Monti, Manuela; Scarpi, Emanuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy)

    2016-06-15

    Typical and atypical carcinoids (TC and AC) represent 20 - 25 % of all neuroendocrine tumours. No standard therapeutic approach is available for patients with advanced disease. The aim of this phase II study was to investigate the efficacy and safety of peptide receptor radionuclide therapy with {sup 177}Lu-DOTATATE (Lu-PRRT) and the role of thyroid transcription factor 1 (TTF-1) and {sup 18}F-FDG PET as prognostic factors in patients with advanced TC or AC. A total of 34 consecutive patients with radiologically documented progressive disease were treated with Lu-PRRT at a therapeutic cumulative activity of 18.5 or 27.8 GBq in four or five cycles according to the patient's kidney function and bone marrow reserve. Information on TTF-1 was available in all patients. FDG PET studies prior to Lu-PRRT were available in 29 patients. The median follow-up was 29 months (range 7 - 69 months). The disease control rate (DCR) in patients with TC was 80 %: 6 % complete response, 27 % partial response and 47 % stable disease. The median progression-free survival (mPFS) was 20.1 months (95 % CI 11.8 - 26.8 months). Stable disease was achieved in 47 % of patients with AC with a mPFS of 15.7 months (95 % CI 10.6 - 25.9 months). No major acute or delayed toxicity occurred in either group or with either cumulative activity. mPFS in patients with TTF-1-negative TC was 26.3 months (95 % CI 12.9 - 45.2 months), but in patients with TTF-1-positive TC mPFS was 7.2 months (4.2 - 14.0 months; p = 0.0009). FDG PET was negative in 13 patients (10 TC and 3 AC) and positive in 16 patients (4 TC and 12 AC). The mPFS in the FDG PET-negative group was 26.4 months (95 % CI 14.2 - 48.9 months) and 15.3 months (11.7 - 31.1 months) in the FDG PET-positive group. Lu-PRRT showed antitumour activity in terms of DCR and PFS and proved safe, even in patients with a higher risk of side effects. TTF-1 would appear to be a prognostic factor. FDG PET positivity in bronchial carcinoids is a hallmark of

  18. Peptide receptor radionuclide therapy with {sup 90}Y/{sup 177}Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours)

    Puranik, Ameya D.; Kulkarni, Harshad R.; Singh, Aviral; Baum, Richard P. [Zentralklinik Bad Berka, THERANOSTICS Centre for Molecular Radiotherapy and Molecular Imaging, ENETS Center of Excellence, Bad Berka (Germany)

    2015-07-15

    Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT. Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using {sup 90}Y/{sup 177}Lu-labelled peptides after positive confirmation of SSTR expression on {sup 68}Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with {sup 68}Ga-DOTATOC PET/CT was carried out every 6 months to assess response to treatment. Clinical (symptomatic) response was also assessed. Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUV{sub max}, accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUV{sub max}. The three asymptomatic patients showed no new lesions or symptomatic worsening. PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or

  19. Role of {sup 18}FDG PET/CT in patients treated with {sup 177}Lu-DOTATATE for advanced differentiated neuroendocrine tumours

    Severi, Stefano; Sansovini, Maddalena; Ianniello, Annarita; Matteucci, Federica [Cancer Institute of Romagna (IRST), Unit of Radiometabolic Medicine, Meldola, FC (Italy); Nanni, Oriana; Scarpi, Emanuela [Cancer Institute of Romagna (IRST), Unit of Biostatistics and Clinical Trials, Meldola, FC (Italy); Bodei, Lisa; Gilardi, Laura; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Nicoletti, Stefania [Cancer Institute of Romagna (IRST), Unit of Medical Oncology, Meldola, FC (Italy)

    2013-06-15

    The prognostic value of FDG PET for neuroendocrine tumours (NETs) has been reported. In this study we evaluated the role of FDG PET in predicting response and progression-free survival (PFS) after {sup 177}Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced well-differentiated grade 1/2 NETs. We retrospectively evaluated 52 patients with progressive advanced NETs overexpressing somatostatin receptors and treated with Lu-PRRT with a cumulative activity up to 27.7 GBq divided into five courses. According to WHO 2010/ENETS classification, patients were stratified into two groups: those with grade 1 tumour (Ki-67 index {<=}2 %, 19 patients), and those with grade 2 tumour (Ki-67 index >3 % to <20 %, 33 patients). On the basis of the FDG PET scan, 33 patients were classified as PET-positive (PET+) and 19 as PET-negative (PET-). FDG PET was positive in 57 % of patients with grade 1 NET and in 66 % of patients with grade 2 NET, and the rates of disease control (DC, i.e. complete response + partial response + stable disease) in grade 1 and grade 2 patients were 95 % and 79 %, respectively (P = 0.232). In PET- and PET+ patients, the DC rates were 100 % and 76 % (P = 0.020) with a PFS of 32 and 20 months, respectively (P = 0.033). Of the PET+ patients with grade 1 NET, 91 % showed disease control, whereas about one in three PET+ patients with grade 2 NET (32 %) progressed after Lu-PRRT (DC rate 68 %). These results suggest that FDG PET evaluation is useful for predicting response to Lu-PRRT in patients with grade 1/2 advanced NETs. Notably, none of PET- patients had progressed at the first follow-up examination after Lu-PRRT. Grade 2 NET and PET+ (arbitrary SUV cutoff >2.5) were frequently associated with more aggressive disease. PET+ patients with grade 2 NET, 32 % of whom did not respond to Lu-PRRT monotherapy, might benefit from more intensive therapy protocols, such as the combination of chemotherapy and PRRT. (orig.)

  20. To study on the gamma cascade and the exited intermediate levels schemata of 153Sm, 182Ta, 59Ni and 239U by method of summation of coincident pulses

    In this project, in order to strengthen the ability of research of nuclear data and nuclear structure on the neutron beam at Dalat Research Reactor, a spectrometer of summation of coincident pulses (SACP) was installed, it is used to study the gamma cascades of 59Ni, 153Sm, 182Ta and 239U. The results are used for postgraduate education. (author)

  1. Metastatic Neuroendocrine Tumor with Extensive Bone Marrow Involvement at Diagnosis: Evaluation of Response and Hematological Toxicity Profile of PRRT with (177)Lu-DOTATATE.

    Basu, Sandip; Ranade, Rohit; Thapa, Pradeep

    2016-01-01

    The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium ((177)Lu)-DOTA-octreotate (DOTATATE) in metastatic neuroendocrine tumor (NET) with extensive bone marrow metastasis at the initial diagnosis. A retrospective evaluation was undertaken for this purpose: Patients with NET with extensive diffuse bone marrow involvement at diagnosis who had received at least three cycles of PRRT with (177)Lu-DOTATATE were considered for the analysis. The selected patients were analyzed for the following: (i) Patient and lesional characteristics, (ii) associated metastatic burden, (iii) hematological parameters at diagnosis and during the course of therapy, (iv) response to PRRT (using a 3-parameter assessment: Symptomatic including Karnofsky/Lansky performance score, biochemical finding, and scan finding), (v) dual tracer imaging features [with somatostatin receptor imaging (SRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT)]. Based on the visual grading, tracer uptake in somatostatin receptor (SSTR)-positive bone marrow lesions were graded by a 4-point scale into four categories (0-III) in comparison with the hepatic uptake on the scan: 0 - no uptake; I - clear focus but less than liver uptake; II - equal to liver uptake; and III - higher than liver uptake]. Hematological toxicity was evaluated using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 score. A total of five patients (age range: 26-62 years; three males and two females) with diffuse bone marrow involvement at the diagnosis was encountered following analysis of the entire patient population of 250 patients. Based on the site of the primary, three had thoracic NET (two patients bronchial carcinoid and one pulmonary NET) and two gastroenteropancreatic NET (one in the duodenum and one patient of unknown primary with liver metastasis). Associated sites

  2. Metastatic Neuroendocrine Tumor with Extensive Bone Marrow Involvement at Diagnosis: Evaluation of Response and Hematological Toxicity Profile of PRRT with 177Lu-DOTATATE

    Basu, Sandip; Ranade, Rohit; Thapa, Pradeep

    2016-01-01

    The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium (177Lu)-DOTA-octreotate (DOTATATE) in metastatic neuroendocrine tumor (NET) with extensive bone marrow metastasis at the initial diagnosis. A retrospective evaluation was undertaken for this purpose: Patients with NET with extensive diffuse bone marrow involvement at diagnosis who had received at least three cycles of PRRT with 177Lu-DOTATATE were considered for the analysis. The selected patients were analyzed for the following: (i) Patient and lesional characteristics, (ii) associated metastatic burden, (iii) hematological parameters at diagnosis and during the course of therapy, (iv) response to PRRT (using a 3-parameter assessment: Symptomatic including Karnofsky/Lansky performance score, biochemical finding, and scan finding), (v) dual tracer imaging features [with somatostatin receptor imaging (SRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT)]. Based on the visual grading, tracer uptake in somatostatin receptor (SSTR)-positive bone marrow lesions were graded by a 4-point scale into four categories (0-III) in comparison with the hepatic uptake on the scan: 0 - no uptake; I - clear focus but less than liver uptake; II - equal to liver uptake; and III - higher than liver uptake]. Hematological toxicity was evaluated using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 score. A total of five patients (age range: 26-62 years; three males and two females) with diffuse bone marrow involvement at the diagnosis was encountered following analysis of the entire patient population of 250 patients. Based on the site of the primary, three had thoracic NET (two patients bronchial carcinoid and one pulmonary NET) and two gastroenteropancreatic NET (one in the duodenum and one patient of unknown primary with liver metastasis). Associated sites of

  3. Production cross-section calculations of medical {sup 32}P, {sup 117}Sn, {sup 153}Sm and {sup 186,188}Re radionuclides used in bone pain palliation treatment

    Demir, Bayram [Istanbul Univ. (Turkey). Physics Dept.; Kaplan, A.; Capali, V. [Univ. Isparta (Turkey). Physics Dept.; Sarpuen, I.H. [Afyon Kocatepe Univ., Afyonkarahisar (Turkey). Physics Dept.; Aydin, A. [Kirikkale Univ. (Turkey). Physics Dept.; Tel, E. [Univ. Osmaniye (Turkey). Physics Dept.

    2015-03-15

    In this study, production cross-section calculations of {sup 32}P, {sup 117}Sn, {sup 153}Sm and {sup 186,188}Re radionuclides used in bone pain palliation treatment produced by {sup 30}Si(d,γ){sup 32}P, {sup 118}Sn(γ,n){sup 117}Sn, {sup 116}Sn(n,γ){sup 117}Sn, {sup 150}Nd(α,n){sup 153}Sm, {sup 154}Sm(n,2n){sup 153}Sm, {sup 152}Sm(n,γ){sup 153}Sm, {sup 186}W(d,2n){sup 186}Re, {sup 187}Re(γ,n){sup 186}Re, {sup 185}Re(n,γ){sup 186}Re and {sup 187}Re(n,γ){sup 188}Re reactions have been investigated in the different incident energy range of 0.003-34 MeV. Two-component exciton and generalised superfluid models of the TALYS 1.6 and exciton and generalised superfluid models of the EMPIRE 3.1 computer codes have been used to pre-equilibrium (PEQ) reaction calculations. The calculated production cross-section results have been compared with available experimental results existing in the experimental nuclear reaction database (EXFOR). Except the {sup 118}Sn(γ,n){sup 117}Sn, {sup 150}Nd(α,n){sup 153}Sm and {sup 185}Re(n,γ){sup 186}Re reactions, the two-component exciton model calculations of TALYS 1.6 code exhibit generally good agreement with the experimental measurements for all reactions used in this present study.

  4. 51Cr-EDTA plasma clearance in severe renal failure determined by one plasma sample

    Kamper, A L; Nielsen, S L

    1989-01-01

    sample clearance' formulas disregarding exact time of plasma sampling. This method might provide values 3.1 ml/min below or 2.9 ml/min above the established method of total 51Cr-EDTA plasma clearance, and would thus provide insufficient agreement. In the other method an estimate of plasma activity at......Two hundred and thirty-four measurements of standard 51Cr-EDTA plasma clearance were made in 50 patients with severe chronic renal failure. Based on these data two calculation methods were attempted using one plasma sample drawn 24 h after injection of 51Cr-EDTA. One of the methods used the 'one...... zero-time was derived from injected dose and body surface area. This method might provide values 1.5 ml/min below or 0.8 ml/min above the established method of 51Cr-EDTA plasma clearance, which would be acceptable for clinical purposes. It is concluded that exact plasma clearance of 51Cr-EDTA in severe...

  5. (51Cr)EDTA intestinal permeability in children with cow's milk intolerance

    Schrander, J.J.; Unsalan-Hooyen, R.W.; Forget, P.P.; Jansen, J. (Academic Hospital Maastricht (Netherlands))

    1990-02-01

    Making use of ({sup 51}Cr)EDTA as a permeability marker, we measured intestinal permeability in a group of 20 children with proven cow's milk intolerance (CMI), a group of 17 children with similar complaints where CMI was excluded (sick controls), and a group of 12 control children. ({sup 51}Cr)EDTA test results (mean +/- SD) were 6.85 +/- 3.64%, 3.42 +/- 0.94%, and 2.61 +/- 0.67% in the group with CMI, the sick control, and the control group, respectively. When compared to both control groups, patients with cow's milk intolerance (CMI) showed a significantly increased small bowel permeability. We conclude that the ({sup 51}Cr)EDTA test can be helpful for the diagnosis of cow's milk intolerance.

  6. [51Cr]EDTA intestinal permeability in children with cow's milk intolerance

    Making use of [51Cr]EDTA as a permeability marker, we measured intestinal permeability in a group of 20 children with proven cow's milk intolerance (CMI), a group of 17 children with similar complaints where CMI was excluded (sick controls), and a group of 12 control children. [51Cr]EDTA test results (mean +/- SD) were 6.85 +/- 3.64%, 3.42 +/- 0.94%, and 2.61 +/- 0.67% in the group with CMI, the sick control, and the control group, respectively. When compared to both control groups, patients with cow's milk intolerance (CMI) showed a significantly increased small bowel permeability. We conclude that the [51Cr]EDTA test can be helpful for the diagnosis of cow's milk intolerance

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

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

  8. Radionuclide Treatment with 153Sm-EDTMP is Effective for the Palliation of Bone Pain in the Context of Extensive Bone Marrow Metastases: A Case Report

    Kairemo, Kalevi; Rasulova, Nigora; Suslaviciute, Justina; Alanko, Tuomo

    2014-01-01

    Radionuclide therapy is widely used as an effective modality in the management of bone pain. The main indication for this treatment is symptomatic bone metastases, confirmed by bone scintigraphy. We present a case of small cell lung cancer (SCLC) stage T4N2M1b, with a good metabolic response to systemic therapy and radiotherapy of the primary tumor and locoregional disease, which became metabolically less active and remarkably smaller in size (reduction to 1/6 of the original volume). In spite of the good overall response, the patient developed a syndrome with severe bone pain and had progression in the bone marrow metastases, confirmed by 18F-FDG PET/CT. The patient received 153Sm-EDTMP treatment with a good clinical response. However, in the whole body bone scan with the therapeutic dose, there was no visual evidence of bone metastasis. Retrospectively, by drawing the region of interest, it was possible to identify one metastatic site. The possible mechanisms of the efficacy of this treatment modality, in this specific setting, are also discussed. PMID:27408870

  9. Radionuclide Treatment with 153Sm-EDTMP is Effective for the Palliation of Bone Pain in the Context of Extensive Bone Marrow Metastases: A Case Report

    Kalevi Kairemo

    2014-10-01

    Full Text Available Radionuclide therapy is widely used as an effective modality in the management of bone pain. The main indication for this treatment is symptomatic bone metastases, confirmed by bone scintigraphy. We present a case of small cell lung cancer (SCLC stage T4N2M1b, with a good metabolic response to systemic therapy and radiotherapy of the primary tumor and locoregional disease, which became metabolically less active and remarkably smaller in size (reduction to 1/6 of the original volume. In spite of the good overall response, the patient developed a syndrome with severe bone pain and had progression in the bone marrow metastases, confirmed by 18F-FDG PET/CT. The patient received 153Sm-EDTMP treatment with a good clinical response. However, in the whole body bone scan with the therapeutic dose, there was no visual evidence of bone metastasis. Retrospectively, by drawing the region of interest, it was possible to identify one metastatic site. The possible mechanisms of the efficacy of this treatment modality, in this specific setting, are also discussed.

  10. 51Cr-EDTA: a marker of early intestinal rejection in the rat

    Intestinal permeability was studied after accessory intestinal transplantation in Lewis rats. Five groups were evaluated: Group 1--isografts (N = 6); Group 2--Lewis X Brown Norway F1 (LBN-F1) allografts (N = 6); Group 3--isografts treated with CsA 2 mg/kg/day X 10 days (N = 6); Group 4--LBN-F1 allografts treated with CsA 2 mg/kg/day X 10 days (N = 6); Group 5--LBN-F1 allografts treated with CsA 4 mg/kg/day X 28 days (N = 6). Chromium-labeled ethylenedimianetetraacetate (51Cr-EDTA) was given through the proximal stoma of the graft. Renal clearance of 51Cr-EDTA and mucosal biopsies were followed post-transplant. The biopsies of the intestinal graft showed no rejection in Groups 1, 3, and 5; fulminant rejection in Group 2; and mild atypical rejection in Group 4. 51Cr-EDTA clearance was elevated in all groups during the first 7 days post-transplant. Thereafter, 51Cr-EDTA excretion fell to lower levels in the animals with histologically normal grafts (Groups 1, 3, and 5). 51Cr-EDTA excretion in Group 4 was increased with the first histological evidence of rejection on Day 14 and remained elevated until sacrifice (P less than 0.02 compared to Groups 3 and 5). A transient permeability defect occurs after intestinal grafting. Once the graft has recovered from this injury, 51Cr-EDTA is a sensitive marker for intestinal rejection

  11. Study of erythropoiesis with 59Fe and erythrocyte survival with 51Cr in aplastic anemia

    A study of erythropoiesis with 59Fe and erythrocyte survival with 51Cr was carried out in 25 patients with aplastic anemia and in a control group of 23 healthy persons. Bone marrow aplasia was uniform in all patients but differences in erythropoiesis were established. According to the state of erythropoiesis, the patients were divided into two groups: 1) patients with severe damage of erythropoiesis and 2) patients with preserved erythropoiesis. Erythrocyte survival in both groups was shortened. The data obtained correlate with the anemic syndrome and help to explain its pathogenesis. It is suggested that the investigation of erythropoiesis with 59Fe and 51Cr is of prognostic value. (author)

  12. Assessment of mineral dust cytotoxicity toward rat alveolar macrophages using a 51Cr release assay

    An assay was developed to assess the cytotoxicity of mineral dust by measuring release of 51Cr from prelabeled rat alveolar macrophages. Optimal conditions for the assay are described, the most notable being use of 2% albumin instead of fetal calf serum. The assay demonstrated loss of label into the supernatant when prelabeled macrophages were cultured with the two pathogenic mineral dusts, quartz and chrysotile asbestos. In contrast the inert mineral dust titanium dioxide had very little effect on 51Cr release by rat alveolar macrophages

  13. Application of 51Cr in examination of patients with hereditary microspherocytic hemolytic anemia

    A total of 20 patients with hereditary microspherocytic hemolytic anemia were examined by the method of erythrocyte labelling with 51Cr. The survival rate of the erythrocytes appeared to be shortened in all the patients. The degree of this shortening corresponded to the severity of the clinico-hematological signs of hemolysis. The sequestrating capacity of the spleen elevated in all patients increased as the organ enlarged. The efficacy of splenectomy was checked in 11 patients by a repeated control examination with 51Cr. The given test can be successfully used for diagnosis of hemolytic conditions, evaluation of their clinical course severity, prognosis and assessment of splenectomy efficacy

  14. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens 177Lu-or 86Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq 177Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm3) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm3 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten 86Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  15. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity {sup 86}Y- or {sup 177}Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    Cheal, Sarah M.; Lee, Sang-gyu; Punzalan, Blesida; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Xu, Hong; Guo, Hong-fen [Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States); Chalasani, Sandhya; Carrasquillo, Jorge A. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Fung, Edward K. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Jungbluth, Achim [Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY (United States); Zanzonico, Pat B.; O' Donoghue, Joseph [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Smith-Jones, Peter M. [Stony Brook University, Department of Psychiatry and Behavioral Science, Stony Brook, NY (United States); Stony Brook University, Department of Radiology, Stony Brook, NY (United States); Wittrup, K.D. [Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA (United States); Cheung, Nai-Kong V. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States)

    2016-05-15

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens {sup 177}Lu-or {sup 86}Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq {sup 177}Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm{sup 3}) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm{sup 3} tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten {sup 86}Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  16. Biological evaluation of 177Lu-labeled DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 for gastrin-releasing peptide receptor-positive prostate tumor targeting

    Bombesin binds with selectivity and high affinity to a Gastrin-releasing peptide receptor (GRPR), which is highly overexpressed in prostate cancer cells. The present study describes the in vitro and in vivo biological characteristics of DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with 177Lu as previously published. A saturation assay on PC-3 human prostate cancer cells revealed that the Kd value of the radiolabeled peptide was 1.88 nM with a maximum binding capacity (Bmax) of 289.3 fmol/106 cells. The radio-peptide slowly internalized, and 24.4 ± 0.5% of the total binding was internalized in 4 hr. Biodistribution studies were conducted in healthy and PC-3 xenografted balb/c mice, which showed high uptake and retention of tumor-associated radioactivity in PC-3 xenografted mice. The tumor-to-blood ratio was 126.02 ± 9.36 at 1.5 hr p.i., and was increased to 216.33 ± 61.58 at 24 hr p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and rapidly cleared from the blood pool. The GRPR is also over-expressed in Korean prostate cancer patients. These results suggest that this 177Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over-expressing prostate tumors

  17. Conventional measurements of GFR using 51Cr-EDTA overestimate true renal clearance by 10 percent

    It is widely believed that measurement of the area under the plasma clearance curve (AUC) following a single intravenous injection of chromium-51 labelled ethylene diamine tetra-acetic acid (51Cr-EDTA) is a gold standard method for determining glomerular filtration rate (GFR). However, there are reports that 51Cr-EDTA may have a significant extrarenal clearance. The aim of this study was to identify the non-renal component of 51Cr-EDTA plasma clearance contributing to the AUC measurement of GFR. Seventy healthy postmenopausal women (mean age 60 years, range 45-79 years) were injected with 3 MBq 51Cr-EDTA and 0.25 MBq iodine-125 labelled human serum albumin and 11 blood samples taken between 0 and 4 h through an indwelling venous cannula. For the first 21 subjects, two complete urine collections were made 0-2 h and 2-4 h after injection, and for the final 49 patients, four 1-h urine collections were made. The mean 51Cr-EDTA total plasma clearance was 84 ml/min (range 50-132 ml/min). The mean ratio (SEM) of urine to total clearance determined from the cumulative 1-, 2-, 3- and 4-h data was 0.903 (0.018), 0.891 (0.013), 0.898 (0.011) and 0.899 (0.010) respectively and remained constant despite the mean urine concentration decreasing from 122% to 15%/litre during this period. A least squares fit to data from the 238 individual urine collections was used to determine the fraction of the total plasma clearance attributable to renal clearance, α0, and the residual urine volume, ΔV. The results were α0=0.910 (95% CI: 0.889-0.932) and ΔV=14 ml (95% CI: -4 to +34 ml). The overestimation of the true renal clearance of 51Cr-EDTA by the AUC method is believed to be due to the failure of the plasma clearance curve to reach the true terminal exponential by 2 h after injection as usually assumed. As a result, conventional measurements of GFR using 51Cr-EDTA overestimate the true renal clearance of tracer by approximately 10%. (orig.)

  18. Evaluation of the radiosensitizing to treatment with 153Sm-EDTMP, of haematopoietic cells of the bone marrow by means of bromodeoxyuridine incorporation into DNA, in a murine model

    Bromodeoxyuridine (BrdU) has been shown to have a radiosensitizing effect, and its incorporation into DNA prior to administration of a bone-seeking radiopharmaceutical could increase the efficiency of bone marrow ablation, and even increase the specificity of radiation exposure for therapeutic purposes. The aim of the present study was to determine the effect of BrdU incorporation into DNA on the genotoxic and cytotoxic effects of samarium-153 ethylenediaminetetra-methylene phosphonate (153Sm-EDTMP) in murine bone marrow cells. BALB/c male mice (N = 5 in each experiment) were treated with one of the following substances: a) BrdU (0.25 mg/g) b) 153-EDTMP (11.5 ± 3 MBq) c) BrdU (0.25 mg/g) plus 153Sm-EDTMP (11.5 ± MBq), there was also an untreated control. Cytotoxicity and genotoxicity were established by time-response and absorbed dose-response curves of polychromatic erythrocyte (PCE) and micro nucleated polychromatic erythrocyte (MN-PCE) frequencies, respectively, in murine peripheral blood samples in vivo. The significance of the differences between groups was determined by a variation of Dunett test for multiple groups and different-sized groups of a student test. Beta-absorbed dose fractions obtained from MNCP4B Monte Carlo computer code were used for mice bone marrow dosimetry calculations. At an average radiation absorbed dose of 0.38 Gy, 0.56 Gy and 0.82 Gy at 24, 40 and 72 h respectively, cells from animals treated with 153Sm-EDTMP showed a clear and significant induction of MN-PCE after 24 h, with the maximum response at 40 h, however, cells from group treated with BrdU plus 153Sm-EDTMP paradoxically showed MN-PCE frequencies only slightly higher than the control at the same absorbed dose. Treatment with 153Sm-EDTMP caused a slight reduction in PCE frequency, but exposure to BrdU or BrdU plus 153Sm-EDTMP induced a substantial and significant reduction in PCE frequency from 32 h to the end of the experiment (72 h). The PCE frequencies in the Brd

  19. Evaluation of the radiosensitizing to treatment with {sup 153}Sm-EDTMP, of haematopoietic cells of the bone marrow by means of bromodeoxyuridine incorporation into DNA, in a murine model; Evaluacion de la radiosensibilizacion al tratamiento con {sup 153}Sm-EDTMP, de las celulas hemotopoyeticas de la medula osea mediante la incorporacion de bromodesoxiuridina (BrdU) en el ADN, en un modelo murino

    Morales A, E.

    2008-07-01

    Bromodeoxyuridine (BrdU) has been shown to have a radiosensitizing effect, and its incorporation into DNA prior to administration of a bone-seeking radiopharmaceutical could increase the efficiency of bone marrow ablation, and even increase the specificity of radiation exposure for therapeutic purposes. The aim of the present study was to determine the effect of BrdU incorporation into DNA on the genotoxic and cytotoxic effects of samarium-153 ethylenediaminetetra-methylene phosphonate ({sup 153}Sm-EDTMP) in murine bone marrow cells. BALB/c male mice (N = 5 in each experiment) were treated with one of the following substances: a) BrdU (0.25 mg/g) b) {sup 153}-EDTMP (11.5 +- 3 MBq) c) BrdU (0.25 mg/g) plus {sup 153}Sm-EDTMP (11.5 +- MBq), there was also an untreated control. Cytotoxicity and genotoxicity were established by time-response and absorbed dose-response curves of polychromatic erythrocyte (PCE) and micro nucleated polychromatic erythrocyte (MN-PCE) frequencies, respectively, in murine peripheral blood samples in vivo. The significance of the differences between groups was determined by a variation of Dunett test for multiple groups and different-sized groups of a student test. Beta-absorbed dose fractions obtained from MNCP4B Monte Carlo computer code were used for mice bone marrow dosimetry calculations. At an average radiation absorbed dose of 0.38 Gy, 0.56 Gy and 0.82 Gy at 24, 40 and 72 h respectively, cells from animals treated with {sup 153}Sm-EDTMP showed a clear and significant induction of MN-PCE after 24 h, with the maximum response at 40 h, however, cells from group treated with BrdU plus {sup 153}Sm-EDTMP paradoxically showed MN-PCE frequencies only slightly higher than the control at the same absorbed dose. Treatment with {sup 153}Sm-EDTMP caused a slight reduction in PCE frequency, but exposure to BrdU or BrdU plus {sup 153}Sm-EDTMP induced a substantial and significant reduction in PCE frequency from 32 h to the end of the experiment (72 h

  20. Intestinal permeability to [51Cr]EDTA in children with cystic fibrosis

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of [51Cr]EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of [51Cr]EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001)

  1. Instant capture of recoil 51Cr(III) from neutron activated K2CrO4

    A new method of measuring the initial 51Cr(III) produced from nuclear recoil of K2CrO4 was developed. In this method K2CrO4 was mixed with MgO in the presence of a small amount of water, and the mixture was irradiated in a nuclear reactor. After irradiation, the mixture was dissolved in water, and MgO precipitate was separated from the solution. The yield of recoil 51Cr(III) could be calculated from the 51Cr activity in the precipitate measured. On the other hand, the yield of retention of 51Cr as chromate could be calculated from the activity found in the supernatant. The 51Cr(III) yield thus obtained is almost a factor of 2 higher than observed in pure K2CrO4 without mixing with MgO, irradiated under the same condition. Another important observation is that the 51Cr(III) yield is independent of irradiation time in presence of MgO. Without MgO the observed 51Cr(III) yield decreases with increasing irradiation time, suggesting possible oxidation of Cr(III) to chromate during irradiation. This variation is not observed in the system of K2CrO4 containing MgO, indicating that the initial Cr(III) is adsorbed immediately after nuclear recoil by MgO and is protected from oxidation by gamma radiation. (author) 4 refs.; 4 figs.; 2 tabs

  2. INTERNAL FRICTION OF 51CrV4 SHAFT INFLUENCED BY THERMO-MECHANICAL COUPLING

    J. G(o)ken; M. Maikranz-Valentin; K. Steinhoff; T.S. Pavlova; T.V. Ivleva; I.S. Golovin

    2008-01-01

    The simultaneous influence of thermal and mechanical treatment was applied to produce a geometrically complex shaft from 51CrV4 steel leading to the formation of microstructures which were significantly different from each other. These microstructural differences were accompanied by a local change of mechanical properties in terms of hardness, electrical resistivity and especially internal friction. The Snoek-Koster peak was recognized and analyzed in the structure of this steel.

  3. Modification of leukocyte adherence inhibition (LAI) assay with 51Cr-labelled leukocytes

    Leukocyte adherence inhibition was measured by a new modified radioisotopic technique. Peripheral blood leukocytes were isolated and labelled with 51Cr. These leukocytes were incubated with medium or buffer alone and with medium or buffer containing tumor antigen or gluten. The glass surface for the adherence was prepared carefully. In all samples the adherence of leukocytes occured under the same conditions. The results of the LAI assay with gluten and stomach cancer antigen are reported and discussed. (author)

  4. Blood loss estimation in Schistosoma incognitum by the use of 51Cr labelled red cells

    C42 Red blood cells labelled with 51Cr were used to study the pathophysiology of S. incognitum infection. Blood volume, cell volume, faecal blood excretion and the half life of the red cells were determined. It was shown that in rabbits infected with the blood fluke, there was loss of blood, which may result in the development of anaemia in the infected animals. (author)

  5. Burn-up cross sections of 51Cr, 59Fe, 65Zn, 86Rb, 103Ru

    Targets of Cr, Fe, Zn, Rb, and Ru were irradiated in the hydraulic tube of the Oak Ridge HFIR reactor at a neutron flux of 2.6 x 1015 n/cm2sec for 1 day and 20 days. The reactor burn-up cross sections (in barns) of the radioactive product nuclides are: 51Cr, 59Fe, 65Zn, 60 +- 30; 86Rb, 103Ru, <20

  6. Studies with nonradioisotopic sodium chromate. II. Single- and double-label 52Cr/51Cr posttransfusion recovery estimations

    A recently developed nonradioisotopic 52Cr technique was used to measure either red cell volume or posttransfusion recovery of stored red cells. The experimental method uses Zeeman electrothermal atomic absorption spectrophotometry to measure red cell chromium. Results from the 52Cr method were compared with those from 51Cr single-label and 125I-albumin/51Cr double-label procedures using 49-day AS-1 red cell concentrates drawn and prepared according to standard procedures. In the first group of five donors, red cell volume was estimated concurrently with both 52Cr-labeled fresh red cells and 125I-albumin. The latter measured plasma volume from which red cell volume was estimated on the basis of the hematocrit (125I red cell volume). 51Cr-labeled stored red cells were transfused to measure posttransfusion recoveries. The correlation between 52Cr and 125I red cell volumes was significant (r = 0.68, p less than 0.01), and, in this group, the differences were not significant (p less than 0.05). Twenty-four-hour posttransfusion recoveries of 51Cr-labeled stored red cells averaged 66 +/- 5 percent when measured with the 125I/51Cr technique and 69 +/- 8 percent when measured with the 52Cr/51Cr method. In the second group of five donors, red cell volume was estimated by the 125I-albumin technique, and the posttransfusion recovery of stored red cells was quantitated by 51Cr- and 52Cr-labeled stored cells simultaneously. In this group, posttransfusion recoveries with 125I/51Cr averaged 73 +/- 7 percent; with 125I/52Cr, they averaged 75 +/- 10 percent. Using the single-label method of calculation, recoveries averaged 76 +/- 7 and 75 +/- 10 percent for the 51Cr and 52Cr methods, respectively

  7. Radiopharmaceutical therapy of bone metastases with {sup 89}SrCl{sub 2}, {sup 186}Re-HEDP and {sup 153}Sm-EDTMP: a dosimetric study using Monte Carlo simulation

    Strigari, L.; D' Andrea, M.; Benassi, M. [Regina Elena Cancer Institute, Laboratory of Medical Physics and Expert Systems, Rome (Italy); Sciuto, R.; Pasqualoni, R.; Maini, C.L. [Regina Elena Cancer Institute, Nuclear Medicine Department, Rome (Italy)

    2007-07-15

    The aim of the paper is to calculate the dose to bone surface and bone volume using a Monte Carlo particle transport model and to give quantitative arguments for activity prescription. This study simulates the dose delivery process to skeletal metastases by bone surface- and bone volume-seeking radiopharmaceuticals. Dose distributions for three radiopharmaceuticals, {sup 186}Re-HEDP, {sup 153}Sm-EDTMP and {sup 89}SrCl{sub 2}, frequently used for pain palliation therapies, were calculated using the EGSnrc Monte Carlo code. The model simulates a cylindrical geometry with regions of different constant density compositions and radioactivity distribution consistent with known biodistribution features of the three radiopharmaceuticals: superficial for phosphonates ({sup 186}Re-HEDP and {sup 153}Sm-EDTMP) and volumetric for {sup 89}SrCl{sub 2}. After 3D dose distribution calculation, dose-volume histogram reduction was carried out using the ''preferred Lyman'' method, which yields effective uniform dose (D{sub eff}) equivalent to the inhomogeneous dose distributions to the reference region (volume and surface). Our simulations showed that to obtain a delivered dose to bone surface equivalent to that obtained from {sup 89}SrCl{sub 2}, the administered activities of {sup 153}Sm-EDTMP and {sup 186}Re-HEDP should be increased by 37% and 48%, respectively, in comparison with those usually administered. These results prove theoretically the empirical results from clinical observations and show that improvement in bone pain palliation by means of radiopharmaceutical therapy should be expected for dose-guided prescription. (orig.)

  8. Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I-, and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts

    S. Lucas

    2015-01-01

    Full Text Available Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like 131I or 90Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of 90Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as 90Y, 177Lu, 131I, 124I, and 188Re are used. Tumour control probability (TCP and normal tissue complication probability (NTCP curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC. 90Y and 188Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases.

  9. 153Sm-lexidronam for augmentation of chemotherapy-based myeloablative regimes in patients with multiple myeloma and other haematological conditions undergoing bone marrow transplantation: a phase I dose-escalation trial

    Full text: Total body irradiation (TBI) is a useful conditioning regimen for bone marrow transplantation (BMT), but has unacceptable toxicity in some patients. High doses of bone-seeking radiopharmaceuticals may offer a useful alternative to TBI in BMT patients with marrow-based tumours. Nine patients (5 multiple myeloma [MM], 2 leukaemia, 1 lymphoma, I myelodysplasia) were enrolled in a dose escalation protocol based upon retained skeletal activity. Infused doses have ranged between 18 and 32 GBq of 153Sm-EDTMP in six patients treated. No adverse effects related to the infusion have been seen. Peripheral blood counts fell from day 7 post-treatment, persisting to the start of cytotoxic conditioning regimen at days 11-14 post-treatment. Five patients have engrafted, with one allogeneic transplant patient dying from acute rejection. Pre-treatment dosimetry was performed by gamma camera and whole-body probe counts. Post-therapy activities were estimated by serial dose meter readings and gamma camera images. The pre-treatment skeletal retention by gamma camera was 1.7-2.4 times the values based on probe data. Retained post-treatment skeletal activity predicted by dosimetry was significantly greater than that actually measured, confirmed in one case by urinary collection. This latter fact is most likely due to the nature of the interaction of 153Sm-EDTMP with bone at high doses

  10. Thermal neutron capture cross sections for the 152Sm(n,γ) 153Sm and 154Sm(n,γ) 155Sm reactions at 0.0536 eV energy

    Uddin, M. S.; Chowdhury, M. H.; Hossain, S. M.; Latif, Sk. A.; Islam, M. A.; Hafiz, M. A.; Mubin, S. H.; Zakaria, A. K. M.; Yunus, S. M.; Azharul Islam, S. M.

    2008-11-01

    The neutron capture cross sections for the 152Sm(n,γ) 153Sm and 154Sm(n,γ) 155Sm reactions at 0.0536 eV neutron energy were measured using an activation technique based on the TRIGA Mark-II research reactor, relative to the reference reaction 197Au(n,γ) 198Au. The activity was measured nondestructively using gamma-ray spectroscopy. Our measured values at this neutron energy are the first ones and are compared with 1/ v based evaluated cross sections reported in the ENDF/B-VII and JENDL-3.3 libraries. The measured value for the 152Sm(n,γ) 153Sm reaction is 0.28% lower than JENDL-3.3 and 0.48% higher than ENDF/B-VII. Our value for the production of 155Sm is about 3% and 2.3% higher than the evaluated value with ENDF/B-VII and JENDL-3.3 at 0.0536 eV, respectively.

  11. Radioassay of granulocyte chemotaxis. Studies of human granulocytes and chemotactic factors. [/sup 51/Cr tracer technique

    Gallin, J.I.

    1974-01-01

    The above studies demonstrate that the /sup 51/Cr radiolabel chemotactic assay is a relatively simple and objective means for studying leukocyte chemotaxis in both normal and pathological conditions. Application of this method to studies of normal human chemotaxis revealed a relatively narrow range of normal and little day-to-day variability. Analysis of this variability revealed that there is more variability among the response of different granulocytes to a constant chemotactic stimulus than among the chemotactic activity of different sera to a single cell source. Utilizing the /sup 51/Cr radioassay, the abnormal granulocyte chemotactic behavior reported in Chediak-Higashi syndrome and a patient with recurrent pyogenic infections and mucocutaneous candidiasis has been confirmed. The /sup 51/Cr chemotactic assay has also been used to assess the generation of chemotactic activity from human serum and plasma. The in vitro generation of two distinct chemotactic factors were examined; the complement product (C5a) and kallikrein, an enzyme of the kinin-generating pathway. Kinetic analysis of complement-related chemotactic factor formation, utilizing immune complexes or endotoxin to activate normal sera in the presence or absence of EGTA as well as kinetic analysis of activation of C2-deficient human serum, provided an easy means of distinguishing the classical (antibody-mediated) complement pathway from the alternate pathway. Such kinetic analysis is necessary to detect clinically important abnormalities since, after 60 min of generation time, normal chemotactic activity may be present despite complete absence or inhibition of one complement pathway. The chemotactic factor generated by either pathway of complement activation appears to be predominately attributable to C5a.

  12. Calorimetric method for determination of {sup 51}Cr neutrino source activity

    Veretenkin, E. P., E-mail: veretenk@inr.ru; Gavrin, V. N.; Danshin, S. N.; Ibragimova, T. V.; Kozlova, Yu. P.; Mirmov, I. N. [Russian Academy of Sciences, Institute for Nuclear Research (Russian Federation)

    2015-12-15

    Experimental study of nonstandard neutrino properties using high-intensity artificial neutrino sources requires the activity of the sources to be determined with high accuracy. In the BEST project, a calorimetric system for measurement of the activity of high-intensity (a few MCi) neutrino sources based on {sup 51}Cr with an accuracy of 0.5–1% is created. In the paper, the main factors affecting the accuracy of determining the neutrino source activity are discussed. The calorimetric system design and the calibration results using a thermal simulator of the source are presented.

  13. Enhanced intestinal permeability to 51Cr-labeled EDTA in dogs with small intestinal disease.

    Hall, E J; Batt, R M

    1990-01-01

    Intestinal permeability in dogs with small intestinal disease was measured by quantitation of 24-hour urinary excretion of 51Cr-labeled EDTA following intragastric administration. Permeability was high in dogs with a variety of naturally acquired small intestinal diseases including wheat-sensitive enteropathy of Irish Setters, small intestinal bacterial over-growth, and giardiasis, and permeability was decreased after successful treatment. These findings indicate that the assessment of intestinal permeability may be a useful technique for detecting small intestinal disease and for monitoring the efficacy of treatment in dogs. PMID:2104825

  14. Reversibility of increased intestinal permeability to 51Cr-EDTA in patients with gastrointestinal inflammatory diseases

    Intestinal permeability in adults with inflammatory gastrointestinal diseases was investigated by measuring the 24-h urinary excretion of orally administered 51Cr-EDTA. Eighty controls along with 100 patients with Crohn's disease, 46 patients with ulcerative colitis, 20 patients with gluten-sensitive enteropathy, and 18 patients with other diseases were studied. In controls, the median 24-h excretion was 1.34%/24 h of the oral dose. Patients with Crohn's disease (median 2.96%/24 h), ulcerative colitis (median 2.12%/24 h), and untreated gluten-sensitive enteropathy (median 3.56%/24 h) had significantly elevated urinary excretion of the probe compared to controls (p less than 0.0001). Increased 24-h urinary excretion of 51Cr-EDTA had a high association with intestinal inflammation (p less than 0.0001). Test specificity and sensitivity were 96% and 57%, respectively. A positive test has a 96% probability of correctly diagnosing the presence of intestinal inflammation, whereas a negative test has a 50% probability of predicting the absence of disease

  15. Uptake studies of environmentally hazardous {sup 51}Cr in Mung beans

    Banerjee, Anupam [Department of Botany, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019 (India); Nayak, Dalia [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064 (India); Chakrabortty, Dipanwita [Sikkim Manipal University, A 15, Paryavaran Complex, New Delhi 110030 (India); Lahiri, Susanta [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064 (India)], E-mail: susanta.lahiri@saha.ac.in

    2008-01-15

    Attempt has been made to study the accumulation behaviour of a common plant, Mung bean (Vigna radiata) towards Cr(III) and Cr(VI) to have an insight on the migration and bio-magnification of Cr. For this purpose healthy germinated Mung bean seeds were sown in the sand in the presence of Hoagland's nutrient solution containing measured amount of K{sub 2}{sup 51}Cr{sub 2}O{sub 7} and {sup 51}Cr(NO{sub 3}){sub 3}.9H{sub 2}O. Growth rate was also studied in the presence and absence of phosphate salts in the medium. It has been found that the transfer of chromium from soil to plant is significantly low (maximum 5% for both Cr(III) and Cr(VI)). Maximum accumulation of Cr occurs in the root with respect to the total chromium accumulation by the plant. Other parts of the Mung bean plant, e.g. cotyledons, shoot and leaves, show negligible accumulation. Therefore, the chance of direct intake of Cr through food as well as through the grazing animals to human body is less. - The chance of bio-magnification of Cr(III) or Cr(VI) to human body via direct or indirect intake of Mung bean is negligible.

  16. Fecal excretion of radiolabelled (51CrCl 3) proteins in patients with Crohn's disease

    Intestinal leakage of plasma proteins was studied in 69 patients with Crohn's disease. In vivo labelling of plasma proteins was performed by intravenous injection of trace amounts of 51CrCl 3. Complete fecal collection was done for 5 days, carefully avoiding contamination with urine. The daily fecal radioactivity was measured in a whole-body counter and expressed as a percentage of given dose. In patients with a classic localization of the disease the mean fecal excretion of radiolabelled proteins was 2.8%. The excretion was significantly higher in patients with extensive ileojejunal involvement and in patients with a toal colitis, but not different from that in patients with prestomal recurrent ileal disease. A close correlation was found between fecal excretion of 51Cr and extent of the small-intestinal disease as measured at laparotomy. A highly significant inverse relationship was also demonstrated between fecal protein excretion and serum albumin concentration in patients without septic complications of the disease. A pre-existing septic complications made the patients hypoalbuminemic despite limited intestinal loss of protein. It is concluded that estimation of intestinal protein loss is a sensitive and simple test for assessment of the extent of the small-intestinal involvement in patients with Crohn's disease. The test may be of value in patients with unclear radiologic findings and in patients with hypoalbuminemia of unknown cause. 25 refs., 3 figs

  17. Use of a /sup 51/Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs

    Lussier, A.; Arsenault, A.; Varady, J.; de Medicis, R.; Lussier, Y.; LeBel, E.

    1987-02-01

    Of techniques used to evaluate gastrointestinal (GI) bleeding, use of radiochromium (/sup 51/Cr)-tagged erythrocytes is the most quantitative and scientifically acceptable method. The value of this technique as well as systematic errors possible with its use are discussed. The medical literature concerning /sup 51/Cr evaluation of GI microbleeding with naproxen therapy is critically reviewed. We suggest that future studies using this technique be parallel, randomized, double-blind, and include a 1-week placebo baseline phase for all subjects. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) should last 3 to 4 weeks. A parallel group of subjects should receive placebo throughout the study. For valid statistical analyses, randomization must achieve baseline comparability of weight, height, age, and sex in the treatment groups. Data transformations may be necessary to satisfy the assumptions of the statistical model. Following these guidelines will enable investigators to better evaluate GI microbleeding during treatment with naproxen or other NSAIDs, and, hopefully, to establish the safety profiles of these drugs.37 references.

  18. Use of a 51Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs

    Of techniques used to evaluate gastrointestinal (GI) bleeding, use of radiochromium (51Cr)-tagged erythrocytes is the most quantitative and scientifically acceptable method. The value of this technique as well as systematic errors possible with its use are discussed. The medical literature concerning 51Cr evaluation of GI microbleeding with naproxen therapy is critically reviewed. We suggest that future studies using this technique be parallel, randomized, double-blind, and include a 1-week placebo baseline phase for all subjects. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) should last 3 to 4 weeks. A parallel group of subjects should receive placebo throughout the study. For valid statistical analyses, randomization must achieve baseline comparability of weight, height, age, and sex in the treatment groups. Data transformations may be necessary to satisfy the assumptions of the statistical model. Following these guidelines will enable investigators to better evaluate GI microbleeding during treatment with naproxen or other NSAIDs, and, hopefully, to establish the safety profiles of these drugs.37 references

  19. Intestinal permeability to (/sup 51/Cr)EDTA in children with Crohn's disease and celiac disease

    Turck, D.; Ythier, H.; Maquet, E.; Deveaux, M.; Marchandise, X.; Farriaux, J.P.; Fontaine, G.

    1987-07-01

    (/sup 51/Cr)EDTA was used as a probe molecule to assess intestinal permeability in 7 healthy control adults, 11 control children, 17 children with Crohn's disease, and 6 children with untreated celiac disease. After subjects fasted overnight, 75 kBq/kg (= 2 microCi/kg) /sup 51/Cr-labeled EDTA was given by mouth; 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the total oral dose. Mean and SD were as follows: control adults 1.47 +/- 0.62, control children 1.59 +/- 0.55, and patients with Crohn's disease or celiac disease 5.35 +/- 1.94. The difference between control children and patients was statistically significant (p less than 0.001). These results show that intestinal permeability to (/sup 51/Cr)EDTA is increased among children with active or inactive Crohn's disease affecting small bowel only or small bowel and colon, and with untreated celiac disease. The (/sup 51/Cr)EDTA permeability test could facilitate the decision to perform more extensive investigations in children suspected of small bowel disease who have atypical or poor clinical and biological symptomatology.

  20. Evaluation of the surface contamination density with 51Cr by direct measurement method using a GM survey-meter

    It is difficult to detect a low level contamination with 51Cr using a scintillation survey-meter because background counting rate of the survey-meter is high and emitted rate of γ-rays (0.320 MeV) from 51Cr is less than 10%. We examined whether a surface contamination with 51Cr can be detected directly with a GM survey-meter. As the result, the detection efficiency and detection limit of the GM survey-meter against the surface contamination were more than 0.6%(4π) and 4.6 Bq/cm2, respectively. From measurement of transmittance of radiations from 51Cr against poly (vinylidene chloride) seat, it became clear that the majority (about 98%) of detected radiations with the GM survey-meter is characteristic X-rays. These results show that the GM survey-meter can be used as a detector to check a surface contamination with 51Cr in controlled area. (author)

  1. Bioaccumulation of Chromium by Perna Viridis from Jakarta Bay Base on Radiotracer 51Cr Study

    The research of bioaccumulation chromium of Perna viridis from Jakarta Bay using 51Cr radiotracer have been done. The experiment was carried out by 3 steps such as: uptake, depuration and modelling. The result of experiment shown that Perna viridis can be used as bioindicator of chromium because its capability to accumulate Cr. Its concentration factor, uptake rate and depuration rate were 148.36 to 414.5, 14.836 to 65.754 μg per days and 9.04 to 15.48 % per days respectively. The value of BCF was under 500 so Perna viridis can not be used for environmental risk assesment. The result of modeling was find the Concentration Factor were 106 to 367 and the its decreasing from Perna viridis tissue can be 90 % after 14 days of depuration. (author)

  2. Mathematical analysis of /sup 51/Cr-labelled red cell survival curves in congenital haemolytic anaemias

    Kasfiki, A.G.; Antipas, S.E.; Dimitriou, P.A.; Gritzali, F.A.; Melissinos, K.G.

    1982-04-01

    The parameters of /sup 51/Cr labelled red cell survival curves were calculated in 26 patients with homozygous ..beta..-thalassaemia, 8 with sickle-cell anaemia and 3 with s-..beta..-thalassaemia, using a non-linear weighted least squares analysis computer program. In thalassaemic children the calculated parameters denote that the shorting of the mean cell life is due to early senescence alone, while there is some evidence that in thalassaemic adults additional extracellular destruction mechanisms participate as well. Red cell survival curves from patients with sickle-cell anaemia and s-..beta..-thalassaemia resemble each other, while their parameters indicate an initial rapid loss of radioactivity, early senescence and the presence of extracellular red cell destruction factors.

  3. Mathematical analysis of 51Cr-labelled red cell survival curves in congenital haemolytic anaemias

    The parameters of 51Cr labelled red cell survival curves were calculated in 26 patients with homozygous β-thalassaemia, 8 with sickle-cell anaemia and 3 with s-β-thalassaemia, using a non-linear weighted least squares analysis computer program. In thalassaemic children the calculated parameters denote that the shorting of the mean cell life is due to early senescence alone, while there is some evidence that in thalassaemic adults additional extracellular destruction mechanisms participate as well. Red cell survival curves from patients with sickle-cell anaemia and s-β-thalassaemia resemble each other, while their parameters indicate an initial rapid loss of radioactivity, early senescence and the presence of extracellular red cell destruction factors. (orig.)

  4. Forces in Hard Turning of 51CrV4 with Wiper Cutting Tool

    HE Xinfeng; WU Su; Hubert Kratz

    2006-01-01

    For precision machining, the hard turning process is becoming an important alternative to some of the existing grinding processes. This paper presents an analytical model for predicting cutting forces in hard turning of 51CrV4 with hardness of 68 HRC. The cutting tool used is made from cubic boron nitride (CBN) with a wiper cutting edge. Formulas for differential chip loads are derived for three different situations, depending on the radial depth of cut. The cutting forces are determined by integrating the differential cutting forces over the tool-workpiece engagement domain. For validation, cutting forces predicted by the model were compared with experimental measurements, and most of the results agree quite well.

  5. Application of 51Cr-RBC life span study and surface counting in blood diseases

    Present article summarized the RBC life span and liver, spleen surface counting in 274 cases of blood diseases. Whole blood labelling of 51Cr labelled auto or normal O type blood was used. The results showed that there was a shortening of the apparent survival time with different magnitude in various blood diseases, therefore it can be used for understanding the severity of hemolytic anemia, detection of latent hemolysis and also the investigation of the destruction and survival of RBC in other blood diseases. The surface counting of spleen, liver and precordium denoted that the S/P, S/L ratio was highest in hyperspleenism, consecutively various hemolytic anemia and cirrhosis of liver, hence this test can be used as an indication for splenectomy

  6. Preliminary results from the 51Cr neutrino source experiment in GALLEX

    The GALLEX collaboration performed a second 51Cr neutrino source experiment during fall 1995. The full results from this second source experiment will not be available before the end of 1996. Meanwhile, we present a short description and preliminary results in this informal note. The (preliminary) value of the activity obtained form direct measurements has been found equal to (68.7 ±0.7) PBq (with 1-sigma error). This value, which is about 10% higher than the activity of the first source, was achieved by optimizing the irradiation conditions in the Siloacute e reactor and doing a longer irradiation of the enriched chromium. Preliminary results show that the ratio, R, of the radiochemically determined activity from 71Ge counting (57.1 ± PBq) to the directly measured activity is (0.83 ± 0.10). The combined value of R for the two source experiments is (0.92 ± 0.08)

  7. Decline in 51Cr-labelled EDTA measured glomerular filtration rate following lung transplantation

    Hornum, Mads; Burton, Christopher M; Iversen, Martin; Hovind, Peter; Hilsted, Linda; Feldt-Rasmussen, Bo

    2007-01-01

    -transplanted patients from a national centre, and the correlation between measured and calculated GFR. METHODS: All lung-transplanted patients 1992-2004 (n = 390) were included in a longitudinal analysis. Seven patients were excluded due to retransplantation. Pre- and post-transplant parameters included (51)Cr......-labelled EDTA clearance (mGFR) and the Cockcroft-Gault calculated clearance (cGFR). Trough cyclosporine levels (C0) and demographic and transplant information were also included in the analysis. RESULTS: A total of 66959 C0 and serum creatinine and 1945 mGFR measurements pertaining to 383 patients were included......GFR. Increasing mean C0, body mass index and early acute renal failure were independent risk factors for a more rapid decline in post-transplant mGFR. CONCLUSION: mGFR decreases dramatically during the first 6 months after lung-transplantation. Avoidance of high dose calcineurin inhibition may postpone the onset...

  8. Revisiting normal {sup 51}Cr-ethylenediaminetetraacetic acid clearance values in children

    Piepsz, A.; Tondeur, M. [Department of Radioisotopes, CHU St Pierre, Brussels (Belgium); Ham, H. [Department of Nuclear Medicine, UZ Ghent, Ghent (Belgium)

    2006-12-15

    Normal {sup 51}Cr-ethylenediaminetetraacetic acid (EDTA) clearance values as a function of age were published a number of years ago. These values were based on data from children with a normal left to right ratio and a normal appearance on DMSA scintigraphy, despite the presence of an acute renal infection. At that time, the authors were unaware that hyperfiltration is a common phenomenon in patients with acute renal infection and that their normal values could have been significantly overestimated. The present work therefore aimed to re-appraise these normal values. In a first step, in order to verify the previous results, the same type of population was selected, namely patients with present or past urinary tract infection but normal images and a normal left to right ratio on DMSA scintigraphy. In a second step, the selection was based on patients who had had no recent urinary tract infection. In both series, a single blood sample method was used for the evaluation of {sup 51}Cr-EDTA clearance. In the first group of patients, the results obtained were almost identical to those previously published. In the second group of patients, the results were significantly lower: after 2 years of age, the mean GFR value was 104 ml/min/1.73 m{sup 2} (10th and 90th percentiles 81 and 135 ml/min/1.73 m{sup 2}, respectively), compared with 117 ml/min/1.73 m{sup 2} in the first group. The data of the second group are probably more representative of the true normal GFR values and can be applied to the entire paediatric population. (orig.)

  9. Preparation of High specific activity of ''51 Cr by the Szilard-Chalmers effect on potassium chromate

    Barrachina Gomez, M.; Villar Castejon, M. A.

    1965-07-01

    The {sup 5}1 Cr enriched Cr{sup 3}+ ions, which appear on putting into solution the potassium chromate irradiated with neutrons, are separated as chromium hydroxide. The CrO{sub 4}{sup 2}- ions occluded by the precipitate are eliminated on re precipitating the hydroxide. The more convenient irradiation time to for the production of {sup 5}1 Cr has been determined as the position of the maximum in the experimental curve P=f(t), where the time-dependent index P used is defined as the product of the number. (Author) 13 refs.

  10. Preparation of High specific activity of 51 Cr by the Szilard-Chalmers effect on potassium chromate

    The 51 Cr enriched Cr3+ ions, which appear on putting into solution the potassium chromate irradiated with neutrons, are separated as chromium hydroxide. The CrO42- ions occluded by the precipitate are eliminated on re precipitating the hydroxide. The more convenient irradiation time to for the production of 51 Cr has been determined as the position of the maximum in the experimental curve P=f(t), where the time-dependent index P used is defined as the product of the number. (Author) 13 refs

  11. Comparison between 125IUdR and 51Cr as cell labels in investigations of tumor cell migration

    Basse, P; Hokland, P; Hokland, M

    1991-01-01

    YAC-1 tumor cells double-labeled with Na2[51Cr]O4 [51Cr] and [125I]iododeoxyuridine [125IUdR] were injected intravenously into Balb/c mice in order to investigate their migration and fate 0-4 h after the injection. Whereas the clearance of tumor cells from the lung tissue was similar as judged with...... overestimation of the number of viable tumor cells in these organs. Moreover, a marked spontaneous release (greater than 10% after 12 h) makes 51Cr less suitable as a cell label than 125IUdR. On the other hand, we found that the release of 125I from dead cells in vivo depends at least partially on host factors...... such as macrophages. Consequently, caution must be exerted when tumor cell migration is investigated in animals treated with drugs that might affect the reticuloendothelial system. We conclude that 125IUdR is superior to 51Cr as a cell label for investigation of tumor cell migration in vivo, even...

  12. Measuring the activity of a {sup 51}Cr neutrino source based on the gamma-radiation spectrum

    Gorbachev, V. V., E-mail: vvgor-gfb1@mail.ru; Gavrin, V. N.; Ibragimova, T. V.; Kalikhov, A. V.; Malyshkin, Yu. M.; Shikhin, A. A. [Russian Academy of Sciences, Institute for Nuclear Research (Russian Federation)

    2015-12-15

    A technique for the measurement of activities of intense β sources by measuring the continuous gamma-radiation (internal bremsstrahlung) spectra is developed. A method for reconstructing the spectrum recorded by a germanium semiconductor detector is described. A method for the absolute measurement of the internal bremsstrahlung spectrum of {sup 51}Cr is presented.

  13. Study by Monte Carlo simulation of the absorbed dose in cells of breast cancer of the line MDA-MB231, due to sources of {sup 111}In, {sup 177}Lu and {sup 99m}Tc internalized in the nucleus. First results; Estudio por simulacion Monte Carlo de la dosis absorbida en celulas de cancer de seno de la linea MDA-MB231, debida a fuentes de {sup 11I}n, {sup 177}Lu y {sup 99m}Tc internalizadas en el nucleo. Primeros resultados

    Rojas C, E. L.; Perez A, M., E-mail: leticia.rojas@inin.gob.mx [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico)

    2011-11-15

    The necessity to design innovative treatments and to diagnose the cancer early, has taken to investigate therapies at cellular and molecular level. The design of appropriate radio-molecules to these therapies makes necessary to characterize in way exhaustive radionuclides that they are of accessible production in our country and to study as distributing the dose at cellular level with bio-molecules glued them. In this context, was realized the present work. Using Monte Carlo simulation, the energy deposited in a geometric model of cells of breast cancer was obtained, MDA-MB231, due to different radionuclides. The energy deposited in the nucleus was evaluated, in the cytoplasm and in the membrane of the cell, using the simulation code Monte Carlo Penelope 2008. A punctual source was simulated in the center of the cell nucleus. In each case all the emissions of each radionuclide majors to 400 eV were simulated. The energies deposited by disintegration in the nucleus, cytoplasm, membrane of the cell and in a sphere of 2 cm surrounding the source (in eV) were: 4.30E3, 4.85E2, 1.07E2 and 3.29E4, correspondingly, for the {sup 111}In; 4.46E3, 3.76E3, 1.26E3 and 1.33E5 for the {sup 177}Lu and; 2.12E3, 2.58E2, 9.33E1 and 1.88E4 for the {sup 99m}Tc. We can conclude that if the union of these radionuclides happens to a compound that was internalized to the cell nucleus, the best for therapy at this level is the conjugate with the {sup 177}Lu, followed by that with {sup 111}In and in third place that with {sup 99m}Tc. (Author)

  14. Grain boundary self-diffusion of 51Cr in Fe-Cr-Ni alloys

    The grain boundary self-diffusion characteristics P=α.δ.Dg (α is the segregation factor, δ is the grain boundary width and Dg is the grain boundary diffusion coefficient) of 51Cr were measured in the two alloys Fe-18 Cr-12 Ni and Fe-21 Cr-31 Ni. Experiments were performed in the temperature range from 973 to 1223 K using the sectioning method. In the frames of experimental errors there was found no significant difference between the results for both alloys. The temperature dependence of the triple product P for both materials can be thus described by the Arrhenius-type equation P(Cr)=(1.17+2.1-0.75).10-10.exp {-(234±19)/RT} m3/s. Within the errors, P values obtained in this paper are identical with those obtained in previous work for diffusion of 59Fe and 63Ni in the same materials. For the diffusion of all three basic constituents in both alloys the following equation is proposed P (Fe, Ni, Cr)=(6.7+9.9-4.0).10-12.exp {-(207±17)/RT} m3/s. (orig.)

  15. Study on iron metabolism in children using double labelling of 51Cr and 59Fe

    In the children before and after treatment for iron deficiency anemia and those on ingesting a long-term low caloric and iron diet, life span of Ashby Technique 1/2(AST) red cells, circulatory blood volume (CBV), plasma iron disappearance(PID), red cell-iron utility(RCIU), plasma-iron turnover rate(PITR), and red cell-ironturnover rate(RCITR) were respectively determined using double labeling of 51Cr and 59Fe, and the following results and conclusions were obtained: In the patients with iron deficiency anemia, the rate of RCIU was highly increased, and simultaneously the shortening in AST was observed. Among the children with the iron deficiency anemia, five patients were examined immediately after the improvement on the anemia by iron drugs; the serum iron (SFe) averaged 74μg/ml. So the erthropiesis appeared to recover to normal, yet AST has hardly changed, still more has it shortened. In five children with celebral palsy associated with disturbance of physical development, who had ingested a long-term liquid low iron diet no evident increase of RCIU was found except for high calues of RCITR. The shortening in AST was not entirely seen in contrast with that of the simple alimentary iron deficiency anemia. Besides the CBV measured par kg of weight showed the remarkable increase. (Oyama, S.)

  16. Separation of 51Cr by Means of the Szilard-Chalmers Effect from Potassium Chromate Irradiated at Low Temperature

    The recombination of 51Cr in K2CrO4 at low temperature as well as under dilute conditions has been investigated. Crystals of K2CrO4 and a 1 % solution of this compound have been irradiated in a thermal column of a nuclear reactor. Lowering of the temperature was observed to cause a decrease in retention. Chemical separations have been carried out both at 0 C and at 20 deg C. The degree of enrichment was determined by reactivating one part of the solution after separation of the hexavalent chromium. Irradiation of K2CrO4 in the frozen aqueous solution was observed to favour the degree of enrichment. The fate of the 51Cr recoil nuclide has been discussed in the light of the thermal spike theory

  17. Separation of {sup 51}Cr by Means of the Szilard-Chalmers Effect from Potassium Chromate Irradiated at Low Temperature

    Brune, D.

    1967-08-15

    The recombination of {sup 51}Cr in K{sub 2}CrO{sub 4} at low temperature as well as under dilute conditions has been investigated. Crystals of K{sub 2}CrO{sub 4} and a 1 % solution of this compound have been irradiated in a thermal column of a nuclear reactor. Lowering of the temperature was observed to cause a decrease in retention. Chemical separations have been carried out both at 0 C and at 20 deg C. The degree of enrichment was determined by reactivating one part of the solution after separation of the hexavalent chromium. Irradiation of K{sub 2}CrO{sub 4} in the frozen aqueous solution was observed to favour the degree of enrichment. The fate of the {sup 51}Cr recoil nuclide has been discussed in the light of the thermal spike theory.

  18. Experimental study of the deformed nucleus {sup 153}Sm via ({rvec d},t) and average resonance capture as a test case for the multiorbit interacting boson fermion model

    Gollwitzer, A.; Hertenberger, R.; Metz, A.; Schiemenz, P.; Valnion, B.D.; Graw, G. [Sektion Physik der Universitaet Muenchen, D-85748 Garching (Germany); Blasi, N.; Lucchini, S.; Micheletti, S.; Pignanelli, M. [Dipartimento di Fisica dellUniversita di Milano, I-20133 Milano (Italy); de Leo, R. [Universita di Bari and Sezione INFN di Bari (Italy); Gill, R.L. [Brookhaven National Laboratory, Upton, New York 11973 (United States); Hategan, C. [Institute of Atomic Physics, Bukarest (Romania); Casten, R.F. [Yale University, A.W. Wright Nuclear Structure Laboratory, New Haven, Connecticut 06520 (United States)

    1998-06-01

    The {sup 154}Sm({rvec d},t) reaction at high energy resolution (n,{gamma}), average resonance capture (ARC), and coincidence measurements were performed to study the deformed nucleus {sup 153}Sm. Strength distributions from ({rvec d},t) and completeness for I{sup {pi}}= (1) /(2) {sup {minus}} and (3) /(2) {sup {minus}} states up to 1500 keV from ARC provide one of the first detailed tests of the interacting boson fermion model (IBFM) in a deformed nucleus in a multiorbit environment. For negative parity states the model accounts for the large number of low spin ( (1) /(2) {sup {minus}}, (3) /(2) {sup {minus}}) states much better than the Nilsson model since the even-even core in the IBFM calculations automatically includes excited vibrational states. The IBFM calculations also predict (d,t) spectroscopic factors better than the Nilsson model with pairing and Coriolis mixing. Neither the IBFM nor the Nilsson approach can explain the low lying positive parity states. The IBFM calculations show that for certain combinations of parameters, the monopole term in the boson-fermion Hamiltonian has more than a scaling effect: it can attenuate the Coriolis mixing (energy staggering). Finally suggested improvements in the treatment of pairing in the IBFM are made. {copyright} {ital 1998} {ital The American Physical Society}

  19. Automatic control system for measuring currents produced by ionization chambers; Automatizacao de um sistema de medidas de correntes produzidas por camaras de ionizacao e aplicacao na calibracao do {sup 18}F e {sup 153}Sm

    Brancaccio, Franco

    2002-07-01

    Ionization Chambers in current mode operation are usually used in Nuclear Metrology. Activity measurements are quickly performed by Ionization Chambers, with very good precision. For this purpose measurements of very low ionization currents, carried out by high quality instrumentation, are required. Usually, electrometers perform the current integration method under command of signals from an automation system, in order to reduce the measurement uncertainties. Among the measurement systems at the Laboratorio de Metrologia Nuclear (LMN) of IPEN, there are two ionization chamber systems. In the present work, an automation system developed for current integration measurements is described. This automation system is composed by software (graphic interface and control) and an electronic module connected to a microcomputer, by means of a commercial data acquisition card. Several test measurements were performed in order to determine the intrinsic uncertainty, linearity and stability of the system. Using calibrated radioactive solutions, the IG12/A20 chamber calibration factors for {sup 18}F and {sup 153}Sm were obtained, making possible to determine activities of these radionuclides. (author)

  20. Interactions of animal age and particle size with deposition and retention of inhaled 51Cr-labeled microspheres

    Newborn, juvenile, weanling, and adult rats were exposed to aerosols of 51Cr-labeled microspheres with AMADs of 0.91, 1.4, 2.3, 3.4, and 4.4 μm. Alveolar deposition was negligible in newborn rats for all particle sizes, and decreased to less than 6% at an AMAD of 2.3 μm in juveniles and weanlings, and an AMAD of 3.4 μm in adults

  1. Determination of 51Cr and 241Am X-ray and gamma-ray emission probabilities per decay

    Full text: In this paper results of X-ray and gamma-ray emission probabilities per decay of 51Cr and 241Am are presented. The measurements were carried out by means of an HPGe planar spectrometer. The radionuclide 51Cr decays with a half-life of 27.7 days by electron capture process populating the excited levels of 51V, which emits X-rays between 4 and 6 keV and a gamma ray of 320 keV. The radionuclide 241Am decays with a half-life of 157,850 days by alpha emission, populating the excited levels of 237Np, which emits X-rays between 11 and 20 keV and two main gamma rays of 26 and 59 keV. The choice of 51Cr was made due to the need of more results since there are two discrepant sets of values for the 320 keV emission probability per decay in the literature. The choice of 241Am was made because, although this radionuclide be considered a primary standard for spectrometers calibration using its well-known 59 keV gamma ray emission probability, the 26 keV gamma ray and the X-rays emission probabilities present large discrepancies in the literature. The activity of 51Cr and 241Am samples was determined in a 4-coincidence counting system. The same sources were measured in an HPGe planar spectrometer with Be window, suitable for measurements in low energy range. The HPGe spectrometer was calibrated in a well defined geometry by means of 54Mn, 55Fe, 57Co, 133Ba, 152Eu, 166mHo and 241Am (59 keV) sources, previously standardized in a coincidence system. The MCNP Monte Carlo code was used for simulation of the spectrometer calibration curve for the selected geometry, and compared with the experimental one

  2. Intestinal permeability of 51Cr-labelled ethylenediaminetetraacetic acid in patients with Crohn's disease and their healthy relatives

    An increased intestinal permeability has been proposed as an aetiologic factor in Crohn's disease. The 24-h urinary excretion of 100 μCi 51Cr-labelled ethylenediaminetetraacetic acid (EDTA) was used to test the permeability in 15 patients with Crohn's disease and in 20 healthy first-degree relatives, who were known to have a genetic predisposition to inflammatory bowel disease. Twenty-eight healthy persons not related to patients with inflammatory bowel disease served as control material. The 51Cr-EDTA excretion of the relatives was not significantly higher than that of the controls, whereas patients with Crohn's disease had a significantly higher excretion than both the relatives and the controls. Among patients the increased excretion was found only if the small intestine was involved. It is concluded that 1) as a group, patient with Crohn's disease in the small intestine have an increased intestinal permeability, in contrast to their healthy relatives, who have a normal permeability; 2) a considerable overlap of the results of the 51Cr-EDTA test was found between the groups studied, and the test is not suitable for evaluating individual patients; 3) the results do not support the hypothesis of an increase in intestinal permeability as an aetiologic factor in Crohn's disease. 29 refs

  3. Intestinal permeability assessed by 51Cr-EDTA in rats with CCl4 - induced cirrhosis Permeabilidade intestinal ao 51-Cr-EDTA em ratos com cirrose induzida por CCl4

    Ana Regina L. Ramos

    2010-06-01

    Full Text Available CONTEXT: The straight relationship between cirrhosis and impaired intestinal barrier has not been elucidated yet. OBJECTIVES: To verify 51Cr-EDTA-intestinal permeability in rats with CCl4-induced cirrhosis and controls. METHOD: Fifty male Wistar rats weighing 150-180 g were separated in three groups: 25 animals received CCl4 0.25 mL/kg with olive oil by gavage with 12 g/rat/day food restriction for 10 weeks (CCl4-induced cirrhosis; 12 received the same food restriction for 10 weeks (CCl4-non exposed. Other 13 rats received indomethacin 15 mg/kg by gavage as positive control of intestinal inflammation. RESULTS: The median (25-75 interquartile range 51Cr-EDTA-IP values of cirrhotic and CCl4-non exposed rats were 0.90% (0.63-1.79 and 0.90% (0.60-1.52 respectively, without significant difference (P = 0.65. Animals from indomethacin group showed 51Cr-EDTA-IP, median 7.3% (5.1-14.7, significantly higher than cirrhotic and CCl4-non exposed rats (PCONTEXTO: A relação direta entre cirrose e alterações na barreira intestinal ainda não foi devidamente esclarecida. OBJETIVO: Verificar a permeabilidade intestinal ao 51Cr-EDTA em ratos com cirrose induzida por tetracloreto de carbono (CCl4 e controles. MÉTODO: Cinquenta ratos Wistar machos pesando 150-180 g foram separados em três grupos: 25 animais receberam CCl4 0,25 mL/kg diluído em óleo de oliva por gavagem com restrição dietética de 12 g/rato/dia por 10 semanas (grupo cirrose induzida por CCl4; 12 receberam a mesma restrição dietética por 10 semanas (grupo não exposto ao CCl4. Outros 13 ratos receberam indometacina 15 mg/kg por gavagem como controle positivo de inflamação intestinal. RESULTADOS: A mediana (intervalo interquartil 25-75 dos valores de permeabilidade intestinal ao 51Cr-EDTA dos grupos cirrose induzida por CCl4 e não exposto ao CCl4 foram 0,90% (0,63-1,79 e 0,90% (0,60-1,52, respectivamente, sem significância estatística (P = 0,65. Os animais do grupo indometacina

  4. Investigation into feed utilisation by fore-aged silver carp (Hypophthalmichthys molitrix) using double-marked algae (14C and 51Cr)

    The blue-green alga Microcystis firma and two green algae, Dunaliella viridis and Chlorella vulgaris, were double-marked with 14C and 51Cr. The 51Cr was used as an indicator to measure the assimilation efficiency of fore-aged silver carp for radiocarbon. The assimilation efficiency values obtained were 89.0 +- 5.43% for M. firma, 61.3 +- 15.28% for D. viridis and 91.3 +- 2.22% for C. vulgaris. (author)

  5. In vivo studies of the long-term 51Cr red cell survival of serologically incompatible red cell units

    The long-term survival of serologically incompatible red cell units was measured in five patients with antibodies to high-frequency antigens. Initially, the survival of 1 ml of 51Cr-labeled incompatible red cells was measured over 1 hour. After demonstrating that the 1-hour survival times were successful (greater than 70%), each patient then received 5 ml of the same 51Cr-labeled red cells followed by the transfusion of the remainder of the red cell unit. The long-term T 1/2Cr survival for each case was patient 1 (anti-McCa), 15 days; patient 2 (anti-JMH), 12 days; patient 3 (anti-Kna), 31 days; patient 4 (anti-McCa), 12 days; and patient 5 (anti-Hya), 14 days. Each antibody tested in an in vitro homologous macrophage assay showed less than 5 percent phagocytosis. Anti-JMH was the only antibody to react with IgG subclass antisera and was determined to be IgG4. The macrophage assay, IgG subclass testing, and short-term (1 hour, 1 ml) 51Cr survival studies all indicated that the short-term survival was good. However, only the measurement of long-term survival with transfused units of serologically incompatible red cells was able to determine the actual survival, and clinical significance of the alloantibodies. Determining the actual long-term survival by the method described here can be of importance for patients requiring chronic red cell transfusion

  6. Rapid decline in 51Cr-EDTA measured renal function during the first weeks following lung transplantation

    Hornum, Mads; Iversen, Martin; Steffensen, Ida; Hovind, Peter; Carlsen, Jørn; Andersen, Lars Willy; Steinbrüchel, Daniel Andreas; Feldt-Rasmussen, Bo Friis

    2009-01-01

    /bronchiectasis or idiopathic pulmonary fibrosis were included in an analysis of renal function before and after LTx. The glomerular filtration rate (GFR) was measured using the (51)Cr-ethylenediaminetetra acetic acid plasma clearance single injection technique (mGFR) at baseline before transplantation and at 1, 2......We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis...

  7. Loss of 51Cr, 54Mn, 57Co, 59Fe, 65Zn and 134Cs by the mussel Mytilus

    The loss of 51Cr, 54Mn, 57Co, 59Fe, 65Zn and 134Cs from naturally growing mussels (Mytilus edulis) was followed in a temperate estuarine environment -a Danish fjord - by individual whole-body countings on a Ge(Li) detector. The mussels accumulated the radionuclides in the laboratory from food and water and were brought back to their natural environment in small plastic cages. The loss curves for 12 animals from July - August 1979 until November 1979 (20-50C) were resolved in a slow compartment with 140-215 d biological half-life for 57Co, 54Mn, 51Cr and 59Fe, and 87 d for 65Zn, and a medium compartment with a biological half-life of 4-7 d for all nuclides. The long-lived compartments of 65Zn, 57Co and 54Mn were followed in four individual animals from August 1979 to August 1980. For 65Zn a seasonal effect was clearly demonstrated as the biological half-life was prolonged from 87 d during autumn 1979 to 347 d in the cold period (0-50C), whereas it decreased again during the summer of 1980. For 57Co and 54Mn the long-term excretion study revealed an extra-slow compartment, as the long half-life in the cold period (approximately 600 d) persisted during the summer of 1980. This is explained by association with the shell. (author)

  8. In Vivo Determination of Site and Rate of Insulin Catabolism Using the Double Tracer Technique with 51Cr And 131I

    Double labelling of a peptide with 51Cr and 125(131)I results in an isotopic ratio that changes when and where the molecule in vivo is catabolized. Intracellular hydrolysis of the peptide liberates the iodine into the iodine pool, whereas the chromium by virtue of being a multivalent ion enters a new linkage at the site of breakdown. The isotopic ratio at the site of breakdown alters concomitantly with the hydrolysis rate. Experiments with 51Cr- and 125I-labelled insulin in mice in vivo and in vitro showed the liver (not muscle), bone (including marrow) and thyroid gland to be the major site of insulin catabolism with a half-life of approximately 10 min. In eight normal persons and diabetic patients insulin catabolism was analysed by the whole body counter following an iv injection of 0.77-0.95 μg insulin labelled with 51Cr and 131I. Counts were taken simultaneously from the area of the liver, thyroid, thigh and posterior pelvis. Again, the.data indicated the liver as the site of insulin catabolism, the normal half-life being approximately 20 min. Iodine- labelled insulin was commercially supplied. 51Cr-labelled insulin, prepared according to the methods of Kavai and Kesztyüs, was analysed by immune precipitation and Sephadex G200 chromatography. In the countercurrent distribution the 51Cr insulin showed enhanced water solubility. (author)

  9. Development of an experimental system for evaluation of the effect of stress on intestinal motility using a radionuclide, 51Cr, in the rat

    We attempted to develop an experimental system for evaluation of the influence of stress on small intestinal motility using a radionuclide, 51Cr, and an acute restraint stress model. Each rat was immobilized in an adjustable restraint device for 1 to 5 h. The rat was given 51Cr immediately after the end of stress loading through a catheter inserted into the duodenum, and sacrificed 20 min after administration. The small intestine was removed and the 51Cr radioactivity was continuously monitored with an NaI-scintillation survey meter. The small intestinal motility was estimated by the distance of the radioactive peak from the top of the duodenum. The small intestinal motility was significantly inhibited by 3 h-restraint stress. This experimental system is easy, rapid, and simple for the evaluation of the effect of stress on small intestinal motility. (author)

  10. Gamma-variate plasma clearance versus urinary plasma clearance of (51) Cr-EDTA in patients with cirrhosis with and without fluid retention

    Fuglsang, Stefan; Henriksen, Ulrik L; Hansen, Hanne B;

    2016-01-01

    In patients with fluid retention, the plasma clearance of (51) Cr-EDTA (Clexp obtained by multiexponential fit) may overestimate the glomerular filtration rate (GFR). The present study was undertaken to compare a gamma-variate plasma clearance (Clgv) with the urinary plasma clearance of (51) Cr......-EDTA (Clu ) in patients with cirrhosis with and without fluid retention. A total of 81 patients with cirrhosis (22 without fluid retention, 59 with ascites) received a quantitative intravenous injection of (51) Cr-EDTA followed by plasma and quantitative urinary samples for 5 h. Clgv was determined from the...... injected dose relative to the plasma concentration-time area, obtained by a gamma-variate iterative fit. Clexp and Clu were determined by standard technique. In patients without fluid retention, Clgv , Clexp and Clu were closely similar. The difference between Clgv and Clu (Clgv - Clu = ΔCl) was mean -0...

  11. Over-estimation of glomerular filtration rate by single injection [51Cr]EDTA plasma clearance determination in patients with ascites

    Henriksen, Jens Henrik Sahl; Brøchner-Mortensen, J; Malchow-Møller, A; Schlichting, P

    1980-01-01

    The total plasma (Clt) and the renal plasma (Clr) clearances of [51Cr]EDTA were determined simultaneously in nine patients with ascites due to liver cirrhosis. Clt (mean 78 ml/min, range 34-115 ml/min) was significantly higher than Clr (mean 52 ml/min, range 13-96 ml/min, P < 0.005). The ascitic...... fluid-plasma activity ratio of [51Cr]EDTA increased throughout the investigation period (5h). The results suggest that [51Cr]EDTA equilibrates slowly with the peritoneal space which indicates that Clt will over-estimate the glomerular filtration rate by approximately 20 ml/min in patients with ascites...

  12. Comparative gastrointestinal blood loss associated with placebo, aspirin, and nabumetone as assessed by radiochromium (/sup 51/Cr)

    Lussier, A.; Davis, A.; Lussier, Y.; Lebel, E.

    1989-03-01

    Nabumetone differs from most other nonsteroidal anti-inflammatory drugs. It is presented to the gut as a nonacidic prodrug, and is metabolized to its active form after absorption. Studies in animals and humans suggest it is less irritating to the gastrointestinal mucosa. This study compared the gastrointestinal microbleeding induced by nabumetone to aspirin (acetylsalicylic acid, ASA), and placebo in a double blind parallel study using chromium /sup 51/Cr labelled red cells to quantitate fecal blood loss (FBL) in healthy volunteers. Thirty subjects were randomized to treatment with nabumetone (2000 mg), ASA (3.6 g) or placebo for 21 days following a 7 day placebo period. Six subjects served as untreated controls. FBL in nabumetone treated subjects was not significantly different to placebo or untreated subjects. In contrast, ASA-treated subjects exhibited significantly increased FBL than the other 3 groups (P less than .0001).

  13. Rapid decline in 51Cr-EDTA measured renal function during the first weeks following lung transplantation

    Hornum, M.; Iversen, M.; Steffensen, I.;

    2009-01-01

    We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis....../bronchiectasis or idiopathic pulmonary fibrosis were included in an analysis of renal function before and after LTx. The glomerular filtration rate (GFR) was measured using the (51)Cr-ethylenediaminetetra acetic acid plasma clearance single injection technique (mGFR) at baseline before transplantation and at 1, 2.......0001), acute renal failure within 2 weeks post-LTx (p = 0.0003), use of heart and lung machine (p = 0.04), and the use of ephedrine (p = 0.048), as well as increasing age, older than 18 years at LTx (p = 0.006). These data demonstrate that renal function, measured with an isotope method, decreases dramatically...

  14. Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with 177Lu- and 90Y-BR96 mAbs

    Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. Methods: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with 90Y- and 177Lu-labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow-up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. Results: A red marrow absorbed dose-dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for 177Lu and 12.5 Gy for 90Y. Conclusions: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom weight, ranging from

  15. Investigation into feed utilization by fore-aged silver carp (Hypophthalmichthys molitrix) using double-marked algae (/sup 14/C and /sup 51/Cr)

    Wessel, B.; Spittler, P.; Heerkloss, R. (Rostock Univ. (German Democratic Republic). Sektion Biologie)

    1982-01-01

    The blue-green alga Microcystis firma and two green algae, Dunaliella viridis and Chlorella vulgaris, were double-marked with /sup 14/C and /sup 51/Cr. The /sup 51/Cr was used as an indicator to measure the assimilation efficiency of fore-aged silver carp for radiocarbon. The assimilation efficiency values obtained were 89.0 +- 5.43% for M. firma, 61.3 +- 15.28% for D. viridis and 91.3 +- 2.22% for C. vulgaris.

  16. Validation of calculated eGFR compared with 51Cr-EDTA clearance on a patient population from northern Jutland in Denmark

    Nielsen, Nikolaj Schandorph

    I mange år har man anvendt patienters plasma-creatinin niveau i blodet som et estimat for nyrefunktionen. I september 2010 blev der i Aalborg indført eGFR som etstimat på nyrefunktion ud fra plasma-creatinin. Det er kendt at GFR bestemt ved 51Cr-EDTA clearence er det bedste bud på patienters...... nyrefunktion, og derfor undersøges validiteten af eGFR i forhold til GFR bestemt ved 51Cr-EDTA clearence....

  17. Evidence for absorption of kelp detritus by the ribbed mussel Aulacomya ater using a new /sup 51/Cr-labelled microsphere technique

    Stuart, V.; Field, J.G.; Newell, R.C.

    1983-09-15

    A modification of the /sup 51/Cr:/sup 14/C twin-labelling technique is described in which the food source is labelled with /sup 14/C but the /sup 51/Cr is enclosed in a polymeric resin membrane and presented as microspheres of a similar diameter to the food particles. This eliminates the major uptake of /sup 51/Cr which is transferred to the ctenidia and palps of the suspension-feeding mussel Aulacomya ater (Molina) from detritus labelled with /sup 51/Cr. The results suggest that although bacterial cultures based on isolates of kelp bacteria can be absorbed with an efficiency of 67 to 70%, the debris itself is also absorbed with an efficiency of approximately 50%. The kelp debris, which forms an important component of the particulate matter potentially available for consumers, may thus represent an important source of carbon for the filter feeding community adjacent to kelp beds. In contrast to the results obtained in other studies with artificial food sources, the data for kelp debris suggest that A. ater is able to maintain a positive scope for grwoth at the concentrations of suspended organic matter which occur under natural conditions in the kelp bed environment.

  18. Evidence for absorption of kelp detritus by the ribbed mussel Aulacomya ater using a new 51Cr-labelled microsphere technique

    A modification of the 51Cr:14C twin-labelling technique is described in which the food source is labelled with 14C but the 51Cr is enclosed in a polymeric resin membrane and presented as microspheres of a similar diameter to the food particles. This eliminates the major uptake of 51Cr which is transferred to the ctenidia and palps of the suspension-feeding mussel Aulacomya ater (Molina) from detritus labelled with 51Cr. The results suggest that althoug bacterial cultures based on isolates of kelp bacteria can be absorbed with an efficiency of 67 to 70%, the debris itself is also absorbed with an efficiency of approximately 50%. The kelp debris, which forms an important component of the particulate matter potentially available for consumers, may thus represent an important source of carbon for the filter feeding community adjacent to kelp beds. In contrast to the results obtained in other studies with artificial food sources, the data for kelp debris suggest that A. ater is able to maintain a positive scope for grwoth at the concentrations of suspended organic matter which occur under natural conditions in the kelp bed environment. (orig.)

  19. Arterio-venous concentration difference of [51Cr]EDTA after a single injection in man. Significance of renal function and local blood flow

    Rehling, M; Hyldstrup, L; Henriksen, Jens Henrik Sahl

    1989-01-01

    The present investigation was undertaken in order to study (1) the difference in arterial (Ca) and venous (Cv) concentration of [51Cr]EDTA (ethylenediaminetetraacetate) after a single intravenous injection, (2) the impact of different physiological variables on this difference, and (3) the error...

  20. Estimating GFR in children with 99mTc-DTPA renography: a comparison with single-sample 51Cr-EDTA clearance

    Gutte, Henrik; Møller, Michael L; Pfeifer, Andreas K; Thorup, Jørgen Mogens; Borgwardt, Line; Borgwardt, Lise; Kristoffersen, Ulrik S; Kjaer, Andreas

    2010-01-01

    Glomerular filtration rate (GFR) measurement by (51)Cr-ethylenediaminetetraacetic acid (EDTA) and blood sampling in children is usually cumbersome for the patient, parents and laboratory technicians. We have previously developed a method accurately estimating GFR in adults. The aim of the present...

  1. Change in Distribution of Heat-Treated 51Cr-Labelled Erythrocytes in the Spleen by Dynamic Digital Scintigraphy

    It is known that in the normal functioning of the spleen, those red cells which do not meet certain minimum requirements from the circulation are able to be removed. The fate of these cells in different normal and abnormal conditions, as well as the role played by the spleen, has been adequately studied since erythrocytes labelled with radioactive substances have been employed. Observations are presented on the changes in the distribution of heat-treated 51Cr-labelled erythrocytes in the spleen against time, by repeated digital scintigraphy during one hour. Heat-treated 51Cr-labelled erythrocytes were injected intravenously in 15 subjects (five normals, five with thalassaemia and five with other different haematological diseases). Measurements were done with a Pho-Gamma Scintillation Camera, connected with a 1600 word memory and an Ampex magnetic tape recorder. Blood samples were taken at first every five minutes, then at twenty- minute intervals for one hour. The results in counts/min were plotted on semilogarithmic paper. The data were collected at intervals of 5 min, digitized by the 1600 word memory and transferred to the magnetic tape recorder from which they could be played back at any time for further analysis. After the end of the study the data from the magnetic tape were printed by a fast digital printer as channel position X and Y and number of counts. The number of counts were transferred to linear millimetre paper in an X and Y format. Isocount lines were then drawn for different levels of activity and the total number of counts inside each isocount line was added and divided by the number of channels. The results are expressed as a mean value of counts in different areas of the spleen; a difference between the counts taken over the whole spleen and the counts of the hot area; and the ratio of the counts of the most hot area and the counts of the whole area of the spleen. The results are discussed. (author)

  2. Determination of optimal sampling times for a two blood sample clearance method using (51)Cr-EDTA in cats.

    Vandermeulen, Eva; De Sadeleer, Carlos; Piepsz, Amy; Ham, Hamphrey R; Dobbeleir, André A; Vermeire, Simon T; Van Hoek, Ingrid M; Daminet, Sylvie; Slegers, Guido; Peremans, Kathelijne Y

    2010-08-01

    Estimation of the glomerular filtration rate (GFR) is a useful tool in the evaluation of kidney function in feline medicine. GFR can be determined by measuring the rate of tracer disappearance from the blood, and although these measurements are generally performed by multi-sampling techniques, simplified methods are more convenient in clinical practice. The optimal times for a simplified sampling strategy with two blood samples (2BS) for GFR measurement in cats using plasma (51)chromium ethylene diamine tetra-acetic acid ((51)Cr-EDTA) clearance were investigated. After intravenous administration of (51)Cr-EDTA, seven blood samples were obtained in 46 cats (19 euthyroid and 27 hyperthyroid cats, none with previously diagnosed chronic kidney disease (CKD)). The plasma clearance was then calculated from the seven point blood kinetics (7BS) and used for comparison to define the optimal sampling strategy by correlating different pairs of time points to the reference method. Mean GFR estimation for the reference method was 3.7+/-2.5 ml/min/kg (mean+/-standard deviation (SD)). Several pairs of sampling times were highly correlated with this reference method (r(2) > or = 0.980), with the best results when the first sample was taken 30 min after tracer injection and the second sample between 198 and 222 min after injection; or with the first sample at 36 min and the second at 234 or 240 min (r(2) for both combinations=0.984). Because of the similarity of GFR values obtained with the 2BS method in comparison to the values obtained with the 7BS reference method, the simplified method may offer an alternative for GFR estimation. Although a wide range of GFR values was found in the included group of cats, the applicability should be confirmed in cats suspected of renal disease and with confirmed CKD. Furthermore, although no indications of age-related effect were found in this study, a possible influence of age should be included in future studies. PMID:20452793

  3. Measurement of the response of a gallium metal solar neutrino experiment to neutrinos from a 51Cr source

    The neutrino capture rate measured by the Russian-American Gallium Experiment is well below that predicted by solar models. To check the response of this experiment to low-energy neutrinos, a 517 kCi source of 51Cr was produced by irradiating 512.7 g of 92.4%-enriched 50Cr in a high-flux fast neutron reactor. This source, which mainly emits monoenergetic 747-keV neutrinos, was placed at the center of a 13.1 ton target of liquid gallium and the cross section for the production of 71Ge by the inverse beta decay reaction 71Ga(νe,e-)71Ge was measured to be [5.55±0.60thinsp(stat)±0.32thinsp(syst)]x10-45thinspcm2. The ratio of this cross section to the theoretical cross section of Bahcall for this reaction is 0.95 ±0.12 (expt)-0.027+0.035 (theor) and to the cross section of Haxton is 0.87±0.11 (expt)±0.09 (theor). This good agreement between prediction and observation implies that the overall experimental efficiency is correctly determined and provides considerable evidence for the reliability of the solar neutrino measurement. copyright 1999 The American Physical Society

  4. Susceptibility of adherent versus suspension target cells derived from adherent tissue culture lines to cell-mediated cytotoxicity in rapid 51Cr-release assays

    Preparation of target cells from tissue culture lines which grow adherent to tissue culture vessels is often desirable for tests of cell-mediated cytotoxicity (CMC). In the present study the authors used cells derived from adherent tissue culture lines to compare the merits of suspension vs. adherent target cells in short-term 51Cr-release assays. Cytotoxic activity of murine spleen cells sensitized in vitro against allogeneic spleen cells or syngeneic sarcoma cells was tested with fibroblast or sarcoma target cells. In parallel tests, aliquots of tissue culture lines were detached and used as either suspension or adherent target cells in CMC assays, matching the concentrations of suspension and adherent target cells. In both allogeneic and syngeneic combinations adherent target cells released less 51Cr spontaneously and were more susceptible to CMC than their suspension counterparts. (Auth.)

  5. Evaluation of the effects of restraint and footshock stress on small intestinal motility by an improved method using a radionuclide, 51Cr, in the rat

    The effect of two different stress stimuli, restraint stress and footshock stress, on small intestinal motility was evaluated by a more reliable method with improvement of the previous method using a radionuclide, 51Cr. The small intestinal transit was significantly inhibited by restraint stress, but not by footshock stress, although plasma corticosterone levels were significantly elevated to the same extent by restraint stress and footshock stress. These results suggest that restraint stress and footshock stress stimuli influence small intestinal motility via different mechanisms, but the reason for the difference is unclear. This experimental system using 51Cr seems to be useful for the elucidation of mechanisms for restraint stress-induced dysfunction of small intestinal motility because of its excellent quantitative evaluation of small intestinal transit. (author)

  6. Total plasma clearance versus urinary plasma clearance of (51)Cr-EDTA in patients with cirrhosis with and without fluid retention

    Henriksen, Ulrik Lütken; Hansen, Hanne B; Ring-Larsen, Helmer;

    2015-01-01

    Abstract Background and aim. In patients with fluid retention, the total plasma clearance of (51)Cr-EDTA (ClP) may overestimate the glomerular filtration rate (GFR). The present study was therefore undertaken in order to compare ClP with the urinary plasma clearance of (51)Cr-EDTA (ClU) in patients...... with cirrhosis with and without fluid retention. Material and methods. A total of 136 patients with cirrhosis (24 without fluid retention, 112 with ascites) received a quantitative intravenous injection of (51)Cr-EDTA followed by plasma and quantitative urinary samples for 5 hours. ClP was determined...... from the injected dose relative to the plasma concentration-time area, extrapolated to infinity. ClU was determined as urinary excretion relative to the plasma concentration-time area up to voiding. Results. In patients without fluid retention, the difference between ClP and ClU (ClP - ClU = ClΔ) was...

  7. Comparison of 51Cr-EDTA- with 99mTc-DTPA-slope-clearance for estimation of glomerular filtration rate using the one-compartment model

    Aim of this study is to determine the relationship between 51Cr-EDTA and 99mTc-DTPA slope clearance applying the 'one-compartment model'. Methods: The 'one-compartment model' was chosen to calculate and to compare the glomerular filtration rates of 25 patients with normal and pathological creatinin values after injection of 51Cr-EDTA and 99mTc-DTPA simultaneously. Results: The two clearance values correlated well (r=0.996), and the 99mTc-DTPA clearance was systematically higher (28%). The 99mTc-DTPA was calculated and compared after taking three plasma samples. Taking two samples, only minor differences were seen and the correlation was high (r=0.992). Conclusion: The results of this study encouraged us to adopt the use of 99mTc-DTPA instead of 51Cr-EDTA in determining the glomerular filtration applying the 'one-compartment model' in slope with two plasma samples. (orig.)

  8. Experience with a gastrointestinal marker (51CrCl3) in a combined study of ileal function using 75SeHCAT and 58CoB12 measured by whole body counting.

    Smith, T.; Bjarnason, I

    1990-01-01

    Introduction of a radioactive gastrointestinal marker (51CrCl3) into a combined study (75SeHCAT + 58CoB12) of ileal function by whole body counting has been undertaken. The technique was assessed in 23 subjects (15 patients with inflammatory bowel disease, six on non-steroidal anti-inflammatory drugs for rheumatoid arthritis, and two normal subjects). Mean (SD) 51CrCl3 retention was only 4.1 (6.0)% on day 4, and was similar on day 7 in subjects given a second dose of 51CrCl3 on day 4. Only on...

  9. Comparative study of conventional PAH and inulin clearance and slope clearance of 131I-o-hippuric acid and 51Cr-EDTA

    ''Classic'' PAH and inulin clearance were determined in 81 patients with renal anomalies or renal diseases of different genesis and severity. In addition, radioisotope nephrography was carried out after administration of I-131-o-hippuric acid, followed by administration of Cr-51-EDTA. The activity decrease was recorded by a sensor located over the patient's right shoulder; the activities of a serum sample and of the urine excreted after 21 or 31 min were measured, and the findings were compared with those of the classic method. The clearance data calculated on the basis of the soulder measurements were hardly compatible with those of the conventional method in the case of 131I-o-hippuric acid (r=0.54) and totally incompatible in the case of 51Cr-EDTA. This means that the method described by Oberhausen is the only accurate method available for a quantitative assessment of the renal function on the basis of measurements of the activity decrease in the body. The activity of urine excreted after 31 min (131I-hippuric acid:r=0.992, 51Cr-EDTA:r=0.79) is a sufficiently accurate parameter although it is inaccurate at PAH clearance, values > 130 ml/min and inulin clearance values > 30 ml/min. Of the many parameters of radioisotope nephrogram curves, in the case of 131I-o-hippuric acid only the parameters related to the ascent between 48 and 120 sec or to the secant ascent yield sufficient quantitative information for certain functional regions (r=0.9 resp. r=0.93). In the case of 51Cr-EDTA, semiquantitative information on the renal function can be obtained by constructing secants on the nephrogram curves (r=0.7 resp. r=0.72). Here as in the case of 131I-hippuric acid, the contribution of each kidney can be determined individually from the functional analysis of both kidneys. (orig.)

  10. 177Lu-octreotate in Neuroendocrine Tumors: Treatment Effects

    van Vliet, Esther

    2013-01-01

    textabstractNeuroendocriene tumoren (NETs) zijn zeer zeldzame tumoren, die ontstaan vanuit neuroendocriene cellen in het lichaam. Deze tumoren produceren vaak hormonen en hormoonachtige stoffen. NETs ontstaan meestal in het maag-darm kanaal, in de alvleesklier, of in de longen. Jaarlijks komen er in Nederland ongeveer 700 nieuwe NET-patiënten bij. De enige mogelijkheid om deze patiënten te genezen is om hen te opereren. Vaak kan dit echter niet meer, omdat de tumor al uitgezaaid is, of te gro...

  11. 177Lu-octreotate in Neuroendocrine Tumors: Treatment Effects

    E.I. van Vliet (Esther)

    2013-01-01

    textabstractNeuroendocriene tumoren (NETs) zijn zeer zeldzame tumoren, die ontstaan vanuit neuroendocriene cellen in het lichaam. Deze tumoren produceren vaak hormonen en hormoonachtige stoffen. NETs ontstaan meestal in het maag-darm kanaal, in de alvleesklier, of in de longen. Jaarlijks komen er in

  12. Excretion of radionuclides in human breast milk following administration of 125I-fibrinogen, 99Tc/sup m/-MAA and 51Cr-EDTA

    Very few biokinetic and dosimetric data for estimating the absorbed dose to a breast-feeding child are available in the literature. The few available are usually case reports. We have measured the activity concentration in breast milk from one patient after administration of 125I-fibrinogen, from two patients after administration of 99Tc/sup m/-macroaggregated albumin, and from one patient after administration of 51Cr-EDTA. We have compared our data with earlier published results and estimated the absorbed dose to the breast-feeding child using biokinetic data presented in this work and recently published S-values for new-born children

  13. Mean retention time of 51Cr-EDTA and 103Ru-phenanthroline in the digestive tract of sheep and bulls after feeding on straw pellets

    Two lots of straw pellets (supplemented with 10% molasses), produced either with a 5 mm sieve in a hammer mill (lot A) or with a 12 mm sieve (lot B) from wheat straw, were tested with 4 sheep (wethers, average live weight 43 kg) and 4 bulls (average live weight 170 kg). After carrying out a digestibility experiment, the mean retention time, the 80% excretion of the markers and the transit time were ascertained with the help of 51Cr-EDTA and 103Ru-phenanthroline. The digestibility of carbohydrates (both crude fiber and N-free extractives) was significantly higher for the bulls than for the sheep. (author)

  14. Glomerular filtration rate measured by 51Cr-EDTA clearance: evaluation of captopril-induced changes in hypertensive patients with and without renal artery stenosis

    Anna Alice Rolim Chaves

    2010-01-01

    Full Text Available INTRODUCTION: Renal artery stenosis can lead to renovascular hypertension; however, the detection of stenosis alone does not guarantee the presence of renovascular hypertension. Renovascular hypertension depends on activation of the renin-angiotensin system, which can be detected by functional tests such as captopril renal scintigraphy. A method that allows direct measurement of the baseline and post-captopril glomerular filtration rate using chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA could add valuable information to the investigation of hypertensive patients with renal artery stenosis. The purposes of this study were to create a protocol to measure the baseline and post-captopril glomerular filtration rate using 51Cr-EDTA, and to verify whether changes in the glomerular filtration rate permit differentiation between hypertensive patients with and without renal artery stenosis. METHODS: This prospective study included 41 consecutive patients with poorly controlled severe hypertension. All patients had undergone a radiological investigation of renal artery stenosis within the month prior to their inclusion. The patients were divided into two groups: patients with (n=21 and without renal artery stenosis, (n=20. In vitro glomerular filtration rate analysis (51Cr-EDTA and 99mTc-DMSA scintigraphy were performed before and after captopril administration in all patients. RESULTS: The mean baseline glomerular filtration rate was 48.6±21.8 ml/kg/1.73 m² in the group wuth renal artery stenosis, which was significantly lower than the GFR of 65.1±28.7 ml/kg/1.73m² in the group without renal artery stenosis (p=0.04. Captopril induced a significant reduction of the glomerular filtration rate in the group with renal artery stenosis (to 32.6±14.8 ml/kg/1.73m², p=0.001 and an insignificant change in the group without RAS (to 62.2±23.6 ml/kg/1.73m², p=0.68. Scintigraphy with technetium-99m dimercapto-succinic acid (DMSA did not show

  15. Glomerular filtration rate measured by {sup 51}Cr-EDTA clearance: evaluation of captopril-induced changes in hypertensive patients with and without renal artery stenosis

    Chaves, Anna Alice Rolim; Buchpiguel, Carlos Alberto; Praxedes, Jose Nery; Bortolotto, Luiz Aparecido; Sapienza, Marcelo Tatit, E-mail: annaalice100@yahoo.com.b [Universidade de Sao Paulo (USP), SP (Brazil). Faculdade de Medicina. Dept. de Neurologia

    2010-07-01

    Introduction: renal artery stenosis can lead to renovascular hypertension; however, the detection of stenosis alone does not guarantee the presence of renovascular hypertension. Renovascular hypertension depends on activation of the renin-angiotensin system, which can be detected by functional tests such as captopril renal scintigraphy. A method that allows direct measurement of the baseline and post-captopril glomerular filtration rate using chromium-51 labeled ethylenediamine tetraacetic acid ({sup 51}Cr-EDTA) could add valuable information to the investigation of hypertensive patients with renal artery stenosis. The purposes of this study were to create a protocol to measure the baseline and post-captopril glomerular filtration rate using {sup 51}Cr-EDTA, and to verify whether changes in the glomerular filtration rate permit differentiation between hypertensive patients with and without renal artery stenosis. Methods: this prospective study included 41 consecutive patients with poorly controlled severe hypertension. All patients had undergone a radiological investigation of renal artery stenosis within the month prior to their inclusion. The patients were divided into two groups: patients with (n=21) and without renal artery stenosis, (n=20). In vitro glomerular filtration rate analysis ({sup 51}Cr-EDTA) and {sup 99m}Tc-DMSA scintigraphy were performed before and after captopril administration in all patients. Results: the mean baseline glomerular filtration rate was 48.6+-21.8 ml/kg/1.73 m{sup 2} in the group with renal artery stenosis, which was significantly lower than the GFR of 65.1+-28.7 ml/kg/1.73m{sup 2} in the group without renal artery stenosis (p=0.04). Captopril induced a significant reduction of the glomerular filtration rate in the group with renal artery stenosis (to 32.6+-14.8 ml/kg/1.73m{sup 2}, p=0.001) and an insignificant change in the group without RAS (to 62.2+-23.6 ml/kg/1.73m{sup 2}, p=0.68). Scintigraphy with technetium-99m dimercapto

  16. Magnetic thermal hysteresis due to paramagnetic-antiferromagnetic transition in Fe-24.4Mn-5.9Si-5.1Cr alloy

    L. Wang

    2013-08-01

    Full Text Available Magnetic thermal hysteresis (MTH associated with a paramagnetic (PM-antiferromagnetic (AFM phase transition was found in an Fe-24.4Mn-5.9Si-5.1Cr shape-memory alloy. Aside from the magnetic field (H, the driving rate (v can also tune the critical temperature of the magnetic transition and cause an increase in MTH. The magnetic phase diagram obtained is discussed. The equation for MTH was deduced based on the Landau model for a PM-AFM transition that includes H and v dependence, which gives a reasonable account of the experimental results.

  17. Feasibility of the instrumental neutron activation analysis of entire archaeological pottery. Part 1: Precision of the results and radiological safety of the process

    The feasibility of the instrumental neutron activation analysis of entire pieces of archaeological pottery, using low thermal neutron fluxes, is examined. The study takes into account the chemical elements relevant for archaeological investigations, as well as the degree of accuracy required for such kind of research. It is shown that after irradiation of a typical pottery sample of about 1 kg during 45 minutes, at a thermal flux of about 109 n.cm-2.s-1, analytical signals are obtained, by gamma spectrometry, with counting statistics better than 1%, for 76As, 131Ba, 141Ce, 60Co, 134Cs, 181Hf, 140La, 24Na, 122Sb, 46Sc, 153Sm and 233Pa, whereas 51Cr, 152Eu, 42K, 86Rb, 175Yb and 65Zn can be detected with counting statistics within 1% and 2%. On the other hand, the statistics of measurement are relatively poor (orders of 3% - 10%) for 177Lu, 147Nd, 239Np, 160Tb and 181Ta. The feasibility of accomplishment reliable quantitative determinations, taking into account the complexity of the analysis of entire pieces of archaeological pottery is discussed, which involves factors such as high masses, as well as asymmetric and variable shapes. (orig.)

  18. Bioelimination of 51Cr and 85Sr by cockroaches, Gromphadorhina portentosa (orthoptera: blaberidae), as affected by mites, Gromphadorholaelaps schaeferi (parasitiformes: laelapidae)

    The rates of Chromium-51 and Strontium-85 assimilation and bioelimination by the hissing cockroach, Gromphadorhina portentosa (Schaum) are described when the symbiotic mite, Gromphadorholaelaps schaeferi Till, was present or removed. Mite-infested cockroaches had significantly higher rates of 51Cr elimination relative to mite-free cockroaches, implying more rapid gut clearance times. The authors did not find a significant mite effect on 85Sr elimination by the host, but mite effects could have been masked by the apparently unique process of nutrient assimilation and elimination by G. portentosa. Conventional models of radioactive tracer bioelimination predict a rapid initial loss of tracer due to gut clearance, followed by a slower loss due to excretion of assimilated tracer. The results indicated that assimilated 85Sr was eliminated earlier than unassimilated 85Sr, which was lost by defecation

  19. Bioelimination of 51Cr and 85Sr by cockroaches, Gromphadorhina portentosa (Orthoptera: Blaberidae), as affected by mites, Gromphadorholaelaps schaeferi (parasitiformes: laelapidae)

    This paper describes rates of Chromium-51 and Strontium-85 assimilation and bioelimination by the hissing cockroach, Gromphadorhina portentosa (Schaum), when the symbiotic mite, Gromphadorholaelaps schaeferi Till, was present or removed. Mite-infested cockroaches had significantly higher rates of 51Cr elimination relative to mite-free cockroaches, implying more rapid gut clearance times. We did not find a significant mite effect on 85Sr elimination by the host, but mite effects could have been masked by the apparently unique process of nutrient assimilation and elimination by G. portentosa. Conventional models of radioactive tracer bioelimination predict a rapid initial loss of tracer due to gut clearance, followed by a slower loss due to excretion of assimilated tracer. Our results indicated that assimilated 85Sr was eliminated earlier than unassimilated 85Sr was lost by defecation

  20. Levels of chromium contamination in the estuary of the Iraja river (Guanabara Bay) and experimental incorporation of 51Cr in barnacles (Balanus sp)

    Levels were determined of chromium contamination in the estuary of Iraja River, produced by an electroplating industry located 3 km upstream the study area. Uptake-and release kinetics of Cr(VI) and Cr(III) in barnacles (Balanus sp.) were studied. Samples of barnacles and suspended particles from Guanabara Bay were analysed. Chromium concentrations (dry weight) ranged from not detectable (ND) to 154,66 μg/g for soft tissues and from ND to 423,76 μg/g for suspended particles. Mean of maximum concentrations of chromium in samples from Guanabara Bay are 3 and 4 times above those of identical samples from control area (Coroa Grande). Soft tissues presented a concentration factor (CF) of 103 related to chromium available in suspended particles. 51Cr(VI) is preferentiably incorparated by soft tissues (biological half life being 100 days). Chromium uptake by Balanus sp from solution is as significant as it is from particulate matter available in sea water from experimental sets. CF for Cr(VI) in soft tissues in laboratory conditions was 102 related to 51Cr present in sea water. Environmental chromium contamination was found to be of the same order of magnitude or above levels reported for other areas subjected to industrial impacts. Barnacles appear to be able to accumulate chromium in soft tissues from the available metal in the environment. Cr(VI) is the critical form, being greatly accumulated in soft tissues of barnacles, that act as a long-term integrator of this metal. For Cr(III), this organism can only be regarded as an instantaneous indicator of environmental contamination of chromium attached to suspended particles. (M.A.)

  1. Radiokinetic study on nucleation process of 65Zn(OH)2, 65Zn3(PO4)2 and 51CrPO4 crystals in gelatin and agar

    Cecal, Al; Palamaru, M.; Chisca, S.; Balan, A.

    1999-01-01

    The nucleation process of 65Zn(OH)2, 65Zn3(PO4)2, and 51CrPO4 crystals in gelatin and agar was studied by using radioactive tracers. The diffusion rate, constants for 65Zn2+ and 51Cr3+ cations through gel, and the reaction rate constants of nucleation process as well as the beginning time of crystal appearance were established. It was found that the reaction rate constant of the low-soluble crystal is higher, and consequently, in a given colloidal medium this parameter varies as follows: k * Zn(PO4)2> k * Zn(OH) 2> k * CrPO 4

  2. What method to use for the renal clearance with {sup 51}Cr-E.D.T.A.: retrospective study among 1157 adults and 286 children; Quelle methode de mesure utiliser pour la clairance renale au 51Cr-EDTA: etude retrospective chez 1157 adultes et 286 enfants

    Lacoeuille, F.; Machefert, N.; Vervueren, L.; Berthelot, C.; Rakotonirina, H.; Le Jeune, J.J.; Couturier, O. [CHU d' Angers, Service de medecine nucleaire, 49 (France); Drablier, G.; Cahouet-Vannier, A. [CHU d' Angers, Service de pharmacie, 49 (France); Denizot, B. [CH Annemasse, service de medecine nucleaire, 74 (France)

    2010-07-01

    Purpose: in the objective to make our practices evolve and to limit the numbers of sampling for patients, we searched to determine if the methods used (4,2 or 1 sampling) to measure the renal clearance to {sup 51}Cr-EDTA give results comparable on the population of patients concerned by this examination. Conclusions: This study allowed to enlighten interchangeability between the four points and two points method for the population studied. It allows to consider a change in our practice for the profit of a two points methods. (N.C.)

  3. Cross sections of the 56Fe(n ,α ) 53Cr and 54Fe(n ,α ) 51Cr reactions in the MeV region

    Wang, Zhimin; Fan, Xiao; Zhang, Luyu; Bai, Huaiyong; Chen, Jinxiang; Zhang, Guohui; Gledenov, Yu. M.; Sedysheva, M. V.; Krupa, L.; Khuukhenkhuu, G.

    2015-10-01

    Cross sections of the 56Fe(n ,α ) 53Cr and 54Fe(n ,α )51Cr reactions were measured at En=5.5 and 6.5 MeV and En=4.0 ,4.5 ,5.5 ,and 6.5 MeV , respectively, using a double-section gridded ionization chamber as the α -particle detector. Natural iron and enriched 56Fe and 54Fe foil samples were prepared. A deuterium gas target was used to produce monoenergetic neutrons through the 2H(d ,n )3He reaction. Two rounds of experiments were performed at the 4.5-MV Van de Graaff Accelerator of Peking University. The foreground and background were measured in separate runs. The neutron flux was monitored by a B F3 long counter, and the cross sections of the 238U(n ,f ) reaction were used as the standard. Present results are compared with those of the talys-1.6 code calculations, existing measurements, and evaluations.

  4. Arterio-venous concentration difference of [51Cr]EDTA after a single injection in man. Significance of renal function and local blood flow

    Rehling, M; Hyldstrup, Lars; Henriksen, Jens Henrik

    1989-01-01

    The present investigation was undertaken in order to study (1) the difference in arterial (Ca) and venous (Cv) concentration of [51Cr]EDTA (ethylenediaminetetraacetate) after a single intravenous injection, (2) the impact of different physiological variables on this difference, and (3) the error...... 180-300 min post-injection (p.i.) Cv was 5.9% higher than Ca (range 0.5-13.9%, P less than 0.001). The more reduced renal function, the smaller was the concentration difference. The areas under the arterial and the venous plasma concentration curves did not differ significantly at either 0-infinity or...... 0-300 min p.i. whereas the venous area 0-100 min p.i. underestimated the arterial area in the same period by 4.1% (P less than 0.05). In a computer simulation model, variation in the forearm capillary permeability-surface area product did not have any significant influence on the Cv-Ca difference...

  5. 51Cr - erythrocyte survival curves

    Sixteen patients were studied, being fifteen patients in hemolytic state, and a normal individual as a witness. The aim was to obtain better techniques for the analysis of the erythrocytes, survival curves, according to the recommendations of the International Committee of Hematology. It was used the radiochromatic method as a tracer. Previously a revisional study of the International Literature was made in its aspects inherent to the work in execution, rendering possible to establish comparisons and clarify phonomena observed in cur investigation. Several parameters were considered in this study, hindering both the exponential and the linear curves. The analysis of the survival curves of the erythrocytes in the studied group, revealed that the elution factor did not present a homogeneous answer quantitatively to all, though, the result of the analysis of these curves have been established, through listed programs in the electronic calculator. (Author)

  6. Determination of Glomerular Filtration Rate with 51Cr, 58Co, 114mIn, 115mIn and 169Yb- Labelled EDTA and DTPA Complexes

    Some metal complexes are suitable for determination of the glomerular filtration rate (GFR). A series of labelled EDTA and DTPA complexes have been produced during the last two years by the Isotope Institute of the Hungarian Academy of Sciences. The common property of EDTA and DTPA complexes is their great stability, which is a major advantage over the iodinated compounds. We have demonstrated that none of the complexes used by us combine with plasma proteins or penetrate into the red blood cells. There is evidence that EDTA and DTPA leave the body exclusively by way of glomerular filtration. The results of more than 600 cases are presented. 169Yb EDTA was used in 315, 51Cr EDTA in 126, 114mIn EDTA in 83, 58Co DTPA in 72 and 115mIn EDTA in 28 cases for determination of GFR. The injected activity was 0.3 -4.0 μCi/kg body weight. In most cases the result has been compared with the 24-h endogenous creatine clearance, and in 50 cases with inulin clearance also. In general the single-shot method was used. Blood samples were taken about the first and the second hour after injection of the isotope. A formula is given for calculating GFR. In a few cases we administered the isotope in the same way as inulin (priming dose and constant plasma concentration sustained by an infusion pump). Our results show that the single-shot method is a very suitable one in routine clinical practice either in states of normal or reduced kidney function. Using the single-shot method for GFR determination is especially important in those cases where the collection of urine is impossible without using a catheter, which always entails the risk of infection. Results are reliable even in disorders of the urinary tract. During or after the procedure no side effects could be observed. (author)

  7. In vitro cytotoxic effects of CTL activated by dendritic cells loaded with esophageal cancer antigen peptide by 51Cr release assay

    Objective: RIT plays an important role in the targeted therapy for tumors. The aim of the paper was to study cytotoxic effects of the cytotoxic T lymphocytes (CTL) to human esophageal cancer cell line TE-1, activated by dendritic cells (DC) loaded with esophageal cancer antigen peptide. Methods: Esophageal cancer TE-1 cell antigen peptide was obtained by citrate phosphate buffer elution. DC were induced and proliferated in vitro and were loaded with the esophageal cancer antigen peptide. The tumor antigen specific CTL were generated from the DC. And the cytotoxicity of CTL to TE-1 was assessed by 51Cr release assay. Results: The killing rate of CTL activated by loaded DC[(81.12±2.93)%] was higher than that of CTL activated by DC unloaded [(11.16±3.07)%]. The killing rate of CTL activated by loaded DC in TE-1 pretreated with interferon (IFN)-γ [(89.15±3.62)%] was higher than that in cells without IFN-γ [(61.19±5.17)%]. The killing rate of CTL was higher than that in TE-1 with acid elution [(9.18±2.52)%]. The killing rate of CTL activated by loaded DC diminished in order in Eta-109, human adenocarcinoma cell line K59 and human suprarenal epithelioma cell line 786-0. Conclusions: Acid elution could get effective esophageal cancer antigen peptide from TE-1 cell membrane. The CTL activated by DC loaded with that peptide had specific cytotoxic effects to TE-1 cells. (authors)

  8. A Clinical Study on the Development of a Simplified Fat Absorption Test by Simultaneous Administration 125I-triolein and Chromic Oxide (51Cr2O3)

    The conventional triolein absorption test has its defect in that the stool collection was cumbersome, time and energy-wasting. In the present study, the triolein absorption test was carried out using double tracer technique with 125I-triolein and 51Cr2O3 to determine if it can overcome the defect of the conventional method also with satisfactory results. Following were the results: 1) The clinical significance of this double tracer method was essentially the same with that previously done by radioactive triolein alone. With the fractional fecal samples, the equation, y=0.626 x+2.010 was substantiated, hence, this method appears to be clinically valuable if the appropriate correction is applied. With the mixed fecal samples, the equation y=0.642 x+1.468 was substantiated (p<0.005) which appears to be also clinically valuable. When these two data were compared, the equation y=0.975 x+0.090 (p<0.05) was substantiated, hence, x≅y. 2) The normal ranges of the fecal triolein excretion rate in this double tracer method were 3.46±1.69%, namely, less than 6.9%. 3) The samplings were done from the first to third defecation in cases of clinically normal, and from the first to second defecation in cases of diarrhea of malabsorption. 4) The intestinal malabsorption of triolein was not observed in whom the triolein absorption was supposed to be clinically normal, however a good number of suspicious malabsorptive cases showed the normal values.

  9. Investigation of the neutron activation of endohedral rare earth metallofullerenes

    Endohedral lanthanide metallofullerenes and their water-soluble biocompatible derivatives have been synthesized. The effect that fast-neutron irradiation has on the stability and nuclear physical properties of endohedral metallofullerenes that are used as magnetocontrast materials (46Sc, 140La, 141Nd, 153Sm, 152Eu, 154Eu, 153Sm, 160Tb, 169Yb, 170Tm (isomers I and III), and 177Lu) is studied. Our hypothesis, according to which carbon-shell relaxation is based on the fast nonradiative processes of an electron shake-off type, is confirmed.

  10. Potential therapeutic agents for bone pain palliation: Sm-153 EDTMP and Lu-177 EDTMP and their comparison

    Full text: In a quest for more effective radiopharmaceutical for palliation of pain experienced by metastatic cancer patients, this article relates the results obtained with therapeutic beta emitter radionuclide of Lutetium-177 complexed to bone seeking phosphonate ligand of ethylenediamine tetramethylene phosphonic acid (EDTMP) and then its comparison with Samarium-153 labelled EDTMP. The objective of this study is to formulate and evaluate 177Lu- EDTMP for bone pain palliation and to compare it with 153Sm-EDTMP that is currently being used in many centers of the world. Materials and Methods: The radionuclide was prepared by n, . reaction. Quality control was checked by paper chromatography. Various parameters were optimized to formulate these radiopharmaceuticals with maximum labelling efficiency. Sprague-Dawley male rats were used for biodistribution and imaging study. Results: The labelling efficiency of 153Sm-EDTMP was found to be > 99% at pH 7.5 with 1:5 (Sm: EDTMP) molar ratio incubated for 20 minutes at room temperature. 177Lu- EDTMP showed that the complex can be prepared with radiochemical purity >95% using ligand: molar ratio from 20-30 at pH 7.5. Among biodistribution study for all these radiopharmaceuticals, skeletal uptake was found to be maximum for 177Lu-EDTMP (70±2.4%), followed by 153Sm-EDTMP ( 5 8 . 5 ± 2 . 8 % ) . B o t h t h e s e radiopharmaceuticals showed good renal and rapid blood clearance. The biodistribution study of free radionuclides showed significant uptake of activity by soft tissues including lungs, liver and spleen, with minimal uptake in the skeletal system (153SmCl3: 7.5±0.04%, 177LuCl3: 2.5±0.1%). Imaging study carried out for 153Sm-EDTMP and 177Lu-EDTMP showed good uptake of activity by the skeletal system (including epiphyses, spine and facial bones). Conclusion: It was concluded that labelled complexes of these lanthides can be used effectively in the therapy for bone pain palliation, having more potential for 177Lu

  11. Evaluation of renal function in rats: Renal clearance of 99mTc-DTPA underestimates glomerular filtration rate (GFR) as compared with renal clearance of eH-inulin or 51 CR-EDTA

    The rat is the most commonly used experimental animal and frequently being used to examine the pathophysiology in renal disease. Thus, it is important to apply techniques where renal function is assessed accurately. A special challenge exists in chronic unilateral renal disease for accurate measurement of single kidney GFR (SKGFR). We therefore examined the possibility of developing a method where SK GFR is measured in rats from the plasma clearance of 99mTc-DTPA and the reno graphically determined renal split function. A detailed comparison of renal clearance (Clr) and plasma clearance (Clp) of 99mTc-DTPA with that of 51-Cr-EDTA and 3H-inulin was performed in conscious rats with permanent catheters in the carotic artery, jugular vein and the urinary bladder using the following protocols: 1) Comparison of Clr of 99mTc-DTPA with 3H-inulin using a constant infusion clearance technique with four periods (P1-P4)(n=11), 2) comparison of Clr of 99m Tc-DTPA with that of 51Cr-EDTA or 3H-inulin (n=8) 3) comparison of Clr of 51Cr-EDTA and 3H-inulin using a constant infusion clearance technique with Clp of 99mTc-DTPA using a single injection technique with plasma sampling 4 hours after injection (n=11) and 4) comparison of Clp of 51Cr-EDTA with 99mTc-DTPA using the single injection technique (n=5). The results surprisingly showed that Clr of 99mTc-DTPA consistently was significantly lower than Clr of 51Cr-EDTA (548±146 vs. 860±49 □1/min/100g (avg±std);p<0.01) and of 3H-inulin (548±146 vs. 975±135 □1/min/100g; p<0.01: Interestingly, Clr of 99mTc-DTPA was progressively reduced with time in contrast to a constant Clr of inulin (P1:693±108 vs 939±118; P2:591±94 vs 877±17, P3:594±74 vs 947±131; P4:569±78 vs 991±122). Furthermore, Clp of 99mTc-DTPA was significantly lower than Clp of 51Cr-EDTA (874±130 vs. 1092±43 □1/min/100g;p<(0.01). The average clearance ratio DTPA/EDTA using constant infusion was 0.65±0.15 and 0.80±0.15 after single injection. In

  12. Radiochemical stability of radiopharmaceutical preparations

    Martins, Patricia de A.; Silva, Jose L. da; Ramos, Marcelo P.S.; Oliveira, Ideli M. de; Felgueiras, Carlos F.; Herrerias, Rosana; Zapparoli Junior, Carlos L.; Mengatti, Jair; Fukumori, Neuza T.O.; Matsuda, Margareth M.N. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2011-07-01

    The 'in vitro' stability studies of the radiopharmaceutical preparations are an essential requirement for routine practice in nuclear medicine and are an important parameter for evaluating the quality, safety and efficacy required for the sanitary registration of pharmaceutical products. Several countries have published guidelines for the evaluation of pharmaceutical stability. In Brazil, the stability studies should be conducted according to the Guide for Conducting Stability Studies published in the Resolution-RE n. 1, of 29th July 2005. There are also for radiopharmaceutical products, two specific resolutions: RDC-63 regulates the Good Manufacturing Practices for Radiopharmaceuticals and RDC-64 provides the Registration of Radiopharmaceuticals, both published on the 18th December 2009. The radiopharmaceutical stability is defined as the time during which the radioisotope can be safely used for the intended purpose. The radiochemical stability can be affected by a variety of factors, including storage temperature, amount of radioactivity, radioactive concentration, presence or absence of antioxidants or other stabilizing agents. The radiochemical stability studies must be established under controlled conditions determined by the effective use of the product. The aim of this work was to evaluate the radiochemical stability of labeled molecules with {sup 131}I, {sup 123}I, {sup 153}Sm, {sup 18}F, {sup 51}Cr, {sup 177}Lu and {sup 111}In as well as {sup 67}Ga and {sup 201}Tl radiopharmaceuticals. Radiochemical purity was evaluated after production and in the validity period, with the maximum activity and in the recommended storage conditions. The analyses were carried out by thin-layer silica gel plate, paper chromatography and gel chromatography. The experimental results showed to be in accordance with the specified limits for all the analysed products. (author)

  13. Effect of background region of interest and time-interval selection on glomerular filtration ratio estimation by percentage dose uptake of (99m)Tc-DTPA in comparison with (51)Cr-EDTA clearance in healthy cats.

    Debruyn, Katrien; Vandermeulen, Eva; Saunders, Jimmy H; Dobbeleir, André A; Ham, Hamphrey R; Peremans, Kathelijne

    2013-08-01

    Evaluation of glomerular function is a useful part of the diagnostic approach in animals suspected of having renal disease. Time-interval and background region of interest (bg ROI) selection are determining factors when calculating the glomerular filtration ratio (GFR) based on percentage uptake of (99m)technetium-labelled diethylene triamine penta-acetic acid ((99m)Tc-DTPA). Therefore, three different time intervals (60-120 s, 120-180 s, 60-180 s) and three different bg ROIs (C-shape, caudolateral, cranial + caudal) were investigated. In addition, global GFRs based on percentage dose uptake of (99m)Tc-DTPA for the different time-intervals and bg ROIs were compared with the global GFR based on (51)chromium-ethylene diaminic tetra-acetic acid ((51)Cr-EDTA) plasma clearance in nine healthy European domestic shorthair cats. Paired Student's t-tests and linear regression analysis were used to analyse the data. Different time intervals seemed to cause significant variation (P <0.01) in absolute GFR values, regardless of the choice of bg ROI. Significant differences (P <0.01) between bg ROIs were only observed in the 120-180s time interval between the C-shape and cranial + caudal bg ROI, and between the caudolateral and cranial + caudal bg ROI. The caudolateral bg ROI in the 60-180 s time interval showed the highest correlation coefficient (r = 0.882) between (99m)Tc-DTPA and (51)Cr-EDTA, although a significant difference (P <0.05) was present between both techniques. PMID:23349527

  14. Development of therapeutic radiopharmaceuticals based on 177Lu for radionuclide therapy

    In operation since October 1966, the MU Research Reactor is the largest and highest power research reactor at a US university. The Center's fundamental mission is to provide quality nuclear research, education and services to the University, to the state of Missouri and to the global population. MURR is outstanding in its breadth of programs, steady source of neutrons for research and industrial applications and safe and reliable operations. The focus is on interdisciplinary R and D programs, centered largely in partnering MU departments, other universities, federal and industrial labs - programs that could not be conducted without the unique MURR facilities and personnel. The Center thus provides leverage for the expertise and talents resident in other departments and institutions, and a high priority is given to collaborative research programs in the life sciences, particularly those with potential to lead to breakthroughs in healthcare. The MURR Center supports the research of hundreds of faculty and students in dozens of disciplines and provides products and services that directly benefit the citizens of Missouri, as well as others throughout the world. MURR's focus on interdisciplinary R and D contributes to MU's educational mission, providing rich research and training opportunities for an international population of graduate and undergraduate students. MURR-based projects cover such disciplines as anthropology and archaeology, chemistry, engineering (chemical, electrical, mechanical and nuclear), geology, materials science, medical and life sciences (including cancer diagnostics, treatment and prevention), nutrition, physics and veterinary medicine. In 2003, MURR supported the research of some 200 faculty and graduate students representing nearly 70 departments at more than 65 academic, federal and industrial labs. In 2003 students conducting thesis research at MURR earned eight doctoral, 10 master's and two bachelor's degrees, and an additional 60 doctoral, 11 master's and 14 bachelor's degree candidates from 20 universities conducted research at MURR relating to their course work. MURR is a vital component of two recently established institutes at MU, the Nuclear Science and Engineering Institute (NSEI) and the Radiopharmaceutical Sciences Institute (RSI). Both of these institutes involve partnering to share key resources, programmatic interests and goals to provide innovative solutions that address real-life scenarios

  15. Radiolabeling of trastuzumab with 177Lu via DOTA, a new radiopharmaceutical for radioimmunotherapy of breast cancer

    Aim: Trastuzumab is a monoclonal antibody that is used in treating breast cancer. We labeled this monoclonal antibody with lutetium-177 and performed in vitro quality control tests as a first step in the production of a new radiopharmaceutical. Material and Methods: Trastuzumab was labeled with lutetium-177 using DOTA as chelator. Radiochemical purity and stability in buffer and human blood serum were determined using thin layer chromatography. Immunoreactivity and toxicity of the complex were tested on MCF7 breast cancer cell line. Results: The radiochemical purity of the complex was 96±0.9%. The stabilities in phosphate buffer and in human blood serum at 96 h postpreparation were 93±1.2% and 85±3.5%, respectively. The immunoreactivity of the complex was 89±1.4%. At a concentration of 1 nM, the complex killed 70±3% of MCF7 cells. At 1.9 nM, 90±5% of the cells were killed. Conclusions: The results showed that the new complex could be considered for further evaluation in animals and possibly in humans as a new radiopharmaceutical for use in radioimmunotherapy against breast cancer.

  16. Evaluation of 177Lu-nimotuzumab for Targeted Radioimmunotherapy of EGFR Expressing Tumors

    Beckford, Denis R.; Balogh, L.; Postenyi, Z.; Mathe, D.; Eigner, Sebastian; Eigner-Henke, Kateřina; Montana, R. L.; Melichar, František

    2012-01-01

    Roč. 39, P0089 (2012), S327-S327. ISSN 1619-7070. [25th Annual Congress of the European-Association-of-Nucelar Medicine. 27.10.2012-31.10.2012, Milan] Institutional support: RVO:61389005 Keywords : radiotherapy * tumor treatment Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders

  17. Production of {sup 177}Lu, a potential radionuclide for diagnostic and therapeutic applications

    Khandaker, Mayeen Uddin; Kassim, Hasan Abu [Department of Physics, University of Malaya, 50603 Kuala Lumpur (Malaysia); Haba, Hiromitsu [Nishina Center for Accelerator-Based Science, RIKEN, Wako, Saitama 351-0198 (Japan)

    2015-04-24

    {sup 177g}Lu (T{sub 1/2}=6.647d; E{sub β{sup −max}}=498.3KeV, I{sub β{sup −total}}=100%; E{sub γ} = 112.9498 keV, I{sub γ} = 6.17%; E{sub γ} = 208.3662 keV, I {sub γ} = 10.36%) is widely used in many clinical procedures due to its excellent decay characteristics. Production cross-sections of the {sup nat}Yb(d,x){sup 177g}Lu reactions have been measured from a 24-MeV deuteron energy down to the threshold by using a stacked-foil activation technique combined with high resolution γ-ray spectrometry. An overall good agreement is found with some of the earlier measurements, whereas a partial agreement is obtained with the theoretical data extracted from the TENDL-2013 library. Physical thick target yield for the {sup 177g}Lu radionuclide was deduced using the measured cross-sections. The deduced yield curves indicate that a low energy (<11 MeV) cyclotron and a highly enriched {sup 176}Yb target could be used to obtain {sup 177g}Lu with negligible impurity from {sup 177m}Lu.

  18. Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: prognostic factors, incidence and course

    H. Bergsma (Hendrik); M. Konijnenberg (Mark); B.L.R. Kam (Boen L. R.); J.J.M. Teunissen (Jaap); P.P.M. Kooij (Peter); W.W. de Herder (Wouter); G. Franssen (Gaston); C.H.J. van Eijck (Casper); E.P. Krenning (Eric); D. Kwekkeboom (Dik)

    2016-01-01

    textabstractPurpose: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from 131I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients t

  19. Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

    Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 (32P), strontium-89 (89Sr), yttrium-90 (90Y ), tin-117 (117mSn), samarium-153 (153Sm), holmium-166 (166Ho), thulium-170 (170Tm), lutetium-177 (177Lu), rhenium-186 (186Re), rhenium-188 (188Re), and radium-223 (223Ra). Results: 223Ra alpha particles, 177Lu beta minus particles, and 170Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by 89Sr and 153Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than 177Lu beta minus particles and 223Ra alpha particles. Conclusions: 223Ra and 177Lu hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing

  20. Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

    Guerra Liberal, Francisco D. C., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S., E-mail: tavares@fe.up.pt [Instituto de Engenharia Mecânica e Gestão Industrial, Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias s/n, Porto 4200-465 (Portugal)

    2014-11-01

    Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all

  1. In vivo comparative study of hydroxyapatite labeled with different radioisotopes: evaluation of the scintigraphic images

    Couto, Renata Martinussi; Barboza, Marycel Figols de; Souza, Adriano Aparecido de; Muramoto, Emiko; Mengatti, Jair; Araujo, Elaine Bortoleti de, E-mail: rmcouto@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Radiofarmacia

    2008-07-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints that is characterized by the inflammation and proliferation of synovial tissues. Approximately 3% of the adult population in the world is affected by this disease which causes pain, joint immobility and disability. Adyo synovectomy (RSV) is a radiotherapeutic modality where a b--emitting radionuclide is administered locally by intra-articular inje