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Sample records for no-carrier added 177lu

  1. An electro-amalgamation approach to isolate no-carrier-added 177Lu from neutron irradiated Yb for biomedical applications

    International Nuclear Information System (INIS)

    Chakravarty, Rubel; Das, Tapas; Dash, Ashutosh; Venkatesh, Meera

    2010-01-01

    Introduction: A novel two-step separation process for the production of no-carrier-added (NCA) 177 Lu from neutron irradiated Yb target through an electrochemical pathway employing mercury-pool cathode has been developed. Methods: A two-cycle electrolysis procedure was adopted for separation of 177 Lu from 177 Lu/Yb mixture in lithium citrate medium. The influence of different experimental parameters on the separation process was investigated and optimized for the quantitative deposition of Yb in presence of 177 Lu. The first electrolysis was performed for 50 min in the 177 Lu/Yb feed solution at pH 6 applying a potential of 8 V using platinum electrode as anode and mercury as the cathode. The second electrolysis was performed under the same conditions using fresh electrodes. The radionuclidic and chemical purity of 177 Lu was determined by using gamma ray spectrometry and atomic absorption spectrometry. The suitability of 177 Lu for biomedical applications was ascertained by labeling 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid D-Phe 1 -Tyr 3 -octreotate(DOTA-TATE) with 177 Lu. Results: This process could provide NCA 177 Lu with >99.99% radionuclidic purity and an overall separation yield of ∼99% was achieved within 3-4 h. The Hg content in the product was determined to be 98% was obtained with DOTA-TATE under the optimized reaction conditions. Conclusions: An efficient strategy for the separation of NCA 177 Lu, suitable for biomedical applications, has been developed.

  2. An electro-amalgamation approach to isolate no-carrier-added 177Lu from neutron irradiated Yb for biomedical applications.

    Science.gov (United States)

    Chakravarty, Rubel; Das, Tapas; Dash, Ashutosh; Venkatesh, Meera

    2010-10-01

    A novel two-step separation process for the production of no-carrier-added (NCA) (177)Lu from neutron irradiated Yb target through an electrochemical pathway employing mercury-pool cathode has been developed. A two-cycle electrolysis procedure was adopted for separation of (177)Lu from (177)Lu/Yb mixture in lithium citrate medium. The influence of different experimental parameters on the separation process was investigated and optimized for the quantitative deposition of Yb in presence of (177)Lu. The first electrolysis was performed for 50 min in the (177)Lu/Yb feed solution at pH 6 applying a potential of 8 V using platinum electrode as anode and mercury as the cathode. The second electrolysis was performed under the same conditions using fresh electrodes. The radionuclidic and chemical purity of (177)Lu was determined by using gamma ray spectrometry and atomic absorption spectrometry. The suitability of (177)Lu for biomedical applications was ascertained by labeling 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid D-Phe(1)-Tyr(3)-octreotate(DOTA-TATE) with (177)Lu. This process could provide NCA (177)Lu with >99.99% radionuclidic purity and an overall separation yield of ∼99% was achieved within 3-4 h. The Hg content in the product was determined to be 98% was obtained with DOTA-TATE under the optimized reaction conditions. An efficient strategy for the separation of NCA (177)Lu, suitable for biomedical applications, has been developed. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. An electro-amalgamation approach to isolate no-carrier-added {sup 177}Lu from neutron irradiated Yb for biomedical applications

    Energy Technology Data Exchange (ETDEWEB)

    Chakravarty, Rubel; Das, Tapas [Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085 (India); Dash, Ashutosh, E-mail: adash@barc.gov.i [Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085 (India); Venkatesh, Meera [Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085 (India)

    2010-10-15

    Introduction: A novel two-step separation process for the production of no-carrier-added (NCA) {sup 177}Lu from neutron irradiated Yb target through an electrochemical pathway employing mercury-pool cathode has been developed. Methods: A two-cycle electrolysis procedure was adopted for separation of {sup 177}Lu from {sup 177}Lu/Yb mixture in lithium citrate medium. The influence of different experimental parameters on the separation process was investigated and optimized for the quantitative deposition of Yb in presence of {sup 177}Lu. The first electrolysis was performed for 50 min in the {sup 177}Lu/Yb feed solution at pH 6 applying a potential of 8 V using platinum electrode as anode and mercury as the cathode. The second electrolysis was performed under the same conditions using fresh electrodes. The radionuclidic and chemical purity of {sup 177}Lu was determined by using gamma ray spectrometry and atomic absorption spectrometry. The suitability of {sup 177}Lu for biomedical applications was ascertained by labeling 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid D-Phe{sup 1}-Tyr{sup 3}-octreotate(DOTA-TATE) with {sup 177}Lu. Results: This process could provide NCA {sup 177}Lu with >99.99% radionuclidic purity and an overall separation yield of {approx}99% was achieved within 3-4 h. The Hg content in the product was determined to be <1 ppm. Radiolabeling yield of >98% was obtained with DOTA-TATE under the optimized reaction conditions. Conclusions: An efficient strategy for the separation of NCA {sup 177}Lu, suitable for biomedical applications, has been developed.

  4. Production of non carrier added (n.c.a.) {sup 177}Lu for radiopharmaceutical applications

    Energy Technology Data Exchange (ETDEWEB)

    Barkhausen, Christoph

    2011-09-06

    The goal of this dissertation was the development of a process to produce non carrier added {sup 177}Lu at the FRM II. For this purpose, preparative chromatographic methods were evaluated and applied. The highest quality of the nuclide which could only be achieved through a complex chemical process, has been already been proven by clinical studies to be very advantageous. The process has been built up in a hot cell as a semi-automated process and is now being adapted to the requirements of the 'Arzneimittelgesetz' in order to establish n.c.a. {sup 177}Lu as a pharmaceutical product.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Production of no carrier added residue free /sup 22/Na

    Energy Technology Data Exchange (ETDEWEB)

    Britto, J L.Q. de; Bastos, M A.V.; Silva, R.F. da; Silva, A.G. da

    1988-05-02

    A method for the production of no carrier added and residue free /sup 22/Na, was developed via the /sup 24/Mg(d,..cap alpha..)/sup 22/Na nuclear reaction applying 14 MeV deuterons and a high current MG-Cu target. The yield for the reaction was measured and the chemical separation was performed using a Dowex 50WX8 resin in H/sup +/ form. The overall yield was higher than 98%. Residue could not be detected. All experiments were carried out at IEN's CV-28 cyclotron. (author) 13 refs.; 2 figs.

  7. The low-energy β(-) and electron emitter (161)Tb as an alternative to (177)Lu for targeted radionuclide therapy.

    Science.gov (United States)

    Lehenberger, Silvia; Barkhausen, Christoph; Cohrs, Susan; Fischer, Eliane; Grünberg, Jürgen; Hohn, Alexander; Köster, Ulli; Schibli, Roger; Türler, Andreas; Zhernosekov, Konstantin

    2011-08-01

    The low-energy β(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging. The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate. We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Automated production of no carrier added holmium-166

    International Nuclear Information System (INIS)

    Izard, M.E.; Dadchova, E.

    1996-01-01

    Full text: An automated system has been developed to produce no carrier added 166 Ho from the decay of 166 Dy produced by neutron activation of 164 Dy 2 O 3 . Targets consisting of 5-10 mg of 164 Dy 2 O 3 are irradiated in HIFAR at 5 x 10 13 n.s -1 .cm -2 for 12h then allowed to cool for 2 days. The irradiation can is then transferred to the automated system located in a 'hot' cell in the radiopharmaceutical research building. A two dimension robotic arm encompassing a grab and motorized screwdriver is used to open the irradiation can. A second arm carrying a teflon tube introduces 9M HCI into the can to dissolve the target. A second tube carries the dissolved target via a peristaltic pump to a heated vial where it is evaporated to dryness under a flow of N 2 . A Peltier cooled trap is used to prevent release of HCl fumes into the cell. A motorized syringe pump dispenses 1 mL of 0.1 M HNO 3 to redissolve the digest which is then transferred by peristaltic pump via a hollow fibre filter and auto injector into an Aminex- A5 HPLC column. 166 Dy is eluted from the column in 0.132 M α-HIBA into a heated cyclone flask and evaporated to dryness under a stream of N 2 heated to about 50 deg C. After two days the evaporated Dy/ 166 Ho digest is dissolved in another 1 mL of 0.1 M HNO 3 and injected onto the HPLC column. 166 Ho is collected in 20-25 mL of α-HIBA and evaporated to dryness as before at about 400 C to ensure complete decomposition of the α-HIBA. The product is finally dissolved in about I mL of 0.1 M HCI and pumped through a 0.22 μM filter to a product vial

  9. Production and Quality Control of 177Lu-Dotatate [177Lu-dota- try3]-Octreotate: Clinical Application

    International Nuclear Information System (INIS)

    Barboza, M.F. de; Herrerias, R.; Souza, A.A. de; Pereira, G.; Pires, J.A.; Fukumori, N.T.O.; Matsuda, M.M.N.; Almeida, E.V.; Mengatti, J.; Belfer, A.J.; Hilario, L.N.

    2009-01-01

    -CNEN/SP. The process was developed and validated in a 'hot-cell' under cGMP conditions. Materials and Methods: The labeling was performed in a 'hot-cell' with 177 LuCl3 (Lutetium trichloride) and peptide (0.4 mg DOTATATE; 42 mg gentisic acid and 210 mg ascorbic acid/mL sodium acetate buffer pH 4.5) from IDB-The Netherlands, using peptide:radionuclide molar relation 2:1, at 82-83 o C for 30 minutes. After cooling, 1 mL of DTPA solution (4 mg DTPA / 3 mL 0.9% NaCl) was added. The volume was completed until a desirable radioactive concentration (approximately 7,400 MBq/ mL) with 0.9% sodium chloride solution, under aseptic conditions and sterilized through 0.2 μm Millipore filter. The doses were fractioned according to demand in sterile vials. Quality Control: The radiochemical purity was determined by ITLC-SG (Instant thin Layer Chromatography-Silica Gel) in 0.1 mol/L sodium citrate, pH 5.5, as solvent. The labeled peptide has retention factor (R f ) of 0.1-0.2 and the free radionuclide migrates with the solvent front R f = 1.0. Radiochemical purity was also determined using C18 Sep-Pak cartridge (Waters, USA). The free radionuclide was eluted with 5 mL of 0.1 mol/L acetate buffer pH 5.5 and the labeled peptide with 5 mL of methanol. The HPLC (High Performance Liquid Chromatographic) system (LC 20AT Prominence) (Shimadzu, Japan) was composed by two pumps, autosampler, system controller and radiometric detector (Bioscan). The analysis was performed at room temperature with a Shim-Pack VP-ODS column (250 x 4.6 mm, 5 μm). A 10 μL sample volume was injected and 1.0 mL/min flow rate was applied. The gradient consisted of a mixture of acetonitrile and water with 0.1% trifluroacetic acid (TFA) for 30 minutes. Each sample was analyzed in triplicate. The stability of the final product was evaluated by ITLC-SG immediately, after 24 and 72 hours under refrigeration. Sterility and pyrogen tests were performed by the microbiology procedures in different culture media and the 'in

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

    International Nuclear Information System (INIS)

    Dah, Ashutosh; Pillai, Maroor Raghavan Ambikalmajan; Knapp, Furn F. Jr.

    2015-01-01

    This review provides a comprehensive summary of the production of 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 177 Lu having the required quality for preparation of a variety of 177 Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of 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 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 177 Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of 177 Lu-labeled radiopharmaceuticals, but also help future developments

  11. Study of the production of 177Lu through 176Yb (n, γ) 177Yb → 177Lu nuclear reaction

    International Nuclear Information System (INIS)

    Silva, Giovana Pasqualini da; Osso Junior, Joao Alberto

    2007-01-01

    The beta minus emitter 177 Lu is a promising therapeutic radioisotope for the curative treatment of cancer using labelled proteins. It has a half - life of T 1/2 = 6.71 day and maximum and average β - energies of 421 and 133 keV, resulting in a short range of radiation in tissue. The decay is accompanied by the emission of low energy γ-radiation with 208.3 keV (11%) and 113 keV (6.4%) suitable for simultaneous imaging, 177 Lu can be produced by two different routes, namely, by irradiation of natural Lu 2 O 3 target ( 176 Lu, 2.6%) or enriched (in 176 Lu) Lu 2 O 3 target, as also by irradiation of Yb target (Yb 2 O 3 ) followed by radiochemical separation of 177 Lu from Yb isotopes. The objective of this work is to study the production of 177 Lu through the indirect 176 Yb(n,γ) 177 Yb → 177 Lu nuclear reaction. The results of the production yield of 177 Lu will be shown and compared with the direct reaction. The method of choice for the chemical separation between Lu and Yb was the ion exchange, using an cation exchange resin in Cl - form and α-HIBA as eluent. Preliminary results showed a good separation of 177 Lu from Yb 2 O 3 indirect targets. (author)

  12. Blood clearance and occupational exposure for {sup 177}Lu-DOTATATE compared to {sup 177}Lu-PSMA radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Abuqbeitah, Mohammad; Demir, Mustafa; Uslu-Besli, Lebriz; Yeyin, Nami; Soenmezoglu, Kerim [Istanbul University, Department of Nuclear Medicine, Cerrahpasa Faculty of Medicine, Istanbul (Turkey)

    2018-03-15

    The main target of this work is to examine blood clearance and external exposure for {sup 177}Lu-DOTATATE compared with new emerging {sup 177}Lu-PSMA therapy. Blood clearance and radiation exposure of 31 patients treated with 5.5 ± 1.1 GBq {sup 177}Lu-DOTATATE were compared to those of 23 patients treated with 7.4 GBq {sup 177}Lu-PSMA. Dose rates were measured at several distances and time points up to 120 h after treatment. Blood samples were collected conjunctively after infusion. Caregiver's cumulative dose was measured by means of an OSL (optically stimulated luminescence) dosimeter for 4-5 days and medical staff's dose was also estimated using electronic personal dosimeters. Finger dose was determined via ring TLD (Thermoluminescence Dosimeter) for radiopharmacists and nurses. Dose rates due to {sup 177}Lu-DOTATATE at a distance of 1 m, 4 h and 6 h after infusion, were 3.0 ± 2.8 and 2 ± 1.9 μSv/(h GBq), respectively, while those due to {sup 177}Lu-PSMA were 3.1 ± 0.8 and 2.2 ± 0.9 μSv/(h GBq). Total effective dose of 17 caregivers was 100-200 μSv for {sup 177}Lu-DOTATATE therapy. Mean effective doses to nurses and radiopharmacists were 5 and 4 μSv per patient, respectively, while those for physicists and physicians were 2 μSv per patient. For {sup 177}Lu-DOTATATE, effective half-life in blood and early elimination phase were 0.31 ± 0.13 and 4.5 ± 1 h, while they were found as 0.4 ± 0.1 and 5 ± 1 h, respectively, for {sup 177}Lu-PSMA. The first micturition time following {sup 177}Lu-DOTATATE infusion was noted after 36 ± 14 min, while the second and third voiding times were after 74 ± 9 and 128 ± 41 min, respectively. It is concluded that blood clearance and radiation exposure for {sup 177}Lu-DOTATATE are very similar to those for {sup 177}Lu-PSMA, and both treatment modalities are reasonably reliable for outpatient treatment, since the mean dose rate [2.1 μSv/(h GBq)] decreased below the dose rate that allows release of the patient

  13. Tumoral fibrosis effect on the radiation absorbed dose of 177Lu-Tyr3-octreotate-gold nanoparticles and 177Lu-Tyr3-octreotate radiopharmaceuticals

    International Nuclear Information System (INIS)

    Zambrano R, O. D.

    2015-01-01

    was added some of the most relevant Auger and internal conversion electron emissions. On the other hand, an experimental array was used to simulate the presence or absence of fibrosis in a tumor of malignant cells (HeLa cells). With this model the retention of the radiopharmaceuticals 177 Lu-Tyr 3 -octreotate-gold nanoparticles (multimeric system) and 177 Lu-Tyr 3 -octreotate (monomeric system) in the micro environments (without fibrosis and with fibrosis) was determined. The experimental tumoral fibrosis array consists of a multilayer repetitive patter of HeLa cells, collagen and gelatin until completing a culture (in a trans well insert) layer by layer (Lbl) of five coatings of HeLa cells. The Lbl cultures were exposed during 24 h, approximate duplicating time of HeLa cells, separately to: 177 LuCl 3 , 177 Lu-Tyr 3 -octreotate, and 177 Lu-Tyr 3 -octreotate-gold nanoparticles with an initial activity of 26 MBq (700 μCi). The radiopharmaceutical retention was calculated by measuring the retained activity in the trans well inserts (radiopharmaceutical retained by HeLa cells and microenvironment) and in the lower chamber where the radiopharmaceutical permeated. The experimental models were essential to determine the radiopharmaceutical permeability which allowed the calculation of the retained activity fraction, and hence the cumulated activity in regions of interest for each of the different cases. This is needed at the same time for the radiation absorbed dose calculation. In this work it was concluded that the presence or absence of fibrosis and yet more, the multimeric and multivalent nature of the radiopharmaceutical had an effect on the radiation absorbed dose in the cell nucleus and in the tumor microenvironment. (Author)

  14. Carrier-added and no-carrier-added syntheses of [18F]spiroperidol and [18F]haloperidol

    International Nuclear Information System (INIS)

    Kilbourn, M.R.; Welch, M.J.; Dence, C.S.; Tewson, T.J.; Saji, H.; Maeda, M.

    1984-01-01

    Syntheses of [ 18 F]haloperidol and [ 18 F]spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added [ 18 F]butyrophenone neuroleptics were prepared in low ( 18 F-neuroleptics were prepared in better (5-17%) yields by 18 F-for- 19 F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described. (author)

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

    International Nuclear Information System (INIS)

    Liang Jixin; Li Hongyu; Xiang Xueqin; Luo Zhifu; Luo Hongyi; Hu Liansheng; Chen Yang; Zhuang Ling; Deng Xinrong

    2012-01-01

    The aim of this project is to evaluate the biodistribution of 177 Lu-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, 177 Lu-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. 177 Lu-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 177 Lu-DOTA-SP in the kidneys, indicating the excretion mainly by renal pathway. In addition, 177 Lu-DOTA-SP was washed out from the blood quickly. Bio- distribution of 177 Lu-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)

  16. The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC.

    Science.gov (United States)

    Schuchardt, Christiane; Kulkarni, Harshad R; Prasad, Vikas; Zachert, Carolin; Müller, Dirk; Baum, Richard P

    2013-01-01

    The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle.

  17. Evidence for inelastic neutron acceleration by the 177Lu isomer

    International Nuclear Information System (INIS)

    Roig, O.; Belier, G.; Meot, V.; Daugas, J.-M.; Abt, D.; Aupiais, J.; Jutier, Ch.; Petit, G. Le; Letourneau, A.; Marie, F.; Veyssiere, Ch.

    2006-01-01

    The neutron burnup cross section σ burnup m on the long-lived metastable state of 177 Lu has been measured from a specially designed isomeric target. The Maxwellian averaged cross section obtained for this reaction on 177 Lu m (J π =23/2 - ) is σ burnup m =626±45 b at the reactor temperature T=323 K. The difference between the burnup cross section and the previously measured capture cross section σ n,γ clearly shows a possible existence of 177 Lu m deexcitation via (n,n ' ) inelastic neutron acceleration channels. The results are interpreted in terms of a statistical approach using parameters from a deformed optical potential calculation

  18. Synthesis of no-carrier-added fluorine-18 2-fluoro-2-deoxy-d-glucose

    International Nuclear Information System (INIS)

    Tewson, T.J.

    1983-01-01

    A new synthetic procedure for the preparation of fluorine-18 2-fluoro-2-deoxy-glucose has been developed. This procedure offers the advantages of flexibility in the source of the fluorine-18, high yields, and short synthesis times. The procedure works at the no-carrier-added level and gives a product of very high specific activity

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

    International Nuclear Information System (INIS)

    Puerta Yepes, N.; Rojo, A.M.; Lopez Bularte, A.C.; Nevares, N.; Zapata, M.; Perez, J.H.; Crudo, J.

    2010-01-01

    DOTA-Substance-P (SP) and DOTA-minigastrin (His2-MG) labeled with 177 Lu 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 177 Lu-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 177 Lu-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

    International Nuclear Information System (INIS)

    Deng Xinrong; Luo Zhifu; Du Jin

    2010-01-01

    The labeling method for 177 Lu-DTPA-BIS-BIOTIN was established, and the biodistribution of 177 Lu-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 177 Lu-DTPA-BIS-BIOTIN is more than 99.0%. 177 Lu-DTPA-BIS-BIOTIN shows pretty good in vitro stability. The biodistribution of 177 Lu-DTPA-BIS-BIOTIN in normal mice shows a rapid blood clearance. The uptake of 177 Lu-DTPA-BIS-BIOTIN is mainly accumulated in liver, spleen and kidney. 177 Lu-DTPA-BIS-BIOTIN is excreted by kidney. The results provide the basis for further study on 177 Lu-DTPA-BIS-BIOTIN used in pretargeted radioimage and radiotherapy of cancer. (authors)

  1. 177Lu-DOTA-Bevacizumab: Radioimmunotherapy Agent for Melanoma.

    Science.gov (United States)

    Camacho, Ximena; Calzada, Victoria; Fernandez, Marcelo; Alonso, Omar; Chammas, Roger; Riva, Eloisa; Gambini, Juan Pablo; Cabral, Pablo

    2017-01-01

    Vascular endothelial growth factor (VEGF) is one of the classic factors to tumor-induced angiogenesis in several types, including melanoma. Bevacizumab is a humanized monoclonal antibody directed against VEGF. To radiolabel Bevacizumab with 177-Lutetium as a potential radioimmunotherapy agent for melanoma. Bevacizumab was derivatized with DOTA-NHS-ester at 4 ºC for 18 h. DOTABevacizumab was radiolabeled with 177LuCl3 (15 MBq/mg) at 37 ºC for 1 h. The studies were performed in healthy and B16F1 tumor-bearing C57BL/6J mice at 24 and 48 h (n = 5). Scinthigraphic imaging studies were performed at 24 h to determine the radiochemical stability, targeting specificity and pharmacokinetics of the 177Lutetium-labeled antibody. DOTA-Bevacizumab was efficiently labeled with 177LuCl3 at 37 °C. The in-vitro stability of labeled product was optimal over 72 h. In-vivo biodistribution studies showed a high liver and tumor uptake of 177Lu-DOTA-Bevacizumab, with tumor-to-muscle ratios of 11.58 and 6.37 at 24 and 48 h p.i. Scintigraphic imaging of melanoma tumor-bearing C57BL/6J mice showed liver and a high tumor selective uptake of 177Lu-DOTA-Bevacizumab at 24 h. Our results support the potential role of 177Lu-DOTA-Bevacizumab as a novel radioimmunotherapy agent for melanoma. We hope that these novel molecular imaging agents will open the path to new diagnostic and therapeutic strategies for Melanoma disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Species dependent studies of no-carrier-added 93mMo: A green method

    International Nuclear Information System (INIS)

    Mandal, Swadesh; Nayak, Dalia

    2010-01-01

    The present paper reports a combination of radioanalytical and green methodology for the ultra-trace scale speciation of molybdenum. The differential attitude of iron-doped calcium alginate (Fe-CA) and chitosan biopolymers towards no-carrier-added 93m Mo radionuclide was studied to develop environmentally sustainable speciation methodology in ultra-trace scale. The affinity of 93m Mo towards the Fe-CA beads is greater than that of chitosan. Species information was obtained by comparing the adsorption profile of 93m Mo on Fe-CA and chitosan biopolymer with the software code CHEAQS PRO program. From the experimental results it is concluded that no-carrier-added 93m Mo radionuclide form mononuclear species instead of polynuclear species in aqueous solution. Use of biodegradable, non-toxic biopolymer makes this method a step forward towards green chemistry.

  3. An 131I iodotamoxifen: no carrier added iodination via a diazonium salt

    International Nuclear Information System (INIS)

    Hunter, D.H.; Strickland, L.A.

    1986-01-01

    An 131 I-labeled iodotamoxifen has been prepared by a ''no carrier added'' procedure in a 40% radiochemical yield via an aryl diazonium ion salt intermediate. Two approaches were used to produce high specific activity iodotamoxifen: nonaqueous solvents and copper catalysis. The use of the nonaqueous solvent acetonitrile has proved successful while neither copper powder, copper-bronze, copper(I)oxide nor Cu(II) sulphate showed any catalytic effects. (author)

  4. Synthesis of no-carrier-added L- and D-[1-11C]-DOPA

    International Nuclear Information System (INIS)

    Bolster, J.M.; Vaalburg, W.; Veen, W. van; Dijk, Th. van; Molen, H.D. van der; Wynberg, H.; Woldring, M.G.; Rijksuniversiteit Groningen

    1983-01-01

    No-carrier-added DL-[1- 11 C]-DOPA has been synthesized by carboxylation of an α-lithioisocyanide with a radiochemical yield of up to 15% without correction for decay. The total synthesis time is 30 min. The resolution of the D- and L-isomers was accomplished within 16 min by HPLC using a chiral stationary phase and a phosphate buffer of pH 4.5 as eluent. (author)

  5. No-carrier-added labeling of the neuroprotective Ebselen with selenium-73 and selenium-75.

    Science.gov (United States)

    Helfer, Andreas; Ermert, Johannes; Humpert, Sven; Coenen, Heinz H

    2015-03-01

    Selenium-73 is a positron emitting non-standard radionuclide, which is suitable for positron emission tomography. A copper-catalyzed reaction allowed no-carrier-added labeling of the anti-inflammatory seleno-organic compound Ebselen with (73) Se and (75) Se under addition of sulfur carrier in a one-step reaction. The new authentically labeled radioselenium molecule is thus available for preclinical evaluation and positron emission tomography studies. Copyright © 2015 John Wiley & Sons, Ltd.

  6. New syntheses of No-carrier-added 123I-labeled agents via organoborane chemistry

    International Nuclear Information System (INIS)

    Kabalka, G.W.

    1985-01-01

    No-carrier-added 123 I-labeled agents are readily prepared via the reaction of organoboranes with sodium iodide- 123 I in the presence of mild oxidizing agents. The reactions are rapid and regiospecific, and they produce excellent yields of the labeled products. The organoboranes are readily prepared from alkenes and alkynes via the hydroboration reaction. A wide variety of functional groups are tolerated by the hydroboration-iodination sequence. The sequence has been utilized to prepare 123 I-labeled steroids and fatty acids, as well as a number of labeled esters, and aromatic derivatives

  7. Preparation and in vitro evaluation of ''no-carrier-added'' 18F-labeled biotin

    International Nuclear Information System (INIS)

    Najafi, A.; Peterson, A.

    1993-01-01

    This paper will describe the preparation of ''no-carrieradded'' 18 F-labeled biotin where the radiolabel bound to an aromatic moiety is described. This has been accomplished by preparation of [ 18 F]fluoro-benzylbromide (yield 20-30%) and its reaction with biotin-LC-hydrazide. This yielded ''no-carrier-added'' radiolabeled biotin (5-10%) which was then purified by reversed phase HPLC. The pure product was found to bind to avidin, thereby demonstrating retention of its biological integrity. Thus this product is potentially useful for imaging tumor tissue following injection of avidin coupled MoAbs. (author)

  8. Primary standardization of a {sup 177}Lu solution; Padronizacao primaria de uma solucao de {sup 177}Lu

    Energy Technology Data Exchange (ETDEWEB)

    Iwahara, Akira; Silva, Carlos Jose da; Tauhata, Luiz; Oliveira, Estela Maria de, E-mail: iwahara@ird.gov.b, E-mail: carlos@ird.gov.b, E-mail: tauhata@ird.gov.b, E-mail: estela@ird.gov.b [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil); Rezende, Eduarda Alexandre, E-mail: eduarda@ird.gov.b [Centro Federal de Educacao Tecnologica de Quimica (CEFET), Nilopolis, RJ (Brazil)

    2009-07-01

    For the purpose to make available reliable standards of {sup 177}Lu to the users and producers, a radionuclide solution was standardized using the primary methods of coincidence 4{pi}{beta}(PC)-{gamma}(NaI(Tl)) and of 4{pi}{beta}(LS)-{gamma}(NaI(Tl)). The results presented a convergence in the range of evaluated uncertainties. The standard uncertainties were of the 0.50 and 0.74% for the anticoincidence and coincidence respectively

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

    International Nuclear Information System (INIS)

    Luna G, M. A.

    2014-01-01

    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 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 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 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 177 Lu-AuNP-c[RGDfK(C)], the 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. 177 Lu-DOTA-GGC, 177 Lu- DOTA-cRGDfK and 177 Lu-DOTA-E-c(RGDfK) 2 were prepared by adding 177 LuCl 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 177 Lu-AuNP-c[RGDfK(C)], the MCF7 cell proliferation was significantly inhibited

  10. Synthesis of no-carrier-added radiobrominated n-alkylated analogues of spiperone

    International Nuclear Information System (INIS)

    Moerlein, S.M.; Laufer, P.; Stoecklin, G.

    1985-01-01

    The synthesis of a series of p-bromo-3-N-alkyl spiperone analogues is described. N-alkylation was achieved via reaction of the potassium salt of the spiperone lactam ring with alkyl iodide; subsequent reactions with elemental bromine gave the p-brominated isomers. Optimization studies using no-carrier-added (n.c.a.) 77 Br - indicated that radio-bromination of N-alkyl spiperone analogues occurs with higher yields and in shorter reaction times when dichloramine-T (DCT) is used rather than H 2 0 2 /acetic acid as an oxidant. The production of the title compounds in high effective specific activity with radiochemical yields of 20-30 % using n.c.a. 77 Br - and DCT is reported. (author)

  11. Complexation study on no-carrier-added astatine with insulin: A candidate radiopharmaceutical

    Energy Technology Data Exchange (ETDEWEB)

    Lahiri, Susanta [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700 064 (India)], E-mail: susanta.lahiri@saha.ac.in; Roy, Kamalika [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700 064 (India); Sen, Souvik [Berhampur Sadar Hospital, Berhampur, Murshidabad 742 101 (India)

    2008-12-15

    No-carrier-added astatine radionuclides produced in the {sup 7}Li-irradiated lead matrix were separated from bulk lead nitrate target by complexing At with insulin, followed by dialysis. The method offers simultaneous separation of At from lead as well as its complexation with insulin. The At-insulin complex might be a potential radiopharmaceutical in the treatment of hepatocellular carcinoma. The stability of At-insulin complex was checked by dialysis against deionized water and Ringer lactate (RL) solution. It has been found that the half-life of At-insulin complex is about {approx}12 h, when dialyzed against deionized water and is only 6 h, when dialyzed against RL solution having the same composition as blood serum. The 6 h half-life of this Insulin-At complex is perfect for killing cancer cells from external cell surfaces as the half-life of internalization of insulin molecule inside the cell is 7-12 h.

  12. Cu(I) assisted radioiodination of hippuran with no carrier added [sup 131]I

    Energy Technology Data Exchange (ETDEWEB)

    Al-Kolaly, M T; El-Bayoumy, S; Raieh, M; El-Mothy, A [Atomic Energy Authority, Cairo (Egypt). Dept. of Radioisotope Production and Labelled Compounds

    1993-11-01

    A study on the labeling of hippuran with no-carrier-added [sup 131]I assisted by Cu(I) and excess of ascorbic acids is described. The role of ascorbic acid is to prevent the oxidation of Cu(I) to Cu(II) which activates the hydrolysis of o-iodohippuric acid to o-iodobenzoic acid. The use of Cu(I) allows an almost quantitative (97-99%) labeling yield to be obtained within 10-15 minutes at 100 deg C. The reaction is assumed to take place via the formation of an organocopper complex favoring the exchange reaction between radioiodine and inactive iodine in the hippuran molecule. The activation energy of the reaction was calculated to be E = 12.2 kcal/mol. (author) 21 refs.; 8 figs.

  13. Cu(I) assisted radioiodination of hippuran with no carrier added 131I

    International Nuclear Information System (INIS)

    Al-Kolaly, M.T.; El-Bayoumy, S.; Raieh, M.; El-Mothy, A.

    1993-01-01

    A study on the labeling of hippuran with no-carrier-added 131 I assisted by Cu(I) and excess of ascorbic acids is described. The role of ascorbic acid is to prevent the oxidation of Cu(I) to Cu(II) which activates the hydrolysis of o-iodohippuric acid to o-iodobenzoic acid. The use of Cu(I) allows an almost quantitative (97-99%) labeling yield to be obtained within 10-15 minutes at 100 deg C. The reaction is assumed to take place via the formation of an organocopper complex favoring the exchange reaction between radioiodine and inactive iodine in the hippuran molecule. The activation energy of the reaction was calculated to be E = 12.2 kcal/mol. (author) 21 refs.; 8 figs

  14. Synthesis of no-carrier-added alpha-[11C]methyl-L-tryptophan

    International Nuclear Information System (INIS)

    Chaly, T.; Diksic, M.

    1988-01-01

    Described here is a synthesis of no-carrier-added alpha-[ 11 C]methyl-L-tryptophan based on alkylation with 11 CH 3 I of an anion generated by reacting the Schiff base of L-tryptophan methyl ester with di-isopropylamine. The synthesis requires approximately 30 min after the end of 11 CO 2 collection and gives alpha-[ 11 C]methyl-L-tryptophan in a 20-25% radiochemical yield calculated at the end of the synthesis and without correction for radioactive decay. The specific activity of the final radiopharmaceutical, measured at the end of the synthesis, was around 2000 Ci/mmol. Data confirming the stereospecificity of the synthesis are also presented

  15. Synthesis of 'no-carrier-added' sup(11)C-labelled nitrosoureas

    Energy Technology Data Exchange (ETDEWEB)

    Diksic, M.; Farrokhzad, S.; Yamamoto, Y.L.; Feindel, W. (Montreal Neurological Inst., Quebec (Canada))

    1985-03-01

    Syntheses for sup(11)C-labelled chemotherapeutic drugs CCNU, BFNU and CFNU (analogs of BCNU) as well as an improved synthesis for sup(11)C-BCNU are described. The procedures for the separation of dual isomers in the case of sup(11)C-labelled CCNU and CFNU are discussed. The specific activity of these 'no-carrier-added' radiopharmaceuticals was approximately 10sup(4) lower than expected for a carrier-free product. The syntheses were normally finished 20-25 min after the end of the collection of sup(11)C-COClsub(2). Chemical and radiochemical purity of the final products as determined by HPLC and TLRC, respectively, was at least 98%. The syntheses yielded 10-25 mCi of nitrosourea ready for use in PET studies.

  16. Synthesis of 'no-carrier-added' sup(11)C-labelled nitrosoureas

    International Nuclear Information System (INIS)

    Diksic, M.; Farrokhzad, S.; Yamamoto, Y.L.; Feindel, W.

    1985-01-01

    Syntheses for sup(11)C-labelled chemotherapeutic drugs CCNU, BFNU and CFNU (analogs of BCNU) as well as an improved synthesis for sup(11)C-BCNU are described. The procedures for the separation of dual isomers in the case of sup(11)C-labelled CCNU and CFNU are discussed. The specific activity of these 'no-carrier-added' radiopharmaceuticals was approximately 10sup(4) lower than expected for a carrier-free product. The syntheses were normally finished 20-25 min after the end of the collection of sup(11)C-COClsub(2). Chemical and radiochemical purity of the final products as determined by HPLC and TLRC, respectively, was at least 98%. The syntheses yielded 10-25 mCi of nitrosourea ready for use in PET studies. (author)

  17. Complexation study on no-carrier-added astatine with insulin: A candidate radiopharmaceutical

    International Nuclear Information System (INIS)

    Lahiri, Susanta; Roy, Kamalika; Sen, Souvik

    2008-01-01

    No-carrier-added astatine radionuclides produced in the 7 Li-irradiated lead matrix were separated from bulk lead nitrate target by complexing At with insulin, followed by dialysis. The method offers simultaneous separation of At from lead as well as its complexation with insulin. The At-insulin complex might be a potential radiopharmaceutical in the treatment of hepatocellular carcinoma. The stability of At-insulin complex was checked by dialysis against deionized water and Ringer lactate (RL) solution. It has been found that the half-life of At-insulin complex is about ∼12 h, when dialyzed against deionized water and is only 6 h, when dialyzed against RL solution having the same composition as blood serum. The 6 h half-life of this Insulin-At complex is perfect for killing cancer cells from external cell surfaces as the half-life of internalization of insulin molecule inside the cell is 7-12 h

  18. Production and Stability Study of High Activity 177Lu-Substance P as a Radiopharmaceutical for Malignant Tumors Treatment

    International Nuclear Information System (INIS)

    Araujo, E.B. de; Lima, C.M. de; Pujatti, P.B.; Mengatti, J.

    2009-01-01

    radiolabeling methodology. The parameters studied were temperature (70 - 90 o C), peptide mass (0,5 - 10 μg), time of reaction (15 - 30 minutes) and 177 LuCl 3 activity (37 - 400 MBq). Radiochemical purity was determined by instant thin layer chromatography (ITLC-SG) and high performance liquid chromatography (HPLC). In vitro stability of 177Lu-DOTA-SP was determined by ITLC-SG after storing at -20 deg. C or 2-8 deg. C for different times (1 to 7 days). Finally, methionine oxidation during radiolabeling procedures was evaluated by HPLC. A high radiochemical purity (> 95%) and high specific activity of 177 Lu-DOTA-SP was achieved when the reaction time was 30 minutes, the temperature was 90 deg. C and the ratio 177Lu activity / mass of DOTA-SP was 18.5 MBq/μg. The peptide remained stable for more than 72 hours of storage at 2 - 8 deg. C. The ratio was used in the experiments applying high activity 177 Lu (925 MBq - 4.81 GBq) and a high radiochemical purity was obtained for all reactions performed. However, these preparations did not remain stable after storing at -20 deg. C, and a solution of gentisic acid (GA) was added to the radiolabeling mixture at the end of the reactions. GA had significant stabilizing effect and inhibited the radiolysis of frozen 177 Lu-DOTA-SP. HPLC analysis confirmed the high radiochemical purity of high activity 177 Lu-DOTA-SP, but also showed considerable methionine oxidation. Methionine oxidation showed to be dependent of 177 Lu activity and can be avoided by the addition of methionine amino acid during 177 Lu incorporation by the molecule. Based on the results described, a formulation method has been development for 177 Lu- DOTA-SP at a therapeutic dose level. Further studies are in development in order to evaluate the radiopharmaceutical's in vitro target to tumor cells. (author)

  19. Alternative method to determine Specific Activity of (177)Lu by HPLC.

    Science.gov (United States)

    Breeman, Wouter A P; de Zanger, Rory M S; Chan, Ho Sze; de Blois, Erik

    2015-01-01

    Peptide Receptor Radionuclide Therapy (PRRT) with (177)Lu-DOTA-peptides requires (177)Lu with high specific activity (SA) and values >740 GBq (177)Lu per mg Lu to maximise the atom% of (177)Lu over total Lu. Vendors provide SA values which are based on activity and mass of the target, whereas due to "burn-up" of target, these SA values are not accurate. For a radiochemist the SA of (177)Lu is of interest prior to radiolabeling. An alternative method to determine SA was developed by HPLC, which includes a metal titration of a known amount of DOTA-peptide with a known amount of activity ((177)Lu), and a unknown amount of metal ((177+nat)Lu). Based on an HPLC separation of radiometal-DOTA-peptide and DOTA-peptide, and the concordant ratio of these components the metal content ((177+nat)Lu) can be calculated, and eventually the SA of (177)Lu can be accurately determined. These experimentally determined SA values exceeded the estimated values provided by vendors by 27 ± 16%, (range 6-73 %). The deviation of SA values for samples from the same Lu batch was <2% (n ≥ 10). the SA of (177)Lu is apparently often higher as stated by vendors in comparison to the experimentally determined actual values. For this reason, the SA of (177)Lu-DOTA-TATE and other Lu-DOTA-peptides could be increased accordingly.

  20. Standard test of labelling efficiency for quality control of no carrier added 90YCl3

    International Nuclear Information System (INIS)

    Beran, M.; Eigner Henke, K.; Srank, J.; Melichar, F.

    2007-01-01

    Particle emitting radionuclides (e.g. beta-emitters 90 Y and 177 Lu, alpha-emitter 211 At, Auger electron emitter 165 Er or positron emitter 86 Y) are beeing more and more frequently used in research and clinical practice for imaging and targeted therapy in nuclear medicine. This radiometals, altogether three valent lanthanides or actinides with high specific radioactivity, coupled to biomolecule carriers (peptides or monoclonal antibodies) through chelating link (e.g. DTPA or DOTA) are targeted against specific antigens and receptors of diseased tissues in order to obtain their image or to cause their radiation ablation. The radionuclide precursor 90 YCl 3 (solution of hard β-emitter 90 Y in a diluted HCl) with high purity and specific activity is already commercially produced and successfully used in nuclear medicine, e.g. for radioimmunotherapy of Lymphoma. Specification and purity of our product obtained by extraction 90 Sr/ 90 Y generator (using technology of centrifuge extractors with di-2-ethylhexylphosphoric acid) is examined and compared to other similar products in this contribution. A standard method for determination of labelling efficiency of the precursor with DOTA Octreotide (DOTATATE) using ITLC/SG chromatography is also described and proposed for quality assesment. (Author)

  1. Tumoral fibrosis effect on the radiation absorbed dose of {sup 177}Lu-Tyr{sup 3}-octreotate-gold nanoparticles and {sup 177}Lu-Tyr{sup 3}-octreotate radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Zambrano R, O. D.

    2015-07-01

    ). To this spectrum was added some of the most relevant Auger and internal conversion electron emissions. On the other hand, an experimental array was used to simulate the presence or absence of fibrosis in a tumor of malignant cells (HeLa cells). With this model the retention of the radiopharmaceuticals {sup 177}Lu-Tyr{sup 3}-octreotate-gold nanoparticles (multimeric system) and {sup 177}Lu-Tyr{sup 3}-octreotate (monomeric system) in the micro environments (without fibrosis and with fibrosis) was determined. The experimental tumoral fibrosis array consists of a multilayer repetitive patter of HeLa cells, collagen and gelatin until completing a culture (in a trans well insert) layer by layer (Lbl) of five coatings of HeLa cells. The Lbl cultures were exposed during 24 h, approximate duplicating time of HeLa cells, separately to: {sup 177}LuCl{sub 3}, {sup 177}Lu-Tyr{sup 3}-octreotate, and {sup 177}Lu-Tyr{sup 3}-octreotate-gold nanoparticles with an initial activity of 26 MBq (700 μCi). The radiopharmaceutical retention was calculated by measuring the retained activity in the trans well inserts (radiopharmaceutical retained by HeLa cells and microenvironment) and in the lower chamber where the radiopharmaceutical permeated. The experimental models were essential to determine the radiopharmaceutical permeability which allowed the calculation of the retained activity fraction, and hence the cumulated activity in regions of interest for each of the different cases. This is needed at the same time for the radiation absorbed dose calculation. In this work it was concluded that the presence or absence of fibrosis and yet more, the multimeric and multivalent nature of the radiopharmaceutical had an effect on the radiation absorbed dose in the cell nucleus and in the tumor microenvironment. (Author)

  2. 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

    Energy Technology Data Exchange (ETDEWEB)

    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

  3. New separation method of no-carrier-added {sup 47}Sc from titanium targets

    Energy Technology Data Exchange (ETDEWEB)

    Bartos, B.; Majkowska, A.; Kasperek, A.; Krajewski, S.; Bilewicz, A. [Institute of Nuclear Chemistry and Technology, Warszawa (Poland). Nuclear Chemistry and Radiochemistry Center

    2012-07-01

    Radionuclides with medium energy beta emission and a several day half-life are attractive candidates for radioimmunotherapy. Among the most promising in this category is {sup 47}Sc produced by fast neutron irradiation (E{sub n} > 1 MeV) of titanium target with high energy neutrons in {sup 47}Ti(n,p){sup 47}Sc nuclear reaction. In the previously reported production scheme the dissolution of the TiO{sub 2} target in hot concentrated H{sub 2}SO{sub 4} and evaporation of the resulting solution were the most time-consuming steps. The present paper describes new, simple and efficient production method of {sup 47}Sc, where the slow dissolution of the target is avoided. After irradiation in fast neutron flux {sup 47}TiO{sub 2} and Li{sub 2}{sup 47}TiF{sub 6} targets were dissolved in HF solutions. Next {sup 47}Sc was separated from the target using anion exchange resin Dowex 1 with 0.4 M HF + 0.06 M HNO{sub 3} solution as eluent. The eluted {sup 47}Sc was adsorbed on cation exchange resin and eluted with 0.5 M of ammonium acetate. The 47Sc separation yield in the proposed procedure is about 90% with the separation time less than 2 h. The obtained no-carrier-added {sup 47}Sc was used to label DOTATATE conjugate with 96% labeling yield. (orig.)

  4. Speciation of no-carrier-added 68Ga prior to its labeling for PET imaging

    International Nuclear Information System (INIS)

    Kamalika Sen; Breeman, W.A.P.; Wolterbeek, H.Th.

    2012-01-01

    The present article describes the probable speciation of 68 Ga radionuclide just before labeling to DOTA peptides for PET imaging. The 68 Ga eluted from an anion exchange column after its purification was analyzed for its elemental composition and pH at several stages. Neutron activation analysis of the eluted fractions yields the concentrations of Na and Cl, pH measurements indicate the concentration of free H + ions in the medium and specific activity calculations indicate the concentration of 68 Ga in the solution. Using all these information we get the idea of speciation of no carrier added Ga in the eluted fractions from CHEAQS programme. The estimations indicate that Ga is mostly present as GaCl 2+ in the total MiliQ eluate. However, just before labeling of DOTA the pH of the Ga-containing eluate is adjusted to ∼3.5 using HEPES buffer and at that condition Ga remains as Ga 3+ species which is responsible for a successful and efficient labeling. The MilliQ eluate collected before actual labeling was estimated for trace elements using inductively coupled plasma atomic emission spectrometry was found to contain a few ppb of Al, Co, Pd and Pt that did not interfere in the actual labeling. A clear idea about the prerequisite of 68 Ga species before labeling to a peptide might be of special interest for its judicious application as a radiopharmaceutical. (author)

  5. Synthesis of DOTMP and biodistribution and imaging study of 177-Lu-DOTMP

    International Nuclear Information System (INIS)

    Deng Xinrong; Luo Zhifu; Xiang Xueqin; Li Fenglin; Fan Caiyun; Liu Zihua; Ye Zhaoyun; Li Hongyu; Chen Yang; Zhuang Ling

    2012-01-01

    Cyclen (1, 4, 7, 10-tetraazacyclododecane) and H 3 PO 3 was used to synthesis DOTMP (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-Tetraamino methylenephosphonate). 177 Lu was produced by irradiating enriched lutetium oxide ( 176 Lu 2 O 3 ) with thermal neutron flux of 2' × 10 13 n/cm 2 /S in swimming pool reactor (SPR) for 10 days. And then DOTMP was labelled by 177 Lu. The biodistribution of 177 Lu-DOTMP in model mice bearing S180 sarcoma and SPECT imaging in Japanese white rabbit were also carried out. The results showed that the total activity of 177 LuCl 3 solution obtained was 9.19 × 10 5 MBq after corresponding chemical process. According to the optimal condition of the labeling experiment, the labelling efficiency of 177 Lu-DOTMP was 99.4%. The results of biodistribution study indicated that 177 Lu-DOTMP eliminated rapidly from blood and was delivered to target bone. The radioactivity uptake was mainly in bone and less in other viscera. The results of SPECT imaging showed that the radioactivity was accumulated in bladder. 177 Lu-DOTMP was mainly excreted by kidney. The uptake of the activity in the skeleton was observed within 22 h postinjection and it became quite significant at 46 h post injection. It indicated that 177 Lu-DOTMP has good bone targeting and is worthy of further research. (authors)

  6. Neoadjuvant Treatment of Nonfunctioning Pancreatic Neuroendocrine Tumors with [177Lu-DOTA0,Tyr3]Octreotate

    NARCIS (Netherlands)

    van Vliet, Esther I.; van Eijck, Casper H.; de Krijger, Ronald R.; Nieveen van Dijkum, Elisabeth J.; Teunissen, Jaap J.; Kam, Boen L.; de Herder, Wouter W.; Feelders, Richard A.; Bonsing, Bert A.; Brabander, Tessa; Krenning, Eric P.; Kwekkeboom, Dik J.

    2015-01-01

    Pancreatic neuroendocrine tumors (NETs) are rare neoplasms for which surgery has almost the only potential for cure. When surgery is not possible because of tumor size and vascular involvement, neoadjuvant treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) may be an option. We

  7. Production of no-carrier-added 64Cu from zinc metal irradiated under boron shielding.

    Science.gov (United States)

    Zinn, K R; Chaudhuri, T R; Cheng, T P; Morris, J S; Meyer, W A

    1994-02-01

    Positron emission tomography offers advantages for radioimmunodiagnosis of cancer but requires radionuclides of appropriate half-life that have high specific activity and high radio-purity. This work was designed to develop a viable method to produce and purify 64Cu, which has high specific activity, for positron emission tomography. 64Cu was produced at the University of Missouri Research Reactor by the nuclear reaction, 64Zn(n,p)64Cu. Highly pure zinc metal (99.9999%) was irradiated in a specially designed boron nitrite lined container, which minimized thermal neutron reactions during irradiation. A new two-step procedure was developed to chemically separate the no-carrier-added 64Cu from the zinc metal target. 64Cu recovery for 24 runs averaged 0.393 (+/- 0.007) mCi per milligram of zinc irradiated. The boron-lined irradiation container reduced unwanted zinc radionuclides 14.3-fold. Zinc radionuclides and non-radioactive zinc were separated successfully from the 64Cu. The new separation technique was fast (2 hours total time) and highly efficient for removing the zinc. The zinc separation factor for this technique averaged 8.5 x 10(-8), indicating less than 0.0000085% of the zinc remained after separation. Thus far, the highest 64Cu specific activity at end of irradiation was 683 Ci/mg Cu, with an average of 512 Ci/mg Cu for the last six analyzed runs. The boron-lined irradiation container has sufficient capacity for 75-fold larger-sized zinc targets (up to 45 g). The new separation technique was excellent for separating 64Cu, which appears to be a radionuclide with great potential for positron emission tomography.

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

    Energy Technology Data Exchange (ETDEWEB)

    Koumarianou, Eftychia [Institute R-RP, NCSR ' Demokritos' , Athens (Greece); IAE, Radioisotope Centre POLATOM, 05-400 Swierk-Otwock (Poland)], E-mail: eytyxiak@yahoo.com; Mikolajczak, Renata; Pawlak, Dariusz [IAE, Radioisotope Centre POLATOM, 05-400 Swierk-Otwock (Poland); Zikos, Xhristos; Bouziotis, Pinelopi [Institute R-RP, NCSR ' Demokritos' , Athens (Greece); Garnuszek, Piotr; Karczmarczyk, Urszula; Maurin, Michal [Department of Radiopharmaceuticals, National Medicines Institute, Chelmska 30/34, 00-725 Warsaw (Poland); Archimandritis, Spyridon C. [Institute R-RP, NCSR ' Demokritos' , Athens (Greece)

    2009-08-15

    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-CONH{sub 2} (BN[2-14]NH{sub 2}), labeled with {sup 90}Y and {sup 177}Lu, 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-CONH{sub 2}), has already been studied and reported; however, the DOTA-chelated one, suitable for labeling with M{sup +3} type radiometals, was not yet described. Methods: The conditions for labeling of DOTA-BN[2-14]NH{sub 2} with noncarrier added {sup 90}Y and with {sup 177}Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide {sup 90}Y-DOTA-BN[2-14]NH{sub 2} and {sup 177}Lu-DOTA-BN[2-14]NH{sub 2} 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: {sup 90}Y-DOTA-BN[2-14]NH{sub 2} and {sup 177}Lu-DOTA-BN[2-14]NH{sub 2} were obtained with radiochemical yield >98% and high SA (67.3 GBq {sup 90}Y/{mu}mol and 33.6 GBq {sup 177}Lu/{mu}mol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2-14]NH{sub 2} and both {sup nat}Y- and {sup nat}Lu-labeled analogs to GRP receptors were high (IC{sub 50}=1.78, 1.99, and 1.34 nM, respectively), especially for the {sup nat}Lu-DOTA-BN[2-14]NH{sub 2} complex. The cytotoxicity study of DOTA-BN[2-14]NH{sub 2} to PC-3 cells revealed an IC{sub 50}=6300 nM after 72 h of exposition, while the labeled derivatives showed no

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

    International Nuclear Information System (INIS)

    Koumarianou, Eftychia; Mikolajczak, Renata; Pawlak, Dariusz; Zikos, Xhristos; Bouziotis, Pinelopi; Garnuszek, Piotr; Karczmarczyk, Urszula; Maurin, Michal; Archimandritis, Spyridon C.

    2009-01-01

    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-CONH 2 (BN[2-14]NH 2 ), labeled with 90 Y and 177 Lu, 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-CONH 2 ), 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]NH 2 with noncarrier added 90 Y and with 177 Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide 90 Y-DOTA-BN[2-14]NH 2 and 177 Lu-DOTA-BN[2-14]NH 2 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: 90 Y-DOTA-BN[2-14]NH 2 and 177 Lu-DOTA-BN[2-14]NH 2 were obtained with radiochemical yield >98% and high SA (67.3 GBq 90 Y/μmol and 33.6 GBq 177 Lu/μmol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2-14]NH 2 and both nat Y- and nat Lu-labeled analogs to GRP receptors were high (IC 50 =1.78, 1.99, and 1.34 nM, respectively), especially for the nat Lu-DOTA-BN[2-14]NH 2 complex. The cytotoxicity study of DOTA-BN[2-14]NH 2 to PC-3 cells revealed an IC 50 =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 177 Lu-labeled peptide (84.87%) than for the 90 Y

  10. Study of the production of {sup 177}Lu through {sup 176}Yb (n, {gamma}) {sup 177}Yb {yields} {sup 177}Lu nuclear reaction

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Giovana Pasqualini da; Osso Junior, Joao Alberto [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)]. E-mail: gpsilva@ipen.br; jaosso@ipen.br

    2007-07-01

    The beta minus emitter {sup 177}Lu is a promising therapeutic radioisotope for the curative treatment of cancer using labelled proteins. It has a half - life of T{sub 1/2} = 6.71 day and maximum and average {beta}{sup -} energies of 421 and 133 keV, resulting in a short range of radiation in tissue. The decay is accompanied by the emission of low energy {gamma}-radiation with 208.3 keV (11%) and 113 keV (6.4%) suitable for simultaneous imaging, {sup 177}Lu can be produced by two different routes, namely, by irradiation of natural Lu{sub 2}O{sub 3} target ({sup 176}Lu, 2.6%) or enriched (in {sup 176}Lu) Lu{sub 2}O{sub 3} target, as also by irradiation of Yb target (Yb{sub 2}O{sub 3}) followed by radiochemical separation of {sup 177}Lu from Yb isotopes. The objective of this work is to study the production of {sup 177}Lu through the indirect {sup 176}Yb(n,{gamma}){sup 177}Yb {yields} {sup 177}Lu nuclear reaction. The results of the production yield of {sup 177}Lu will be shown and compared with the direct reaction. The method of choice for the chemical separation between Lu and Yb was the ion exchange, using an cation exchange resin in Cl{sup -} form and {alpha}-HIBA as eluent. Preliminary results showed a good separation of {sup 177}Lu from Yb{sub 2}O{sub 3} indirect targets. (author)

  11. Solvent extraction of no-carrier-added 103Pd from irradiated rhodium target with α-furyldioxime

    International Nuclear Information System (INIS)

    Mahdi Sadeghi; Behrouz Shirazi; Nami Shadanpour

    2006-01-01

    Solvent extraction of no-carrier-added 103 Pd was investigated from irradiated rhodium target with a-furyldioxime in chloroform from diluted hydrochloric acid. Extraction yield was 85.3% for a single extraction from 0.37M HCl and 103 Pd purity was better than 99%. (author)

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

    Energy Technology Data Exchange (ETDEWEB)

    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. [{sup 177}Lu]pertuzumab: experimental studies on targeting of HER-2 positive tumour cells

    Energy Technology Data Exchange (ETDEWEB)

    Persson, Mikael; Gedda, Lars [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Experimental Urology, Rudbeck Laboratory, Uppsala (Sweden); Tolmachev, Vladimir; Andersson, Karl; Carlsson, Joergen [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Sandstroem, Mattias [Uppsala University, Medical Radiation Physics, Uppsala University Hospital, Uppsala (Sweden)

    2005-12-01

    The new antibody pertuzumab (Omnitarg) targets the dimerisation subdomain of HER-2. The purpose of this study was to analyse whether pertuzumab retains HER-2 targeting capacity after labelling with the therapeutically interesting beta emitter {sup 177}Lu and to make initial characterisations in vitro and in vivo. Pertuzumab was conjugated with isothiocyanate-benzyl-CHX-A{sup ''}-DTPA and chelated to {sup 177}Lu. Immunoreactivity, affinity, cellular retention and internalisation were analysed using SKOV-3 cells. The affinity of non-radioactive pertuzumab was measured using a surface plasmon resonance biosensor. In vivo targeting and specific binding were assessed in Balb/c (nu/nu) mice carrying SKOV-3 xenografts. The biodistribution of {sup 177}Lu was determined 1, 3 and 7 days after [{sup 177}Lu]pertuzumab administration. Gamma camera images were taken after 3 days. The immunoreactivity of [{sup 177}Lu]pertuzumab was 85.8{+-}1.3%. The affinity of non-radioactive pertuzumab was 1.8{+-}1.1 nM, and that of [{sup 177}Lu]pertuzumab, 4.1{+-}0.7 nM. The cellular retention after 5 h pre-incubation was 90{+-}2% at 20 h. The targeting was HER-2 specific both in vitro and in vivo, since excess amounts of non-labelled antibody inhibited the uptake of labelled antibody (p<0.0001 and p<0.01, respectively). The biodistribution and gamma camera images of {sup 177}Lu showed extensive tumour uptake. Normal tissues had a surprisingly low uptake. Pertuzumab was efficiently labelled with {sup 177}Lu and showed good intracellular retention and HER-2 specific binding both in vitro and in vivo. The gamma camera images and the biodistribution study gave excellent tumour targeting results. Thus, [{sup 177}Lu]pertuzumab is of interest for further studies aimed at radionuclide therapy. (orig.)

  14. Additional lesions detected in therapeutic scans with 177Lu-DOTATATE reflect higher affinity of 177Lu-DOTATATE for somatostatin receptors.

    Science.gov (United States)

    Mirzaei, Siroos; Bastati, Brigitte; Lipp, Rainer W; Knoll, Peter; Zojer, Niklas; Ludwig, Heinz

    2011-01-01

    Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of (99m)Tc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with (177)Lu-DOTATATE used for PRRT. 8 patients (4 women, 4 men, age range 46-76 years) with histologically proven NETs, who showed high SR loads by (99m)Tc-EDDA/HYNIC-TOC scintigraphy, were treated with (177)Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. All patients demonstrated (177)Lu-DOTATATE accumulation in all lesions previously detected by (99m)Tc- EDDA/HYNIC-TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. SPECT-CT after (177)Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using (99m)Tc-EDDA/HYNIC-TOC. This could reflect the broader affinity of (177)Lu-DOTATATE for SRs compared with (99m)Tc-EDDA/HYNIC-TOC. Copyright © 2011 S. Karger AG, Basel.

  15. [{sup 177}Lu]DOTA-anti-CD20: Labeling and pre-clinical studies

    Energy Technology Data Exchange (ETDEWEB)

    Audicio, Paola F., E-mail: paudicio@cin.edu.u [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay); Castellano, Gustavo, E-mail: gcas@famaf.unc.edu.a [FaMAF, Universidad Nacional de Cordoba, Ciudad Universitaria, 5016 Cordoba (Argentina); Tassano, Marcos R.; Rezzano, Maria E.; Fernandez, Marcelo [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay); Riva, Eloisa [Clinica Hematologica ' Prof. Dra. L. Diaz' , Hospital de Clinicas. Av. Italia. sn, Montevideo (Uruguay); Robles, Ana; Cabral, Pablo; Balter, Henia; Oliver, Patricia [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay)

    2011-07-15

    Anti-CD20 (Rituximab), a specific chimeric monoclonal antibody used in CD20-positive Non-Hodgkin's Lymphoma, was conjugated to a bifunctional quelate (DOTA) and radiolabeled with {sup 177}Lu through a simple method. [{sup 177}Lu]-DOTA-anti-CD20 was obtained with a radiochemical purity higher than 97%, and showed good chemical and biological stability, maintaining its biospecificity to CD20 antigens. Monte Carlo simulation showed high doses deposited on a spheroid tumor mass model. This method seems to be an appropriate alternative for the production of [{sup 177}Lu]-DOTA-anti-CD20 as therapeutic radiopharmaceutical.

  16. Carrier-added and no-carrier-added syntheses of (/sup 18/F)spiroperidol and (/sub 18/F)haloperidol

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, M R; Welch, M J; Dence, C S; Tewson, T J; Saji, H; Maeda, M

    1984-07-01

    Syntheses of (18F)haloperidol and (18F)spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added (18F)butyrophenone neuroleptics were prepared in low (less than 2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added 18F-neuroleptics were prepared in better (5-17%) yields by 18F-for-19F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.

  17. Carrier-added and no-carrier-added syntheses of (/sup 18/F)spiroperidol and (/sup 18/F)haloperidol

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, M R; Welch, M J; Dence, C S; Tewson, T J; Saji, H; Maeda, M [Washington Univ., St. Louis, MO (USA). Edward Mallinckrodt Inst. of Radiology

    1984-07-01

    Syntheses of (/sup 18/F)haloperidol and (/sup 18/F)spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added (/sup 18/F)butyrophenone neuroleptics were prepared in low (<2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added /sup 18/F-neuroleptics were prepared in better (5-17%) yields by /sup 18/F-for-/sup 19/F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.

  18. Development of 177Lu-phytate Complex for Radiosynovectomy

    Directory of Open Access Journals (Sweden)

    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

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

    International Nuclear Information System (INIS)

    Costa, Gustavo Coelho Alves; Sa, Lidia Vasconcellos de

    2011-01-01

    This paper investigated the treatment of neuroendocrine tumors (abdominal tumors) using of 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 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

  20. Reactor production and separation of no-carrier added 32P for medical applications

    International Nuclear Information System (INIS)

    Vimalnath, K.V.; Shetty, P.; Rajeswari, A.; Chirayil, V.; Chakraborty, S.; Dash, A.

    2014-01-01

    Phosphorous-32 is an attractive and widely used therapeutic radionuclide owing to its favorable nuclear characteristics. The major application of 32 P is the treatment option for a distinct subgroup of elderly patients with polycythemia vera and leukemia. The tremendous prospects associated with the use of 32 P along with the challenge of providing 32 P of acceptable specific activity and purity amenable for in vivo therapy, led to development of a 32 P production strategy. The 32 S(n,p) 32 P route of production provide the scope of obtaining high specific activities or no carrier added (NCA) 32 P. In a typical batch of 14 nos. of neutron irradiated Al containers, each containing 18 g of sulphur, were processed. In the quest for an effective separation method to isolate micro gram of 32 P formed during the neutron irradiation of sulphur, the prospect of using distillation under reduced pressure to achieve complete removal of sulfur seemed to be an effective proposition and motivated us to adopt. The experimental parameters that influence the distillation were identified and a careful control has been exercised to ensure complete removal of sulphur from 32 P within reasonable time period. The 32 P remained in the distillation flask was quantitatively collected by leaching with 0.05 N HCl with gentle heating at 80℃ for 3 hours. In the light of the perceived need to remove cationic impurities from the 32 P leachate, it was passed through an ion-exchange chromatography column containing a cation exchange resin (Dowex 50 x 8 H + , 100-200 mesh) wherein all the cationic impurities get trapped and H 3 32 PO 4 solution was collected as effluent. Recognizing the fact that H 3 32 PO 4 produced is to be used for clinical applications, a thorough quality assessment was carried out. Radionuclidic purity was ascertained by a measurement of its half-life. In order to establish the absence of extraneous gamma emitting radionuclide impurities, gamma spectrum of the appropriately

  1. Separation of no-carrier-added 107,109Cd from proton induced silver target. Classical chemistry still relevant

    International Nuclear Information System (INIS)

    Moumita Maiti; Susanta Lahiri; Tomar, B.S.

    2011-01-01

    The classical chemistry like precipitation technique is relevant even in modern days trans-disciplinary research from the view point of green chemistry. A definite demand of no-carrier-added (nca) cadmium tracers, namely, 107,109 Cd, has been realized for diverse applications. Development of efficient separation technique is therefore important to address the purity of the tracers for various applications. No-carrier-added 107,109 Cd radionuclides were produced by bombarding natural silver target matrix with 13 MeV protons, which gave ∼15 MBq/μA h yield for nca 107 Cd. The nca cadmium radionuclides were separated from the natural silver target matrix by precipitating Ag as AgCl. The developed method is an example wherein green chemistry is used in trans-disciplinary research. The method is also simple, fast, cost effective and environmentally benign. (author)

  2. Production of no-carrier-added {sup 123}I via heavy-ion activation of natural antimony oxide

    Energy Technology Data Exchange (ETDEWEB)

    Maji, S. [The Univ. of Burdwan (India). Dept. of Chemistry; Lahiri, S. [Saha Institute of Nuclear Physics, Kolkata (India). Chemical Sciences Div.

    2007-07-01

    Activation of natural Sb{sub 2}O{sub 3} with 48 MeV {sup 7}Li{sup 3+} beam results in the formation of no-carrier-added {sup 123}I in the matrix along with the radionuclides {sup 123,125}Xe and {sup 122}Sb. The {sup 123}I yield amounts to about 400 kBq/{mu}Ah and the radionuclidic impurity of {sup 124}I to {proportional_to}1.2% of {sup 123}I. Attempts to separate no-carrier-added iodine from bulk antimony target involved liquid-liquid extraction with TOA and HDEHP as well as precipitation of Sb{sub 2}S{sub 3} with thioacetamide. The precipitation technique was found to be the most effective for quantitative separation of {sup 123}I from the bulk antimony oxide target. (orig.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  4. Radiolabeling parameters of 177Lu-DOTA-RITUXIMAB

    International Nuclear Information System (INIS)

    Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de

    2013-01-01

    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 177 LuCl 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)

  5. Targeting angiogenesis for radioimmunotherapy with a {sup 177}Lu-labeled antibody

    Energy Technology Data Exchange (ETDEWEB)

    Ehlerding, Emily B.; Hernandez, Reinier [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); Lacognata, Saige; Jiang, Dawei [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); Ferreira, Carolina A. [University of Wisconsin - Madison, Department of Biomedical Engineering, Madison, WI (United States); Goel, Shreya [University of Wisconsin - Madison, Department of Materials Science and Engineering, Madison, WI (United States); Jeffery, Justin J. [University of Wisconsin - Madison, Small Animal Imaging Facility, Madison, WI (United States); Theuer, Charles P. [TRACON Pharmaceuticals, Inc., San Diego, CA (United States); Cai, Weibo [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); University of Wisconsin - Madison, Department of Biomedical Engineering, Madison, WI (United States); University of Wisconsin - Madison, Department of Materials Science and Engineering, Madison, WI (United States)

    2018-01-15

    Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy. The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with {sup 177}Lu (t{sub 1/2} 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: {sup 177}Lu only, TRC105 only, {sup 177}Lu-DTPA-IgG (a nonspecific antibody), {sup 177}Lu-DTPA-TRC105 low-dose, and {sup 177}Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of {sup 177}Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose {sup 177}Lu-DTPA-TRC105. Biodistribution studies indicated steady uptake of {sup 177}Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses. {sup 177}Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a

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

    International Nuclear Information System (INIS)

    Sheng Feng; Jia Bing; Wang Fan; He Weiwei; Liu Zhaofei; Zhao Huiyun

    2008-01-01

    177 Lu-DOTA-Bz-Cys-RGD dimer and 177 Lu-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 177 Lu-DOTA-Bz-Cys- RGD dimer is higher than 177 Lu-DTPA-Bz-Cys-RGD dimer. The uptake of 177 Lu-DTPA-Bz-Cys- RGD dimer in other tissues is significantly higher than that of 177 Lu-DOTA-Bz-Cys-RGD dimer at 4 h postinjection, except for blood and spleen. The in vivo stability of 177 Lu-DOTA-Bz-Cys-RGD dimer is much better than 177 Lu-DTPA-Bz-Cys-RGD dimer. Bz-DOTA is an ideal bifunctional chelator for 177 Lu labeling of RGD dimer. (authors)

  7. Toxicity of trastuzumab labeled {sup 177}Lu on MCF7 and SKBr3 cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Rasaneh, Samira [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran (Iran, Islamic Republic of); Rajabi, Hossein, E-mail: hrajabi@modares.ac.i [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran (Iran, Islamic Republic of); Hossein Babaei, Mohammad; Johari Daha, Fariba [Department of Radioisotope, Nuclear Science and Technology Research Institute, Tehran (Iran, Islamic Republic of)

    2010-10-15

    In this study, we labeled trastuzumab with {sup 177}Lu to synthesize a new radiopharmaceutical for therapy of breast cancer and at the first stage investigated its therapeutic effects on SKBr3 and MCF7 breast cancer cell lines. Trastuzumab-{sup 177}Lu showed very good in-vitro characteristics such as high radiochemical purity (91{+-}0.9%), good stability in PBS buffer (86{+-}2.3%) and blood serum (81{+-}2.7%) up to 96 h, appropriate immunoreactivity (85.4{+-}1.1%) and high cytotoxicity in HER2 expression cells. 5 fold increase in toxicity of trastuzumab-{sup 177}Lu was observed when compared with unlabeled trastuzumab on SKBr3 cells.

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

    International Nuclear Information System (INIS)

    Lopez Bularte, A.C.; Nevares, N.N.; Zapata, A.M.; Perez, J.H.; Crudo, J.L.; Puerta Yepes, N.; Rojo, A.M.

    2010-01-01

    The aim of this work is to obtain 177 Lu-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) 177 LuCl 3 of an intermediate level of Ae (between 6.36 to 17.95 Ci/mg of 176 Lu) ) and also to perform in vitro and in vivo stability tests, dose calculation in normal mice and its extrapolation to a human model. (authors) [es

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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...... 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...

  10. Preparation and in vitro evaluation of ''no-carrier-added'' 18F-labeled biotin

    International Nuclear Information System (INIS)

    Najafi, A.; Peterson, A.

    1993-01-01

    This paper will describe the preparation of ''no-carrieradded'' 18 F-labeled biotin where the radiolabel bound to an aromatic moiety is described. This has been accomplished by preparation of [ 18 F]fluorobenzylbromide (yield 20-30%) and its reaction with biotin-LC-hydrazide. This yielded ''nocarrier-added'' radiolabeled biotin(5-10%) which was then purified by reversed phase HPLC. The pure product was found to bind to avidin, thereby demonstrating retention of its biological integrity. Thus this product is potentially useful for imaging tumor tissue following injection of avidin coupled MoAbs. (Author)

  11. The synthesis of no-carrier-added DL-4-[18F]fluorodeprenyl via the nucleophilic aromatic substitution reaction

    International Nuclear Information System (INIS)

    Plenevaux, Alain; Guillaume, Marcel

    1991-01-01

    No-carrier-added DL-α-methyl-β-4-[ 18 F]fluorophenyl-N-methyl-N-propynylethylamine (DL-4-[ 18 F]fluorodeprenyl) was synthesized via a 3-step procedure. The overall yield was 11%, the synthesis time was 90 min and the specific activity >0.57 Ci/μmol (end of synthesis). This synthesis approach, the conversion of an aromatic aldehyde to a homologous methyl ketone, extends the flexibility of the nucleophilic aromatic substitution reaction by applying it to the synthesis of radiotracers which do not bear electron-withdrawing activating groups on the aromatic ring. The tissue distribution of DL-4-[ 18 F]fluorodeprenyl in mice at 1, 10 and 50 min was also measured and showed that metabolic defluorination was not significant. Clearance or radioactivity from brain after injection of DL-4-[ 18 F]fluorodeprenyl was more rapid than that previously observed for [ 11 C]L-deprenyl. (author)

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

    Czech Academy of Sciences Publication Activity Database

    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

  13. Effects of therapy with [177Lu-DOTA0,Tyr3]octreotate on endocrine function

    International Nuclear Information System (INIS)

    Teunissen, Jaap J.M.; Kwekkeboom, Dik J.; Krenning, Eric P.; Jong, Frank H. de; Feelders, Richard A.; Aken, Maarten O. van; Herder, Wouter W. de; Rijke, Yolanda B. de

    2009-01-01

    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 [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate ( 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 4 ) levels decreased (17.7 ± 0.4 to 15.6 ± 0.6 pmol/l, p 3 ) levels did not change. Reverse triiodothyronine (rT 3 ) levels decreased (0.38 ± 0.03 to 0.30 ± 0.01 nmol/l, p 550 nmol/l, n = 18). Five patients developed elevated HbA 1c levels (> 6.5%). In men 177 Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA 1c . Therefore, PRRT with 177 Lu-octreotate can be regarded as a safe treatment modality with respect to short- and long-term endocrine function. (orig.)

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

    International Nuclear Information System (INIS)

    Dalmo, J.; Forssell-Aronsson, E.; Westberg, E.; Toernqvist, M.; Svedborn, L.; Barregaerd, L.

    2015-01-01

    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). [ 177 Lu-DOTA0, Tyr3]-octreotate ( 177 Lu-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 177 Lu-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 177 Lu-octreotate treatment. BALB/c nude mice (n=6/group) were i.v. injected with 60 MBq or 120 MBq of 177 Lu-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 177 Lu-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

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

    International Nuclear Information System (INIS)

    Miao Yubin; Fisher, Darrell R.; Quinn, Thomas P.

    2006-01-01

    Objective: The purpose of this study was to improve the tumor-to-kidney uptake ratios of 9 Y- and 177 Lu-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Re-Cys 3,4,1 , D-Phe 7 , Arg 11 ]α-melanocyte stimulating hormone 3-13 {DOTA-Re(Arg 11 )CCMSH} through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. Methods: A new peptide of DOTA-Re(Glu 2 , Arg 11 )CCMSH was designed, synthesized and labeled with 9 Y and 177 Lu. Pharmacokinetics of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH was determined in B16/F1 murine melanoma-bearing C57 mice. Results: 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH exhibited significantly (P 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The renal uptake values of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH were 28.16% and 28.81% of those of 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH, respectively, at 4 h postinjection. 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH displayed higher tumor-to-kidney uptake ratios than 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The tumor-to-kidney uptake ratio of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH was 2.28 and 1.69 times of 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH, respectively, at 4 h postinjection. The 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )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 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma

  16. In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy.

    Science.gov (United States)

    Chan, Ho Sze; de Blois, Erik; Morgenstern, Alfred; Bruchertseifer, Frank; de Jong, Marion; Breeman, Wouter; Konijnenberg, Mark

    2017-01-01

    Absorbed doses for α-emitters are different from those for β-emitters, as the high linear energy transfer (LET) nature of α-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE), 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu-DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Carlo model of a cylindrical 6-well plate geometry for the exposure by the radioactive incubation medium. Absorbed doses were compared to conventional irradiation of cells with 137Cs and the relative biological effect (RBE) at 10% survival was calculated. IC50 of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq 213Bi-DOTATATE, in majority the dose was caused by α-particle radiation. Cellular internalization determined with 111In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of 213Bi-DTPA and 213Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of 213Bi. The survival of CA20948 after exposure to 177Lu-DOTATATE and the reference 137Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with 213Bi-DOTATATE, a factor 6 lower than the 18 Gy found for 177Lu

  17. In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy.

    Directory of Open Access Journals (Sweden)

    Ho Sze Chan

    Full Text Available Absorbed doses for α-emitters are different from those for β-emitters, as the high linear energy transfer (LET nature of α-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE, 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu-DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Carlo model of a cylindrical 6-well plate geometry for the exposure by the radioactive incubation medium. Absorbed doses were compared to conventional irradiation of cells with 137Cs and the relative biological effect (RBE at 10% survival was calculated.IC50 of (labelled DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq 213Bi-DOTATATE, in majority the dose was caused by α-particle radiation. Cellular internalization determined with 111In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of 213Bi-DTPA and 213Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of 213Bi. The survival of CA20948 after exposure to 177Lu-DOTATATE and the reference 137Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with 213Bi-DOTATATE, a factor 6 lower than the 18 Gy found

  18. Separation and purification of no-carrier-added arsenic from bulk amounts of germanium for use in radiopharmaceutical labelling

    Energy Technology Data Exchange (ETDEWEB)

    Jahn, M.; Radchenko, V.; Roesch, F.; Jennewein, M. [Mainz Univ. (Germany). Inst. of Nuclear Chemsistry; Filosofov, D. [Joint Inst. for Nuclear Research, Dubna (Russian Federation). Lab. of Nuclear Problems; Hauser, H.; Eisenhut, M. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Radiopharmaceutical Chemistry

    2010-07-01

    Radioarsenic labelled radiopharmaceuticals could add special features to molecular imaging with positron emission tomography (PET). For example the long physical half-lives of {sup 72}As (T{sub 1/2}=26 h) and {sup 74}As (T{sub 1/2}=17.8 d) in conjunction with their high positron branching rates of 88% and 29%, respectively, allow the investigation of slow physiological or metabolical processes, like the enrichment and biodistribution of monoclonal antibodies in tumour tissue or the characterization of stem cell trafficking. A method for separation and purification of no-carrier-added (nca) arsenic from irradiated metallic germanium targets based on distillation and anion exchange is developed. It finally converts the arsenic into an {sup *}As(III) synthon in PBS buffer and pH 7 suitable for labelling of proteins via As-S bond formations. The method delivers radioarsenic in high purity with separation factors of 10{sup 6} from germanium and an overall yield from target to labelling synthon of > 40%. In a proof-of-principle experiment, the monoclonal antibody Bevacizumab, directed against the human VEGF receptor, was labelled with a radiochemical yield > 90% within 1 h at room temperature with nca {sup 72/74/77}As. (orig.)

  19. Production of no-carrier-added 139Pr via precursor decay in the proton bombardment of natPr

    International Nuclear Information System (INIS)

    Steyn, G.F.; Vermeulen, C.; Nortier, F.M.; Szelecsenyi, F.; Kovacs, Z.; Qaim, S.M.

    2006-01-01

    Excitation functions and production rates are presented for various Pr and Nd radionuclides formed in the bombardment of Pr with protons, from their respective thresholds up to 100 MeV. The indirect production route 141 Pr(p, 3n) 139m Nd → 139 Pr is investigated as an alternative to the direct production route 140 Ce(p, 2n) 139 Pr for producing no-carrier-added 139 Pr of high radionuclidic purity. The simultaneous production of 139 Pr and 140 Nd using Pr as target is investigated. The advantages and disadvantages of both production routes are discussed. Experimental thick-target production rates are presented for selected Pr radionuclides formed in the bombardment of nat Ce with protons at incident energies of 20, 26 and 32 MeV. All the experimental excitation functions obtained in this work are compared with theoretical predictions by means of the geometry-dependent hybrid (GDH) model as implemented in the code ALICE-IPPE. The results of this work are also compared with previous literature experimental data, if available

  20. Production and separation of no-carrier-added 73As and 75Se from 7Li irradiated germanium oxide target

    International Nuclear Information System (INIS)

    Mandal, A.; Lahiri, S.

    2012-01-01

    This work reports for the first time 7 Li-induced accelerator based production of 71,72,73,74 As, 75,76,77 Br and 73,75 Se radionuclides in their no-carrier-added (nca) state. After the decay of all short-lived radionuclides 75 Se and 73 As were only existing radionuclides in germanium oxide target, which were subsequently separated by liquid-liquid extraction (LLX) using trioctylamine (TOA) dissolved in cyclohexane as liquid ion exchanger. The presence of stable germanium in various fractions was examined by Inductively Coupled Plasma Optical Spectrometry (ICP-OES). At 0.1 M TOA and 10 M HCl concentration, 75 Se and stable Ge were extracted into the organic phase leaving 73 As in the aqueous phase. The bulk Ge was stripped back to the aqueous phase by 1 M NaOH, keeping 75 Se in the organic phase. Therefore complete separation between 73 As, 75 Se and bulk Ge was achieved. (orig.)

  1. Automated chemoenzymatic synthesis of no-carrier-added [carbonyl-11C]propionyl L-carnitine for pharmacokinetic studies

    International Nuclear Information System (INIS)

    Davenport, R.J.; Pike, V.W.; Dowsett, K.; Turton, D.R.; Poole, K.

    1997-01-01

    Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t 1/2 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [ 11 C]propionyl chloride as labelling agent via 11 C-carboxylation of ethylmagnesium bromide with cyclotron-produced [ 11 C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [ 11 C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [ 11 C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [ 11 C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier added (NCA) level of specific radioactivity. [ 11 C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [ 11 C]carbon dioxide and hydrolysis. NCA [ 11 C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [ 11 C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [ 11 C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [ 11 C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [ 11 C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [ 11 C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo. (Author)

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

    International Nuclear Information System (INIS)

    Rolleman, Edgar J.; Krenning, Eric P.; Bernard, Bert F.; Visser, Monique de; Bijster, Magda; Jong, Marion de; Visser, Theo J.; Vermeij, Marcel; Lindemans, Jan

    2007-01-01

    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 [ 177 Lu-DOTA 0 ,Tyr 3 ]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 [ 177 Lu-DOTA 0 ,Tyr 3 ]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 [ 177 Lu-DOTA 0 ,Tyr 3 ]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; p 177 Lu-DOTA 0 ,Tyr 3 ]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.)

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

    International Nuclear Information System (INIS)

    Schüler, Emil; Rudqvist, Nils; Parris, Toshima Z.; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

    2014-01-01

    Introduction: The kidneys are one of the main dose limiting organs in 177 Lu-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 177 Lu-octreotate exposure. Methods: Female Balb/c nude mice were i.v. injected with 1.3, 3.6, 14, 45 or 140 MBq 177 Lu-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 177 Lu-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

  4. Development of a lyophilized formulation for preparing the radiopharmaceutical 177Lu-DOTA-Anti-CD20

    International Nuclear Information System (INIS)

    Serrano E, L. A.

    2015-01-01

    The radiolabeled proteins are molecules of interest in nuclear medicine for their diagnostic and therapeutic application in cancer. Antibodies, such as chimeric monoclonal antibody Anti-CD20 rituximab, have established themselves as suitable vectors of radionuclides (e.g. 177 Lu) , introducing high affinity by the surface antigens over- expressed and widely distributed in cells involved in certain diseases. The aim of this work was to design, optimize and document the production process of radiopharmaceutical 177 Lu-DOTA-Anti-CD20 for sanitary registration request to the Comision Federal para la Proteccion contra Riesgos Sanitarios (COFEPRIS). First, a raw material analysis using the Ft-Mir technique and gamma spectrometry was performed. Then, was carried out the development of the lyophilized formulation for the preparation of 177 Lu-DOTA-Anti-CD20, in which an ANOVA was performed where the dependent variable was the radiochemical purity. The optimal pharmaceutical formulation was: 5 mg DOTA-CD20 and 80 mg Mannitol to be reconstituted with 1 m L of acetate buffer 0.25 M, ph 7, with an incubation time of 15 min at 37 degrees Celsius in a dry bath. Once completed the development of the lyophilized formulation, we proceeded to the optimization of the production process, development and validation of the analytical method. Three batches were prepared under protocols of Good Manufacturing Practice, which met pre-established specifications as sterile and endotoxin-free of bacterial formulations, with greater that 95% of radiochemical purity. Currently, is conducting the study of shelf stability. Upon completion of the stability studies, the legal record of 177 Lu-DOTA-Anti-CD20 will be integrated with documented evidence of the quality and stability of the formulation of this radiopharmaceutical. (Author)

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

    International Nuclear Information System (INIS)

    Rodriguez C, J.; Murphy, C.A. de; Pedraza L, M.; Ferro F, G.; Murphy S, E.

    2006-01-01

    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 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 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 177 Lu-DOTA-TATE will act as expected in man considering its kidney radiotoxicity. (Author)

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

    International Nuclear Information System (INIS)

    Romer, A.; Seiler, D.; Brunner, P.; Ng, Q.K.T.; Mueller-Brand, J.; Marincek, N.; Walter, M.A.; Koller, M.T.; Maecke, H.R.; Rochlitz, C.; Briel, M.; Schindler, C.

    2014-01-01

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90 Y or 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 [ 90 Y-DOTA]-TOC or [ 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 [ 90 Y-DOTA]-TOC and 141 patients underwent 259 cycles of [ 177 Lu-DOTA]-TOC. The median survival after [ 177 Lu-DOTA]-TOC and after [ 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 [ 177 Lu-DOTA]-TOC over [ 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 [ 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 [ 177 Lu-DOTA]-TOC and [ 90 Y-DOTA]-TOC. Furthermore, [ 177 Lu-DOTA]-TOC was less haematotoxic than [ 90 Y-DOTA]-TOC. (orig.)

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

    Science.gov (United States)

    Romer, A; Seiler, D; Marincek, N; Brunner, P; Koller, M T; Ng, Q K T; Maecke, H R; Müller-Brand, J; Rochlitz, C; Briel, M; Schindler, C; Walter, M A

    2014-02-01

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides (90)Y or (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 [(90)Y-DOTA]-TOC or [(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 [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(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 [(177)Lu-DOTA]-TOC over [(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 [(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 [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.

  8. Internal radiotherapy and dosimetric study for 111In/177Lu-pegylated liposomes conjugates in tumor-bearing mice

    International Nuclear Information System (INIS)

    Wang, H.-E.; Yu, H.-M.; Lu, Y.-C.; Heish, N.-N.; Tseng, Yun-Long; Huang, K.-L.; Chuang, K.-T.; Chen, Chin-Hsiung; Hwang, J.-J.; Lin, W.-J.; Wang, Shyh-Jen; Ting, G.; Whang-Peng, Jacqueline; Deng, W.-P.

    2006-01-01

    In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. Methods: The DTPA/PEG-liposomes were synthesized with a medium size of 110 nm, conjugated with 111 In/ 177 Lu-(oxine) 3 to afford 111 In/ 177 Lu-liposome. The stability of 111 In/ 177 Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of 111 In/ 177 Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. Results: The incorporation efficiency of 111 In/ 177 Lu into liposomes was 95%. After incubation at 37 o C for 72 h in serum, more than 83% of radioactivity was still retained in the intact 111 In/ 177 Lu-liposomes. The biodistribution of 111 In-liposomes showed that the radioactivity in the blood decreased from 23.14±8.16%ID/g at 1 h to 0.02±0.00%ID/g at 72 h post-injection (p.i.), while reaching its maximum accumulation in tumors at 48 h p.i., with half-life in blood of 10.2 h. The results were supported by that of 177 Lu-liposomes. Scintigraphic imaging with 111 In-liposomes showed unambiguous tumor images at 48 h p.i. Dose estimation showed that the absorbed dose in tumor from 177 Lu-liposomes was 5.74x10 -5 Gy/MBq. Conclusions: This study provides an in vivo characterization and dosimetric evaluation for the use of liposome systems as carriers in targeted radionuclide therapy. The results suggest that adequate tumor targeting as well as dose delivered to tumors could be achieved by the use of radionuclide targeted liposomes

  9. Somatostatin-based Radiopeptide Therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in Neuroendocrine Tumors

    OpenAIRE

    Romer A Seiler D Marincek N Brunner P Koller MT Ng QK Maecke HR Muller-Brand J Rochlitz C B

    2014-01-01

    PURPOSE: Somatostatin based radiopeptide treatment is generally performed using the ß emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. METHODS: In a comparative cohort study patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y DOTA] TOC or [(177)Lu DOTA] TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were emplo...

  10. Metastatic Bone Pain Palliation using 177Lu-Ethylenediaminetetramethylene Phosphonic Acid

    International Nuclear Information System (INIS)

    Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R.; Bahrami-Samani, Ali

    2015-01-01

    177 Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177 Lu-EDTMP for MBP palliation. 177 Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177 Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177 Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for

  11. Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid.

    Science.gov (United States)

    Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R; Bahrami-Samani, Ali

    2015-01-01

    (177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using (177)Lu-EDTMP for MBP palliation. (177)Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. (177)Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. (177)Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for

  12. Metastatic Bone Pain Palliation using 177Lu-Ethylenediaminetetramethylene Phosphonic Acid

    Science.gov (United States)

    Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R.; Bahrami-Samani, Ali

    2015-01-01

    177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177Lu-EDTMP for MBP palliation. 177Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  14. Studies on low-carrier radiofluorination of non-active aromatics with no-carrier-added [18F]fluoride

    International Nuclear Information System (INIS)

    Cardinale, Jens

    2013-01-01

    In vivo imaging with positron emission tomography generally demands radiotracers with a high specific activity. In case of fluorine-18 the required no-carrier-added (n.c.a.) starting material is only available in form of fluoride. This and the short half-life of 109.7 minutes of the radionuclide lead to the demand of special methods for radiosyntheses. The only practical procedure for manufacturing n.c.a. [ 18 F]fluoro-compounds is therefore nucleophilic substitution. There is, however, still a lack of effective procedures for the labelling of electron rich aromatic molecules starting from n.c.a. [ 18 F]fluoride. A process for n.c.a. radiofluorination of these compounds is offered by the reaction of iodonium compounds as starting materials. In this study modern procedures for the synthesis of iodoniumsalts and -ylides were investigated. Several precursor molecules for the versatile synthetic building block 4-[ 18 F]fluoroiodobenzene were synthesised. In this course, a new one-pot procedure for the synthesis of iodoniumylides was developed. Further on, the syntheses of suitable iodonium precursors for two fluorophenoxy-derivatives, which are possible antidepressants, were investigated. Due to their binding profile these compounds can be considered as ligands for the serotonin reuptake transporter (SERT) and the norepinephrin reuptake transporter (NET), respectively. The preparation of appropriate iodonium salts proved to be too problematic, while the synthesis of suitable iodoniumylides could be accomplished with satisfactory yields of about 30% and 40 %, respectively. Both compounds were labelled with n.c.a. [ 18 F]fluoride and deprotected to the desired target compounds 4-((3-[ 18 F]fluorophenoxy)(phenyl)methyl)piperidine and 4-((4-[ 18 F]fluorophenoxy)(phenyl)methyl)piperidine in radiochemical yields of about 40 % and 25 %, respectively. Those are now available for preclinical evaluation studies. Furthermore, a process for the palladium catalysed synthesis of 18

  15. Antitenascin antibody 81C6 armed with {sup 177}Lu: in vivo comparison of macrocyclic and acyclic ligands

    Energy Technology Data Exchange (ETDEWEB)

    Yordanov, Alexander T. [Department of Radiology, Duke University Medical Center Durham, NC 27710 (United States); Hens, Marc [Department of Radiology, Duke University Medical Center Durham, NC 27710 (United States); Pegram, Charles [Department of Pathology, Duke University Medical Center Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center Durham, NC 27710 (United States)]. E-mail: zalut001@mc.duke.edu

    2007-02-15

    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 {gamma}-ray properties, lutetium-177 might be a better low-energy {beta}-emitter for this type of therapy. Materials and Methods: Chimeric 81C6 (ch81C6) was labeled with {sup 177}Lu 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 {sup 177}Lu-labeled immunoconjugates plus {sup 125}I-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-{sup 177}Lu and {sup 125}I-labeled ch81C6, and ch81C6-MeO-DOTA-{sup 177}Lu and {sup 125}I-labeled ch81C6. Similar comparisons were done using murine (mu) instead of ch81C6. The primary parameter utilized for evaluation was the {sup 177}Lu/{sup 125}I uptake ratio in each tissue. Results: In the studies performed in normal mice, the NHS-DOTA ligand yielded the highest {sup 177}Lu/{sup 125}I uptake ratios in tissues indicative of loss of label from the chelate; for this reason, only 1B4M and MeO-DOTA were evaluated further. The {sup 177}Lu/{sup 125}I ratio in bone increased gradually with time for the chimeric conjugates; however, there were no significant differences between ch81C6-1B4M-DTPA-{sup 177}Lu and ch81C6-MeO-DOTA-{sup 177}Lu. In contrast, mu81C6-1B4M-DTPA-{sup 177}Lu and mu81C6-MeO-DOTA-{sup 177}Lu showed a more dramatic increase in the {sup 177}Lu/{sup 125}I 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 {sup 177}Lu from these

  16. 68Ga/177Lu-labeled DOTA-TATE shows similar imaging and biodistribution in neuroendocrine tumor model.

    Science.gov (United States)

    Liu, Fei; Zhu, Hua; Yu, Jiangyuan; Han, Xuedi; Xie, Qinghua; Liu, Teli; Xia, Chuanqin; Li, Nan; Yang, Zhi

    2017-06-01

    Somatostatin receptors are overexpressed in neuroendocrine tumors, whose endogenous ligands are somatostatin. DOTA-TATE is an analogue of somatostatin, which shows high binding affinity to somatostatin receptors. We aim to evaluate the 68 Ga/ 177 Lu-labeling DOTA-TATE kit in neuroendocrine tumor model for molecular imaging and to try human-positron emission tomography/computed tomography imaging of 68 Ga-DOTA-TATE in neuroendocrine tumor patients. DOTA-TATE kits were formulated and radiolabeled with 68 Ga/ 177 Lu for 68 Ga/ 177 Lu-DOTA-TATE (M-DOTA-TATE). In vitro and in vivo stability of 177 Lu-DOTA-TATE were performed. Nude mice bearing human tumors were injected with 68 Ga-DOTA-TATE or 177 Lu-DOTA-TATE for micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging separately, and clinical positron emission tomography/computed tomography images of 68 Ga-DOTA-TATE were obtained at 1 h post-intravenous injection from patients with neuroendocrine tumors. Micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging of 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE both showed clear tumor uptake which could be blocked by excess DOTA-TATE. In addition, 68 Ga-DOTA-TATE-positron emission tomography/computed tomography imaging in neuroendocrine tumor patients could show primary and metastatic lesions. 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE could accumulate in tumors in animal models, paving the way for better clinical peptide receptor radionuclide therapy for neuroendocrine tumor patients in Asian population.

  17. 177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: Synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model

    International Nuclear Information System (INIS)

    Ogbomo, Sunny M.; Shi, Wen; Wagh, Nilesh K.; Zhou, Zhengyuan; Brusnahan, Susan K.; Garrison, Jered C.

    2013-01-01

    Introduction: A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods: In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177 Lu, the peptide–polymer conjugates were renamed 177 Lu-metabolically active copolymers ( 177 Lu-MACs) with the corresponding designations: 177 Lu-MAC0, 177 Lu-MAC1 and 177 Lu-MAC2. Results: In vivo evaluation of the 177 Lu-MACs was performed in an HPAC human pancreatic cancer xenograft mouse model. 177 Lu-MAC1 and 177 Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control ( 177 Lu-MAC0) at 72 h post-injection. With regard to spleen retention, 177 Lu-MAC1 and 177 Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72 h time point. However, the tumor accumulation of the 177 Lu-MAC0 was two to three times greater than 177 Lu-MAC1 and 177 Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177 Lu-labeled HPMA copolymers. Conclusions: While further studies are needed to optimize the

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

    International Nuclear Information System (INIS)

    Hassan Yousefnia; Amir Reza Jalilian; Ali Bahrami-Samani; Simindokht Shirvani-Arani; Mohammad Ghannadi-Maragheh; Azim Arbabi; Edalat Radfar

    2011-01-01

    Rituximab was successively labeled with 177 Lu-lutetium chloride. 177 Lu chloride was obtained by thermal neutron flux (4 x 1013 n cm -2 s -1 ) of natural Lu 2 O 3 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 CH 2 Cl 2 . 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 177 Lu-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)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  20. Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody.

    Science.gov (United States)

    D'Huyvetter, Matthias; Vincke, Cécile; Xavier, Catarina; Aerts, An; Impens, Nathalie; Baatout, Sarah; De Raeve, Hendrik; Muyldermans, Serge; Caveliers, Vicky; Devoogdt, Nick; Lahoutte, Tony

    2014-01-01

    RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles. Smaller radiolabeled antibody fragments and peptides feature highly specific target accumulation, resulting in low accumulation in healthy tissue, except for the kidneys. Nanobodies are the smallest (MWnanobodies is predominantly dictated by the number of polar residues in the C-terminal amino acid tag. Three nanobodies were produced with different C-terminal amino-acid tag sequences (Myc-His-tagged, His-tagged, and untagged). Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70% drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i.. In addition, coinfusion of untagged nanobodies with the plasma expander Gelofusin led to a final reduction of 90%. Similar findings were obtained with different 177Lu-DTPA-2Rs15d nanobody constructs in HER2pos tumor xenografted mice at 1 h p.i.. Kidney accumulation decreased 88% when comparing Myc-His-tagged to untagged 2Rs15d nanobody, and 95% with a coinfusion of Gelofusin, without affecting the tumor targeting capacity. Consequently, we identified a generic method to reduce kidney retention of radiolabeled nanobodies. Dosimetry calculations of Gelofusin-coinfused, untagged 177Lu-DTPA-2Rs15d revealed a dose of 0.90 Gy/MBq that was delivered to both tumor and kidneys and extremely low doses to healthy tissues. In a comparative study, 177Lu-DTPA-Trastuzumab supplied 6 times more radiation to the tumor than untagged 177Lu-DTPA-2Rs15d, but concomitantly also a 155, 34, 80, 26 and 4180 fold higher radioactivity burden to lung, liver, spleen, bone and blood. Most importantly, nanobody-based targeted radionuclide therapy in mice bearing small estiblashed HER2pos tumors led to an almost complete blockade of tumor growth and a significant difference in event-free survival

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  2. Direct no-carrier-added 18F-labelling of arenes via nucleophilic substitution on aryl(2-thienyl)iodonium salts

    International Nuclear Information System (INIS)

    Ross, T.L.

    2006-01-01

    For in vivo imaging of molecular processes via positron emission tomography (PET) radiotracers of high specific activity are demanded. In case of the most commonly used positron emitter fluorine-18, this is only achievable with no-carrier-added [ 18 F]fluoride, which implies nucleophilic methods of 18 F-substitution. Whereas electron deficient aromatic groups can be labelled in one step using no-carrier-added [ 18 F]fluoride, electron rich 18 F-labelled aromatic molecules are only available by multi-step radiosyntheses or carrier-added electrophilic reactions. Here, diaryliodonium salts represent an alternative, since they have been proven as potent precursor for a direct nucleophilic 18 F-introduction into aromatic molecules. Furthermore, as known from non-radioactive studies, the highly electron rich 2-thienyliodonium leaving group leads to a high regioselectivity in nucleophilic substitution reactions. Consequently, a direct nucleophilic no-carrier-added 18 F-labelling of electron rich arenes via aryl(2-thienyl)iodonium precursors was developed in this work. The applicability of direct nucleophilic 18 F-labelling was examined in a systematic study on eighteen aryl(2-thienyl)iodonium salts. As electron rich precursors the ortho-, meta- and para-methoxyphenyl(2-thienyl)iodonium bromides, iodides, tosylates and triflates were synthesised. In addition, para-substituted (R=BnO, CH 3 , H, Cl, Br, I) aryl(2-thienyl)iodonium bromides were prepared as precursors with a systematically varying electron density. As first approach, the general reaction conditions of the nucleophilic 18 F-substitution procedure were optimised. The best conditions for direct nucleophilic no-carrier-added 18 F-labelling via aryl(2-thienyl)iodonium salts were found with dimethylformamide as solvent, a reaction temperature of 130±3 C and 25 mmol/l as concentration of the precursor. (orig.)

  3. Direct no-carrier-added {sup 18}F-labelling of arenes via nucleophilic substitution on aryl(2-thienyl)iodonium salts

    Energy Technology Data Exchange (ETDEWEB)

    Ross, T L

    2006-01-15

    For in vivo imaging of molecular processes via positron emission tomography (PET) radiotracers of high specific activity are demanded. In case of the most commonly used positron emitter fluorine-18, this is only achievable with no-carrier-added [{sup 18}F]fluoride, which implies nucleophilic methods of {sup 18}F-substitution. Whereas electron deficient aromatic groups can be labelled in one step using no-carrier-added [{sup 18}F]fluoride, electron rich {sup 18}F-labelled aromatic molecules are only available by multi-step radiosyntheses or carrier-added electrophilic reactions. Here, diaryliodonium salts represent an alternative, since they have been proven as potent precursor for a direct nucleophilic {sup 18}F-introduction into aromatic molecules. Furthermore, as known from non-radioactive studies, the highly electron rich 2-thienyliodonium leaving group leads to a high regioselectivity in nucleophilic substitution reactions. Consequently, a direct nucleophilic no-carrier-added {sup 18}F-labelling of electron rich arenes via aryl(2-thienyl)iodonium precursors was developed in this work. The applicability of direct nucleophilic {sup 18}F-labelling was examined in a systematic study on eighteen aryl(2-thienyl)iodonium salts. As electron rich precursors the ortho-, meta- and para-methoxyphenyl(2-thienyl)iodonium bromides, iodides, tosylates and triflates were synthesised. In addition, para-substituted (R=BnO, CH{sub 3}, H, Cl, Br, I) aryl(2-thienyl)iodonium bromides were prepared as precursors with a systematically varying electron density. As first approach, the general reaction conditions of the nucleophilic {sup 18}F-substitution procedure were optimised. The best conditions for direct nucleophilic no-carrier-added {sup 18}F-labelling via aryl(2-thienyl)iodonium salts were found with dimethylformamide as solvent, a reaction temperature of 130{+-}3 C and 25 mmol/l as concentration of the precursor. (orig.)

  4. The research on biodistribution of bearing sarcoma mice and rabbit SPECT imaging of 177Lu-DOTMP

    International Nuclear Information System (INIS)

    Deng Xinrong; Xiang Xueqin; Li Fenglin; Fan Caiyun; Liu Zihua; Luo Zhifu; Chen Yang

    2012-01-01

    Cyclen (1, 4, 7, 10-tetraazacyclododecane) and H 3 PO 3 were used to synthesis DOTMP (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-Tetraaminomethylenephosphonate), and then DOTMP was labelled with 177 Lu. The research of biodistribution of 177 Lu-DOTMP in model mice bearing S180 sarcoma and SPECT imaging in Japanese white rabbit were also carried out. The results of biodistribution of bearing S180 mice indicated that 177 Lu-DOTMP cleared rapidly from blood and was selectively delivered to target bone. The radioactivity uptake was mainly in bone and less in other organs and tissues. The results of SPECT imaging of Japanese white rabbit showed that the radioactivity was accumulated in bladder. 177 Lu-DOTMP was mainly excreted by kidney. The uptake of the activity in the skeleton was observed significantly within 22 h post-injection and it became quite significant at 46 h post-injection. It indicated that 177 Lu-DOTMP has good bone targeting and is worthy of further study. (authors)

  5. Green methods for the radiochemical separations of no-carrier-added 61Cu, 62Zn from 7Li irradiated cobalt target

    International Nuclear Information System (INIS)

    Moumita Maiti; Kaustab Ghosh; Susanta Lahiri

    2015-01-01

    A nat Co target was irradiated with 47 MeV 7 Li beam to produce no-carrier-added 61 Cu, 62 Zn in the target matrix. Two new green radiochemical methods were developed for separation of 61 Cu and 62 Zn from the target matrix, (i) liquid-liquid extraction (LLX) technique using room temperature ionic liquid (RTIL) 1-butyl-3-methylimidazolium hexafluorophosphate ([C 4 mim][PF 6 ]) and ammonium pyrrolidinedithiocarbamate (APDC) (ii) adsorption on calcium alginate beads. (author)

  6. Use of liquid chromatography for separation and determination of carrier species associated with the synthesis of no carrier-added sup(11)C labelled compounds

    International Nuclear Information System (INIS)

    Emran, Ali M.; Boothe, Th.E.; Finn, R.D.; Vora, M.M.; Kothari, P.J.

    1985-01-01

    An analytical technique using reversed-phase liquid chromatography was developed for the determination of urea at quantities as low as 1 ng to quantitate the amount of non-labelled urea produced during the synthesis of no-carrier-added [sup(11)C] urea starting from sup(11)CNsup(-). As a result, the specific activity of the [sup(11)C] urea thus prepared was calculated to be as high as 3.5+-0.8 Ci/μmol. (author)

  7. 177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

    Directory of Open Access Journals (Sweden)

    Ada H V Repetto-Llamazares

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

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

    International Nuclear Information System (INIS)

    Murphy, M. A de; Pedraza L, M.; Rodriguez C, J.; Ferro F, G.; Murphy S, E.

    2006-01-01

    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 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 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- 177 -DOTA-TATE will act as expected in man, considering kidney radiation. (Author)

  9. Preparation and biological evaluation of {sup 177}Lu conjugated PR81 for radioimmunotherapy of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Salouti, Mojtaba, E-mail: saloutim@yahoo.com [Department of Biology, Faculty of Sciences, Zanjan Branch, Islamic Azad University, Zanjan 45156-58145 (Iran, Islamic Republic of); Babaei, Mohammad Hossein [Nuclear Biomolecule Laboratory, Radioisotope Department, Nuclear Science and Technology Research Institute, Tehran 14144-1339 (Iran, Islamic Republic of); Rajabi, Hossein [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14115-111 (Iran, Islamic Republic of); Rasaee, Mohammad javad [Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14115-111 (Iran, Islamic Republic of)

    2011-08-15

    Aim: PR81 is a monoclonal antibody that binds with high affinity to MUC1 antigen that is over expressed in 80% of breast cancers. In this study, we developed a method for indirect labeling of PR81 with lutetium-177 and performed all preclinical qualifications in production of a biologic agent for radioimmunotherapy of breast cancer. Materials and Methods: The radiochemical purity and in vitro stability of {sup 177}Lu labeled PR81 was determined by instant thin layer chromatography. The immunoreactivity and cell toxicity of the complex were tested on MCF7 cell line. The biodistribution and scintigraphy studies were performed in BALB/c mice with breast tumor. Results: The radiochemical purity was 91.2{+-}3.8% after 2 h. The in vitro stabilities in phosphate buffer and human blood serum were 83.1{+-}3.4% and 76.2{+-}3.6% at 96 h, respectively. The immunoreactivity of the complex was 83.4{+-}2.4%. The cell toxicity study showed that the complex inhibited 85.2{+-}3.4% growth of MCF7 cells at a concentration of 2500 ng/ml after 96 h. The biodistribution and scintigraphy studies showed the accumulation of the complex at the site of tumors with high sensitivity and specificity. Conclusion: The results showed that one may consider {sup 177}Lu-DOTA-PR81 as a potential radiopharmaceutical for therapy of human breast cancer, which needs further investigations.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. Radiosynthesis and preclinical studies of 177Lu-labeled sulfadiazine. A possible theranostic agent for deep-seated bacterial infection

    International Nuclear Information System (INIS)

    Syed Ali Raza Naqvi; Rashid Rasheed; Muhammad Tauqeer Ahmed; Ameer Fawad Zahoor

    2017-01-01

    Sulfadiazine acts through inhibition of bacterial dihydropteroate synthetase. The radio-labeling of sulfadiazine with lutetium-177 ( 177 Lu) is expected to serve as a theranostic agent for deep-seated bacterial infections. The radiosynthesis of 177 Lu-sulfadiazine indicated a > 95% yield under optimized reaction conditions, and promising stability was found in blood serum. Biodistribution data in the absence of infection revealed minimal accumulation in key body organs. Kidneys were the main excretory organs, showed an uptake of 1.76 ± 0.09% ID/g organ at 6-h post-injection. Biodistribution, scintigraphic data, glomerular filtration rate, and cytotoxicity results encourage clinical investigation of 177 Lu-sulfadiazine as a novel theranostic agent for deep-seated bacterial infection. (author)

  12. Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after 177Lu[Lu]-octreotate therapy.

    Science.gov (United States)

    Spetz, Johan; Rudqvist, Nils; Langen, Britta; Parris, Toshima Z; Dalmo, Johanna; Schüler, Emil; Wängberg, Bo; Nilsson, Ola; Helou, Khalil; Forssell-Aronsson, Eva

    2018-05-01

    Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with 177 Lu[Lu]-octreotate. Despite being highly effective in animal models, 177 Lu[Lu]-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for 177 Lu[Lu]-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice. GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq 177 Lu[Lu]-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed. Distribution of differentially expressed transcripts indicated a time-dependent treatment response in GOT1 tumors after 177 Lu[Lu]-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively. Transcriptional analysis showed radiation-induced apoptosis as an early response after 177 Lu[Lu]-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents. Copyright © 2018 The Authors. Published by Elsevier Inc. All

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

    International Nuclear Information System (INIS)

    Rolleman, Edgar J.; Forrer, Flavio; Bernard, Bert; Bijster, Magda; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de; Vermeij, Marcel

    2007-01-01

    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 [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate. Male Lewis rats were injected with 278 or 555 MBq [ 177 Lu-DOTA 0 ,Tyr 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 99m Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [ 177 Lu-DOTA 0 ,Tyr 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 [ 177 Lu-DOTA 0 ,Tyr 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 99m Tc-DMSA SPECT scintigrams at 130 days after [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate therapy correlated well with 1/creatinine (r 2 = 0.772, p 177 Lu-DOTA 0 ,Tyr 3 ]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy. (orig.)

  14. Preparation and in vitro evaluation of 177Lu-iPSMA-RGD as a new heterobivalent radiopharmaceutical

    International Nuclear Information System (INIS)

    Escudero-Castellanos, Alondra; Universidad Autonoma del Estado de Mexico, Toluca, Estado de Mexico; Ocampo-Garcia, B.E.; Ferro-Flores, Guillermina; Santos-Cuevas, C.L.; Isaac-Olive, Keila; Olmos-Ortiz, Andrea; Garcia-Quiroz, Janice; Garcia-Becerra, Rocio; Diaz, Lorenza

    2017-01-01

    This study aimed to synthesize a new 177 Lu-iPSMA-RGD heterobivalent radiopharmaceutical, as well as to assess the in vitro radiopharmaceutical potential to target cancer cells overexpressing PSMA and α(v) β(3) integrins. The radiotracer prepared with a radiochemical purity of 98.8 ± 1.0% showed stability in human serum, specific recognition with suitable affinity to PSMA and α(v)β(3) integrins, and capability to inhibit cancer cell proliferation and VEGF signaling (antiangiogenic effect). Results warrant further preclinical studies to establish the 177 Lu-iPSMA-RGD potential as a dual therapeutic radiopharmaceutical. (author)

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

    International Nuclear Information System (INIS)

    Mathe, Domokos; Balogh, Lajos; Polyak, Andras; Kiraly, Reka; Marian, Terez; Pawlak, Dariusz; Zaknun, John J.; Pillai, Maroor R.A.; Janoki, Gyozo A.

    2010-01-01

    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 β- energy, 177 Lu [T 1/2 =6.73 days, E βmax =497 keV, E γ =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 177 Lu-EDTMP to collect preclinical data for starting human clinical trials. Methods: 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 177 Lu-EDTMP were injected in four groups of three dogs each to study the toxicological effects. Results: 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 177 Lu-EDTMP in bone supports that modifying the EDTMP molecule by introducing 177 Lu does not alter its biological behaviour as a specific bone-seeking tracer. Species-specific pharmacokinetic behavior

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  18. Development of a therapeutic radiopharmaceutical {sup 177}Lu-DOTA- Minigastrin for potential use in PRRT; Desarrollo de un radiofarmaco terapeutico {sup 177}Lu-DOTA-Minigastrina para su potencial uso en PRRT

    Energy Technology Data Exchange (ETDEWEB)

    Lopez Bularte, A. C.; Nevares, N. N.; Zapata, A. M.; Perez, J. H.; Crudo, J. L. [Comision Nacional de Energia Atomica (Argentina); Puerta Yepes, N.; Rojo, A. M. [Autoridad Regulatoria Nuclear (Argentina)

    2010-07-01

    The aim of this work is to obtain {sup 177}Lu-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) {sup 177}LuCl{sub 3} of an intermediate level of Ae (between 6.36 to 17.95 Ci/mg of {sup 176}Lu) ) and also to perform in vitro and in vivo stability tests, dose calculation in normal mice and its extrapolation to a human model. (authors) [Spanish] El objetivo de este trabajo consistio en obtener {sup 177}Lu-DOTA-Minigastrina con una alta pureza radioquimica (PR) y la mayor actividad especifica (Ae) posible, empleando {sup 177}LuCl{sub 3} de media Ae (entre 6,36-17,95 Ci/mg de {sup 176}Lu) de produccion local (Reactor Nuclear RA-3, Centro Atomico Ezeiza), y realizar los ensayos de estabilidad in vitro e in vivo, el calculo de dosis en ratones normales y su extrapolacion a un modelo humano. (autores)

  19. Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination with Docetaxel

    National Research Council Canada - National Science Library

    Vallabhajosula, Shankar

    2007-01-01

    Phase I dose escalation studies with 177Lu-DOTA-huJ591 using dose fractionation regimen will be performed in patients with PCa and who have recurrent and/or metastatic disease. The 177Lu dose (20-45 mCi/m2...

  20. Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination With Docetaxel

    National Research Council Canada - National Science Library

    Vallabhajosula, Shankar

    2006-01-01

    Phase I dose escalation studies with 177Lu-DOTA-huJ591 using dose fractionation regimen will be performed in patients with PCa and who have recurrent and/or metastatic disease. The 177Lu dose (20-45 mCi/m2...

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

    International Nuclear Information System (INIS)

    Oliva González, Juan P.; Baum, Richard

    2016-01-01

    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 90 Y as 177 Lu. (author)

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

    International Nuclear Information System (INIS)

    Nguyen Thanh Binh; Dang Ho Hong Quang; Duong Van Dong; Chu Van Khoa; Nguyen Thi Hien

    2011-01-01

    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 177 Lu, 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)

  3. Alternative labelling of the cocaine analogue isomers α-CIT and β-CIT by direct iodination with no-carrier-added Na125I

    International Nuclear Information System (INIS)

    Mueller, L.; Foged, C.; Halldin, C.; Swahn, C.-G.

    1994-01-01

    An alternative labelling of the cocaine analogue isomers α-CIT and β-CIT with no-carrier-added 125 I by direct iodination of 2α- and 2β-carbomethoxy-3β-phenyltropane with Na 125 I/sulfuric acid/nitric acid/acetic acid and peracetic acid under different reaction conditions, is described. The maximum radiolabelling yield obtained with the two isomers was 48% for [ 125 I]α-CIT and 28% for [ 125 I]β-CIT. (author)

  4. 177Lu-DTPA-BIS-BIOTIN Binding of Octreotide-dextran-avidinated PANC-1 Cell Lines in Vitro

    International Nuclear Information System (INIS)

    Deng Xinrong; Zhai Shizhen; Shen Yijia; Luo Zhifu; Du Jin

    2011-01-01

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

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

    Czech Academy of Sciences Publication Activity Database

    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

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

    International Nuclear Information System (INIS)

    Forrer, Flavio; Mueller-Brand, Jan; Chen, Jianhua; Fani, Melpomeni; Powell, Pia; Maecke, Helmut R.; Lohri, Andreas; Moldenhauer, Gerhard

    2009-01-01

    131 I- and 90 Y-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 ( 177 Lu or 90 Y. 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 10 5 times excess of diethylenetriaminepentaacetic acid (DTPA, 37 C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m 2 body surface 177 Lu-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 177 Lu-DOTA-rituximab was tolerated well. Our results show that DOTA-rituximab (4:1) can be labelled with 177 Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177 Lu-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.)

  7. Preparation and bioevaluation of {sup 177}Lu-labelled anti-CD44 for radioimmunotherapy of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, So Young; Hong, Young Don; Jung, Sung Hee; Choi, Sun Ju [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-12-15

    CD44 is a particular adhesion molecule and facilitates both cell-cell and cell-matrix interactions. In particular, splice variants of CD44 are particularly overexpressed in a large number of malignancies and carcinomas. In this study, the {sup 177}Lu-labelled CD44 targeting antibody was prepared and bioevaluated in vitro and in vivo. Anti-CD44 was immunoconjugated with the equivalent molar ratio of cysteine-based dtPA-ncS and radioimmunoconjugated with {sup 177}Lu at room temperature within 15 minutes. the stability was tested in human serum. An in vitro study was carried out in Ht-29 human colon cancer cell lines. For the biodistribution study {sup 177}Lu-labelled anti-CD44 was injected in xenograft mice. Anti-CD44 was immunoconjugated with cysteinebased dtPA-ncS and purified by a centricon filter system having a molecular cut-off of 50 kda. radioimmunoconjugation with {sup 177}Lu was reacted for 15 min at room temperature. the radiolabeling yield was >99%, and it was stable in human serum without any fragmentation or degradation. The radioimmunoconjugate showed a high binding affinity on HT-29 colon cancer cell surfaces. In a biodistribution study, the tumor-to-blood ratio of the radioimmunoconjugate was 43 : 1 at 1 day post injection (p.i) in human colon cancer bearing mice. the anti-CD44 monoclonal antibody for the targeting of colon cancer was effectively radioimmunoconjugated with {sup 177}Lu. the in vitro high immunoactivity of this radioimmunoconjugate was determined by a cell binding assay. In addition, the antibody's tumor targeting ability was demonstrated with very high uptake in tumors. this radioimmunoconjugate is applicable to therapy in human colon cancer with highly expressed CD44.

  8. An assessment tumor targeting ability of 177Lu labeled cyclic CCK analogue peptide by binding with cholecystokinin receptor

    Directory of Open Access Journals (Sweden)

    Eun-Ha Cho

    2016-07-01

    Full Text Available The cholecystokinin (CCK receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2 (DOTA-[Nle]-cCCK, were synthesized and radiolabeled with 177Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for 177Lu-labeling, in which the peptides were radiolabeled with 177Lu by a high radiolabeling yield. A competitive displacement of 125I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50 was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that 177Lu-DOTA-[Nle]-cCCK has higher binding affinity than 177Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors.

  9. The synthesis of no-carrier-added [11C]urea from [11C]carbon dioxide and application to [11C]uracil synthesis

    International Nuclear Information System (INIS)

    Chakraborty, P.K.; Mangner, T.J.; Chugani, H.T.

    1997-01-01

    No-carrier-added [ 11 C]urea has been synthesized by bubbling cyclotron-produced [ 11 C]-carbon dioxide directly into a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide, followed by hydrolysis of the C-11 labeled adduct with aqueous ammonium chloride. Using this simple, one-pot method, [ 11 C]urea was produced in 55-70% radiochemical yield (decay-corrected) in 16 min following end-of-bombardment (or in 10 min following the introduction of the [ 11 C]carbon dioxide. The [ 11 C]urea thus produced was converted to [ 11 C]uracil (carrier-added) in 40-75% decay-corrected radiochemical yield by condensation with diethyl malate in presence of fuming sulfuric acid. (author)

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

    International Nuclear Information System (INIS)

    Hippeläinen, E; Tenhunen, M; Sohlberg, A

    2015-01-01

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

    Science.gov (United States)

    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. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Personalized {sup 177}Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Del Prete, Michela; Buteau, Francois-Alexandre; Beauregard, Jean-Mathieu [Laval Univ., QC (Canada). Dept. of Radiology and Nuclear Medicine, and Cancer Research Center; CHU de Quebec - Laval Univ., QC (Canada). Dept. of Medical Imaging, and Oncology Branch of Research Center

    2017-08-15

    Peptide receptor radionuclide therapy (PRRT) with {sup 177}Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course. Thirty-six patients underwent 122 fixed-IA {sup 177}Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6 ± 2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 ± 5.5, 1.3 ± 0.8, and 114 ± 66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle. In the P-PRRT regime, cumulative IA could have been increased to 43.7 ± 16.5 GBq over four induction cycles (10.9 ± 5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 ± 2.5, 1.63 ± 0.61, and 163.4 ± 85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68-2.64-fold; P = 0.0013). By standardizing the renal absorbed dose delivered

  13. Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

    International Nuclear Information System (INIS)

    Edler von Eyben, Finn; Roviello, Giandomenico; Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo; Uprimny, Christian; Virgolini, Irene

    2018-01-01

    There is a controversy as to the relative efficacy of 177 Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether 177 Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported 177 Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with 177 Lu-PSMA RLT. The treatment with 177 Lu-PSMA-617 and 177 Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. 177 Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). 177 Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ 2 test). Median survival was longer after 177 Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for 177 Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ 2 test). As for patients with mCRPC, treatment with 177 Lu

  14. Third-line treatment and {sup 177}Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

    Energy Technology Data Exchange (ETDEWEB)

    Edler von Eyben, Finn [Center of Tobacco Control Research, Odense (Denmark); Roviello, Giandomenico [San Donato Hospital, Department of Oncology, Medical Oncology Unit, Arezzo (Italy); University of Trieste, Department Medical, Surgery, and Health Sciences, Trieste (Italy); Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo [Docrates Cancer Center, Helsinki (Finland); Uprimny, Christian; Virgolini, Irene [University Hospital Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

    2018-03-15

    There is a controversy as to the relative efficacy of {sup 177}Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether {sup 177}Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported {sup 177}Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with {sup 177}Lu-PSMA RLT. The treatment with {sup 177}Lu-PSMA-617 and {sup 177}Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. {sup 177}Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). {sup 177}Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ{sup 2} test). Median survival was longer after {sup 177}Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for {sup 177}Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ{sup 2

  15. Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, 125Sn–177Lu is superior to 90Y–177Lu in peptide receptor radiotherapy

    International Nuclear Information System (INIS)

    Walrand, Stephan; Hanin, François-Xavier; Pauwels, Stanislas; Jamar, François

    2012-01-01

    Clinical trials on 177 Lu– 90 Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace 90 Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1–25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for 93 Y, 90 Y and 125 Sn in combination with 177 Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75–25% combination of 177 Lu and 90 Y activity. However, 125 Sn– 177 Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. 125 Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics 125 Sn is the best RN for combination with 177 Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of 125 Sn-labelled somatostatin analogues. (paper)

  16. Formulation of an inhibitor radiopharmaceutical of prostatic antigen of {sup 177}Lu-Glu-Nh-CO-Nh-Lys membrane; Formulacion de un radiofarmaco inhibidor del antigeno prostatico de membrana {sup 177}Lu-Glu-NH-CO-NH-Lys

    Energy Technology Data Exchange (ETDEWEB)

    Ortega S, D.

    2015-07-01

    The prostate specific membrane antigen (PSMA) is a zinc metalloenzyme that is expressed on the cell membrane and highly expressed in prostate cancer. Recently, it has been demonstrated that the peptide sequence Glu-Nh-CO-Nh-Lys inhibit PSMA activity through an electrostatic interaction with the Zn. Several theragnostic radiopharmaceuticals with base in {sup 177}Lu have been developed for radiotherapy of specific molecular targets because gamma and beta emissions of the radionuclide (β = 0.498 MeV and γ= 0.133 MeV). However, there is currently no label a formulation for preparing a radiopharmaceutical of {sup 177}Lu-Glu-Nh-CO-Nh-Lys useful treatment of prostate cancer. The aim of this research was to optimize and document the process of production of the radiopharmaceutical {sup 177}Lu-Glu-Nh-CO-Nh-Lys for sanitary registration application before the Comision Federal para la Proteccion contra Riesgos Sanitarios (COFEPRIS). The optimization of the production process was assessed a factorial design of three variables with mixed levels (3 x 3 x 2) where the dependent variable is the radiochemical purity, the analytical method was validated by UV-Vis spectrophotometry. Next, process validation was carried out by labeling 3 lots of the optimized formulation of the radiopharmaceutical (5.55 GBq (2.16 μg) of {sup 177}LuCl{sub 3}, 90 mg peptide PSMA, 50 mg ascorbic acid and 150 μL of acetate buffer 1 M ph 5), long-term stability was performed by high resolution liquid chromatography) to determine its useful shelf life. 3 validation batches were prepared under protocols of Good Manufacturing Practice (GMP) in the Production Plant of Radiopharmaceuticals of the Instituto Nacional de Investigaciones Nucleares (ININ), meet specifications preset by obtaining a sterile and free development of bacterial endotoxin yields of labeled 100% and which retains its quality characteristics radiochemical purity greater than 90% for at least 15 days. (Author)

  17. Fission neutron spectrum averaged cross sections of some threshold reactions on cadmium: production feasibility of no-carrier-added 103Pd in a nuclear reactor

    International Nuclear Information System (INIS)

    Abbasi, I.A.; Subhani, M.S.; Zaidi, J.H.; Arif, M.

    2006-01-01

    Systematic studies on fission neutron spectrum averaged cross sections of some threshold reactions like (n, p) and (n, α) on cadmium were carried out using the activation technique in combination with radiochemical separations and high-resolution γ-ray spectroscopy. Special attention was paid to the formation of 103 Pd via the 106 Cd(n,a α) 103 Pd reaction since it is an important therapeutic radionuclide. At a fast flux neutron density of 7.5 x 10 13 cm 2 s -1 and an irradiation time of 120 h, using 100% enriched 106 Cd target 340 MBq of no-carrier-added 103 Pd per batch could be produced. The method is thus suitable for medium-scale production of this radionuclide. (orig.)

  18. Ionic Liquid-salt based aqueous biphasic system for quick separation of no-carrier-added 203Pb from proton irradiated natTl2CO3 target

    International Nuclear Information System (INIS)

    Choudhury, Dibyasree; Ghosh, Kaustab; Lahiri, Susanta; Sarkar, Kangkana; Naskar, Nabanita

    2016-01-01

    In the present study, no-carrier-added (NCA) 203 Pb was radiochemically separated from bulk Tl target applying the ABS composing of 4 M K 2 HPO 4 and 0.1 mL of different strengths of IL (bmim)Cl ranging from 40% to 80% (w/v). Bulk Tl was spiked with 200Tl (T 1/2 = 26.1 h). A separation condition was achieved with 70% IL concentration and with 10 min shaking and 10 min settling time, where ∼84% of NCA 203 Pb was extracted into the IL rich phase with ∼10% contamination from bulk Tl. Therefore, further studies, i.e. variation in shaking and settling time were carried out keeping the concentration of IL fixed at 70%

  19. Technology of DTPA and immunoglobulins conjugation and their attachment to 90Y and 177Lu radionuclides

    International Nuclear Information System (INIS)

    Rekova, M.; Jedinakova-Krizova, V.

    2010-01-01

    The aim of the study of labeling of ligand-antibody conjugates was to find optimal conditions of preparing of these conjugates and appropriate radioactivity of selected nuclide for applications in nuclear medicine. Conjugation of the γ-immunoglobulin G (human or bovine IgG, polyclonal antibodies) and bifunctional chelating agent, diethylenetriaminepentaacetic acid dianhydride (cDTPAA), was carried out. Various values of the cDTPAA/antibody ratio, the weight concentration of polyclonal or monoclonal antibodies (MEM-97) and buffers were used. Further, the labeling conditions of the DTPA-IgG conjugate by radionuclides 90 Y and 177 Lu were optimized, and the labeling yield and the conjugation ratio of prepared radionuclide-DTPA-IgG conjugates was determined. Optimal incubation time of the immunoglobulin conjugation was obtained at 30 min from mixing of individual components. The labeling yield of radionuclide-DTPA-antibody conjugate higher than 95% was achieved. Higher values of conjugation ratio of radionuclide-DTPA-antibody conjugate were achieved in 0.1 mol L -1 carbonate buffer, pH 8.5, and the 0.1 mol L -1 carbonate buffer is suitable for studied conjugation systems. This study showed that the labeling yield as well as the conjugation ratio of tested systems depend on the amount of antibody substance, bifunctional chelating agent/antibody molar ratio and pH value of the buffer used. (author)

  20. Use of 177Lu-dotatate in the treatment of iodine refractory thyroid carcinomas.

    Science.gov (United States)

    Oliván-Sasot, P; Falgás-Lacueva, M; García-Sánchez, J; Vera-Pinto, V; Olivas-Arroyo, C; Bello-Arques, P

    In a patient with a differentiated thyroid cancer the standard treatment protocol to be followed is surgery, ablation of thyroid remnants with 131 Iodine ( 131 I), and TSH suppression. However, the treatment with 131 I is not effective in some cases, and it no longer becomes a therapeutic option due to cell de-differentiation with loss of 131 I uptake. Systemic treatment can be used as other options, although patients are not always responsive; thus, the disease may progress and therapeutic options may run out. Endocrine tumours may express somatostatin receptors,and this characteristic has been used, not only for diagnosis, but also for their treatment through somatostatin analogue labelling with radioactive isotopes. This was the case of a patient suffering from iodine-refractory follicular thyroid carcinoma, with somatostatin receptors expression, treated with 177 Lu-DOTATATE, showing an excellent clinical and analytical response. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  1. Synthesis and in vitro evaluation of an antiangiogenic cancer-specific dual-targeting 177Lu-Au-nanoradiopharmaceutical

    International Nuclear Information System (INIS)

    Gonzalez-Ruiz, Abraham; Ferro-Flores, Guillermina; Azorin-Vega, Erika; Ocampo-Garcia, Blanca; Maria Ramirez, Flor de; Santos-Cuevas, Clara; Luna-Gutierrez, Myrna; Leon-Rodriguez, Luis De; Isaac-Olive, Keila; Morales-Avila, Enrique

    2017-01-01

    The aim of this research was to synthesize and chemically characterize a cancer-specific 177 Lu-Au-nanoradiopharmaceutical based on gold nanoparticles (NPs), the nuclear localization sequence (NLS)-Arg-Gly-Asp peptide and an aptamer (HS-pentyl-pegaptanib) to target both the α(v)β(3) integrin and the vascular endothelial growth factor (VEGF) overexpressed in the tumor neovasculature, as well as to evaluate by the tube formation assay, the nanosystem capability to inhibit angiogenesis. 177 Lu-NP-RGD-NLS-Aptamer was obtained with a radiochemical purity of 99 ± 1%. Complete inhibition of tube formation (angiogenesis) was demonstrated when endothelial cells (EA.hy926), cultured in a 3D-extracellular matrix support, were treated with the developed nanosystem. (author)

  2. Long-term toxicity of [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate in rats

    Energy Technology Data Exchange (ETDEWEB)

    Rolleman, Edgar J.; Krenning, Eric P.; Bernard, Bert F.; Visser, Monique de; Bijster, Magda; Jong, Marion de [Erasmus MC Rotterdam, Department of Nuclear Medicine, Rotterdam (Netherlands); Visser, Theo J. [Erasmus MC Rotterdam, Department of Internal Medicine, Rotterdam (Netherlands); Vermeij, Marcel [Erasmus MC Rotterdam, Department of Pathology, Rotterdam (Netherlands); Lindemans, Jan [Erasmus MC Rotterdam, Department of Clinical Chemistry, Rotterdam (Netherlands)

    2007-02-15

    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 [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]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 [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]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 [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469{+-}18, 134{+-}70 and 65{+-}15 {mu}mol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Injection of high doses of [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]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.)

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

    International Nuclear Information System (INIS)

    Lim, Jae Cheong; Cho, Eun Ha; Lee, So Young

    2015-01-01

    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 177 Lu-labeled bombesin derivative has promising characteristics as a novel nuclear medicine, especially for the treatment of GRPR over-expressing prostate tumors

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

    International Nuclear Information System (INIS)

    Souza, Adriano A.; Herrerias, Rosana; Pires, Jose A.; Alves, Geraldo P.; Fukumori, Neuza T.O.; Matsuda, Margareth M.N.; Almeida, Erika V.; Mengatti, Jair; Barboza, Marycel F. de

    2009-01-01

    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 [ 177 Lu-DOTA-Tyr 3 ]octreotate (DOTATATE) for therapy. The aim of this work is to establish and validate the labeling, the quality control procedures of DTPA-Tyr 3 -Octreotide (DTPA-Oct) and DOTA-Tyr 3 -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 111 InCl 3 (Nordion) and in hot-cell with 177 LuCl 3 (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 111 In-DTPA-Oct and 177 Lu-DOTATATE was confirmed in the first comparative clinical groups. The methods were validated and 46.287 GMBq of 111 In-DTPA-Oct and 1,193 GBq of 177 Lu-DOTATATE were distributed in 2008, to nuclear medicine services in Brazil. (author)

  5. [Treatment of Gastroenteropancreatic Neuroendocrine Tumors with 177Lu-DOTA-TATE: Experience of the Portuguese Institute of Oncology in Porto].

    Science.gov (United States)

    Sampaio, Inês Lucena; Luiz, Henrique Vara; Violante, Liliana Sobral; Santos, Ana Paula; Antunes, Luís; Torres, Isabel; Sanches, Cristina; Azevedo, Isabel; Duarte, Hugo

    2016-11-01

    The purpose of this article is to report the experience of the Portuguese Institute of Oncology - Porto in the treatment of gastroenteropancreatic neuroendocrine tumors with 177Lu-DOTA-TATE, regarding the safety and efficacy of this treatment modality. A retrospective analysis of clinical reports of patients with gastroenteropancreatic neuroendocrine tumors undergoing treatment with 177Lu-DOTA-TATE between April 2011 and November 2013 was performed. Thirty six cases were reviewed and 30 completed all 3 cycles of 177Lu-DOTA-TATE (83.3%). In these patients it was registered: acute side effects in 8.9% of cycles; grade 3 CTCAE liver toxicity in 13.3% of patients (all with previous abnormal liver function); absence of significant renal or hematologic toxicity; symptomatic improvement in 71.4% of patients; median overall time to progression of 25.6 months; median overall survival from diagnosis of 121.7 months. Patients with higher expression of somatostatin receptors had longer progression-free survival and overall survival times (p DOTA-TATE is an effective, safe and well-tolerated treatment, as evidenced in our study by the following findings: symptomatic improvement in most patients and increased time to disease progression and survival (especially in those with higher sstr expression), with acute and significant subacute/chronic side effects reported only in a minority of cases. Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE is a promising treatment for patients with gastroenteropancreatic neuroendocrine tumors, with demonstrated benefits in terms of safety and efficacy.

  6. 177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

    Directory of Open Access Journals (Sweden)

    Héctor Mendoza-Nava

    2016-01-01

    Full Text Available 177Lu-labeled nanoparticles conjugated to biomolecules have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this research was to synthesize 177Lu-dendrimer(PAMAM-G4-folate-bombesin with gold nanoparticles (AuNPs in the dendritic cavity and to evaluate the radiopharmaceutical potential for targeted radiotherapy and the simultaneous detection of folate receptors (FRs and gastrin-releasing peptide receptors (GRPRs overexpressed in breast cancer cells. p-SCN-Benzyl-DOTA was conjugated in aqueous-basic medium to the dendrimer. The carboxylate groups of Lys1Lys3(DOTA-bombesin and folic acid were activated with HATU and also conjugated to the dendrimer. The conjugate was mixed with 1% HAuCl4 followed by the addition of NaBH4 and purified by ultrafiltration. Elemental analysis (EDS, particle size distribution (DLS, TEM analysis, UV-Vis, and infrared and fluorescence spectroscopies were performed. The conjugate was radiolabeled using 177LuCl3 or 68GaCl3 and analyzed by radio-HPLC. Studies confirmed the dendrimer functionalization with high radiochemical purity (>95%. Fluorescence results demonstrated that the presence of AuNPs in the dendritic cavity confers useful photophysical properties to the radiopharmaceutical for optical imaging. Preliminary binding studies in T47D breast cancer cells showed a specific cell uptake (41.15±2.72%. 177Lu-dendrimer(AuNP-folate-bombesin may be useful as an optical and nuclear imaging agent for breast tumors overexpressing GRPR and FRs, as well as for targeted radiotherapy.

  7. Formulation of an inhibitor radiopharmaceutical of prostatic antigen of 177Lu-Glu-Nh-CO-Nh-Lys membrane

    International Nuclear Information System (INIS)

    Ortega S, D.

    2015-01-01

    The prostate specific membrane antigen (PSMA) is a zinc metalloenzyme that is expressed on the cell membrane and highly expressed in prostate cancer. Recently, it has been demonstrated that the peptide sequence Glu-Nh-CO-Nh-Lys inhibit PSMA activity through an electrostatic interaction with the Zn. Several theragnostic radiopharmaceuticals with base in 177 Lu have been developed for radiotherapy of specific molecular targets because gamma and beta emissions of the radionuclide (β = 0.498 MeV and γ= 0.133 MeV). However, there is currently no label a formulation for preparing a radiopharmaceutical of 177 Lu-Glu-Nh-CO-Nh-Lys useful treatment of prostate cancer. The aim of this research was to optimize and document the process of production of the radiopharmaceutical 177 Lu-Glu-Nh-CO-Nh-Lys for sanitary registration application before the Comision Federal para la Proteccion contra Riesgos Sanitarios (COFEPRIS). The optimization of the production process was assessed a factorial design of three variables with mixed levels (3 x 3 x 2) where the dependent variable is the radiochemical purity, the analytical method was validated by UV-Vis spectrophotometry. Next, process validation was carried out by labeling 3 lots of the optimized formulation of the radiopharmaceutical (5.55 GBq (2.16 μg) of 177 LuCl 3 , 90 mg peptide PSMA, 50 mg ascorbic acid and 150 μL of acetate buffer 1 M ph 5), long-term stability was performed by high resolution liquid chromatography) to determine its useful shelf life. 3 validation batches were prepared under protocols of Good Manufacturing Practice (GMP) in the Production Plant of Radiopharmaceuticals of the Instituto Nacional de Investigaciones Nucleares (ININ), meet specifications preset by obtaining a sterile and free development of bacterial endotoxin yields of labeled 100% and which retains its quality characteristics radiochemical purity greater than 90% for at least 15 days. (Author)

  8. [177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

    Science.gov (United States)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  10. Report on the 1. research coordination meeting on 'Development of therapeutic radiopharmaceuticals based on {sup 177}Lu for radionuclide therapy'

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-07-01

    Radionuclide therapy (RNT) employing radiopharmaceuticals labelled with emitting radionuclides is fast emerging as an important part of nuclear medicine. Radionuclide therapy is effectively utilized for bone pain palliation, thus providing significant improvement in quality of life of patients suffering from pain resulting from bone metastasis. Targeting primary diseases by using specific carrier molecules labelled with radionuclides is also widely investigated and efficacious products have been emerging for the treatment of Lymphoma and Neuroendocrine tumours. In order to ensure the wider use of radiopharmaceuticals, it is essential to carefully consider the choice of radionuclides that together with the carrier molecules will give suitable pharmacokinetic properties and therapeutic efficacy. The criteria for the selection of a radionuclide for radiotherapy are suitable decay characteristics and amenable chemistry. However, the practical considerations in selecting a radionuclide for targeted therapy are availability in high radionuclidic purity as well as high specific activity and low production cost and comfortable delivery logistics. {sup 177}Lu is one of the isotopes emerging as a clear choice for therapy. Worldwide, the isotope is under investigation for approximately 30 different clinical applications, including treatment of colon cancer, metastatic bone cancer, non-Hodgkin's lymphoma, and lung cancer. {sup 177}Lu decays with a half-life of 6.71 d by emission of particles with E{sub max} of 497 keV (78.6%), 384 keV (9.1%) and 176 keV (12.2%). It also emits photons of 113 keV (6.4%) and 208 keV (11%), that are ideally suited for imaging the in-vivo localization and dosimetric calculations applying a gamma camera. The physical half-life of {sup 177}Lu is comparable to that of {sup 131}I, the most widely used therapeutic radionuclide. The long halflife of {sup 177}Lu provides logistic advantage for production, QA/QC of the products as well as feasibility to

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

    2006-01-01

    Radionuclide therapy (RNT) employing radiopharmaceuticals labelled with emitting radionuclides is fast emerging as an important part of nuclear medicine. Radionuclide therapy is effectively utilized for bone pain palliation, thus providing significant improvement in quality of life of patients suffering from pain resulting from bone metastasis. Targeting primary diseases by using specific carrier molecules labelled with radionuclides is also widely investigated and efficacious products have been emerging for the treatment of Lymphoma and Neuroendocrine tumours. In order to ensure the wider use of radiopharmaceuticals, it is essential to carefully consider the choice of radionuclides that together with the carrier molecules will give suitable pharmacokinetic properties and therapeutic efficacy. The criteria for the selection of a radionuclide for radiotherapy are suitable decay characteristics and amenable chemistry. However, the practical considerations in selecting a radionuclide for targeted therapy are availability in high radionuclidic purity as well as high specific activity and low production cost and comfortable delivery logistics. 177 Lu is one of the isotopes emerging as a clear choice for therapy. Worldwide, the isotope is under investigation for approximately 30 different clinical applications, including treatment of colon cancer, metastatic bone cancer, non-Hodgkin's lymphoma, and lung cancer. 177 Lu decays with a half-life of 6.71 d by emission of particles with E max of 497 keV (78.6%), 384 keV (9.1%) and 176 keV (12.2%). It also emits photons of 113 keV (6.4%) and 208 keV (11%), that are ideally suited for imaging the in-vivo localization and dosimetric calculations applying a gamma camera. The physical half-life of 177 Lu is comparable to that of 131 I, the most widely used therapeutic radionuclide. The long halflife of 177 Lu provides logistic advantage for production, QA/QC of the products as well as feasibility to supply the products to places

  13. Encapsulation of a radiolabeled cluster inside a fullerene cage, (177)Lu(x)Lu((3-x))N@C(80): an interleukin-13-conjugated radiolabeled metallofullerene platform.

    Science.gov (United States)

    Shultz, Michael D; Duchamp, James C; Wilson, John D; Shu, Chun-Ying; Ge, Jiechao; Zhang, Jianyuan; Gibson, Harry W; Fillmore, Helen L; Hirsch, Jerry I; Dorn, Harry C; Fatouros, Panos P

    2010-04-14

    In this communication, we describe the successful encapsulation of (177)Lu into the endohedral metallofullerene (177)Lu(x)Lu(3-x)N@C(80) (x = 1-3) starting with (177)LuCl(3) in a modified quartz Kraschmer-Huffman electric generator. We demonstrate that the (177)Lu (beta-emitter) in this fullerene cage is not significantly released for a period of up to at least one-half-life (6.7 days). We also demonstrate that this agent can be conjugated with an interleukin-13 peptide that is designed to target an overexpressed receptor in glioblastoma multiforme tumors. This nanoparticle delivery platform provides flexibility for a wide range of radiotherapeutic and radiodiagnostic multimodal applications.

  14. 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

    International Nuclear Information System (INIS)

    Vilchis J, A.

    2013-01-01

    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 177 Lu-AuNP-RGD in athymic mice bearing α(v)β(3)-integrin-positive C6 gliomas and compare with that of 177 Lu-AuNP or 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 177 Lu-AuNP-RGD, 177 Lu-AuNP or 177 Lu-RGD were assessed. Of the radiopharmaceuticals evaluated, 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 177 Lu-AuNP-RGD significantly (p 177 Lu). There was a low uptake in non-target organs and no induction of renal toxicity. 177 Lu-AuNP-RGD demonstrates properties suitable for use as an agent for molecular targeting radiotherapy. (Author)

  15. 177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi

    International Nuclear Information System (INIS)

    Seidl, Christof; Zoeckler, Christine; Beck, Roswitha; Senekowitsch-Schmidtke, Reingard; Quintanilla-Martinez, Leticia; Bruchertseifer, Frank

    2011-01-01

    213 Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the β-emitter 177 Lu has proven to be beneficial in targeted therapy, 177 Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of 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 177 Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific 177 Lu-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of 177 Lu-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically. Treatment with 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 177 Lu-d9MAb conjugates were superior to nonspecific 177 Lu-d8MAb. Treatment with 7.4 MBq of 177 Lu-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of 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 213 Bi-d9MAb at comparable therapeutic efficacy. The therapeutic efficacy of 177 Lu-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with 213 Bi-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis. (orig.)

  16. Safety, Pharmacokinetics and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analogue 177Lu-DOTA-EB-TATE in Patients with Advanced Metastatic Neuroendocrine Tumors.

    Science.gov (United States)

    Zhang, Jingjing; Wang, Hao; Jacobson Weiss, Orit; Cheng, Yuejuan; Niu, Gang; Li, Fang; Bai, Chunmei; Zhu, Zhaohui; Chen, Xiaoyuan

    2018-04-13

    Radiolabeled somatostatin analogue therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogues in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-human study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analogue, lutetium-177-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate ( 177 Lu-DOTA-EB-TATE). Methods: Eight patients (6 males and 2 females; age range, 27-61 y) with advanced metastatic neuroendocrine tumors were recruited. Five patients received a single dose 0.35-0.70 GBq (9.5-18.9 mCi) of 177 Lu-DOTA-EB-TATE and underwent serial whole body planar and single-photon emission computed tomography-computed tomography (SPECT-CT) scans at 2, 24, 72, 120 and 168 h after injection. The other 3 patients received intravenous injection of 0.28-0.41 GBq (7.5-11.1 mCi) of 177 Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24 and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Results: Administration of 177 Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177 Lu-DOTATATE, 177 Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved 7.9-fold increase of tumor dose delivery. The total body effective doses were 0.205 ± 0.161 mSv/MBq for 177 Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177 Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177 Lu-DOTA-EB-TATE than those receiving 177 Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin binding moiety, 177 Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NET

  17. Selective in vitro targeting of GRP and NMB receptors in human tumours with the new bombesin tracer 177Lu-AMBA

    International Nuclear Information System (INIS)

    Waser, Beatrice; Eltschinger, Veronique; Reubi, Jean C.; Linder, Karen; Nunn, Adrian

    2007-01-01

    To investigate the in vitro binding properties of a novel radiolabelled bombesin analogue, 177 Lu-AMBA, in human neoplastic and non-neoplastic tissues selected for their expression of the bombesin receptor subtypes GRP-R, NMB-R and BRS-3. In vitro receptor autoradiography was performed in cancers expressing the various bombesin receptor subtypes. The novel radioligand 177 Lu-AMBA was used and compared with established bombesin radioligands such as 125 I-Tyr 4 -bombesin and 125 I-[D-Tyr 6 ,β-Ala 11 ,Phe 13 ,Nle 14 ]-bombesin(6-14). In vitro incidence of detection of each of the three bombesin receptor subtypes was evaluated in each tumour. 177 Lu-AMBA identified all GRP-R-expressing tumours, such as prostatic, mammary and renal cell carcinomas as well as gastrointestinal stromal tumours. 177 Lu-AMBA also identified all NMB-expressing tumours, but did not detect BRS-3-expressing tumours or BRS-3-expressing pancreatic islets. GRP-R-expressing peritumoural vessels were heavily labelled with 177 Lu-AMBA. In contrast to the strongly GRP-R-positive mouse pancreas, the human pancreas was not labelled with 177 Lu-AMBA unless chronic pancreatitis was diagnosed. In general, the sensitivity was slightly better with 177 Lu-AMBA than with the conventional bombesin radioligands. The present in vitro study suggests that 177 Lu-AMBA may be a very useful in vivo targeting agent for GRP-R-expressing tumours, NMB-R-expressing tumours and GRP-R-expressing neoangiogenic vessels. (orig.)

  18. Selective in vitro targeting of GRP and NMB receptors in human tumours with the new bombesin tracer {sup 177}Lu-AMBA

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Eltschinger, Veronique; Reubi, Jean C. [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Bern (Switzerland); Linder, Karen; Nunn, Adrian [Bracco Research USA Inc, Princeton, NJ (United States)

    2007-01-15

    To investigate the in vitro binding properties of a novel radiolabelled bombesin analogue, {sup 177}Lu-AMBA, in human neoplastic and non-neoplastic tissues selected for their expression of the bombesin receptor subtypes GRP-R, NMB-R and BRS-3. In vitro receptor autoradiography was performed in cancers expressing the various bombesin receptor subtypes. The novel radioligand {sup 177}Lu-AMBA was used and compared with established bombesin radioligands such as {sup 125}I-Tyr{sup 4}-bombesin and {sup 125}I-[D-Tyr{sup 6},{beta}-Ala{sup 11},Phe{sup 13},Nle{sup 14}]-bombesin(6-14). In vitro incidence of detection of each of the three bombesin receptor subtypes was evaluated in each tumour. {sup 177}Lu-AMBA identified all GRP-R-expressing tumours, such as prostatic, mammary and renal cell carcinomas as well as gastrointestinal stromal tumours. {sup 177}Lu-AMBA also identified all NMB-expressing tumours, but did not detect BRS-3-expressing tumours or BRS-3-expressing pancreatic islets. GRP-R-expressing peritumoural vessels were heavily labelled with {sup 177}Lu-AMBA. In contrast to the strongly GRP-R-positive mouse pancreas, the human pancreas was not labelled with {sup 177}Lu-AMBA unless chronic pancreatitis was diagnosed. In general, the sensitivity was slightly better with {sup 177}Lu-AMBA than with the conventional bombesin radioligands. The present in vitro study suggests that {sup 177}Lu-AMBA may be a very useful in vivo targeting agent for GRP-R-expressing tumours, NMB-R-expressing tumours and GRP-R-expressing neoangiogenic vessels. (orig.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

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

    Energy Technology Data Exchange (ETDEWEB)

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    International Nuclear Information System (INIS)

    Makis, William; Mccann, Karey; Mcewan, Alexander J. B.

    2015-01-01

    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 177 Lu-[DOTA0,Tyr3]octreotate (DOTATATE) radioisotope therapy using established protocols. Three paraganglioma patients were treated with 4–5 cycles of 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 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 177 Lu-DOTATATE. Subsequent 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. 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

  3. 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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  4. Quantitative 177Lu-SPECT/CT imaging and validation of a commercial dosimetry software

    International Nuclear Information System (INIS)

    D'Ambrosio, L.; Aloj, L.; Morisco, A.; Aurilio, M.; Prisco, A.; Di Gennaro, F.; Lastoria, S.; Madesani, D.

    2015-01-01

    Full text of publication follows. Aim: 3D dosimetry is an appealing yet complex application of SPECT/CT in patients undergoing radionuclide therapy. In this study we have developed a quantitative imaging protocol and we have validated commercially available dosimetry software (Dosimetry Tool-kit Package, GE Heathcare) in patients undergoing 177 Lu-DOTATATE therapy. Materials and methods: dosimetry tool-kit uses multi SPECT/CT and/or WB planar datasets for quantifying changes in radiopharmaceutical uptake over time to determine residence times. This software includes tools for performing reconstruction of SPECT/CT data, registration of all scans to a common reference, segmentation of the different organs, creating time activity curves, curve fitting and calculation of residence times. All acquisitions were performed using a hybrid dual-head SPECT-CT camera (Discovery 670, GE Heathcare) equipped with medium energy collimator using a triple-energy window. SPECT images were reconstructed using an iterative reconstruction algorithm with attenuation, scatter and collimator depth-dependent three-dimensional resolution recovery correction. Camera sensitivity and dead time were evaluated. Accuracy of activity quantification was performed on a large homogeneous source with addition of attenuating/scattering medium. A NEMA/IEC body phantom was utilized to measure the recovery coefficient that the software does not take into account. The residence times for organs at risk were calculated in five patients. OLINDA-EXM software was used to calculate absorbed doses. Results: 177 Lu-sensitivity factor was 13 counts/MBq/s. Dead time was <3% with 1.11 GBq in the field of view. The measured activity was consistent with the decay-corrected calibrated activity for large volumes (>100 cc). The recovery coefficient varied from 0.71 (26.5 ml) to 0.16 (2.5 ml) in the absence of background activity and from 0.58 to 0.13 with a source to background activity concentration ratio 20:1. The

  5. Individualised {sup 177}Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Sundloev, Anna; Tennvall, Jan [Lund University, Department of Oncology and Pathology, Clinical Sciences, Lund (Sweden); Skaane University Hospital, Department of Oncology, Lund (Sweden); Sjoegreen-Gleisner, Katarina; Ljungberg, Michael [Lund University, Department of Medical Radiation Physics, Clinical Sciences, Lund (Sweden); Svensson, Johanna [Sahlgrenska University Hospital, Department of Oncology, Gothenburg (Sweden); Olsson, Tomas [Skaane University Hospital, Department of Oncology, Lund (Sweden); Bernhardt, Peter [University of Gothenburg, Department of Radiation Physics, Gothenburg (Sweden); Sahlgrenska University Hospital, Department of Medical Physics and Biomedical Engineering, Gothenburg (Sweden)

    2017-08-15

    To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED). Treatment was given with repeated cycles of 7.4 GBq {sup 177}Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT + planar imaging). All patients received treatment up to a renal BED of 27 ± 2 Gy (α/β = 2.6 Gy) (Step 1). Selected patients were offered further treatment up to a renal BED of 40 ± 2 Gy (Step 2). Renal function was followed by estimation and measurement of the glomerular filtration rate (GFR). Fifty-one patients were included in the present analysis. Among the patients who received treatment as planned, the median number of cycles in Step 1 was 5 (range 3-7), and for those who completed Step 2 it was 7 (range 5-8); 73% were able to receive >4 cycles. Although GFR decreased in most patients after the completion of treatment, no grade 3-4 toxicity was observed. Patients with a reduced baseline GFR seemed to have an increased risk of GFR decline. Five patients received treatment in Step 2, none of whom exhibited a significant reduction in renal function. Individualising PRRT using renal dosimetry seems feasible and safe and leads to an increased number of cycles in the majority of patients. The trial will continue as planned. (orig.)

  6. Indirect and direct measurement of thermal neutron acceleration by inelastic scattering on the 177Lu isomer

    International Nuclear Information System (INIS)

    Belier, G.; Roig, O.; Meot, V.; Daugas, J.M.; Aupiais, J.; Jutier, Ch.; Le Petit, G.; Veyssiere, Ch.

    2008-01-01

    When neutrons interact with isomers, these isomers can de-excite and in such a reaction the outgoing neutron has an energy greater than the in-going one. This process is referred as Inelastic Neutron Acceleration or Super-elastic Scattering. Up to now this process was observed for only two nucleus, 152m Eu and 180m Hf by measuring the number of fast neutrons produced by isomeric targets irradiated with thermal neutrons. In these experiments the energies of the accelerated neutrons were not measured. This report presents an indirect measurement of inelastic neutron acceleration on 177m Lu, based on the burn-up and the radiative capture cross sections measurements. Since at thermal energies the inelastic scattering and the radiative capture are the only processes that contribute to the isomer burn-up, the inelastic cross section can be deduced from the difference between the two measured quantities. Applying this method for the 177 Lu isomer with different neutron fluxes we obtained a value of (257 ± 50) barns (for a temperature of 323 K) and determined that there is no integral resonance for this process. In addition the radiative capture cross section on 177g Lu was measured with a much better accuracy than the accepted value. Since the acceleration cross section is quite high, a direct measurement of this process was undertaken, sending thermal neutrons and measuring the fast neutrons. The main goal now is to measure the outgoing neutron energies in order to identify the neutron transitions in the exit channel. In particular the K conservation question can be addressed by such a measurement. (author)

  7. 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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  8. Automated radiosynthesis of no-carrier-added 4-[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry.

    Science.gov (United States)

    Way, Jenilee Dawn; Wuest, Frank

    2014-02-01

    4-[18F]Fluoroiodobenzene ([18F]FIB) is a versatile building block in 18F radiochemistry used in various transition metal-mediated C-C and C-N cross-coupling reactions and [18F]fluoroarylation reactions. Various synthesis routes have been described for the preparation of [18F]FIB. However, to date, no automated synthesis of [18F]FIB has been reported to allow access to larger amounts of [18F]FIB in high radiochemical and chemical purity. Herein, we describe an automated synthesis of no-carrier-added [18F]FIB on a GE TRACERlab™ FX automated synthesis unit starting from commercially available(4-iodophenyl)diphenylsulfonium triflate as the labelling precursor. [18F]FIB was prepared in high radiochemical yields of 89 ± 10% (decay-corrected, n = 7) within 60 min, including HPLC purification. The radiochemical purity exceeded 95%, and specific activity was greater than 40 GBq/μmol. Typically, from an experiment, 6.4 GBq of [18F]FIB could be obtained starting from 10.4 GBq of [18F]fluoride.

  9. Synthesis of no carrier added F-18 16-fluorohexadecanoic acid (FHDA) and investigation of its labeled metabolites and its kinetics in the heart

    International Nuclear Information System (INIS)

    DeGrado, T.R.; Bernstein, D.R.; Gatley, S.J.; Ng, C.K.; Holden, J.E.

    1984-01-01

    No carrier added FHDA was prepared via saponification of the product of silver oxide assisted reaction of near-anhydrous tetraethylammonium fluoride with methyl 16-iodohexadecanoate. The labeled fatty acid was injected into isolated perfused rat hearts. Coronary perfusate was collected for 4-9 minutes, when hearts were chilled and homogenized. F-18 in perfusate was analysed by HPLC (NH column; 50mM amm. acetate in 50% acetonitrile). Material with the same retention time as F-18 fluoroacetate (prepared by F-for-I exchange with ethyl iodoacetate) was found. Some F-18 stuck permanently to the column and was assigned as fluoride since the same fraction of label in perfusate was retained on alumina columns eluted with water. Anion exchange HPLC (SAX column; 20mM pot. phosphate, pH 7) of homogenates gave peaks corresponding to fluoroacetate plus fluoride and minor peaks which could be fluoroacetylCoA and fluorocitrate. The authors interpret their data as follows. Beta-oxidation of FHDA results in fluoroacetylCoA which either undergoes ''lethal synthesis'' to fluorocitrate or is hydrolysed to fluoroacetate which diffuses out of the heart. The source of the fluoride is not yet clear, but could complicate interpretation of FHDA kinetics measured in vivo with positron tomography. Clearance of label from FHDA in isolated perfused hearts was faster than for labeled 16-iodohexadecanoic acid, indicating that the F-18 tracer may be a more sensitive probe of myocardial fatty acid metabolism

  10. Automated chemoenzymatic synthesis of no-carrier-added [carbonyl-{sup 11}C]propionyl L-carnitine for pharmacokinetic studies

    Energy Technology Data Exchange (ETDEWEB)

    Davenport, R.J.; Pike, V.W.; Dowsett, K.; Turton, D.R.; Poole, K. [Hammersmith Hospital, London (United Kingdom). MRC Cyclotron Unit

    1997-07-30

    Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t{sub 1/2} = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [{sup 11}C]propionyl chloride as labelling agent via {sup 11}C-carboxylation of ethylmagnesium bromide with cyclotron-produced [{sup 11}C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [{sup 11}C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [{sup 11}C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [{sup 11}C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier added (NCA) level of specific radioactivity. [{sup 11}C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [{sup 11}C]carbon dioxide and hydrolysis. NCA [{sup 11}C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [{sup 11}C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [{sup 11}C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [{sup 11}C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [{sup 11}C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [{sup 11}C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo. (Author).

  11. Tumor-targeting properties of 90Y- and 177Lu-labeled α-melanocyte stimulating hormone peptide analogues in a murine melanoma model

    International Nuclear Information System (INIS)

    Miao Yubin; Hoffman, Timothy J.; Quinn, Thomas P.

    2005-01-01

    The purpose of this study was to compare the tumor-targeting properties of 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH in a murine melanoma mouse model. Methods: The in vitro properties of cellular internalization and retention of 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH were studied in B16/F1 murine melanoma cells. The pharmacokinetics of 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH were determined in B16/F1 melanoma-bearing C57 mice. Results: 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH exhibited fast cellular internalization and extended cellular retention in B16/F1 cells. High receptor-mediated tumor uptake and retention coupled with fast whole-body clearance of 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH were demonstrated in B16/F1 tumor-bearing C57 mice. The tumor uptakes of 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH were 25.70±4.64 and 14.48±0.85 %ID/g at 2 h, and 14.09±2.73 and 17.68±3.32 %ID/g at 4 h postinjection. There was little activity accumulated in normal organs except for kidney. Conclusions: High tumor-targeting properties of 90 Y-DOTA-Re(Arg 11 )CCMSH and 177 Lu-DOTA-Re(Arg 11 )CCMSH highlighted their potential as radiopharmaceuticals for targeted radionuclide therapy of melanoma in further investigations

  12. 68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology.

    Science.gov (United States)

    Dalm, Simone U; Bakker, Ingrid L; de Blois, Erik; Doeswijk, Gabriela N; Konijnenberg, Mark W; Orlandi, Francesca; Barbato, Donato; Tedesco, Mattia; Maina, Theodosia; Nock, Berthold A; de Jong, Marion

    2017-02-01

    Because overexpression of the gastrin-releasing peptide receptor (GRPR) has been reported on various cancer types, for example, prostate cancer and breast cancer, targeting this receptor with radioligands might have a significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTA-coupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of 68 Ga-NeoBOMB1 and 177 Lu-NeoBOMB1. PC-3 tumor-xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol 68 Ga-NeoBOMB1 or a low (∼1 MBq/200 pmol) versus high (∼1 MBq/10 pmol) peptide amount of 177 Lu-NeoBOMB1, after which biodistribution and imaging studies were performed. At 6 time points (15, 30, 60, 120, 240, and 360 min for 68 Ga-NeoBOMB1 and 1, 4, 24, 48, 96, and 168 h for 177 Lu-NeoBOMB1) postinjection tumor and organ uptake was determined. To assess receptor specificity, additional groups of animals were coinjected with an excess of unlabeled NeoBOMB1. Results of the biodistribution studies were used to determine pharmacokinetics and dosimetry. Furthermore, PET/CT and SPECT/MRI were performed. Injection of approximately 250 pmol 68 Ga-NeoBOMB1 resulted in a tumor and pancreas uptake of 12.4 ± 2.3 and 22.7 ± 3.3 percentage injected dose per gram (%ID/g) of tissue, respectively, at 120 min after injection. 177 Lu-NeoBOMB1 biodistribution studies revealed a higher tumor uptake (17.9 ± 3.3 vs. 11.6 ± 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 ± 6.9 vs. 105 ± 13 %ID/g of tissue at 240 min after injection) with the higher peptide amount injected, leading to a significant increase in the absorbed dose to the tumor versus the pancreas (200 pmol, 570 vs. 265 mGy/MBq; 10 pmol, 435 vs. 1393 mGy/MBq). Using these data to predict patient dosimetry, we found

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  14. Safety of multiple repeated cycles of {sup 177}Lu-octreotate in patients with recurrent neuroendocrine tumour

    Energy Technology Data Exchange (ETDEWEB)

    Yordanova, Anna; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Mayer, Karin; Brossart, Peter [University Hospital Bonn, Department of Internal Medicine 3, Bonn (Germany); Gonzalez-Carmona, Maria A.; Strassburg, Christian P. [University Hospital Bonn, Department of Internal Medicine 1, Bonn (Germany)

    2017-07-15

    Peptide receptor radionuclide therapy (PRRT) is an effective therapy in patients with a somatostatin receptor-positive neuroendocrine tumour (NET). Still unclear is how many cycles of {sup 177}Lu-octreotate can be repeated while maintaining an acceptable toxicity profile. The purpose of this study was to assess the safety of repeated PRRT in patients with recurrent NET. We retrospectively evaluated data from 15 patients treated with repeated PRRT between 2004 and 2015. The median administered activity was 63.8 GBq (range 52-96.6 GBq) in a median of 9 cycles (range 8-13 cycles). Nonhaematological and haematological toxicities were assessed from clinical reports and laboratory data. The rates of adverse events in three therapy groups were compared: during cycles 1 to 4, cycles 5 to 8, and cycles 9 to 13. Baseline laboratory assessments were also compared with data obtained at the end of treatment. The overall survival in the study patients was compared with survival data in patients who received only a baseline PRRT of three or four cycles. We observed no life-threatening adverse events (CTC-4) during {sup 177}Lu-octreotate treatment. Reversible haematological toxicity (CTC-3) occurred in two patients (13%). No CTC-3/4 nephrotoxicity was recorded. More CTC-3 adverse events were recorded in the first therapy group than in the other two groups. Furthermore, there were no significant changes in the mean values of thrombocytes, leucocytes and serum creatinine before and after therapy. However, the mean haemoglobin levels fell from 14 g/dL to 11 g/dL. Finally, compared with those patients who received three or four cycles, there was a survival benefit in patients treated with repeated PRRT (censored overall survival 85.6 vs. 69.7 months, p < 0.001). Therapy with eight or more cycles of {sup 177}Lu-octreotate was well tolerated and led to a survival benefit in patients with recurrent NET. (orig.)

  15. In vivo quantification of {sup 177}Lu with planar whole-body and SPECT/CT gamma camera imaging

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, Dale L. [Department of Nuclear Medicine, Royal North Shore Hospital, St Leonards, NSW 2065 (Australia); Faculty of Health Sciences, University of Sydney, Cumberland, NSW (Australia); Sydney Medical School, University of Sydney, Camperdown, NSW (Australia); NETwork, Sydney Vital, St Leonards, Sydney, NSW (Australia); Hennessy, Thomas M.; Willowson, Kathy P.; Henry, E. Courtney [Institute of Medical Physics, University of Sydney, Camperdown, NSW (Australia); Chan, David L.H. [Department of Nuclear Medicine, Royal North Shore Hospital, St Leonards, NSW 2065 (Australia); NETwork, Sydney Vital, St Leonards, Sydney, NSW (Australia); Aslani, Alireza [Department of Nuclear Medicine, Royal North Shore Hospital, St Leonards, NSW 2065 (Australia); Roach, Paul J. [Department of Nuclear Medicine, Royal North Shore Hospital, St Leonards, NSW 2065 (Australia); Sydney Medical School, University of Sydney, Camperdown, NSW (Australia)

    2015-09-17

    Advances in gamma camera technology and the emergence of a number of new theranostic radiopharmaceutical pairings have re-awakened interest in in vivo quantification with single-photon-emitting radionuclides. We have implemented and validated methodology to provide quantitative imaging of {sup 177}Lu for 2D whole-body planar studies and for 3D tomographic imaging with single-photon emission computed tomography (SPECT)/CT. Whole-body planar scans were performed on subjects to whom a known amount of [{sup 177}Lu]-DOTA-octreotate had been administered for therapy. The total radioactivity estimated from the images was compared with the known amount of the radionuclide therapy administered. In separate studies, venous blood samples were withdrawn from subjects after administration of [{sup 177}Lu]-DOTA-octreotate while a SPECT acquisition was in progress and the concentration of the radionuclide in the venous blood sample compared with that estimated from large blood pool structures in the SPECT reconstruction. The total radioactivity contained within an internal SPECT calibration standard was also assessed. In the whole-body planar scans (n = 28), the estimated total body radioactivity was accurate to within +4.6 ± 5.9 % (range −17.1 to +11.2 %) of the correct value. In the SPECT reconstructions (n = 12), the radioactivity concentration in the cardiac blood pool was accurate to within −4.0 ± 7.8 % (range −16.1 to +7.5 %) of the true value and the internal standard measurements (n = 89) were within 2.0 ± 8.5 % (range −16.3 to +24.2 %) of the known amount of radioactivity contained. In our hands, state-of-the-art hybrid SPECT/CT gamma cameras were able to provide accurate estimates of in vivo radioactivity to better than, on average, ±10 % for use in biodistribution and radionuclide dosimetry calculations.

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

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

    Science.gov (United States)

    de Blois, Erik; Chan, Ho Sze; de Zanger, Rory; Konijnenberg, Mark; Breeman, Wouter A P

    2014-02-01

    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, (111)In- and (177)Lu-labelled somatostatin analogs can be stored and transported in a single-vial ready-for-use liquid formulation up to 7 days after radiolabelling. © 2013 Published by Elsevier Ltd.

  18. Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added 18F-Labelling Methods

    Directory of Open Access Journals (Sweden)

    Christian Drerup

    2016-09-01

    Full Text Available Nitric oxide (NO, an important multifunctional signaling molecule, is produced by three isoforms of NO-synthase (NOS and has been associated with neurodegenerative disorders. Selective inhibitors of the subtypes iNOS (inducible or nNOS (neuronal are of great interest for decoding neurodestructive key factors, and 18F-labelled analogues would allow investigating the NOS-function by molecular imaging with positron emission tomography. Especially, the highly selective nNOS inhibitor 6-((3-((3-fluorophenethylaminomethylphenoxymethyl-4-methylpyridin-2-amine (10 lends itself as suitable compound to be 18F-labelled in no-carrier-added (n.c.a. form. For preparation of the 18F-labelled nNOS-Inhibitor [18F]10 a “build-up” radiosynthesis was developed based on a corresponding iodonium ylide as labelling precursor. The such activated phenethyl group of the compound was efficiently and regioselectively labelled with n.c.a. [18F]fluoride in 79% radiochemical yield (RCY. After conversion by reductive amination and microwave assisted displacement of the protecting groups, the desired nNOS-inhibitor was obtained in about 15% total RCY. Alternatively, for a simplified “late-stage” 18F-labelling procedure a corresponding boronic ester precursor was synthesized and successfully used in a newer, copper(II mediated n.c.a. 18F-fluoro-deboroniation reaction, achieving the same total RCY. Thus, both methods proved comparatively suited to provide the highly selective NOS-inhibitor [18F]10 as probe for preclinical in vivo studies.

  19. Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added (18)F-Labelling Methods.

    Science.gov (United States)

    Drerup, Christian; Ermert, Johannes; Coenen, Heinz H

    2016-09-01

    Nitric oxide (NO), an important multifunctional signaling molecule, is produced by three isoforms of NO-synthase (NOS) and has been associated with neurodegenerative disorders. Selective inhibitors of the subtypes iNOS (inducible) or nNOS (neuronal) are of great interest for decoding neurodestructive key factors, and (18)F-labelled analogues would allow investigating the NOS-function by molecular imaging with positron emission tomography. Especially, the highly selective nNOS inhibitor 6-((3-((3-fluorophenethylamino)methyl)phenoxy)methyl)-4-methylpyridin-2-amine (10) lends itself as suitable compound to be (18)F-labelled in no-carrier-added (n.c.a.) form. For preparation of the (18)F-labelled nNOS-Inhibitor [(18)F]10 a "build-up" radiosynthesis was developed based on a corresponding iodonium ylide as labelling precursor. The such activated phenethyl group of the compound was efficiently and regioselectively labelled with n.c.a. [(18)F]fluoride in 79% radiochemical yield (RCY). After conversion by reductive amination and microwave assisted displacement of the protecting groups, the desired nNOS-inhibitor was obtained in about 15% total RCY. Alternatively, for a simplified "late-stage" (18)F-labelling procedure a corresponding boronic ester precursor was synthesized and successfully used in a newer, copper(II) mediated n.c.a. (18)F-fluoro-deboroniation reaction, achieving the same total RCY. Thus, both methods proved comparatively suited to provide the highly selective NOS-inhibitor [(18)F]10 as probe for preclinical in vivo studies.

  20. Automated no-carrier-added synthesis of [1-{sup 11}C]-labeled D- and L-enantiomers of lactic acid

    Energy Technology Data Exchange (ETDEWEB)

    Drandarov, Konstantin [Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, University Hospital Zuerich, CH-8091 Zurich (Switzerland); Paul Scherrer Institute, CH-5232 Villigen (Switzerland); Schubiger, P. August [Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, University Hospital Zuerich, CH-8091 Zurich (Switzerland); Paul Scherrer Institute, CH-5232 Villigen (Switzerland); Westera, Gerrit [Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, University Hospital Zuerich, CH-8091 Zurich (Switzerland) and Paul Scherrer Institute, CH-5232 Villigen (Switzerland)]. E-mail: gerrit.westera@usz.ch

    2006-12-15

    The first purely chemical method for automated no-carrier-added synthesis of [1-{sup 11}C]-labeled D(R)- and L(S)-2-hydroxypropanoic acid (lactic acid) was developed for experimental neurophysiology studies and position emission tomography (PET) diagnosis. Starting from sodium 1-hydroxyethanesulfonate and [{sup 11}C]HCN (trapped as [{sup 11}C]KCN) the intermediate DL-(R,S)-[1-{sup 11}C]-2-hydroxypropanenitrile was prepared. Its rapid acid hydrolysis gave DL-(R,S)-[1-{sup 11}C]lactic acid, which was isolated by preparative reversed phase HPLC and automatically injected on a second preparative C{sub 18} HPLC column coated with a chiral selector, where both [1-{sup 11}C]lactic acid enantiomers were separated by chiral ligand-exchange chromatography. Two novel chiral selectors for HPLC enantiomeric separation of {alpha}-hydroxy acids, namely D(R)- or L(S)-2-amino-3-methyl-3-(5-phenylpentylsulfanyl)-butanoic acid were utilized for the preparative HPLC separation of the [1-{sup 11}C]lactic acid enantiomers. The preparation of the selectors and the coating procedure for the manufacturing of the preparative chiral HPLC columns are described. A highly efficient trap for [{sup 11}C]HCN is presented. The whole radiosynthesis is automated, takes about 45 min and leads to more than 80% decay corrected overall radiochemical yield of each enantiomer (up to 2.5 GBq) with over 99% radiochemical, chemical and enantiomeric purity. The specific activity at the end of the synthesis is about 400 GBq/{mu}mol.

  1. Automated no-carrier-added synthesis of [1-11C]-labeled D- and L-enantiomers of lactic acid

    International Nuclear Information System (INIS)

    Drandarov, Konstantin; Schubiger, P. August; Westera, Gerrit

    2006-01-01

    The first purely chemical method for automated no-carrier-added synthesis of [1- 11 C]-labeled D(R)- and L(S)-2-hydroxypropanoic acid (lactic acid) was developed for experimental neurophysiology studies and position emission tomography (PET) diagnosis. Starting from sodium 1-hydroxyethanesulfonate and [ 11 C]HCN (trapped as [ 11 C]KCN) the intermediate DL-(R,S)-[1- 11 C]-2-hydroxypropanenitrile was prepared. Its rapid acid hydrolysis gave DL-(R,S)-[1- 11 C]lactic acid, which was isolated by preparative reversed phase HPLC and automatically injected on a second preparative C 18 HPLC column coated with a chiral selector, where both [1- 11 C]lactic acid enantiomers were separated by chiral ligand-exchange chromatography. Two novel chiral selectors for HPLC enantiomeric separation of α-hydroxy acids, namely D(R)- or L(S)-2-amino-3-methyl-3-(5-phenylpentylsulfanyl)-butanoic acid were utilized for the preparative HPLC separation of the [1- 11 C]lactic acid enantiomers. The preparation of the selectors and the coating procedure for the manufacturing of the preparative chiral HPLC columns are described. A highly efficient trap for [ 11 C]HCN is presented. The whole radiosynthesis is automated, takes about 45 min and leads to more than 80% decay corrected overall radiochemical yield of each enantiomer (up to 2.5 GBq) with over 99% radiochemical, chemical and enantiomeric purity. The specific activity at the end of the synthesis is about 400 GBq/μmol

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  3. Preparation of (177Lu-DOTAn-PAMAM-[Nimotuzumab-F(ab’2] as a Therapeutic Radioimmunoconjugate for EGFR Overexpressed Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Titis Sekar Humani

    2017-12-01

    Full Text Available Intact monoclonal antibodies with a high molecular weight tend to have a poor pharmacokinetic profile and tumor penetration, and potential for eliciting host antibody responses. F(ab’2 fragments smaller than intact monoclonal antibodies that still maintain antigen binding could solve this problem. The objective of this study was to optimize the digestion process of nimotuzumab, an anti-EGFR monoclonal antibody, into its F(ab’2 fragment and investigate its potential as a therapeutic radioimmunoconjugate. Optimal conditions for digestion of nimotuzumab to its F(ab’2 fragment were found to be 6 hours of digestion time with a pH of 3.5 and 1:100 mol ratio of pepsin to nimotuzumab. The purity of the F(ab’2-nimotuzumab was confirmed by SDS-PAGE and HPLC analysis. Prior to its labeling with lutetium-177 radionuclide, the nimotuzumab-F(ab’2 was conjugated to DOTA-PAMAM dendrimer [DOTA denotes 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, PAMAM denotes poly(amidoamine] to form conjugate of (DOTAn-PAMAM-[nimotuzumab-F(ab’2]. Radiolabeling of DOTA-PAMAM-[nimotuzumab-F(ab’2] conjugate with 177Lu resulted in (177Lu-DOTAn-PAMAM-[nimotuzumab-F(ab’2] with radiochemical purity > 99% after purification with a PD-10 column. Further studies still need to be performed in order to confirm the potential of this radioimmunoconjugate as a radioimmunotherapeutic agent for EGFR overexpressed cancers.

  4. PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy.

    Science.gov (United States)

    Bodei, Lisa; Kidd, Mark S; Singh, Aviral; van der Zwan, Wouter A; Severi, Stefano; Drozdov, Ignat A; Cwikla, Jaroslaw; Baum, Richard P; Kwekkeboom, Dik J; Paganelli, Giovanni; Krenning, Eric P; Modlin, Irvin M

    2018-07-01

    Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs. The development and validation of the PPQ was undertaken in three independent 177 Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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....... The rats suffered from reversible myelotoxicity after treatment. CONCLUSIONS: Sequential administration of 177Lu-BR96 and 211At-BR96 resulted in tolerable toxicity providing halogen blocking but did not enhance the therapeutic effect....

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

    Directory of Open Access Journals (Sweden)

    Kwon Joong Yong

    2016-05-01

    Full Text Available 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.

  7. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors.

    Science.gov (United States)

    Brabander, Tessa; van der Zwan, Wouter A; Teunissen, Jaap J M; Kam, Boen L R; Feelders, Richard A; de Herder, Wouter W; van Eijck, Casper H J; Franssen, Gaston J H; Krenning, Eric P; Kwekkeboom, Dik J

    2017-08-15

    Purpose: Bronchial and gastroenteropancreatic neuroendocrine tumors (NET) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for therapy with Lutetium-177-labeled somatostatin analogues. We have treated over 1,200 patients with peptide receptor radionuclide therapy (PRRT) with [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate ( 177 Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival, and toxicity of this therapy. Experimental Design: For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177 Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq) 177 Lu-DOTATATE before 2013 was further analyzed for efficacy and survival. Results: The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). No therapy-related long-term renal or hepatic failure occurred. Conclusions: PRRT with 177 Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with 177 Lu-DOTATATE is safe with few side-effects and shows good response rates with PFS of 29 months and OS of 63 months. Clin Cancer Res; 23(16); 4617-24. ©2017 AACR . ©2017 American Association for Cancer Research.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

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

    Science.gov (United States)

    Seregni, E; Maccauro, M; Chiesa, C; Mariani, L; Pascali, C; Mazzaferro, V; De Braud, F; Buzzoni, R; Milione, M; Lorenzoni, A; Bogni, A; Coliva, A; Lo Vullo, S; Bombardieri, E

    2014-02-01

    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 [(90)Y]DOTA-TATE and [(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 ((90)Y) and a medium-energy beta/gamma emitter ([(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 [[(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [[(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 [(90)Y]DOTA-TATE and [[(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 [(90)Y]DOTA-TATE and [(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.

  10. Internal radiotherapy and dosimetric study for {sup 111}In/{sup 177}Lu-pegylated liposomes conjugates in tumor-bearing mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang, H.-E. [Institute of Radiological Sciences, National Yang Ming University, Taipei, Taiwan (China); Yu, H.-M. [Institute of Radiological Sciences, National Yang Ming University, Taipei, Taiwan (China); Lu, Y.-C. [Institute of Radiological Sciences, National Yang Ming University, Taipei, Taiwan (China); Heish, N.-N. [National Health Research Institute, Taipei, Taiwan (China); Tseng, Yun-Long [Taiwan Liposome Co. Ltd., Taipei, Taiwan (China); Huang, K.-L. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Chuang, K.-T. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Chen, Chin-Hsiung [Institute of Radiological Sciences, National Yang Ming University, Taipei, Taiwan (China); Hwang, J.-J. [Institute of Radiological Sciences, National Yang Ming University, Taipei, Taiwan (China); Lin, W.-J. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Wang, Shyh-Jen [Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Ting, G. [National Health Research Institute, Taipei, Taiwan (China); Whang-Peng, Jacqueline [National Health Research Institute, Taipei, Taiwan (China); Deng, W.-P. [Graduate Institute of Biomedical Materials, Taipei Medical University, Taipei, Taiwan (China)]. E-mail: wpdeng@tmu.edu.tw

    2006-12-20

    In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. Methods: The DTPA/PEG-liposomes were synthesized with a medium size of 110 nm, conjugated with {sup 111}In/{sup 177}Lu-(oxine){sub 3} to afford {sup 111}In/{sup 177}Lu-liposome. The stability of {sup 111}In/{sup 177}Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of {sup 111}In/{sup 177}Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. Results: The incorporation efficiency of {sup 111}In/{sup 177}Lu into liposomes was 95%. After incubation at 37 {sup o}C for 72 h in serum, more than 83% of radioactivity was still retained in the intact {sup 111}In/{sup 177}Lu-liposomes. The biodistribution of {sup 111}In-liposomes showed that the radioactivity in the blood decreased from 23.14{+-}8.16%ID/g at 1 h to 0.02{+-}0.00%ID/g at 72 h post-injection (p.i.), while reaching its maximum accumulation in tumors at 48 h p.i., with half-life in blood of 10.2 h. The results were supported by that of {sup 177}Lu-liposomes. Scintigraphic imaging with {sup 111}In-liposomes showed unambiguous tumor images at 48 h p.i. Dose estimation showed that the absorbed dose in tumor from {sup 177}Lu-liposomes was 5.74x10{sup -5} Gy/MBq. Conclusions: This study provides an in vivo characterization and dosimetric evaluation for the use of liposome systems as carriers in targeted radionuclide therapy. The results suggest that adequate tumor targeting as well as dose delivered to tumors could be achieved by the use of radionuclide targeted liposomes.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-03-15

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

  12. Bulk Scale Formulation of Therapeutic Doses of Clinical Grade Ready-to-Use 177Lu-DOTA-TATE: The Intricate Radiochemistry Aspects.

    Science.gov (United States)

    Mathur, Anupam; Prashant, Vrinda; Sakhare, Navin; Chakraborty, Sudipta; Vimalnath, K V; Mohan, Repaka Krishna; Arjun, Chanda; Karkhanis, Barkha; Seshan, Ravi; Basu, Sandip; Korde, Aruna; Banerjee, Sharmila; Dash, Ashutosh; Sachdev, Satbir Singh

    2017-09-01

    177 Lu-DOTA-TATE is a clinically useful and promising therapeutic radiopharmaceutical for peptide receptor radionuclide therapy of neuroendocrine tumors (NETs) overexpressing somatostatin receptors. Currently, the radiopharmaceutical is prepared in-house at nuclear medicine centers, thereby restricting its use to limited centers only. In this article, the authors describe systematic studies toward bulk scale formulation of "ready-to-use" 177 Lu-DOTA-TATE using medium specific activity 177 Lu (740-1110 GBq/mg) at a centralized radiopharmacy facility. In an optimized protocol, 177 Lu-DOTA-TATE synthesis was carried out by direct heating of 177 LuCl 3 (Sp. act. 740-1110 GBq/mg) with DOTA-TATE peptide (1.5-3.0 equivalents) in ammonium acetate buffer (0.2 M) containing 2,5-dihydroxy benzoic acid (gentisic acid). Thereafter, the crude labeled product was purified using a Sep-Pak ® C18 column and diluted with acetate buffer-gentisic acid (1.5% w/v) solution to final radioactive concentration of 740 MBq/mL. This was further sterilized and dispensed as 7.4 GBq patient dose/vial with 2 days postformulation calibration. A peptide/metal ratio of 1.5-3.0 is essential for complexation wherein radiolabeling yields >90% are obtained minimizing free 177 Lu waste. For formulation of 7.4 GBq patient dose (2 days postproduction), even specific activity of about 555 GBq/mg was found to be adequate for the radiometal. The ready-to-use 740 MBq/mL 177 Lu-DOTA-TATE formulation with gentisic acid (1.5% w/v) is observed to be safe for human use for more than 1 week (radiochemical purity >98%) from the day of production when stored at -70°C. However, the target specificity may get affected beyond 2 days as the total peptide content for 7.4 GBq dose may exceed the critical peptide limit of 300 μg. Patient treatment carried with several batches of present formulation in diseased NET patients exhibited desired distribution at the tumor and its metastatic site. A ready

  13. Preparation and biological evaluation of 111In-, 177Lu- and 90Y-labeled DOTA analogues conjugated to B72.3

    International Nuclear Information System (INIS)

    Mohsin, Huma; Fitzsimmons, Jonathan; Shelton, Tiffani; Hoffman, Timothy J.; Cutler, Cathy S.; Lewis, Michael R.; Athey, Phillip S.; Gulyas, Gyongyi; Kiefer, Garry E.; Frank, R. Keith; Simon, Jaime; Lever, Susan Z.; Jurisson, Silvia S.

    2007-01-01

    Three 1,4,7,10-tetraazacyclododecane-N,N',N '' ,N '' '-tetraacetic acid (DOTA) analogues were evaluated for relative in vivo stability when radiolabeled with 111 In, 90 Y and 177 Lu and conjugated to the monoclonal antibody B72.3. The DOTA analogues evaluated were 'NHS-DOTA' [N-hydroxysuccinimdyl (NHS) group activating one carboxylate], 'Arm-DOTA' (also known as MeO-DOTA; with a p-NCS, o-MeO-benzyl moiety on the methylene group of one acetic acid arm) and 'Back-DOTA' (with a p-NCS-benzyl moiety on a backbone methylene group of the macrocycle). The B72.3 was conjugated to the DOTA analogues to increase the retention time of the radioloabeled conjugates in vivo in mice. The serum stability of the various radiometalated DOTA conjugates showed them to have good stability out to 168 h (all >95% except 111 In-NHS-DOTA-B72.3, which was 91% stable). Hydroxyapatite stability for the 111 In and 177 Lu DOTA-conjugates was >95% at 168 h, while the 90 Y DOTA-conjugates were somewhat less stable (between 90% and 95% at 168 h). The biodistribution studies of the radiometalated DOTA-conjugates showed that no significant differences were observed for the 111 In and 177 Lu analogues; however, the 90 Y analogues showed lower stabilities, as evidenced by their increased bone uptake relative to the other two [2-20% injected dose per gram (% ID/g) for 90 Y and 2-8% ID/g for 111 In and 177 Lu]. The lower stability of the 90 Y analogues could be due to the higher beta energy of 90 Y and/or to the larger ionic radius of Y 3+ . Based on the bone uptake observed, the 177 Lu-NHS-DOTA-B72.3 had slightly lower stability than the 177 Lu-Arm-DOTA-B72.3 and 177 Lu-Back-DOTA-B72.3, but not significantly at all time points. For 90 Y, the analogue showing the lowest stability based on bone uptake was 90 Y-Arm-DOTA-B72.3, perhaps because of the metal's larger ionic radius and potential steric interactions minimizing effective complexation. The 111 In analogues all showed similar biological

  14. Evaluation of cell cycle changes activated by the administration of {sup 177}Lu-DOTA-antiCD20; Evaluacion de cambios en el ciclo celular activados por la administracion de {sup 177}Lu-DOTA-antiCD20

    Energy Technology Data Exchange (ETDEWEB)

    Ramos B, J. C.

    2016-07-01

    In the present project, cytometric evaluation of cell cycle changes induced by the {sup 177}Lu-DOTA-antiCD20 thermostatic radiopharmaceutical was performed, in which a cell culture of Raji cells from Burkitts lymphoma were used, which are CD20+; for flow cytometry different parameters were measured in which the cells were synchronized in G0/G1 and G2/M, to calculate the dose to nucleus that were given to the cells the Monte Carlo method was used at a dose interval from 1 to 5 Gy. The purpose of this work is to be able to observe by flow cytometry the arrest in the cell cycle with a lower dose interval than the one applied in other papers. (Author)

  15. 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    International Nuclear Information System (INIS)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar; Sahoo, Ranjit Kumar; Seth, Amlesh

    2017-01-01

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, 177 Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic 68 Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly 177 Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. 177 Lu

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  18. {sup 177}Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Schrader, Andres Jan; Boegemann, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany)

    2017-09-15

    Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with {sup 177}Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of {sup 177}Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of {sup 177}Lu-PSMA-617

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

    International Nuclear Information System (INIS)

    Schüler, Emil; Rudqvist, Nils; Parris, Toshima Z.; Langen, Britta; Spetz, Johan; Helou, Khalil; Forssell-Aronsson, Eva

    2014-01-01

    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 177 LuCl 3 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 177 LuCl 3 , 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 177 LuCl 3 , 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  1. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate

    International Nuclear Information System (INIS)

    Sabet, Amir; Ezziddin, Khaled; Reichman, Karl; Haslerud, Torjan; Ahmadzadehfar, Hojjat; Biersack, Hans-Juergen; Ezziddin, Samer; Pape, Ulrich-Frank; Nagarajah, James

    2014-01-01

    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 99m Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with 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 99m Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m 2 per year, relative yearly reduction -1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2-10 ml/min/m 2 per year) and 16 patients (22 %) a significant (>10 ml/min/m 2 per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m 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 patients. None of the investigated

  2. uPAR Targeted Radionuclide Therapy with 177Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer

    DEFF Research Database (Denmark)

    Persson, Morten; Juhl, Karina; Rasmussen, Palle

    2014-01-01

    The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect...... of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific...... value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted 177Lu groups (p

  3. Evaluation of cell cycle changes activated by the administration of "1"7"7Lu-DOTA-antiCD20

    International Nuclear Information System (INIS)

    Ramos B, J. C.

    2016-01-01

    In the present project, cytometric evaluation of cell cycle changes induced by the "1"7"7Lu-DOTA-antiCD20 thermostatic radiopharmaceutical was performed, in which a cell culture of Raji cells from Burkitts lymphoma were used, which are CD20+; for flow cytometry different parameters were measured in which the cells were synchronized in G0/G1 and G2/M, to calculate the dose to nucleus that were given to the cells the Monte Carlo method was used at a dose interval from 1 to 5 Gy. The purpose of this work is to be able to observe by flow cytometry the arrest in the cell cycle with a lower dose interval than the one applied in other papers. (Author)

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  5. Absorbed dose estimates from a single measurement one to three days after the administration of 177Lu-DOTATATE/-TOC.

    Science.gov (United States)

    Hänscheid, Heribert; Lapa, Constantin; Buck, Andreas K; Lassmann, Michael; Werner, Rudolf A

    2017-01-01

    To retrospectively analyze the accuracy of absorbed dose estimates from a single measurement of the activity concentrations in tumors and relevant organs one to three days after the administration of 177 Lu-DOTA-TATE/TOC assuming tissue specific effective half-lives. Activity kinetics in 54 kidneys, 30 neuroendocrine tumor lesions, 25 livers, and 27 spleens were deduced from series of planar images in 29 patients. After adaptation of mono- or bi-exponential fit functions to the measured data, it was analyzed for each fit function how precise the time integral can be estimated from fixed tissue-specific half-lives and a single measurement at 24, 48, or 72 h after the administration. For the kidneys, assuming a fixed tissue-specific half-life of 50 h, the deviations of the estimate from the actual integral were median (5 % percentile, 95 % percentile): -3 °% (-15 %>; +16 °%) for measurements after 24 h, +2 %> (-9 %>; +12 %>) for measurements after 48 h, and 0 % (-2 %; +12 %) for measurements after 72 h. The corresponding values for the other tissues, assuming fixed tissue-specific half-lives of 67 h for liver and spleen and 77 h for tumors, were +2 % (-25 %; +20 %) for measurements after 24 h, +2 °% (-16 %>; +17 %>) for measurements after 48 h, and +2 %> (-11 %>; +10 %>) for measurements after 72 h. Especially for the kidneys, which often represent the dose limiting organ, but also for liver, spleen, and neuroendocrine tumors, a meaningful absorbed dose estimate is possible from a single measurement after 2, more preferably 3 days after the administration of 177 Lu-DOTA-TATE/-TOC assuming fixed tissue specific effective half-lives. Schattauer GmbH.

  6. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

    International Nuclear Information System (INIS)

    Forrer, Flavio; Krenning, Eric P.; Kooij, Peter P.; Bernard, Bert F.; Bakker, Willem H.; Teunissen, Jaap J.M.; Jong, Marion de; Kwekkeboom, Dik J.; Konijnenberg, Mark; Lom, Kirsten van; Herder, Wouter W. de

    2009-01-01

    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 [ 177 Lu-DOTA 0 ,Tyr 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 177 Lu-DOTA 0 ,Tyr 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 marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary. (orig.)

  7. 177Lu labeling of Herceptin and preclinical validation as a new radiopharmaceutical for radioimmunotherapy of breast cancer

    International Nuclear Information System (INIS)

    Rasaneh, Samira; Rajabi, Hossein; Babaei, Mohammad Hossein; Daha, Fariba Johari

    2010-01-01

    Introduction: In the present study, Herceptin was labeled with lutetium-177 via DOTA, and the necessary preclinical quality control tests (in vitro and in vivo) were performed to evaluate its use as a radioimmunotherapy agent. Material and Methods: Herceptin was conjugated to DOTA as a chelator in three different conjugation buffers (ammonium acetate, carbonate and HEPES buffer); each of the resulting conjugates was compared with respect to in vitro characteristics such as number of chelates per antibody, incorporated activity, immunoreactivity and in vitro stability in PBS buffer and blood serum. The biodistribution study and gamma camera imaging were performed in mice bearing breast tumors. To assess the therapeutic effects of 177 Lu-Herceptin, cytotoxicity was investigated for 7 days in a SKBr3 breast cancer cell line. Results: Carbonate buffer was the best conjugation buffer (number of chelates per antibody: 6; incorporated activity: 81%; immunoreactivity: 87%; buffer stability: 86%; serum stability: 81%, after 4 days). The efficient tumor uptake observed in the biodistribution studies was consistent with the gamma camera image results. At a concentration of 4 μg ml -1 , 177 Lu-Herceptin (surviving cells: 5±0.6% of the total cells) of the total cells corresponded to an approximately eightfold increase in cytotoxicity in comparison to unmodified Herceptin (surviving cells: 43±3.9%). Conclusion: The new complex described herein could be considered for further evaluation in animals and potentially in humans as a radiopharmaceutical for use in the radioimmunotherapy of breast cancer. These results may be important for patients who cannot tolerate the therapeutic dosage of Herceptin currently used because of heart problems.

  8. 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

    International Nuclear Information System (INIS)

    Pujatti, Priscilla B.; Santos, Josefina S.; Couto, Renata M.; Araujo, Elaine B. de; Mengatti, Jair; Suzuki, Miriam F.

    2009-01-01

    In this work we describe the radiolabeling with 177 Lu 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. 177 Lu-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 177 LuCl3 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, 177 Lu-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)

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

    International Nuclear Information System (INIS)

    Vilchis J, A.

    2010-01-01

    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 177 Lu and to evaluate their in vitro and in vivo stability as potential specific therapeutic radiopharmaceuticals. Labelled was carried out by direct reaction of 177 LuCl 3 with c-DOTA-RGD peptides in 1 M acetate buffer ph 5.5 at 90 o 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. 177 Lu-DOTA-RGD and 177 Lu-DOTA-RGDf were obtained with radiochemical purities > 95%, showing adequate in vitro and in vivo stability and specific binding to □ v □ 3 receptors. (Author)

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

    International Nuclear Information System (INIS)

    Caldeira Filho, Jose de Souza

    2009-01-01

    The aim of this work was to propose rationalization in the synthesis, analysis and purification of radiopharmaceutical 177 Lu 3+ - 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 177 Lu 3+ :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 177 Lu 3+ - DOTATATO permits high economy in production costs. Chemical studies on the synthesis of radiopharmaceuticals also placed in evidence the interference of 177 Hf 4+ , the decay product of 177 Lu 3= , as the 177 Lu 3= 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)

  11. In vitro characterization of {sup 177}Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

    Energy Technology Data Exchange (ETDEWEB)

    Forrer, Flavio; Mueller-Brand, Jan [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Chen, Jianhua; Fani, Melpomeni; Powell, Pia; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Lohri, Andreas [Basel University Medical Clinic, Liestal (Switzerland); Moldenhauer, Gerhard [German Cancer Research Center, Division of Molecular Immunology, Heidelberg (Germany)

    2009-09-15

    {sup 131}I- and {sup 90}Y-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 (<20 min) with either {sup 177}Lu or {sup 90}Y. 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 10{sup 5} times excess of diethylenetriaminepentaacetic acid (DTPA, 37 C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m{sup 2} body surface {sup 177}Lu-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 {sup 177}Lu-DOTA-rituximab was tolerated well. Our results show that DOTA-rituximab (4:1) can be labelled with {sup 177}Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. {sup 177}Lu-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.)

  12. Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β--emitting 177Lu in human pancreatic adenocarcinoma cells

    International Nuclear Information System (INIS)

    Nayak, Tapan K.; Norenberg, Jeffrey P.; Anderson, Tamara L.; Prossnitz, Eric R.; Stabin, Michael G.; Atcher, Robert W.

    2007-01-01

    Introduction: Advance clinical cancer therapy studies of patients treated with somatostatin receptor (sstr)-targeted [DOTA 0 -Tyr 3 ]octreotide (DOTATOC) labeled with low-linear-energy-transfer (LET) β - -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 α-emitting 213 Bi to that of low-LET β - -emitting 177 Lu by determining relative biological effectiveness (RBE) using the external γ-beam of 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 213 Bi and 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 PLUS 10x kit. Results: Using equimolar DOTATOC treatment with concurrent irradiation with a 137 Cs source as reference radiation, the calculated RBE of [ 213 Bi]DOTATOC was 3.4, as compared to 1.0 for [ 177 Lu]DOTATOC. As measured in terms of absorbance units, [ 213 Bi]DOTATOC caused a 2.3-fold-greater release of apoptosis-specific mononucleosomes and oligonucleosomes than [ 177 Lu]DOTATOC at the final treatment time of 96 h (P 213 Bi]DOTATOC is therapeutically more effective in decreasing survival than is [ 177 Lu]DOTATOC in human pancreatic adenocarcinoma cells due to its comparatively higher RBE

  13. Standardization of Procedures for the Preparation of (177)Lu- and (90)Y-labeled DOTA-Rituximab Based on the Freeze-dried Kit Formulation.

    Science.gov (United States)

    Wojdowska, Wioletta; Karczmarczyk, Urszula; Maurin, Michal; Garnuszek, Piotr; Mikołajczak, Renata

    2015-01-01

    Rituximab when radiolabelled with (177)Lu or (90)Y has been investigated for the treatment of patients with Non-Hodgkin's Lymphoma. In this study, we optimized the preparation of antibody conjugates with chelating agent in the freeze-dried kit. It shortens procedures needed for the successful radiolabeling with lutetium-177 and yttrium-90 and assures reproducible labelling yields. Various molar ratios of Rituximab:DOTA (from 1:5 to 1:100) were used at the conjugation step and different purification method to remove unbound DOTA were investigated (size-exclusion chromatography, dialysis, ultrafiltration). The final monoclonal antibody concentration was quantified by Bradford method, and the number of DOTA molecules was determined by radiolabeling assay using (64)Cu. The specific activity of (177)Lu-DOTA-Rituximab and (90)Y-DOTA-Rituximab were optimized using various amounts of radiometal. Quality control (SE-HPLC, ITLC) and stability study were performed. An average of 4.2 ± 0.8 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab. The ultrafiltration system was the most efficient for purification and resulted in the highest recovery efficiency (77.2%). At optimized conditions the (177)Lu-DOTARituximab and (90)Y-DOTA-Rituximab were obtained with radiochemical purity >99% and specific activity ca. 600 MBq/mg. The radioimmunoconjugates were stable in human serum and 0.9% NaCl. After 72 h of incubation the radiochemical purity of (177)Lu-DOTA-Rituximab decreased to 94% but it was still more than 88% for (90)Y-DOTA-Rituximab. The radioimmunoconjugate showed stability after six months storage at 2 - 8(0)C, as a lyophilized formulation. Our study shows that Rituximab-DOTA can be efficiently radiolabeled with (177)Lu and (90)Y via p-SCN-Bn-DOTA using a freezedried kit.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Fast GPU-based Monte Carlo code for SPECT/CT reconstructions generates improved 177Lu images.

    Science.gov (United States)

    Rydén, T; Heydorn Lagerlöf, J; Hemmingsson, J; Marin, I; Svensson, J; Båth, M; Gjertsson, P; Bernhardt, P

    2018-01-04

    Full Monte Carlo (MC)-based SPECT reconstructions have a strong potential for correcting for image degrading factors, but the reconstruction times are long. The objective of this study was to develop a highly parallel Monte Carlo code for fast, ordered subset expectation maximum (OSEM) reconstructions of SPECT/CT images. The MC code was written in the Compute Unified Device Architecture language for a computer with four graphics processing units (GPUs) (GeForce GTX Titan X, Nvidia, USA). This enabled simulations of parallel photon emissions from the voxels matrix (128 3 or 256 3 ). Each computed tomography (CT) number was converted to attenuation coefficients for photo absorption, coherent scattering, and incoherent scattering. For photon scattering, the deflection angle was determined by the differential scattering cross sections. An angular response function was developed and used to model the accepted angles for photon interaction with the crystal, and a detector scattering kernel was used for modeling the photon scattering in the detector. Predefined energy and spatial resolution kernels for the crystal were used. The MC code was implemented in the OSEM reconstruction of clinical and phantom 177 Lu SPECT/CT images. The Jaszczak image quality phantom was used to evaluate the performance of the MC reconstruction in comparison with attenuated corrected (AC) OSEM reconstructions and attenuated corrected OSEM reconstructions with resolution recovery corrections (RRC). The performance of the MC code was 3200 million photons/s. The required number of photons emitted per voxel to obtain a sufficiently low noise level in the simulated image was 200 for a 128 3 voxel matrix. With this number of emitted photons/voxel, the MC-based OSEM reconstruction with ten subsets was performed within 20 s/iteration. The images converged after around six iterations. Therefore, the reconstruction time was around 3 min. The activity recovery for the spheres in the Jaszczak phantom was

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

    International Nuclear Information System (INIS)

    Sanchez G, M. F.

    2013-01-01

    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 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 ( 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 177 Lu-DOTA-Nal 3 -Octreotide ( 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 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 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 Instituto Nacional de

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Science.gov (United States)

    Bozon-Petitprin, A; Bacot, S; Gauchez, A S; Ahmadi, M; Bourre, J C; Marti-Batlle, D; Perret, P; Broisat, A; Riou, L M; Claron, M; Boturyn, D; Fagret, D; Ghezzi, Catherine; Vuillez, J P

    2015-02-01

    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])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(-) emitters in a nude mouse model of αvβ3 integrin-expressing tumours. Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (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 (90)Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours. (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy.

  20. High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours.

    Science.gov (United States)

    Kong, Grace; Callahan, Jason; Hofman, Michael S; Pattison, David A; Akhurst, Tim; Michael, Michael; Eu, Peter; Hicks, Rodney J

    2017-03-01

    Bulky disease is an adverse prognostic factor for 177 Lu-DOTA-octreotate ( 177 Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). 90 Y-DOTA-octreotate ( 90 Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than 177 Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially. We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of 90 Y-DOTATATE followed by 2-3 cycles of 177 Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival. Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq 90 Y-DOTATATE, and 21 GBq 177 Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months. PRCRT with 90 Y -DOTATATE followed by 177 Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either agent used alone or other approved

  1. On the conversion of the high multipole transition between the 23/2- 3qp state and the 17/2+ rotational state in 177Lu

    International Nuclear Information System (INIS)

    Deepa, S.; Vijay Sai, K.; Ashish, T.; Venkataramaniah, K.; Kailas, S.

    2012-01-01

    Gerl et al through a compilation of Internal Conversion Coefficients (ICCs) of high multipole transitions and a comparison with various theoretical calculations and experimental data concluded that the theoretical values of BRICC are close to experimental values within 1-2% when compared to Hager and Seltzer and Rosel et al values. In a programme supported through a DAE BRNS project, we have been trying to experimentally determine the ICCs of high multipole transitions with high precision to garner support and evidence for the findings of Gerl et al. The present measurement is a part of such an effort. The prolate deformed nucleus 177 Lu lies in the rare earth region with Z = 71 and N = 106 between closed shells. Several three-quasiparticle states as well as states originating from the coupling of a quasi-particle to the γ-vibration of the core were established in 177 Lu at energies above 1200 keV by different groups

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  3. Gamma-ray impurities of {sup 111}In, {sup 201}Tl, {sup 177}Lu and {sup 99m}Tc determined by means of a HPGE spectrometer

    Energy Technology Data Exchange (ETDEWEB)

    Koskinas, Marina F.; Almeida, Jamille da Silveira; Moreira, Denise Simões; Semmler, Renato; Dias, Mauro da Silva, E-mail: koskinas@ipen.br, E-mail: jamillealmeida@gmail.com, E-mail: denise.moreira@ipen.br, E-mail: rsemmler@ipen.br, E-mail: msdias@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2017-11-01

    This work aims to present the radioactive impurities gamma rays emitters detected in some radiopharmaceuticals widely applied to diagnosis and therapy purposes, supplied to nuclear medicine services in Brazil by the Radiopharmaceutical Center(CR) of Nuclear and Energy Research Institute, IPEN, in São Paulo. The analysis was undertaken by means of an HPGe gamma spectrometer. The radiopharmaceuticals analyzed were: {sup 111}In, {sup 201}Tl, {sup 177}Lu and {sup 99m}Tc. (author)

  4. Labelling of 90Y- and 177Lu-DOTA-Bioconjugates for Targeted Radionuclide Therapy: A Comparison among Manual, Semiautomated, and Fully Automated Synthesis

    Directory of Open Access Journals (Sweden)

    Michele Iori

    2017-01-01

    Full Text Available In spite of the hazard due to the radiation exposure, preparation of 90Y- and 177Lu-labelled radiopharmaceuticals is still mainly performed using manual procedures. In the present study the performance of a commercial automatic synthesizer based on disposable cassettes for the labelling of 177Lu- and 90Y-DOTA-conjugated biomolecules (namely, DOTATOC and PSMA-617 was evaluated and compared to a manual and a semiautomated approach. The dose exposure of the operators was evaluated as well. More than 300 clinical preparations of both 90Y- and 177Lu-labelled radiopharmaceuticals have been performed using the three different methods. The mean radiochemical yields for 90Y-DOTATOC were 96.2±4.9%, 90.3±5.6%, and 82.0±8.4%, while for 177Lu-DOTATOC they were 98.3%  ± 0.6, 90.8%  ± 8.3, and 83.1±5.7% when manual, semiautomated, and automated approaches were used, respectively. The mean doses on the whole hands for yttrium-90 preparations were 0.15±0.4 mSv/GBq, 0.04±0.1 mSv/GBq, and 0.11±0.3 mSv/GBq for manual, semiautomated, and automated synthesis, respectively, and for lutetium-177 preparations, they were 0.02±0.008 mSv/GBq, 0.01±0.03 mSv/GBq, and 0.01±0.02 mSv/GBq, respectively. In conclusion, the automated approach guaranteed reliable and reproducible preparations of pharmaceutical grade therapeutic radiopharmaceuticals in a decent RCY. The radiation exposure of the operators remained comparable to the manual approach mainly due to the fact that a dedicated shielding was still not available for the system.

  5. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2014-09-01

    Irene Karpenko Lauren Tyrell Olivera Calukovic Gillian Hodes June Greenberg Jessica Campbell PATIENTS AND THEIR FAMILIES Biostatistics...myelosuppression or need for >2 platelet (plt) transfusions, febrile neutropenia , or grade >2 non-heme toxicity following 177Lu- J591. PSA was assessed prior to...toxicity • Grade 4 neutropenia or thrombocytopenia > 14 days • Need for > 2 platelet transfusions or hemorrhage • Febrile neutropenia • > 3 week delay for

  6. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients With High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2017-09-01

    on a federally funded study (as compared to pharmaceutical -sponsored). Therefore, after discussions with the site PI’s, additional key opinion...location (printed) APPENDIX C iv SCHEMA Informed Consent Screening Labs (CBC, chemistry, PSA, testosterone), CT/ MRI abd/pelvis, bone scan, CXR...111In-J591, continue ketoconazole, J591 scan Infusion of 177Lu-J591 x1, continue ketoconazole, J591 scan CT/ MRI abd/pelvis, bone scan, CXR q 6

  7. Mono(pyridine-N-oxide) DOTA analog and its G1/G4-PAMAM dendrimer conjugates labeled with 177Lu: Radiolabeling and biodistribution studies

    International Nuclear Information System (INIS)

    Laznickova, A.; Biricova, V.; Laznicek, M.; Hermann, P.

    2014-01-01

    177 Lu radiolabeling of the first (G1-) or fourth (G4-) generation polyaminoamide (PAMAM) dendrimer conjugates with DOTA-like bifunctional chelator with one methylenepyridine-N-oxide pendant arm (DO3A-py NO-C ) stability of the radiolabeled species and their pharmacokinetic characteristics were evaluated in preclinical experiments. The results showed that the G1- and G4-dendrimer conjugates, modified in average with 7.5 or 57 DO3A-py NO-C chelating units, respectively, can also be labeled with 177 Lu with a high specific activity and radiochemical purity even at 37 °C. The radiolabeled species were stable for at least 24 h. Distribution profile of G1-dendrimer conjugate in organs and tissues of rats was more favorable than that of G4 one. On the other hand, the later dendrimer conjugate bears a substantially higher number of metal chelators per molecule enabling binding of a considerably larger number of radiometals. Our results indicate that an employment of dendrimer-chelate conjugates with bound radiometals might represent a prospective way for radiolabeling of biologically active target-specific macromolecules to obtain markedly high specific activity. - Highlights: • Chelation of DOTA-like ligands suitable for biomacromolecules modification. • Radiolabeling of modified PAMAM-dendrimers with 177 Lu. • Determination of stability of the labeled conjugates. • Pharmacokinetic characteristics evaluated in preclinical experiments

  8. Radiolabelled of c-DOTA-RGD and c-DOTA-RGDf with {sup 177}Lu and evaluation in vitro and in vivo stability; Radiomarcado del peptido c-DOTA-RGD y c-DOTA-RGDf con {sup 177}Lu y evaluacion de su estabilidad in vitro e in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Vilchis J, A.

    2010-07-01

    Integrin {alpha}v{beta}3 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 {alpha}v{beta}3 integrin. The aim of this study was to label c-DOTA-RGD and c-DOTA-RGDf peptides with {sup 177}Lu and to evaluate their in vitro and in vivo stability as potential specific therapeutic radiopharmaceuticals. Labelled was carried out by direct reaction of {sup 177}LuCl{sub 3} with c-DOTA-RGD peptides in 1 M acetate buffer ph 5.5 at 90{sup o} 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 {alpha}v{beta}3) 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. {sup 177}Lu-DOTA-RGD and {sup 177}Lu-DOTA-RGDf were obtained with radiochemical purities > 95%, showing adequate in vitro and in vivo stability and specific binding to {open_square}{sub v}{open_square}{sub 3} receptors. (Author)

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    International Nuclear Information System (INIS)

    Persson, Morten; Rasmussen, Palle; Madsen, Jacob; Ploug, Michael; Kjaer, Andreas

    2012-01-01

    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 64 Cu and 177 Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with 177 Lu-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 177 Lu-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel 18 F-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 177 Lu-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 64 Cu-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using 177 Lu-DOTA-AE105, where a significant effect on tumor size and the number of uPAR-positive cells in the tumor was found (p 18 F-FLT PET/CT imaging study revealed a significant correlation between 18 F-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

  12. Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.

    Science.gov (United States)

    Beaino, Wissam; Nedrow, Jessie R; Anderson, Carolyn J

    2015-06-01

    Malignant melanoma is a highly aggressive cancer, and the incidence of this disease is increasing worldwide at an alarming rate. Despite advances in the treatment of melanoma, patients with metastatic disease still have a poor prognosis and low survival rate. New strategies, including targeted radiotherapy, would provide options for patients who become resistant to therapies such as BRAF inhibitors. Very late antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels in more aggressive and metastatic disease and may provide an ideal target for drug delivery and targeted radiotherapy. In this study, we evaluated (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A as a VLA-4-targeted radiotherapeutic with a companion PET agent for diagnosis and monitoring metastatic melanoma treatment. DOTA-PEG4-LLP2A was synthesized by solid-phase synthesis. The affinity of (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A to VLA-4 was determined in B16F10 melanoma cells by saturation binding and competitive binding assays, respectively. Biodistribution of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10 subcutaneous tumors, while PET/CT imaging was performed in subcutaneous and metastatic models. (177)Lu-DOTA-PEG4-LLP2A showed high affinity to VLA-4 with a Kd of 4.1 ± 1.5 nM and demonstrated significant accumulation in the B16F10 melanoma tumor after 4 h (31.5 ± 7.8%ID/g). The tumor/blood ratio of (177)Lu-DOTA-PEG4-LLP2A was highest at 24 h (185 ± 26). PET imaging of metastatic melanoma with (68)Ga-DOTA-PEG4-LLP2A showed high uptake in sites of metastases and correlated with bioluminescence imaging of the tumors. These data demonstrate that (177)Lu-DOTA-PEG4-LLP2A has potential as a targeted therapeutic for treating melanoma as well as other VLA-4-expressing tumors. In addition, (68)Ga-DOTA-PEG4-LLP2A is a readily translatable companion PET tracer for imaging of metastatic melanoma.

  13. Indirect and direct measurement of thermal neutron acceleration by inelastic scattering on the {sup 177}Lu isomer

    Energy Technology Data Exchange (ETDEWEB)

    Belier, G.; Roig, O.; Meot, V.; Daugas, J.M. [CEA Bruyeres-le-Chatel, Dept. de Physique Theorique et Appliquee, 91 (France); Aupiais, J.; Jutier, Ch.; Le Petit, G. [CEA Bruyeres-le-Chatel, Service de Physique Nucleaire, 91 (France). Dept. de Physique Theorique et Appliquee; Letourneau, A.; Marie, F. [CEA Saclay, Dept. d' Astrophysique de Physique des Particules, de Physique Nucleaire et de l' Instrumentation Associee, Service de Physique Nucleaire, 91- Gif sur Yvette (France); Veyssiere, Ch. [CEA Saclay, Dept. d' Astrophysique de Physique des Particules, de Physique Nucleaire et de l' Instrumentation Associee, Service d' Ingenierie des Systemes, 91- Gif sur Yvette (France)

    2008-07-01

    When neutrons interact with isomers, these isomers can de-excite and in such a reaction the outgoing neutron has an energy greater than the in-going one. This process is referred as Inelastic Neutron Acceleration or Super-elastic Scattering. Up to now this process was observed for only two nucleus, {sup 152m}Eu and {sup 180m}Hf by measuring the number of fast neutrons produced by isomeric targets irradiated with thermal neutrons. In these experiments the energies of the accelerated neutrons were not measured. This report presents an indirect measurement of inelastic neutron acceleration on {sup 177m}Lu, based on the burn-up and the radiative capture cross sections measurements. Since at thermal energies the inelastic scattering and the radiative capture are the only processes that contribute to the isomer burn-up, the inelastic cross section can be deduced from the difference between the two measured quantities. Applying this method for the {sup 177}Lu isomer with different neutron fluxes we obtained a value of (257 {+-} 50) barns (for a temperature of 323 K) and determined that there is no integral resonance for this process. In addition the radiative capture cross section on {sup 177g}Lu was measured with a much better accuracy than the accepted value. Since the acceleration cross section is quite high, a direct measurement of this process was undertaken, sending thermal neutrons and measuring the fast neutrons. The main goal now is to measure the outgoing neutron energies in order to identify the neutron transitions in the exit channel. In particular the K conservation question can be addressed by such a measurement. (author)

  14. Peptide receptor radionuclide therapy with 177Lu-DOTA-octreotate: dosimetry, nephrotoxicity, and the effect of hematological toxicity on survival.

    Science.gov (United States)

    Löser, Anastassia; Schwarzenböck, Sarah M; Heuschkel, Martin; Willenberg, Holger S; Krause, Bernd J; Kurth, Jens

    2018-03-01

    Peptide receptor radionuclide therapy (PRRT) with lutetium-177 (Lu)-DOTATATE is regarded as a safe treatment option with promising results for patients with neuroendocrine neoplasia (NEN). We aimed to study the absorbed organ and tumor doses, the renal and hematological toxicity as well as their mutual interaction. Another aim was the identification of adverse effects as possible predictors which may affect survival. A total of 30 (14 female and 16 male) patients with inoperable/metastatic NEN were treated with 7.4 GBq of Lu-DOTATATE. Occurrence of renal and hematological toxicity wasretrospectively studied. Morever, we examined the effects of hematological toxicity on survival after Lu-DOTATATE-PRRT. In 49 treatment cycles, the mean absorbed dose to the kidneys was 5.13±2.12, 4.49±2.49 Gy to the liver, and 14.44±8.97 Gy to the spleen, whereas tumor lesions absorbed a mean dose of 31.43±36.86 Gy. Comparing different localizations of metastases, no significant differences in absorbed dose were observed. Clinical response status revealed regressive disease in 47.6%, stable disease in 38.1%, and progressive disease in 14.3% of cases (n=21). Biochemically, 81.3% of patients showed reduced serotonin values (n=16; P<0.05) following Lu-DOTATATE-PRRT. No severe subacute renal or hematological toxicity occurred (one Common Terminology Criteria for Adverse Events-grade 3 for thrombocytopenia and another one for leukocytopenia). No statistically significant relation between baseline kidney function and post-therapeutic hematological changes was identified. The findings indicate that Lu-DOTATATE-PRRT is a safe and effective treatment method for patients with NEN. Moreover, these data strongly suggest that hematological parameters may affect survival so a further re-evaluation in prospective studies is warranted.

  15. 177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study

    Energy Technology Data Exchange (ETDEWEB)

    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.)

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

    International Nuclear Information System (INIS)

    Staudacher, A.H.; Brown, M.P.

    2015-01-01

    Full text of publication follows. Aim: We have identified a murine monoclonal antibody (APOMAB R ) 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 APOMAB R a dead tumour cell-specific marker. We hypothesise that APOMAB R radio-labelled with the β-particle emitting radionuclide Lutetium-177 ( 177 Lu) will be an effective anti-tumour treatment in vivo, particular after chemotherapy, as the targeting of radio-labelled APOMAB R 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 APOMAB R 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 APOMAB R was determined. We then administered escalating activities of 177 Lu-labelled APOMAB R or a 177 Lu-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 177 Lu-labelled APOMAB R in LL2 tumour-bearing mice which had or had not been treated with chemotherapy to determine whether the uptake of APOMAB R after chemotherapy treatment was tumour-specific. Results: In vitro analysis revealed that APOMAB R 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 APOMAB R compared to LL2 tumour-bearing mice that did not receive chemotherapy. Administration of escalating doses of 177 Lu-labelled APOMAB R alone to tumour-bearing mice was well tolerated but showed only modest anti-tumour activity which was comparable to the response seen

  17. 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

    Energy Technology Data Exchange (ETDEWEB)

    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

  18. A comparison of 2D and 3D kidney absorbed dose measures in patients receiving 177Lu-DOTATATE

    Directory of Open Access Journals (Sweden)

    Kathy Willowson

    2018-06-01

    Full Text Available Objective(s: To investigate and compare quantitative accuracy of kidney absorbed dose measures made from both 2D and 3D imaging in patients receiving 177LuDOTATATE (Lutate for treatment of neuroendocrine tumours (NETs. Methods: Patients receiving Lutate therapy underwent both whole body planar imaging and SPECT/CT imaging over the kidneys at time points 0.5, 4, 24, and 96-120 hours after injection. Planar data were corrected for attenuation using transmission data, and were converted to units of absolute activity via two methods, using either a calibration standard in the field of view or relative to pre-voiding image total counts. Hand drawn regions of interest were used to generate time activity curves and kidney absorbed dose estimates in OLINDA-EXM. Fully quantitative SPECT data were generated using CT-derived corrections for both scatter and attenuation, before correction for dead time and application of a camera specific sensitivity factor to convert data to units of absolute activity. Volumes of interest were defined for kidney using the co-registered x-ray CT, before time activity curves and absorbed dose measures were generated in OLINDA-EXM, both with and without corrections made to the model for patient specific kidney volumes. Quantitative SPECT data were also used to derive dose maps through dose kernel convolution (DKC, which was treated as the gold standard. Results: A total of 50 studies were analysed, corresponding to various cycles of treatment from 21 patients. Planar absorbed dose estimates were consistently higher than SPECT derived estimates by, on average, a factor of 3. Conclusion: Quantitative SPECT is considered the gold standard approach for organ specific dosimetry however often relies on in house software. As such planar methods for estimating absorbed dose are much more widely available, and in particular, are often the only source of reference in previously published data. For the case of Lutate dosimetry, planar

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

    International Nuclear Information System (INIS)

    Puranik, Ameya D.; Kulkarni, Harshad R.; Singh, Aviral; Baum, Richard P.

    2015-01-01

    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 90 Y/ 177 Lu-labelled peptides after positive confirmation of SSTR expression on 68 Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with 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 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 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 distant spread. Though these

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

    International Nuclear Information System (INIS)

    Melis, M.; Swart, J. de; Groen, H.C.; Konijnenberg, M.W.; Van der Graaf, L.M.; Kaemmerer, D.; Kulkami, H.R.; Baum, R.P.; Lupp, A.; Saenger, J.; Jong, M. de

    2015-01-01

    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 68 Ga-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 177 Lu-DOTA-octreotate. Methods: a patient diagnosed with neuroendocrine neoplasm of the pancreatic tail (SUV max on 68 Ga-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 177 Lu-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 111 In-DOTA-octreotate in-vitro autoradiography after decay of 177 Lu. 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: 177 Lu-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 177 Lu). The

  1. The impact of repeated cycles of radioligand therapy using [{sup 177}Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yordanova, Anna; Becker, Anja; Eppard, Elisabeth; Kuerpig, Stefan; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Fisang, Christian [University Hospital Bonn, Department of Urology, Bonn (Germany); Feldmann, Georg [University Hospital Bonn, Department of Internal Medicine, MED3, Bonn (Germany)

    2017-08-15

    [{sup 177}Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring. Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [{sup 177}Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson's correlation coefficient and the corresponding p values. None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1 or 2 . There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C. Renal toxicity in patients treated with [{sup 177}Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity. (orig.)

  2. Evaluation of the cell death mechanisms activated by the radiopharmaceutical 177Lu-DOTA-anti-CD20 in a dose range of 1 to 5 Gy

    International Nuclear Information System (INIS)

    Azorin V, E.P.; Rojas C, E. L.; Martinez V, B. E.; Ramos B, J. C.; Jimenez M, N. P.; Ferro F, G.

    2016-10-01

    The radio immunotherapy with anti-CD20 antibodies significantly increases the remission rate of patients with B-cell lymphomas over expressing the CD20. The radiolabeled antibodies directed to surface antigens allow delivering scaled doses of radiation to specific targets thus limiting the dose to healthy tissue. The anti-CD20 causes cell death by two major pathways; activating the immune system to destroy malignant cells and inducing the activation of cell death pathways. The 177 Lu is a beta particle emitter (max. 0.497 MeV) with a maximum reach on soft tissue of 0.7 mm and a half-life of 6.7 days. Several clinical studies have established a maximum tolerated dose (45 m Ci/m 2 ) for 177 Lu-DOTA-rituximab, which shows a favorable clinical response without hematological toxicity. However, the molecular mechanisms of action by synergistic effect of anti-CD20 and radionuclide have not been studied. In this work was evaluated; by flow cytometry, the activation kinetics of the cell death mechanisms induced by the treatment with 177 Lu-DOTA-Anti-CD20 in non-Hodgkin (Raji) lymphoma cells. The absorbed radiation dose delivered to the cell nucleus was calculated by Monte Carlo simulation, considering the contribution of the beta emissions of the radiopharmaceutical present in the cell membrane and surrounding environment, as well as crossfire. This work shows that the application of radiation doses of 1 to 5 Gy of the radiopharmaceutical 177 Lu-DOTA-anti-CD20, are sufficient to induce cell death by apoptosis and arrest of the cell cycle. The combination of these factors (continuous delivery of radiation, activation of repair mechanisms and increased radio sensitivity) causes the acute activation of the apoptotic program resulting in significant cell death after 96 h of treatment. The temporal analysis of cell death suggests the early activation of apoptosis that is counteracted by the activation of repair processes caused by sustained irradiation, which leads to cell

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

    DEFF Research Database (Denmark)

    Persson, Morten; Rasmussen, Palle; Madsen, Jacob

    2012-01-01

    -of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model. MethodsA 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...... for the first time the in vivo efficacy of an uPAR-targeted radionuclide therapeutic intervention on both tumor size and its content of uPAR expressing cells thus setting the stage for future translation into clinical use. © 2012 Elsevier Inc. All rights reserved....

  4. Monte Carlo simulation of radiation transport and dose deposition from locally released gold nanoparticles labeled with 111In, 177Lu or 90Y incorporated into tissue implantable depots

    Science.gov (United States)

    Lai, Priscilla; Cai, Zhongli; Pignol, Jean-Philippe; Lechtman, Eli; Mashouf, Shahram; Lu, Yijie; Winnik, Mitchell A.; Jaffray, David A.; Reilly, Raymond M.

    2017-11-01

    Permanent seed implantation (PSI) brachytherapy is a highly conformal form of radiation therapy but is challenged with dose inhomogeneity due to its utilization of low energy radiation sources. Gold nanoparticles (AuNP) conjugated with electron emitting radionuclides have recently been developed as a novel form of brachytherapy and can aid in homogenizing dose through physical distribution of radiolabeled AuNP when injected intratumorally (IT) in suspension. However, the distribution is unpredictable and precise placement of many injections would be difficult. Previously, we reported the design of a nanoparticle depot (NPD) that can be implanted using PSI techniques and which facilitates controlled release of AuNP. We report here the 3D dose distribution resulting from a NPD incorporating AuNP labeled with electron emitters (90Y, 177Lu, 111In) of different energies using Monte Carlo based voxel level dosimetry. The MCNP5 Monte Carlo radiation transport code was used to assess differences in dose distribution from simulated NPD and conventional brachytherapy sources, positioned in breast tissue simulating material. We further compare these dose distributions in mice bearing subcutaneous human breast cancer xenografts implanted with 177Lu-AuNP NPD, or injected IT with 177Lu-AuNP in suspension. The radioactivity distributions were derived from registered SPECT/CT images and time-dependent dose was estimated. Results demonstrated that the dose distribution from NPD reduced the maximum dose 3-fold when compared to conventional seeds. For simulated NPD, as well as NPD implanted in vivo, 90Y delivered the most homogeneous dose distribution. The tumor radioactivity in mice IT injected with 177Lu-AuNP redistributed while radioactivity in the NPD remained confined to the implant site. The dose distribution from radiolabeled AuNP NPD were predictable and concentric in contrast to IT injected radiolabeled AuNP, which provided irregular and temporally variant dose distributions

  5. Indigenous development of TBq levels of "1"7"7Lu radioisotope production at RPhD for nuclear medicine applications - a successful venture

    International Nuclear Information System (INIS)

    Chakraborty, Sudipta; Vimalnath, K.V.; Dash, Ashutosh

    2017-01-01

    Lutetium-177 ("1"7"7Lu) has emerged as a potential radionuclide during last decade for the development of radionuclide therapy owing to its favorable nuclear decay characteristics (T_1_/_2=6.65 d, E_β_(_m_a_x) = 0.497 MeV, E_γ = 113 keV (6.4%) and 208 keV (11%)). The long half-life of this promising radioisotope offering distinct logistical advantage and feasibility of its large-scale production in medium flux Dhruva research reactor contributed to its success story

  6. Evaluation of cytotoxic and tumor targeting capability of (177)Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy.

    Science.gov (United States)

    Arora, Geetanjali; Dubey, Priyanka; Shukla, Jaya; Ghosh, Sourabh; Bandopadhyaya, Gurupad

    2016-06-01

    We propose an innovative strategy of nanoparticle-mediated-peptide receptor radionuclide therapy (PRRT) employing PLGA-nanoparticles together with anti-β-hCG antibodies that can protect kidneys from radiation damage while simultaneously enhancing its tumor targeting and cytotoxic ability for somatostatin receptor (SSR) positive tumors. PEG-coated-(177)Lu-DOTATATE-PLGA-nanoparticles (PEG-LuD-NP) were formulated and characterized. In vitro toxicity of these particles was tested on human glioblastoma cell line U87MG over a radiation dose range of 19-78 Gy, using MTT assay and flow cytometry. To further enhance cytotoxicity and test the feasibility of active tumor targeting, apoptosis-inducing anti-β-hCG monoclonal antibodies were employed in vitro, after confirming expression of β-hCG on U87MG. In vivo tumor targeting ability of these particles, in comparison to uncoated particles and un-encapsulated (177)Lu-DOTATATE, was assessed by intravenous administration in tumor-induced wistar rats. Rats were first imaged in a gamma camera followed by euthanasia for organ extraction and counting in gamma counter. The particles were spherical in shape with mean diameter of 300 nm. Highest cytotoxicity that could be achieved with PEG-LuD-NP, on radio-resistant U87MG cells, was 35.8 % due to complex cellular response triggered by ionizing radiation. Interestingly, synergistic action of antibodies and PEG-LuD-NP doubled the cytotoxicity (80 %). PEG-LuD-NP showed the highest tumor uptake (4.3 ± 0.46 % ID/g) as compared to (177)Lu-DOTATATE (3.5 ± 0.31 %) and uncoated-(177)Lu-DOTATATE-nanoparticles (3.4 ± 0.35 %) in tumor-inoculated wistar rats (p targeting SSR positive tumors for enhanced cytoxicity and reduced renal radiation dose associated with conventional PRRT. To our knowledge of literature, this is the first study to establish in vitro and in vivo efficacy profile of nanoparticles in PRRT providing a stepping-stone for undergoing and future research

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  8. Radiolabeled Antibody Fragment for Preparation of (177Lu-DOTAm-PAMAM G3.0-F(ab’2 trastuzumab as a Radiopharmaceutical for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    R.D. Haryuni

    2017-06-01

    Full Text Available Several radiolabeled monoclonal antibodies (mAbs have been used as radioimmunotherapy (RIT agents for cancer therapy. The use of mAbs as RIT agents is due to their ability to carry effectors, in the form of radionuclides which emit alpha (α particles, beta (β particles, or auger electrons, and bind specifically to cancer expressed receptor. This paper reports the preparation of radiolabelled trastuzumab in form of (177Lu-DOTAm-PAMAM G3-F(ab'2-trastuzumab, which will be expected as a potential RIT agent for therapy of breast cancer overexpressed human epidermal growth factor receptor 2 (HER2. Due to its reduced molecular weight, the use of F(ab'2-trastuzumab on the aforementioned RIT agent candidate is expected to reach its target much faster compared to the intact trastuzumab. Meanwhile, the role of PAMAM G3 is to increase the specific activity of the radiotherapeutic agent of Lu-177 due to the ability of its 32 –NH2 functional groups that are able to bind many DOTAs (£ 31 which in turn can bind a large number of 177Lu. The preparation was initiated by fragmentation of trastuzumab using pepsin enzyme in 0.02 M acetic acid buffer with a pH of 4.5 to produce F(ab'2-trastuzumab with a purity of 95 % after purification with PD-10 column. The F(ab'2-trastuzumab was then reacted with succinimidyl 4-(N-maleimidomethyl cyclohexane-1-carboxylate (SMCC to produce SMCC-F(ab'2-trastuzumab. The next reaction was to conjugate SMCC-F(ab'2-trastuzumab with DOTA-PAMAM G3.0-SH, which was prepared by reaction NHS-DOTA with PAMAM G3.0 and followed by reacting it with 2-iminothiolane to give (DOTAm-PAMAM G3.0-F(ab'2-trastuzumab. Finally, the (DOTAm-PAMAM G3.0-F(ab'2-trastuzumab was radiolabelled with 177Lu to produce (177Lu-DOTAm-PAMAM G3.0-F(ab'2-trastuzumab, resulting in a radiochemical purity of 98 % after purification with PD-10 column.Received: 31 October 2015; Revised: 30 June 2016; Accepted: 25 September 2016

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Preclinical Evaluation of a Novel 177Lu- Radiopharmaceutical Based on Bombesin Structure for Prostate Tumor Diagnosis and Radionuclide Therapy

    International Nuclear Information System (INIS)

    Pujatti, P.B.; Santos, J.S.; Mengatti, J.; Araujo, E.B. de; Suzuki, M.F.; Soares, C.R.J.

    2009-01-01

    evaluation of cold bombesin derivative effect in PC-3 cells proliferation by MTS assay. Bombesin derivative (20□g) was successfully radiolabeled with 97.5 MBq of 177 Lu at 90 deg. C for 30 minutes and pH 4.5. This mixture kept stable for more than 96 hours at 4 deg. C and 1 hour in fresh human serum. Investigations in Balb-c mice showed a multicompartimental model of biodistribution, with fast blood clearance, rapid excretion, performed mainly by renal pathway, low abdominal accumulation in pancreas and intestines and low retention in organism, with 90% of total radioactivity excreted in the first 4 hours p.i. The studies in Nude mice bearing human prostate (PC-3) tumor showed that the radiopeptide exhibited significant target to tumor cells. Higher tumor uptake was observed at 1 hour post injection (0.88 + 0.11% ID/g and 4.38 + 0.54% of the radioactivity presented in organism) and showed to be specific in vivo. The pre-injection of unlabeled peptide reduced 88% of labeled peptide target to tumor cells. Moreover, tumor uptake allowed tumor detection by scintigraphy imaging, especially one hour post injection, but also 4 hours p.i. In addition, the studied bombesin derivative did not present proliferative or citotoxic effect to PC-3 cells in vitro and can be characterized as a weak agonist or antagonist of bombesin receptors. The results of this work showed that this novel radiopharmaceutical based on bombesin structure is promising for applications in prostate tumor detection and treatment. (author)

  12. 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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  13. Conversion of no-carrier-added [11C]carbon dioxide to [11C]carbon monoxide on molybdenum for the synthesis of 11C-labelled aromatic ketones

    International Nuclear Information System (INIS)

    Zeisler, S.K.; Nader, M.; Theobald, A.; Oberdorfer, F.

    1997-01-01

    A new method for the efficient conversion of no-carrier-added [ 11 C]carbon dioxide into [ 11 C]carbon monoxide is described. [ 11 C]Carbon dioxide produced by proton bombardment of ultra high purity nitrogen is pre-concentrated in a cryo trap and then passed through a quartz tube filled with a mesh of thin molybdenum wire heated to 850 o C. [ 11 C]Carbon dioxide readily reacts with molybdenum to form [ 11 C]carbon monoxide and molybdenum(IV) oxide. The latter also reduces carbon dioxide to carbon monoxide and helps improve the performance of the converter. [ 11 C]Carbon monoxide is purified from remaining [ 11 C]carbon dioxide and collected in a small silica trap from which it is eluted into a reaction mixture for the palladium-mediated synthesis of a 11 C-labelled aromatic ketone. Radiochemical yields of up to 81% (decay-corrected) for [ 11 C]carbon monoxide were obtained. Radiochemical purity and specific radioactivity of both [ 11 C]carbon monoxide and the 11 C-labelled ketone are sufficient for nuclear medical studies with PET. (Author)

  14. No-carrier-added (NCA) N-(3-( sup 18 F)fluoropropyl)-N-norbuprenorphine and N-(3-( sup 18 F)fluoropropyl)-N-nordiprenorphine -synthesis, anatomical distribution in mice and rats, and tomographic studies in a baboon

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Lanqin; Teng, Renrui; Shiue, Chyngyann; Wolf, A P; Dewey, S L [Brookhaven National Lab., Upton, NY (USA); Holland, M J; Simon, E J [New York Univ., NY (USA). Medical Center

    1990-01-01

    N-(3-Fluoropropyl)-N-norbuprenorphine (3a) and N-(3-fluoropropyl)-N-nordiprenorphine (4a) were synthesized by N-alkylation of norbuprenorphine (1) and nordiprenorphine (2) with 1-bromo-3-fluoropropane. The corresponding no-carrier-added (NCA) N-(3-({sup 18}F)fluoropropyl)-N-norbuprenorphine (3b) and N-(3-({sup 18}F)fluoropropyl)-N-nordiprenorphine (4b) were synthesized by N-alkylation of 1 and 2 with NCA 1-({sup 18}F)fluoro-3-iodopropane. In vitro studies indicate that in the absence of sodium chloride, compounds 3a, 4a, N-propyl-N-norbuprenorphine (5), buprenorphine and diprenorphine are reasonably comparable in binding affinity for opioid receptors. In the presence of 100 mM sodium chloride, however, compounds 3a, 4a and 5, are clearly less potent than buprenorphine and diprenorphine. The anatomical distribution study of compound 3b in mice shows radioactivity accumulating in bone. Rat studies of both compounds 3b and 4b indicate the specific distribution of these two radioligands within certain cortical and subcortical regions of rat brain. However, the absolute uptake of compound 4b in rat brain was only half that of compound 3b. PET studies of 3b in a baboon revealed specific binding of compound 3b in striatum and cerebellum. At 1 h after injection, ratios of specific/non-specific binding of 3b in striatum and cerebellum of a baboon were 1.9 and 1.7 respectively. (author).

  15. No-carrier-added (NCA) N-(3-[18F]fluoropropyl)-N-norbuprenorphine and N-(3-[18F]fluoropropyl)-N-nordiprenorphine -synthesis, anatomical distribution in mice and rats, and tomographic studies in a baboon

    International Nuclear Information System (INIS)

    Lanqin Bai; Renrui Teng; Chyngyann Shiue; Wolf, A.P.; Dewey, S.L.; Holland, M.J.; Simon, E.J.

    1990-01-01

    N-(3-Fluoropropyl)-N-norbuprenorphine (3a) and N-(3-fluoropropyl)-N-nordiprenorphine (4a) were synthesized by N-alkylation of norbuprenorphine (1) and nordiprenorphine (2) with 1-bromo-3-fluoropropane. The corresponding no-carrier-added (NCA) N-(3-[ 18 F]fluoropropyl)-N-norbuprenorphine (3b) and N-(3-[ 18 F]fluoropropyl)-N-nordiprenorphine (4b) were synthesized by N-alkylation of 1 and 2 with NCA 1-[ 18 F]fluoro-3-iodopropane. In vitro studies indicate that in the absence of sodium chloride, compounds 3a, 4a, N-propyl-N-norbuprenorphine (5), buprenorphine and diprenorphine are reasonably comparable in binding affinity for opioid receptors. In the presence of 100 mM sodium chloride, however, compounds 3a, 4a and 5, are clearly less potent than buprenorphine and diprenorphine. The anatomical distribution study of compound 3b in mice shows radioactivity accumulating in bone. Rat studies of both compounds 3b and 4b indicate the specific distribution of these two radioligands within certain cortical and subcortical regions of rat brain. However, the absolute uptake of compound 4b in rat brain was only half that of compound 3b. PET studies of 3b in a baboon revealed specific binding of compound 3b in striatum and cerebellum. At 1 h after injection, ratios of specific/non-specific binding of 3b in striatum and cerebellum of a baboon were 1.9 and 1.7 respectively. (author)

  16. Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides

    Science.gov (United States)

    Schuchardt, Christiane; Kulkarni, Harshad R.; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P.; Beer, Ambros J.

    2016-01-01

    In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the

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

    International Nuclear Information System (INIS)

    Suzauki, Miriam Fussae; Silva, Marcia Augusta da; Caldeira Filho, Jose de Souza; Colturato, Maria Tereza; Araujo, Elaine Bortoleti de; Bartolini, Paolo; Okazaki, Kayo

    2005-01-01

    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, Tyr 3 ]octreotate has been used because of its high affinity to somatostatin subtype receptors sstr 2 and sstr 5 . 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, Tyr 3 ]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, Tyr 3 ]octreotate labeled with with 131 I (n=3) and 177 Lu (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. 131 I and 177 Lu 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) (P 131 I-DOTA, Tyr 3 ]octreotate was Y = (1.634 ± 0.236) + (0.912 ± 0.137) 10 -3 X and for [ 177 Lu-DOTA, Tyr 3 ]octreotate was Y = (1.715 ± 0.342) + (0.743 ± 0.135) 10 -3 X. The non labeled molecule, [DOTA, Tyr 3 ]octreotate, has no influence in the induction of cytogenetic damage. The micronucleus assay with rat pancreatic tumor cells

  18. {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    Energy Technology Data Exchange (ETDEWEB)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India); Sahoo, Ranjit Kumar [All India Institute of Medical Sciences, Department of Medical Oncology, BR Ambedkar Rotary Cancer Hospital, New Delhi (India); Seth, Amlesh [All India Institute of Medical Sciences, Department of Urology, New Delhi (India)

    2017-01-15

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic{sup 68}Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly {sup 177}Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity

  19. "1"7"7Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz; Schrader, Andres Jan; Boegemann, Martin

    2017-01-01

    Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with "1"7"7Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of "1"7"7Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of "1"7"7Lu-PSMA-617 and an initial ALP level <220 U/L were predictors of a longer OS in patients with end-stage mCRPC. An ALP level <220 U/L was additionally associated with a longer PPFS. (orig.)

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

    International Nuclear Information System (INIS)

    Sainz-Esteban, Aurora; Carril, Jose Manuel; Prasad, Vikas; Schuchardt, Christiane; Zachert, Carolin; Baum, Richard P.

    2012-01-01

    The aim of the study was to compare sequential 177 Lu-DOTA-TATE planar scans ( 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 68 Ga-DOTA-TATE positron emission tomography (PET)/CT ( 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 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE imaging within 7.9 ± 7.5 days between the two examinations. 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 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 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 68 Ga-DOTA-TATE positive and 177 Lu-DOTA-TATE negative, whereas 9 were 68 Ga-DOTA-TATE negative and 177 Lu-DOTA-TATE positive. The sensitivity, positive predictive value and accuracy for 177 Lu-DOTA-TATE as compared to 68 Ga-DOTA-TATE were 91, 97 and 88%, respectively. Significantly more lesions were seen on the delayed (72 h) 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 max ). However, concordant liver lesions with a score from 1 to 3 in the 72-h 177 Lu-DOTA-TATE scan had a lower SUV max

  1. 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

    Energy Technology Data Exchange (ETDEWEB)

    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

  2. PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues

    Science.gov (United States)

    2012-01-01

    Background Radiolabelled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumours, in which BN2/gastrin-releasing peptide receptors are overexpressed. We describe the influence of the specific activity of a 177Lu-DOTA-PEG5k-Lys-B analogue on its therapeutic efficacy and compare it with its non-PEGylated counterpart. Methods Derivatisation of a stabilised DOTA-BN(7–14)[Cha13,Nle14] analogue with a linear PEG molecule of 5 kDa (PEG5k) was performed by PEGylation of the ϵ-amino group of a β3hLys-βAla-βAla spacer between the BN sequence and the DOTA chelator. The non-PEGylated and the PEGylated analogues were radiolabelled with 177Lu. In vitro evaluation was performed in human prostate carcinoma PC-3 cells, and in vivo studies were carried out in nude mice bearing PC-3 tumour xenografts. Different specific activities of the PEGylated BN analogue and various dose regimens were evaluated concerning their therapeutic efficacy. Results The specificity and the binding affinity of the BN analogue for BN2/GRP receptors were only slightly reduced by PEGylation. In vitro binding kinetics of the PEGylated analogue was slower since steady-state condition was reached after 4 h. PEGylation improved the stability of BN conjugate in vitro in human plasma by a factor of 5.6. The non-PEGylated BN analogue showed favourable pharmacokinetics already, i.e. fast blood clearance and renal excretion, but PEGylation improved the in vivo behaviour further. One hour after injection, the tumour uptake of the PEG5k-BN derivative was higher compared with that of the non-PEGylated analogue (3.43 ± 0.63% vs. 1.88 ± 0.4% ID/g). Moreover, the increased tumour retention resulted in a twofold higher tumour accumulation at 24 h p.i., and increased tumour-to-non-target ratios (tumour-to-kidney, 0.6 vs. 0.4; tumour-to-liver, 8.8 vs. 5.9, 24 h p.i.). In the therapy study, both 177Lu-labelled BN analogues significantly inhibited tumour

  3. Evaluation of 177Lu[Lu]-CHX-A″-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII.

    Science.gov (United States)

    Fiedler, L; Kellner, M; Gosewisch, A; Oos, R; Böning, G; Lindner, S; Albert, N; Bartenstein, P; Reulen, H-J; Zeidler, R; Gildehaus, F J

    2018-05-01

    Due to their infiltrative growth behavior, gliomas have, even after surgical resection, a high recurrence tendency. The approach of intracavitary radioimmunotherapy (RIT) is aimed at inhibiting tumor re-growth by directly administering drugs into the resection cavity (RC). Direct application of the radioconjugate into the RC has the advantage of bypassing the blood-brain barrier, which allows the administration of higher radiation doses than systemic application. Carbonic anhydrase XII (CA XII) is highly expressed on glioma cells while being absent from normal brain and thus an attractive target molecule for RIT. We evaluated a CA XII-specific 6A10 Fab (fragment antigen binding) labelled with 177 Lu as an agent for RIT. 6A10 Fab fragment was modified and radiolabelled with 177 Lu and characterized by MALDI-TOF, flow cytometry and radio-TLC. In vitro stability was determined under physiological conditions. Biodistribution studies, autoradiography tumor examinations and planar scintigraphy imaging were performed on SCID-mice bearing human glioma xenografts. The in vitro CA XII binding capacity of the modified Fab was confirmed. Radiochemical purity was determined to be >90% after 72 h of incubation under physiological conditions. Autoradiography experiments proved the specific binding of the Fab to CA XII on tumor cells. Biodistribution studies revealed a tumor uptake of 3.0%ID/g after 6 h and no detectable brain uptake. The tumor-to-contralateral ratio of 10/1 was confirmed by quantitative planar scintigraphy. The radiochemical stability in combination with a successful in vivo tumor uptake shows the potential suitability for future RIT applications with the 6A10 Fab. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Evaluation of cell death mechanisms activated by the administration of the theranostics radiopharmaceutical {sup 177}Lu-DOTA-anti-CD20 in a dose range of 1-5 Gy; Evaluacion de los mecanismos de muerte celular activados por la administracion del radiofarmaco teranostico {sup 177}Lu-DOTA-anti-CD20 en un rango de dosis de 1-5 Gy

    Energy Technology Data Exchange (ETDEWEB)

    Martinez V, B. E.

    2016-07-01

    Radio-immunotherapy with anti-CD20 antibodies significantly increases the rate of remission in patients with CD20 over expressing B-cell lymphomas. Radio-labeled antibodies directed to surface antigens allow delivering scaled doses of radiation to specific targets thus limiting the dose to healthy tissue. Anti-CD20 causes cell death by two major pathways; activating the immune system to destroy malignant cells and inducing the activation of cell death pathways. The {sup 177}Lu is a beta particle emitter (max. 0.497 MeV) with a maximum soft tissue reach of 0.7 mm and a half-life of 6.7 days. Several clinical studies have established a maximum tolerated dose (45m Ci/m{sup 2}) for {sup 177}Lu-DOTA-rituximab, which shows a favorable clinical response without hematological toxicity. However, the molecular mechanisms of synergistic activation of anti-CD20 and radionuclide have not been studied. In this work we evaluated by flow cytometry, the activation kinetics of the cell death mechanisms induced by the treatment with {sup 177}Lu-DOTA-anti-CD20 from non-Hod king lymphoma cells (Raji). The absorbed radiation dose delivered to the cell nucleus was calculated by Monte Carlo simulation, considering the contribution of the beta emissions of the radiopharmaceutical present in the cell membrane and surrounding environment, as well as crossfire. This work shows that the application of radiation doses of 1 to 5 Gy of the radiopharmaceutical {sup 177}Lu-DOTA-anti-CD20 are sufficient to induce cell death by apoptosis and arrest of the cell cycle. The combination of these factors (continuous delivery of radiation activation of repair mechanisms and increased radio-sensitivity) causes acute activation of the apoptotic program resulting in significant cell death after 96 h of treatment. The temporal analysis of cell death suggests the early activation of apoptosis that is counteracted by the activation of repair processes caused by sustained irradiation, which leads to cell arrest

  5. Evaluation of the cell death mechanisms activated by the radiopharmaceutical {sup 177}Lu-DOTA-anti-CD20 in a dose range of 1 to 5 Gy; Evaluacion de los mecanismos de muerte celular activados por el radiofarmaco {sup 177}Lu-DOTA-anti-CD20 en un intervalo de dosis de 1 a 5 Gy

    Energy Technology Data Exchange (ETDEWEB)

    Azorin V, E.P.; Rojas C, E. L.; Martinez V, B. E.; Ramos B, J. C.; Jimenez M, N. P.; Ferro F, G., E-mail: erica.azorin@inin.gob.mx [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico)

    2016-10-15

    The radio immunotherapy with anti-CD20 antibodies significantly increases the remission rate of patients with B-cell lymphomas over expressing the CD20. The radiolabeled antibodies directed to surface antigens allow delivering scaled doses of radiation to specific targets thus limiting the dose to healthy tissue. The anti-CD20 causes cell death by two major pathways; activating the immune system to destroy malignant cells and inducing the activation of cell death pathways. The {sup 177}Lu is a beta particle emitter (max. 0.497 MeV) with a maximum reach on soft tissue of 0.7 mm and a half-life of 6.7 days. Several clinical studies have established a maximum tolerated dose (45 m Ci/m{sup 2}) for {sup 177}Lu-DOTA-rituximab, which shows a favorable clinical response without hematological toxicity. However, the molecular mechanisms of action by synergistic effect of anti-CD20 and radionuclide have not been studied. In this work was evaluated; by flow cytometry, the activation kinetics of the cell death mechanisms induced by the treatment with {sup 177}Lu-DOTA-Anti-CD20 in non-Hodgkin (Raji) lymphoma cells. The absorbed radiation dose delivered to the cell nucleus was calculated by Monte Carlo simulation, considering the contribution of the beta emissions of the radiopharmaceutical present in the cell membrane and surrounding environment, as well as crossfire. This work shows that the application of radiation doses of 1 to 5 Gy of the radiopharmaceutical {sup 177}Lu-DOTA-anti-CD20, are sufficient to induce cell death by apoptosis and arrest of the cell cycle. The combination of these factors (continuous delivery of radiation, activation of repair mechanisms and increased radio sensitivity) causes the acute activation of the apoptotic program resulting in significant cell death after 96 h of treatment. The temporal analysis of cell death suggests the early activation of apoptosis that is counteracted by the activation of repair processes caused by sustained irradiation

  6. {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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Pujatti, Priscilla B.; Santos, Josefina S.; Couto, Renata M.; Araujo, Elaine B. de; Mengatti, Jair [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Diretoria de Radiofarmacia], e-mail: priscillapujatti@yahoo.com.br; Suzuki, Miriam F. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Biotecnologia

    2009-07-01

    In this work we describe the radiolabeling with {sup 177}Lu 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. {sup 177}Lu-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 {sup 177}LuCl3 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, {sup 177}Lu-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)

  8. Chemical processing for production of no-carrier-added selenium-73 from germanium and arsenic targets and synthesis of L-2-amino-4-([73Se]methylseleno) butyric acid (L-[73Se]selenomethionine)

    International Nuclear Information System (INIS)

    Plenevaux, A.; Guillaume, M.; Brihaye, C.; Lemaire, C.; Cantineau, R.

    1990-01-01

    The Ge( 4 He,xn) and 75 As(p,3n) reactions were compared as the best potential routes for routine production of selenium-73 ( 73 Se) for medical applications. With 26 MeV α particles, available with compact cyclotrons, the first reaction required an enriched 70 Ge target of sodium metagermanate to give a production yield of 1 mCi/μAh (0.037 GBq/μAh) in a 105 mg/cm 2 target. With 55 MeV protons the As(p,3n) reaction on natural arsenic yielded 20 mCi/μAh (0.74 GBq/μAh) in a 685 mg/cm 2 target. A simple method was developed and optimized for both targets in order to isolate and purify the no-carrier-added selenium in the elemental form with a radiochemical yield greater than 75% in less than 90 min. An automated radiochemical processing unit has been designed for the routine production of 100-150 mCi(3.7-5.5 GBq) batches of carrier-free 73 Se ready for radiopharmaceutical labeling. 30 mCi (1.11 GBq) (EOS) of L-2-amino-4-([ 73 Se]methylseleno) butyric acid (L-[ 73 Se]selenomethionine) ready for injection with a specific activity of 5 Ci/mmol (185 GBq/mmol) (EOS) were obtained through a fast chemical synthesis. Radiation absorbed dose estimates for L-[ 73 Se ]selenomethionine have been determined. A value of 0.70 rem/mCi (0.19 mSv/MBq) administered was calculated for the risk from irradiation in man. The first human PET investigation with [ 73 Se]selenomethionine showed a very good delineation between liver and pancreas. (author)

  9. Preparation of therapeutic dose of 177Lu-DOTA-TATE using a novel single vial freeze-dried kit: a comparison with 'in-situ' preparation at hospital radiopharmacy.

    Science.gov (United States)

    Das, Tapas; Banerjee, Sharmila; Shinto, Ajit; Kamaleshwaran, K K; Sarma, H D

    2014-01-01

    Patient dose of (177)Lu-DOTA-TATE, used for providing radiotherapeutic treatment to the patients suffering from cancers of neuroendocrine origin, could be prepared at the hospital radiopharmacy either 'in-situ' or by using freezedried kits. The objective of the present work is to formulate and evaluate a single vial freeze-dried DOTA-TATE kit, which is capable of producing up to 7.4 GBq (200 mCi) dose of (177)Lu-DOTA-TATE and to compare the two methodologies presently used for the preparation of the agent. Freeze-dried DOTA-TATE kits, comprising a lyophilized mixture of DOTA-TATE, gentisic acid and ammonium acetate, were prepared and used for the formulation of patient doses of (177)Lu-DOTA-TATE. The kits were subjected to detailed radiochemical evaluation and the shelf-life of the kits was determined. The pharmacokinetic behavior of the agent was studied in normal Wistar rats. These kits were utilized for treating the patients suffering from various types of neuroendocrine cancers. The freeze-dried kits were used for the preparation of up to 7.4 GBq (200 mCi) therapeutic doses of (177)Lu- DOTA-TATE with a radiochemical purity of >99% and were found to have sufficiently long shelf-life. Biological studies carried out in normal Wistar rats exhibited no significant accumulation of activity in any of the vital organs/tissue except in kidneys and non-accumulated activity showed major renal clearance. Clinical studies carried out in cancer patients exhibited accumulation of activity in the cancerous lesions and metastatic sites. The kit was useful for the convenient preparation of therapeutic dose of (177)Lu-DOTA-TATE, suitable for human administration. The use of kit is expected to reduce the batch failure and radiation exposure to the working personnel.

  10. Studies on low-carrier radiofluorination of non-active aromatics with no-carrier-added [{sup 18}F]fluoride; Untersuchungen zur traegerarmen Radiofluorierung nicht-aktiver Aromaten mit n.c.a. [{sup 18}F]Fluorid

    Energy Technology Data Exchange (ETDEWEB)

    Cardinale, Jens

    2013-01-15

    In vivo imaging with positron emission tomography generally demands radiotracers with a high specific activity. In case of fluorine-18 the required no-carrier-added (n.c.a.) starting material is only available in form of fluoride. This and the short half-life of 109.7 minutes of the radionuclide lead to the demand of special methods for radiosyntheses. The only practical procedure for manufacturing n.c.a. [{sup 18}F]fluoro-compounds is therefore nucleophilic substitution. There is, however, still a lack of effective procedures for the labelling of electron rich aromatic molecules starting from n.c.a. [{sup 18}F]fluoride. A process for n.c.a. radiofluorination of these compounds is offered by the reaction of iodonium compounds as starting materials. In this study modern procedures for the synthesis of iodoniumsalts and -ylides were investigated. Several precursor molecules for the versatile synthetic building block 4-[{sup 18}F]fluoroiodobenzene were synthesised. In this course, a new one-pot procedure for the synthesis of iodoniumylides was developed. Further on, the syntheses of suitable iodonium precursors for two fluorophenoxy-derivatives, which are possible antidepressants, were investigated. Due to their binding profile these compounds can be considered as ligands for the serotonin reuptake transporter (SERT) and the norepinephrin reuptake transporter (NET), respectively. The preparation of appropriate iodonium salts proved to be too problematic, while the synthesis of suitable iodoniumylides could be accomplished with satisfactory yields of about 30% and 40 %, respectively. Both compounds were labelled with n.c.a. [{sup 18}F]fluoride and deprotected to the desired target compounds 4-((3-[{sup 18}F]fluorophenoxy)(phenyl)methyl)piperidine and 4-((4-[{sup 18}F]fluorophenoxy)(phenyl)methyl)piperidine in radiochemical yields of about 40 % and 25 %, respectively. Those are now available for preclinical evaluation studies. Furthermore, a process for the palladium

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  12. Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome.

    Science.gov (United States)

    Naik, Chinna; Basu, Sandip

    2017-01-01

    Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177 Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region ( n = 1), duodenum ( n = 1), and pancreas ( n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25-75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [ 99m Tc]-hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/ 68 Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET-CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor-based imaging in the cases with low MiB1 index. In our series, good palliative response to 177 Lu-DOTA-octreotate (DOTATATE) PRRT was

  13. The intratumoral distribution of radiolabeled 177Lu-BR96 monoclonal antibodies changes in relation to tumor histology over time in a syngeneic rat colon carcinoma model.

    Science.gov (United States)

    Örbom, Anders; Eriksson, Sophie E; Elgström, Erika; Ohlsson, Tomas; Nilsson, Rune; Tennvall, Jan; Strand, Sven-Erik

    2013-08-01

    The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of (177)Lu-DOTA-BR96 monoclonal antibodies targeting the Lewis Y antigen over 7 d using a syngeneic rat model of colon carcinoma. Thirty-eight tumor-bearing rats were intravenously given 25 or 50 MBq of (177)Lu-DOTA-BR96 per kilogram of body weight and were sacrificed 2, 8, 24, 48, 72, 96, 120, or 168 h after injection, with activity measured in blood and tumor samples. Adjacent cryosections of each tumor were analyzed in 3 ways: imaging using a silicon-strip detector for digital autoradiography, staining for histologic characterization, or staining to determine the distribution of the antigen, vasculature, and proliferating cells using immunohistochemistry. Absorbed-dose rate distribution images at the moment of sacrifice were calculated using the activity distribution and a point-dose kernel. The correlations between antigen expression and both activity uptake and absorbed-dose rate were calculated for several regions of interest in each tumor. Nine additional animals with tumors were given unlabeled antibody to evaluate possible immunologic effects. At 2-8 h after injection, activity was found in the tumor margins; at 24 h, in viable antigen-expressing areas within the tumor; and at 48 h and later, increasingly in antigen-negative areas of granulation tissue. The correlation between antigen expression and both the mean activity and the absorbed-dose rate in regions of interest changed from positive to negative after 24 h after injection. Antigen-negative areas also increased over time in animals injected with unlabeled BR96, compared with untreated tumors. The results indicate that viable Lewis Y-expressing tumor cells are most efficiently treated during the initial uptake period. The activity then seems

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

    Science.gov (United States)

    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 (177)Lu-labeled hydroxyapatite ((177)Lu-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 (177)Lu-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 body scan. Static scans of the joint at 1 month revealed complete retention of (177)Lu-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 level was not different before and after RSV. RSV side-effects assessed for the whole follow-up period were minor and not significant. RSV with (177)Lu-HA was safe and effective in patients with knee joint chronic painful synovitis of rheumatoid origin. It exhibited significant therapeutic effect after 6 months follow-up period with no significant side-effects. The preliminary investigations reveal that (177)Lu-labeled HA particles hold considerable promise as a cost-effective agent for RSV. More elaborate and

  15. High clinical and morphologic response using {sup 90}Y-DOTA-octreotate sequenced with {sup 177}Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours

    Energy Technology Data Exchange (ETDEWEB)

    Kong, Grace; Callahan, Jason; Pattison, David A.; Akhurst, Tim; Eu, Peter [Peter MacCallum Cancer Centre, Centre for Cancer Imaging, Melbourne, VIC (Australia); Hofman, Michael S. [Peter MacCallum Cancer Centre, Centre for Cancer Imaging, Melbourne, VIC (Australia); The University of Melbourne, Department of Medicine, Parkville (Australia); Michael, Michael [Peter MacCallum Cancer Centre, Division of Cancer Medicine, Neuroendocrine Tumour Unit, Melbourne, VIC (Australia); The University of Melbourne, The Sir Peter MacCallum Department of Oncology, Parkville (Australia); Hicks, Rodney J. [Peter MacCallum Cancer Centre, Centre for Cancer Imaging, Melbourne, VIC (Australia); The University of Melbourne, The Sir Peter MacCallum Department of Oncology, Parkville (Australia)

    2017-03-15

    Bulky disease is an adverse prognostic factor for {sup 177}Lu-DOTA-octreotate ({sup 177}Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). {sup 90}Y-DOTA-octreotate ({sup 90}Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than {sup 177}Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially. We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of {sup 90}Y-DOTATATE followed by 2-3 cycles of {sup 177}Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival. Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq {sup 90}Y-DOTATATE, and 21 GBq {sup 177}Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months. PRCRT with {sup 90}Y -DOTATATE followed by {sup 177}Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either

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

    Energy Technology Data Exchange (ETDEWEB)

    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. Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases?

    Science.gov (United States)

    Basu, Sandip; Ranade, Rohit

    2016-06-01

    This report illustrates an excellent partial response of Merkel cell carcinoma with multiple bilobar hepatic metastases to a single cycle of peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE. This response, coupled with minimal side effects, warrants consideration of this therapy early in the disease course (rather than at an advanced stage after failure of other therapies) if the metastatic lesions exhibit adequate tracer avidity on somatostatin receptor-based imaging. Our patient showed progression of systemic disease after having undergone a second surgery and adjuvant radiotherapy to the head and neck, as well as chemotherapy, and hence was considered a candidate for PRRT. In a pretreatment study, the metastatic lesions demonstrated avidity to both somatostatin receptors and (18)F-FDG. Three months after the first cycle of treatment, when the patient was being evaluated for a second cycle, both imaging parameters showed evidence of a partial response that included nearly complete resolution of the two previously seen lesions. In view of the relatively good tolerability, minimal side effects, and targeted nature of the treatment, PRRT may evolve to become the first-line therapy for metastatic Merkel cell carcinoma and should be examined further in a larger number of patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  18. Development of a lyophilized formulation for preparing the radiopharmaceutical {sup 177}Lu-DOTA-Anti-CD20; Desarrollo de una formulacion liofilizada para la preparacion del radiofarmaco {sup 177}-DOTA-Anti-CD20

    Energy Technology Data Exchange (ETDEWEB)

    Serrano E, L. A.

    2015-07-01

    The radiolabeled proteins are molecules of interest in nuclear medicine for their diagnostic and therapeutic application in cancer. Antibodies, such as chimeric monoclonal antibody Anti-CD20 rituximab, have established themselves as suitable vectors of radionuclides (e.g. {sup 177}Lu) , introducing high affinity by the surface antigens over- expressed and widely distributed in cells involved in certain diseases. The aim of this work was to design, optimize and document the production process of radiopharmaceutical {sup 177}Lu-DOTA-Anti-CD20 for sanitary registration request to the Comision Federal para la Proteccion contra Riesgos Sanitarios (COFEPRIS). First, a raw material analysis using the Ft-Mir technique and gamma spectrometry was performed. Then, was carried out the development of the lyophilized formulation for the preparation of {sup 177}Lu-DOTA-Anti-CD20, in which an ANOVA was performed where the dependent variable was the radiochemical purity. The optimal pharmaceutical formulation was: 5 mg DOTA-CD20 and 80 mg Mannitol to be reconstituted with 1 m L of acetate buffer 0.25 M, ph 7, with an incubation time of 15 min at 37 degrees Celsius in a dry bath. Once completed the development of the lyophilized formulation, we proceeded to the optimization of the production process, development and validation of the analytical method. Three batches were prepared under protocols of Good Manufacturing Practice, which met pre-established specifications as sterile and endotoxin-free of bacterial formulations, with greater that 95% of radiochemical purity. Currently, is conducting the study of shelf stability. Upon completion of the stability studies, the legal record of {sup 177}Lu-DOTA-Anti-CD20 will be integrated with documented evidence of the quality and stability of the formulation of this radiopharmaceutical. (Author)

  19. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers.

    Science.gov (United States)

    Villard, Linda; Romer, Anna; Marincek, Nicolas; Brunner, Philippe; Koller, Michael T; Schindler, Christian; Ng, Quinn K T; Mäcke, Helmut R; Müller-Brand, Jan; Rochlitz, Christoph; Briel, Matthias; Walter, Martin A

    2012-04-01

    Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of radioisotopes. In a cohort study, patients with metastasized neuroendocrine cancer were treated with repeated cycles of (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) or with cycles alternating between [(90)Y-DOTA]-TOC and (177)lutetium-labeled DOTA-TOC ([(177)Lu-DOTA]-TOC) until tumor progression or permanent toxicity. Multivariable Cox regression and competing risk regression were used to study predictors of survival and renal toxicity in patients completing three or more treatment cycles. A total of 486 patients completed three or more treatment cycles; 237 patients received [(90)Y-DOTA]-TOC and 249 patients received [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC. Patients receiving [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC had a significantly longer survival than patients receiving [(90)Y-DOTA]-TOC alone (5.51 v 3.96 years; hazard ratio, 0.64; 95% CI, 0.47 to 0.88; P = .006). The rates of severe hematologic toxicities (6.3% v 4.4%; P = .25) and severe renal toxicity (8.9% v 11.2%; P = .47) were comparable in both groups. [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC was associated with improved overall survival compared with [(90)Y-DOTA]-TOC alone in patients completing three or more cycles of treatment. Contrary to the current practice in radiopeptide therapy, our results suggest an advantage of using a combination of radioisotopes.

  20. The {sup 68}Ga/{sup 177}Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUV{sub max} values and absorbed dose estimates

    Energy Technology Data Exchange (ETDEWEB)

    Scarpa, Lorenza; Buxbaum, Sabine; Kendler, Dorota; Decristoforo, Clemens; Uprimny, Christian; Virgolini, Irene [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Fink, Katharina [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Medical University of Innsbruck, Department of Radiotherapy / Radiation Oncology, Innsbruck (Austria); Bektic, Jasmin; Horninger, Wolfgang [Medical University of Innsbruck, Department of Urology, Innsbruck (Austria); Gruber, Leonhard [Medical University of Innsbruck, Department of Radiology, Innsbruck (Austria); Lukas, Peter [Medical University of Innsbruck, Department of Radiotherapy / Radiation Oncology, Innsbruck (Austria)

    2017-05-15

    A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Ten consecutive mCRPC patients were selected for {sup 177}Lu-PSMA617 therapy on the basis of PSMA-targeted {sup 68}Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging ({sup 68}Ga-PSMA-HBED-CC and {sup 18}F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 ± 1 weeks apart. PET/CT scans were compared to {sup 177}Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. {sup 177}Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased {sup 177}Lu-PSMA617 and {sup 68}Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following {sup 177}Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study. (orig.)

  1. 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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  3. Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [{sup 177}Lu]Lu-PSMA-617

    Energy Technology Data Exchange (ETDEWEB)

    Ahmadzadehfar, Hojjat; Wegen, Simone; Yordanova, Anna; Kuerpig, Stefan; Eppard, Elisabeth; Wei, Xiao; Schlenkhoff, Carl; Essler, Markus [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Fimmers, Rolf [University of Bonn, Institute for Medical Biometry, Informatics and Epidemiology, Bonn (Germany); Hauser, Stefan [University Hospital Bonn, Department of Urology, Bonn (Germany)

    2017-08-15

    Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [{sup 177}Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT. CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation. Fifty-two patients underwent a total of 190 cycles of RLT (3-6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA. Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles. (orig.)

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

    International Nuclear Information System (INIS)

    Kashyap, Raghava; Eu, Peter; Jackson, Price; Hofman, Michael S.; Hicks, Rodney J.; Beauregard, Jean-Mathieu; Zannino, Diana

    2013-01-01

    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 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.)

  5. Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [177Lu]Lu-PSMA-617.

    Science.gov (United States)

    Ahmadzadehfar, Hojjat; Wegen, Simone; Yordanova, Anna; Fimmers, Rolf; Kürpig, Stefan; Eppard, Elisabeth; Wei, Xiao; Schlenkhoff, Carl; Hauser, Stefan; Essler, Markus

    2017-08-01

    Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [ 177 Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT. CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation. Fifty-two patients underwent a total of 190 cycles of RLT (3-6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA. Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

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

    International Nuclear Information System (INIS)

    Severi, Stefano; Sansovini, Maddalena; Ianniello, Annarita; Nicolini, Silvia; Caroli, Paola; Paganelli, Giovanni; Bodei, Lisa; Ibrahim, Toni; Di Iorio, Valentina; D'Errico, Vincenzo; Monti, Manuela

    2015-01-01

    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 177 Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with 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.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  9. Synthesis and stability test of radioimmunoconjugate 177Lu-DOTA-F(ab′2-trastuzumab for theranostic agent of HER2 positive breast cancer

    Directory of Open Access Journals (Sweden)

    Sandra Hermanto

    2016-10-01

    Full Text Available The use of trastuzumab as intact IgG labeling radionuclide for HER2 positive breast cancer theranostic agent is not ideal because it is slowly eliminated from the blood and normal tissues resulting in low tumor/blood (T/B and tumor/normal tissue (T/NT ratios. To overcome this limitation, we developed the trastuzumab F(ab′2 fragments and radiolabeling of the fragments by β and γ-particle of Lutetium-177. F(ab2 fragments were produced by digestion of trastuzumab IgG (Herceptin with pepsin for 18 h at 37 °C. The F(ab′2 fragment fractionated in PD-10 column, followed by the conjugation with 2-(4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA as a metal chelator and radiolabeling with 177LuCl3. Molecular weight of fragments was calculated by LCMS (Liquid Chromatography Mass Spectroscopy and the radiochemical purity was evaluated by ITLC-SG (Instan Thin Layer Chromatography. Our study showed that the purity of F(ab′2 fragment generated by PD-10 fractions was >98% and the molecular weight of F(ab′2 was 98.35 kDa. The average numbers of pSCN-Bn-DOTA chelates per antibody fragment were 5.03 ± 1.5 and the optimum conjugation reactions was performed at molar ratio 20:1 (chelator to antibody. The stability test of the radioimmunoconjugate in the human serum albumin (HSA at 37 °C showed the radiochemical purity was 91.96 ± 0.26% after 96 h storage. This indicated that the radioimmunoconjugate is relatively stable when applied to the human body's physiological condition.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  11. 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

    International Nuclear Information System (INIS)

    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 177 Lu-labeled hydroxyapatite ( 177 Lu-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 177 Lu-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 < 25), fair (VAS ≥ 25-50), good (VAS ≥ 50-75) and excellent (VAS ≥ 75), with excellent and good results considered to be success, while fair and poor as failure and also by range of motion. Three phase bone scan (BS) was repeated after 6 months and changes in the second phase of BS3 were assessed visually, using a four-degree scale and in the third phase, semiquantitatively with J/B ratio to see the response. Biochemical analysis of C-reactive protein (CRP) and fibrinogen was repeated after 48 h, 4 and 24 weeks. In all 10 patients, no leakage of administered activity to nontarget organs was visible in the whole-body scan. Static scans of the joint at 1 month revealed complete retention of 177 Lu-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

  12. Evaluation of cell death mechanisms activated by the administration of the theranostics radiopharmaceutical "1"7"7Lu-DOTA-anti-CD20 in a dose range of 1-5 Gy

    International Nuclear Information System (INIS)

    Martinez V, B. E.

    2016-01-01

    Radio-immunotherapy with anti-CD20 antibodies significantly increases the rate of remission in patients with CD20 over expressing B-cell lymphomas. Radio-labeled antibodies directed to surface antigens allow delivering scaled doses of radiation to specific targets thus limiting the dose to healthy tissue. Anti-CD20 causes cell death by two major pathways; activating the immune system to destroy malignant cells and inducing the activation of cell death pathways. The "1"7"7Lu is a beta particle emitter (max. 0.497 MeV) with a maximum soft tissue reach of 0.7 mm and a half-life of 6.7 days. Several clinical studies have established a maximum tolerated dose (45m Ci/m"2) for "1"7"7Lu-DOTA-rituximab, which shows a favorable clinical response without hematological toxicity. However, the molecular mechanisms of synergistic activation of anti-CD20 and radionuclide have not been studied. In this work we evaluated by flow cytometry, the activation kinetics of the cell death mechanisms induced by the treatment with "1"7"7Lu-DOTA-anti-CD20 from non-Hod king lymphoma cells (Raji). The absorbed radiation dose delivered to the cell nucleus was calculated by Monte Carlo simulation, considering the contribution of the beta emissions of the radiopharmaceutical present in the cell membrane and surrounding environment, as well as crossfire. This work shows that the application of radiation doses of 1 to 5 Gy of the radiopharmaceutical "1"7"7Lu-DOTA-anti-CD20 are sufficient to induce cell death by apoptosis and arrest of the cell cycle. The combination of these factors (continuous delivery of radiation activation of repair mechanisms and increased radio-sensitivity) causes acute activation of the apoptotic program resulting in significant cell death after 96 h of treatment. The temporal analysis of cell death suggests the early activation of apoptosis that is counteracted by the activation of repair processes caused by sustained irradiation, which leads to cell arrest and increases cytotoxicity, thus favoring the sudden activation of apoptosis after several days of treatment. (Author)

  13. 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?

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  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

    Energy Technology Data Exchange (ETDEWEB)

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

    International Nuclear Information System (INIS)

    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

  16. Absorbed dose profiles for 32P, 90Y, 188Re, 177Lu, 51Cr, 153Sm and 169Er: radionuclides used in radiosynoviortheses treatment

    International Nuclear Information System (INIS)

    Torres, M.; Ayra, E.; Albuerne, O.; Delgado, M.

    2008-01-01

    The remarkable advances in the design and synthesis of radiopharmaceuticals has created the opportunity of generating new agents for the treatment of radiosynoviortheses (RSV) which exhibit a minimum leakage from the synovial joint reducing, this way, the non desired absorbed doses to non target organs such as liver, spleen, kidney. Nowadays, the variety of beta emitters used in RSV ranges between 0.34 MeV - 0.33 mm penetration in tissue ( 169 Er) and 2.27 MeV - 3.6 mm penetration in tissue ( 90 Y). The half life of these isotopes goes from 2.3 hours ( 165 Dy) to 27.8 days ( 51 Cr). The selection criterion on which radionuclide should be used, in modern clinics, depends on which joints are to be treated. Thus, the smaller the joint, the lowest should be the energy of the beta emitted and the penetration in soft tissue of these particles. This leads to the use of fixed radionuclides and doses for each kind of joint. In the Isotopes Centre, we've been carrying on studies for the development of radiopharmaceuticals for the radiosynoviortheses treatment and focused our attention in the following radionuclides: 32 P, 90 Y, 188 Re, 177 Lu, 51 Cr, 153 Sm and 169 Er. The main objective of this paper was to obtain the absorbed dose profiles for radionuclides of frequent or potential use in radiosynoviortheses. These profiles reveal the absorbed dose imparted per unit activity of injected radionuclide (Gy/h*MBq) in the synovial membrane and the articular cartilage. The researched radionuclides were those previously mentioned. Also were calculated the therapeutic range of each radionuclides in synovial tissue. The therapeutic range is defined as the deepness at which the absorbed dose equals the 10 % of the maximum dose deposited in the synovial surface. This range determines the synovial thickness that can be sufficiently irradiated and thus successfully treated. The synovial membrane model consisted on a cylinder with the source uniformly distributed in its volume. This

  17. 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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  18. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    International Nuclear Information System (INIS)

    Cheal, Sarah M.; Lee, Sang-gyu; Punzalan, Blesida; Larson, Steven M.; Xu, Hong; Guo, Hong-fen; Chalasani, Sandhya; Carrasquillo, Jorge A.; Fung, Edward K.; Jungbluth, Achim; Zanzonico, Pat B.; O'Donoghue, Joseph; Smith-Jones, Peter M.; Wittrup, K.D.; Cheung, Nai-Kong V.

    2016-01-01

    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 177 Lu-or 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 177 Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm 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 3 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten 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.)

  19. 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

    International Nuclear Information System (INIS)

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Choi, Sang Mu; Lee, So young; Nam, Sung Soo; Park, Ul Jae; Park, Soo Hyun

    2015-01-01

    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(SO 3 H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH 2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with 177 Lu 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/10 6 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 177 Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over-expressing prostate tumors

  20. Synthesis of 'no carrier added' carbon-11 fotemustine

    International Nuclear Information System (INIS)

    Lasne, M.C.; Piarraud, A.; Lalaoui, K.; Barre, L.; Derlon, J.M.; Giroux, B.

    1990-01-01

    Nitrosoureas are commonly used for chemotherapeutic treatment of some tumors and the search for new drugs less toxic amd more selective is always under investigation. Efficacy of fotemustine, a nitrosourea type compound in the treatment of malignant gliomas prompted us to label it with carbon-11 so that its pharmacokinetics and metabolic behavior in human brain tumors could be studied in vivo using PET. The synthetic pathway for labelling with carbon-11 is outlined

  1. 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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  2. Synthesis of no-carrier-added and carrier-added YF-labelled haloperidol

    Energy Technology Data Exchange (ETDEWEB)

    Farrokhzad, S; Diksic, M

    1985-07-01

    Fluorine-18 labelled haloperidol ( YF-HP) was synthesized by a fluorine-fluorine exchange reaction on haloperidol, fluorine-chlorine exchange on a chloro-analog of haloperidol, and from YF-labelled p-fluorobenzonitrile prepared by two different exchange reactions. Nucleophilic fluorine was used in the form of tetra n-butylammonium fluoride. The overall radiochemical yield, expressed at the end of syntheses was 5% for exchange in haloperidol and about 2%-3% for exchange in chloroanalog in a 40 min synthesis (from the end of the irradiation). Specific activities up to 1 Ci/mmol for haloperidol and up to 5000 Ci/mmol for chloro-analog as substrates were obtained. The syntheses using p-substituted chloro-and nitro-benzonitriles as starting materials for the exchange reaction gave a product with an average specific activity of about 2000 Ci/mmol and in general an overall radiochemical yield of 5%-10%. Purification of ( YF)haloperidol was done by HPLC on a C-18 column. The radiochemical purity as assessed by thin layer radiochromatography (TLRC) of the final product was at least 95%, with high chemical purity.

  3. The synthesis of no-carrier-added and carrier-added 18F-labelled haloperidol

    International Nuclear Information System (INIS)

    Farrokhzad, S.; Diksic, M.

    1985-01-01

    Fluorine-18 labelled haloperidol ( 18 F-HP) was synthesized by a fluorine-fluorine exchange reaction on haloperidol, fluorine-chlorine exchange on a chloro-analog of haloperidol, and from 18 F-labelled p-fluorobenzonitrile prepared by two different exchange reactions. Nucleophilic fluorine was used in the form of tetra n-butylammonium fluoride. The overall radiochemical yield, expressed at the end of syntheses was 5% for exchange in haloperidol and about 2%-3% for exchange in chloroanalog in a 40 min synthesis (from the end of the irradiation). Specific activities up to 1 Ci/mmol for haloperidol and up to 5000 Ci/mmol for chloro-analog as substrates were obtained. The syntheses using p-substituted chloro-and nitro-benzonitriles as starting materials for the exchange reaction gave a product with an average specific activity of about 2000 Ci/mmol and in general an overall radiochemical yield of 5%-10%. Purification of [ 18 F]haloperidol was done by HPLC on a C-18 column. The radiochemical purity as assessed by thin layer radiochromatography (TLRC) of the final product was at least 95%, with high chemical purity. (author)

  4. The use of 99mTc-HYNIC-TOC and 18F-FDG PET/CT in the evaluation of duodenal neuroendocrine tumor with atypical and extensive metastasis responding dramatically to a single fraction of PRRT with 177Lu-DOTATATE.

    Science.gov (United States)

    Basu, Sandip; Abhyankar, Amit

    2014-12-01

    This report describes a case of extensive diffuse bone marrow involvement with bilateral breast metastases from duodenal neuroendocrine tumor giving rise to a superscan-like appearance on somatostatin receptor-targeted (99m)Tc-hydrazinonicotinamide-TOC scintigraphy. The metastatic lesions demonstrated partial concordance with (18)F-FDG PET/CT findings, signifying varying tumor biology and heterogeneity among metastatic lesions in the same individual, as illustrated with a dual-tracer approach. There was a dramatic symptomatic and biochemical response and better health-related quality of life with a single fraction of peptide receptor radionuclide therapy with (177)Lu-DOTATATE, and radiologically there was stable disease at that point. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  5. 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 {sup 177}Lu- and {sup 90}Y-BR96 mAbs

    Energy Technology Data Exchange (ETDEWEB)

    Larsson, Erik; Ljungberg, Michael; Martensson, Linda; Nilsson, Rune; Tennvall, Jan; Strand, Sven-Erik; Joensson, Bo-Anders [Department of Medical Radiation Physics, Clinical Sciences, Lund University, Lund (Sweden); Department of Oncology, Clinical Sciences, Lund University, Lund (Sweden); Department of Medical Radiation Physics, Clinical Sciences, Lund University, Lund (Sweden)

    2012-07-15

    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 {sup 90}Y- and {sup 177}Lu-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 {sup 177}Lu and 12.5 Gy for {sup 90}Y. 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

  6. Enantioselective synthesis of no-carrier added (NCA) 6-[18F]Fluoro-L-Dopa

    International Nuclear Information System (INIS)

    Duanzhi Yin; Lan Zhang; Yongxian Wang; Ganghua Tang; First Military Medical Univ., Guangzhou; Xiaolan Tang

    2003-01-01

    6-[ 18 F]Fluoro-L-Dopa (6-FDOPA) is the analogue of L-Dopa, the biosynthesis precursor for dopamine. As a PET tracer, it was widely applied for the presynaptic dopamine function studies in human brain. The application of a chiral phase-transfer-catalyst (PTC) in enantioselective synthesis of N.C.A. 6-[ 18 F]Fluoro-L-Dopa has been developed recently. An improved procedure was described. The labeling precursor (6-Trimethylammoniumveratraldehyde Triflate) and PTC (O-Allyl-N-(9)-anthracenylcinchonidinium Bromide) were synthesized. A successful synthesis route was developed for the preparation of 6-[ 18 F]Fluoro-L-Dopa with high radiochemical yields (4-9%, decay uncorrected) and short synthesis time(80min). The radiochemical purity was over 99% and no D-isomer was detected by HPLC analysis using a chiral mobile phase. (author)

  7. Synthesis of ''no carrier added'' 1,3-bis-(2-chloroethyl)nitrosourea (BCNU)

    International Nuclear Information System (INIS)

    Diksic, M.; Farrokhzad, S.; Yamamoto, L.; Feindel, W.

    1982-01-01

    A chemotherapeutic agent, C-11-labeled BCNU, has been prepared by nitrosation of C-11-labeled BCU, which was synthesized by reacting C-11-labeled phosgene with ethylenimine. Two methods of nitrosation are outlined and the results of both are discussed. The specific activity of C-11 BCNU was about 85 Ci/mmole at the end of bombardment and 30 Ci/mmole at the time of administration. Chemical and radiochemical purity of the final material was at least 98%

  8. A new approach to the synthesis of no-carrier-added fluorine-18 labeled fluorocatechols

    International Nuclear Information System (INIS)

    Chakraborty, P.K.; Kilbourn, M.R.

    1990-01-01

    A new method of synthesizing fluorine-18 labelled fluorocatechols has been developed using a salicylaldehyde as a 'synthon' for a catechol. 2-Methoxy-4-nitrobenzaldehyde was treated with [ 18 F]fluoride ion, followed by cleavage of the anisole to yield the free phenol. The phenol was oxidized to the desired fluorocatechol

  9. Lutetium-177 DOTATATE Production with an Automated Radiopharmaceutical Synthesis System.

    Science.gov (United States)

    Aslani, Alireza; Snowdon, Graeme M; Bailey, Dale L; Schembri, Geoffrey P; Bailey, Elizabeth A; Pavlakis, Nick; Roach, Paul J

    2015-01-01

    Peptide Receptor Radionuclide Therapy (PRRT) with yttrium-90 ((90)Y) and lutetium-177 ((177)Lu)-labelled SST analogues are now therapy option for patients who have failed to respond to conventional medical therapy. In-house production with automated PRRT synthesis systems have clear advantages over manual methods resulting in increasing use in hospital-based radiopharmacies. We report on our one year experience with an automated radiopharmaceutical synthesis system. All syntheses were carried out using the Eckert & Ziegler Eurotope's Modular-Lab Pharm Tracer® automated synthesis system. All materials and methods used were followed as instructed by the manufacturer of the system (Eckert & Ziegler Eurotope, Berlin, Germany). Sterile, GMP-certified, no-carrier added (NCA) (177)Lu was used with GMP-certified peptide. An audit trail was also produced and saved by the system. The quality of the final product was assessed after each synthesis by ITLC-SG and HPLC methods. A total of 17 [(177)Lu]-DOTATATE syntheses were performed between August 2013 and December 2014. The amount of radioactive [(177)Lu]-DOTATATE produced by each synthesis varied between 10-40 GBq and was dependant on the number of patients being treated on a given day. Thirteen individuals received a total of 37 individual treatment administrations in this period. There were no issues and failures with the system or the synthesis cassettes. The average radiochemical purity as determined by ITLC was above 99% (99.8 ± 0.05%) and the average radiochemical purity as determined by HPLC technique was above 97% (97.3 ± 1.5%) for this period. The automated synthesis of [(177)Lu]-DOTATATE using Eckert & Ziegler Eurotope's Modular-Lab Pharm Tracer® system is a robust, convenient and high yield approach to the radiolabelling of DOTATATE peptide benefiting from the use of NCA (177)Lu and almost negligible radiation exposure of the operators.

  10. Direct flow separation strategy, to isolate no-carrier-added {sup 90}Nb from irradiated Mo or Zr targets

    Energy Technology Data Exchange (ETDEWEB)

    Radchenko, Valery; Roesch, Frank [Mainz Univ. (Germany). Inst. of Nuclear Chemistry; Filosofov, Dmitry V.; Dadakhanov, Jakhongir [Joint Institute of Nuclear Research, Dubna (Russian Federation). Dzhelepov Laboratory of Nuclear Problems; Karaivanov, Dimitar V. [Joint Institute of Nuclear Research, Dubna (Russian Federation). Dzhelepov Laboratory of Nuclear Problems; Bulgarian Academy of Sciences, Sofia (Bulgaria). Inst. for Nuclear Research and Nuclear Energy; Marinova, Atanaska [Joint Institute of Nuclear Research, Dubna (Russian Federation). Dzhelepov Laboratory of Nuclear Problems; Sofia Univ. (Bulgaria). Faculty of Chemistry and Pharmacy; Baimukhanova, Ayagoz [Joint Institute of Nuclear Research, Dubna (Russian Federation). Dzhelepov Laboratory of Nuclear Problems; Institute of Nuclear Physics of the Republic of Kazakhstan, Almaty (Kazakhstan)

    2016-11-01

    {sup 90}Nb has an intermediate half-life of 14.6 h, a high positron branching of 53% and optimal β{sup +} emission energy of only E{sub mean} 0.35 MeV per decay. These favorable characteristics suggest it may be a potential candidate for application in immuno-PET. Our recent aim was to conduct studies on distribution coefficients for Zr{sup IV} and Nb{sup V} in mixtures of HCl/H{sub 2}O{sub 2} and HCl/oxalic acid for anion exchange resin (AG 1 x 8) and UTEVA resin to develop a ''direct flow'' separation strategy for {sup 90}Nb. The direct flow concept refers to a separation accomplished using a single eluent on multiple columns, effectively streamlining the separation process and increasing the time efficiency. Finally, we also demonstrated that this separation strategy is applicable to the production of the positron emitter {sup 90}Nb via the irradiation of molybdenum targets and isolation of {sup 90}Nb from the irradiated molybdenum target.

  11. Evaluation of 177Lu-nimotuzumab for Targeted Radioimmunotherapy of EGFR Expressing Tumors

    Czech Academy of Sciences Publication Activity Database

    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

  12. Quality control of no-carrier-added (YCl3)-Y-90 by estimating the labeling efficiency using its reaction with DOTATOC

    Czech Academy of Sciences Publication Activity Database

    Eigner-Henke, Kateřina; Beran, Miloš; Šrank, Jiří; Melichar, František

    2008-01-01

    Roč. 278, č. 1 (2008), s. 25-29 ISSN 0236-5731 R&D Projects: GA MPO FT-TA2/081 Institutional research plan: CEZ:AV0Z10480505 Keywords : TERNARY COMPLEX-FORMATION * NEUROENDOCRINE TUMORS * SOMATOSTATIN ANALOGS Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 0.659, year: 2008

  13. Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added $^{18}$F-Labelling Methods

    OpenAIRE

    Drerup, Christian; Ermert, Johannes; Coenen, Heinrich Hubert

    2016-01-01

    Nitric oxide (NO), an important multifunctional signaling molecule, is produced by three isoforms of NO-synthase (NOS) and has been associated with neurodegenerative disorders. Selective inhibitors of the subtypes iNOS (inducible) or nNOS (neuronal) are of great interest for decoding neurodestructive key factors, and 18F-labelled analogues would allow investigating the NOS-function by molecular imaging with positron emission tomography. Especially, the highly selective nNOS inhibitor 6-((3-((...

  14. Preparation of no-carrier-added [1-11C]ethylene and [1-11C]1,2-dibromoethane as new labelling agents

    International Nuclear Information System (INIS)

    Shah, F.; Pike, V.W.; Dowsett, K.

    1997-01-01

    A method is described for the preparation of NCA [1- 11 C] ethylene based on the passage of [1- 11 C]ethanol over heated (550 o C) quartz glass in a stainless steel tube (in preference to dehydration by catalysis on γ-alumina or pyrolysis). The [1- 11 C]ethanol is prepared from cyclotron-produced NCA [ 11 C]carbon dioxide by 11 C-carboxylation of methylmagnesium bromide, freshly prepared in dibutyl ether, and reduction of the adduct with lithium aluminium hydride in diglyme. The use of involatile solvents avoids the formation of carrier ethylene and radioactive and stable diethyl ether by cracking processes over the heated catalyst. The preparation takes 21 min from the end of radionuclide production and has a radiochemical yield of 44%, decay-corrected from [ 11 C]carbon dioxide. NCA [1- 11 C] ethylene is converted quantitatively into [1- 11 C]1,2-dibromoethane when collected in a solution of bromine in carbon tetrachloride. The NCA [1- 11 C]ethylene and [1- 11 C]1,2-dibromoethane may serve as new and useful labelling agents. (Author)

  15. A solid-phase technique for preparation of no-carrier-added technetium-99m radiopharmaceuticals: application to the streptavidin/biotin system

    International Nuclear Information System (INIS)

    Dunn-Dufault, Robert; Pollak, Alfred; Fitzgerald, Jane; Thornback, John R.; Ballinger, James R.

    2000-01-01

    A high effective specific activity (HESA) formulation of a biotin-containing 99m Tc ligand [RP488: dimethyl-Gly-Ser-Cys(Acm)-Lys(Biotin)-Gly] conveniently prepared from solid phase was compared to a typical low effective specific activity (LESA) solution formulation to demonstrate improved targeting to streptavidin in an in vitro assay and in an in vivo rat model. RP488 was coupled to a maleimide-functionalized polyethylene glycol resin via a thiol ether linkage and labeled with 99m Tc-gluconate at room temperature, followed by elution of the HESA 99m Tc-RP488 in saline (minimum specific activity ∼ 1000 TBq/mmol by amino acid analysis). Both HESA and LESA 99m Tc-RP488 labeled at > 90% purity. In vitro, HESA 99m Tc-RP488 incubated with streptavidin-agarose was bound quantitatively, but there was competition from addition of increasing amounts of cold RP488. In rats, radiotracer uptake was evident at the site of implantation of streptavidin-agarose beads for the HESA dose, less uptake of low effective specific activity (LESA) material, and no appreciable uptake in the control rats of the LESA or HESA dose. The target-to-background ratio for HESA 99m Tc-RP488 was 5.4 times that of the control. The solid-phase technology offers a convenient way to prepare high specific activity receptor-targeting 99m Tc radiopharmaceuticals

  16. Hairy AdS solitons

    International Nuclear Information System (INIS)

    Anabalón, Andrés; Astefanesei, Dumitru; Choque, David

    2016-01-01

    We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

  17. Hairy AdS solitons

    Energy Technology Data Exchange (ETDEWEB)

    Anabalón, Andrés, E-mail: andres.anabalon@uai.cl [Departamento de Ciencias, Facultad de Artes Liberales and Facultad de Ingeniería y Ciencias, Universidad Adolfo Ibáñez, Av. Padre Hurtado 750, Viña del Mar (Chile); Astefanesei, Dumitru, E-mail: dumitru.astefanesei@pucv.cl [Instituto de Física, Pontificia Universidad Católica de Valparaíso, Casilla 4059, Valparaíso (Chile); Choque, David, E-mail: brst1010123@gmail.com [Instituto de Física, Pontificia Universidad Católica de Valparaíso, Casilla 4059, Valparaíso (Chile); Universidad Técnica Federico Santa María, Av. España 1680, Valparaíso (Chile)

    2016-11-10

    We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

  18. Radiolabeling of trastuzumab with {sup 177}Lu via DOTA, a new radiopharmaceutical for radioimmunotherapy of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rasaneh, Samira [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Rajabi, Hossein [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of)], E-mail: hrajabi@modares.ac.ir; Babaei, Mohammad Hossein; Daha, Fariba Johari [Department of Radioisotope, Nuclear Science and Technology Research Institute, Tehran (Iran, Islamic Republic of); Salouti, Mojtaba [Department of Biology, School of Sciences, Islamic Azad University - Zanjan Branch, Zanjan (Iran, Islamic Republic of)

    2009-05-15

    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.

  19. Investigation of models with temporal and spatial interference in image based dosimetry of {sup 177}Lu-labelled radioligand therapies

    Energy Technology Data Exchange (ETDEWEB)

    Delker, Andreas

    2016-07-12

    In targeted radio ligand therapy determination of the regional distribution of the radiation dose is mandatory for the development of therapy strategies which aim for maximizing the therapeutic effect on the tumor, while reducing radiation exposure to healthy tissue. For this purpose, after administration of the therapeutic agent, sequential measurements with a scintillation camera are required to quantitatively assess the kinetics and distribution of the radiopharmaceutical in the body. To improve the accuracy and robustness of existing dosimetric concepts, the kinetic of Lu-177-DOTATATE, a radiopharmaceutical for the treatment of patients with neuroendocrine tumors, was examined in depth. Subsequently, the findings from this study were used to carry out the first image-based dosimetry for the new active substance Lu-177-PSMA, a radiopharmaceutical for the treatment of patients with metastatic prostate cancer. Due to the specific distribution pattern of this ligand, overlay effects in the 2-dimensional (2-D) planar projection were observed. Therefore a quantitative 3-dimensional (3-D) SPECT imaging technique was established and optimized for dosimetry. To characterize the dynamics of Lu-177-DOTATATE, whole-body planar projections of 105 patients were recorded at 1, 24, 48 and 72 h after injection. Furthermore, the first hour beginning with the start of the therapeutic agent administration was measured in 12 time frames with duration of 5 min each. An optimal dose model was introduced for the kidneys, for those being a risk organ in this therapy, which consisted of three phases: a linear increase of tracer accumulation during infusion, followed by a 2-phase model being described by a bi-exponential decline. This full data model served as a basis for comparison with reduced data models based on mono-exponentials which made use of all four (at 1, 24, 48 and 72 h after injection) or the last three whole-body scintigraphies. The established quantitative 3-D SPECT technique presented a sufficient recovery of known activity in medium size spherical objects with more than 30 mm diameter (approx. 80 % and above), although a significant underestimation of activity was observed in smaller spheres. With this 3-D dosimetry an estimated dose of 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq) and 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq) could be reported. The dose to the salivary glands, being assessed with 2-D dosimetry, was 5.1 ± 1.8 Gy (1.4 Gy/GBq). By combining all available 2-D- and 3-D-dosimetric data the absorbed dose of the bone marrow was estimated with 44 ± 19 mGy (0.012 Gy/GBq). Kinetic analyses of the renal uptake revealed a fast and slow washout phase. Thereby, the slow phase component was found to be responsible to cause the major fraction of the absorbed dose (98.9 %). Although the fast phase did not contribute substantially to the estimated renal dose, it had a high likelihood of interfering with the slow phase within the initial hours after injection. The unexpected dose underestimation which was observed with dosimetry calculations relying on these early time points, such as the reduced data model including the 1h measurement, could finally be explained with this discovery. These underestimations could lead to an over dosage of the therapy activity and thus to a critical radiation exposure to healthy tissue. By omitting this influenced measurement point and the solely use of the last three data points in the reduced data model, the dose delivering phase could be accurately displayed. With the insights gained in this study we were therefore able to develop a dosimetry model and workflow with increased robustness and higher confidence in the reported dose estimates, which at the same time relied on fewer measurements and therefore provided a significant reduction of work load for the staff and overall burden for the patients. This model was then applied in the dose assessment of the new radiopharmaceutical Lu-177-PSMA to avoid the above reported temporal interference effects. Furthermore we observed increased activity accumulations in the intestine after 24 h, which superimposed with the renal activity in the planar image projections and would thus lead to a falsified determination of activity for this risk organ in 2-D dosimetry. To avoid this spatial interference, the quantitative 3-D SPECT method was established in the clinic and optimized for imaging with Lu-177. The results of the final dosimetry calculations for Lu-177-PSMA indicate a high tumor dose while low dose on healthy tissue was observed. Therefore, an increased therapeutic activity could be recommended in order to maximize the therapeutic effect.

  20. Delayed response after repeated {sup 177}Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rahbar, Kambiz; Schaefers, Michael [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegeman, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, Anna; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, Maria [University Hospital Muenster, Institute for Biostatistics, Muenster (Germany)

    2018-02-15

    Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA. Seventy-one patients (median age: 72 years; range 44-87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 ± 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline ≥50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle. A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline ≥50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles. RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy. (orig.)

  1. Dosimetric analysis of 177Lu-DOTA-rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

    Science.gov (United States)

    Yadav, Madhav P; Singla, Suhas; Thakral, Parul; Ballal, Sanjana; Bal, Chandrasekhar

    2016-07-01

    Radioimmunotherapy targeting CD20 receptors in lymphoma using radiolabeled chimeric antibodies may lead to better therapeutic responses than cold anti-CD20 antibodies. This study aimed to assess the biodistribution and present reasonable estimates of normal organ doses, including red marrow using Lu-DOTA-rituximab. Patients with relapsed/refractory CD20+ B-cell non-Hodgkin's lymphoma were recruited into this prospective study. In-house labeling of Lu-DOTA-rituximab was performed and administered after quality assurance. Rituximab (375 mg/m), followed by 50 mCi (1850 MBq) of Lu-DOTA-rituximab was administered as a slow intravenous infusion and emission images were acquired. Regions of interest were drawn for kidney, liver, heart, bladder, spleen, and tumor lesions on both anterior and posterior images. Internal dose estimation was performed using OLINDA v1.0 software. The mean age of the 10 patients (eight men and two women) was 52±13 years. The uptake of radiolabeled antibody was visualized within 30 min of administration in the liver, kidneys, heart, spleen, and bladder. The coefficient of determination (R) was greater than 0.95 for organs and the whole body in all patients. The effective half-life of radioimmunoconjugate was 100±28 h (42-126 h). The critical organ in our study was the red marrow. The average total body dose, effective dose, and effective dose equivalent calculated in all 10 patients were 0.13±0.02, 0.15±0.03, and 0.22±0.04 mGy/MBq, respectively. There may be considerable interindividual differences in absorbed doses of organs and generalization or extrapolation of doses in the clinical setting at present is not feasible with Lu-DOTA-rituximab in non-Hodgkin's lymphoma patients. Patient-specific dosimetry is thus recommended to eliminate the variations and reduce the possibility of dose-limiting toxicity.

  2. Adding Ajax

    CERN Document Server

    Powers, Shelley

    2007-01-01

    Ajax can bring many advantages to an existing web application without forcing you to redo the whole thing. This book explains how you can add Ajax to enhance, rather than replace, the way your application works. For instance, if you have a traditional web application based on submitting a form to update a table, you can enhance it by adding the capability to update the table with changes to the form fields, without actually having to submit the form. That's just one example.Adding Ajax is for those of you more interested in extending existing applications than in creating Rich Internet Applica

  3. Bubbling AdS3

    International Nuclear Information System (INIS)

    Martelli, Dario; Morales, Jose Francisco

    2005-01-01

    In the light of the recent Lin, Lunin, Maldacena (LLM) results, we investigate 1/2-BPS geometries in minimal (and next to minimal) supergravity in D = 6 dimensions. In the case of minimal supergravity, solutions are given by fibrations of a two-torus T 2 specified by two harmonic functions. For a rectangular torus the two functions are related by a non-linear equation with rare solutions: AdS 3 x S 3 , the pp-wave and the multi-center string. 'Bubbling', i.e. superpositions of droplets, is accommodated by allowing the complex structure of the T 2 to vary over the base. The analysis is repeated in the presence of a tensor multiplet and similar conclusions are reached, with generic solutions describing D1D5 (or their dual fundamental string-momentum) systems. In this framework, the profile of the dual fundamental string-momentum system is identified with the boundaries of the droplets in a two-dimensional plane. (author)

  4. Synthesis and in vitro evaluation of no-carrier-added 2-(3-(4-(4-[{sup 18}F]fluorobenzyl)piperazin-1-yl)propyl)benzo[d]thiazole, a potential dopamine D{sub 4} receptor radioligand

    Energy Technology Data Exchange (ETDEWEB)

    Li, Gu-Cai; Zhang, Ru [Hunan Institute of Engineering, Hunan Xiangtan (China). College of Chemistry and Chemical Engineering; Xia, Jiao-yun [Changsha Univ. of Science and Technology (China). School of Chemistry and Biology Engineering

    2016-07-01

    The dopamine D{sub 4} receptor has been shown to play important roles in some central nervous system pathologies. Specific radioligands for the D{sub 4} receptor may be useful to understand the function of the D{sub 4} receptor and its correlations with various disorders. 2-(3-(4-(4-[{sup 18}F]Fluorobenzyl)piperazin-1-yl)propyl)benzo[d]thiazole ([{sup 18}F]4) was synthesized through a one-pot two-step procedure with total yield 18.6% (decay corrected). The specific activity of the radioligand was 112 GBq/μmol and its radiochemical purity was >95.0%. Its affinity and selectivity for dopamine D{sub 2}-like receptors were measured through in vitro receptor binding evaluation and the K{sub i} value for the D{sub 4} receptor was determined to be 2.9±0.2 nM, and its selectivity for the dopamine D{sub 4} receptor is 709-fold versus D{sub 2long} receptor, 823-fold versus D{sub 3} receptor. The partition coefficient (Log D) of it was determined to be 2.6±0.1 through octanol-water partition experiment. The ligand presents desirable combination of lipophilicity, affinity and selectivity for the dopamine D{sub 4} receptor. The results suggested that the radioligand shows promises for the in vivo study of the dopamine D{sub 4} receptor.

  5. Low temperature synthesis of no-carrier-added [{sup 11}C]formaldehyde with metal hydrides and preparation of [1-{sup 11}C]1,2,3,4-Tetrahydro-{beta}-Carboline Derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Nader, M.W.; Zeisler, S.K.; Theobald, A.; Oberdorfer, F

    1998-12-01

    A comparative study has been performed on the selective reduction of cyclotron-produced [{sup 11}C]carbon dioxide to [{sup 11}C]formaldehyde with solutions of various complex metal hydrides at temperatures between -52 and +25 deg. C. Under optimal reaction conditions, lithium tetrahydridoaluminate gave the highest yield of [{sup 11}C]formaldehyde (58%, decay-corrected), followed by lithium triethylhydridoborate (34%) and sodium tetrahydridoborate (22%). Radiochemically pure [{sup 11}C]formaldehyde could be obtained with lithium tetrahydridoaluminate and sodium tetrahydridoborate, but not with lithium triethyl hydridoborate. The produced [{sup 11}C]formaldehyde was used for the synthesis of [1-{sup 11}C]1,2,3,4-tetrahydro-{beta}-carboline derivatives by the Pictet-Spengler reaction.

  6. PET studies of potential chemotherapeutic agents: Pt. 10; Synthesis of ''no-carrier-added'' ( sup 11 C)-HECNU: the hydroxyethyl analog of the chemotherapeutic agent BCNU

    Energy Technology Data Exchange (ETDEWEB)

    Conway, T.; Diksic, M. (Montreal Neurological Inst. and Hospital, PQ (Canada). McConnell Brain Imaging Centre McGill Univ., Montreal, PQ (Canada). Dept. of Neurology and Neurosurgery)

    1991-01-01

    Carbon-11-labeled HECNU (1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea) a potential chemotherapeutic agent, has been prepared by the nitrosation of the corresponding carbon-11-labeled urea, HECU, (1-(2-chloroethyl)-3-(2-hydroxyethyl) urea). The isomeric byproduct of nitrosation, 1-(2-chloroethyl)-3-nitroso-3-(2-hydroxyethyl) urea can be efficiently removed by preparative scale HPLC on a Partisil column. ({sup 11}C)-HECU was prepared by reacting ethanolamine with ({sup 11}C)-2-chloroethyl-isocyanate which was itself prepared by reacting ({sup 11}C)-phosgene with 2-chloroethylamine hydrochloride suspended in dioxane at 60-65{sup o}C. This synthesis yielded ({sup 11}C)-HECNU with an average radiochemical purity of 98% in an average radiochemical yield of 18% relative to the radioactivity measured at the end of the {sup 11}C-phosgene introduction. (author).

  7. String Theory on AdS Spaces

    NARCIS (Netherlands)

    de Boer, J.

    2000-01-01

    In these notes we discuss various aspects of string theory in AdS spaces. We briefly review the formulation in terms of Green-Schwarz, NSR, and Berkovits variables, as well as the construction of exact conformal field theories with AdS backgrounds. Based on lectures given at the Kyoto YITP Workshop

  8. Warped AdS3 black holes

    International Nuclear Information System (INIS)

    Anninos, Dionysios; Li Wei; Padi, Megha; Song Wei; Strominger, Andrew

    2009-01-01

    Three dimensional topologically massive gravity (TMG) with a negative cosmological constant -l -2 and positive Newton constant G admits an AdS 3 vacuum solution for any value of the graviton mass μ. These are all known to be perturbatively unstable except at the recently explored chiral point μl = 1. However we show herein that for every value of μl ≠ 3 there are two other (potentially stable) vacuum solutions given by SL(2,R) x U(1)-invariant warped AdS 3 geometries, with a timelike or spacelike U(1) isometry. Critical behavior occurs at μl = 3, where the warping transitions from a stretching to a squashing, and there are a pair of warped solutions with a null U(1) isometry. For μl > 3, there are known warped black hole solutions which are asymptotic to warped AdS 3 . We show that these black holes are discrete quotients of warped AdS 3 just as BTZ black holes are discrete quotients of ordinary AdS 3 . Moreover new solutions of this type, relevant to any theory with warped AdS 3 solutions, are exhibited. Finally we note that the black hole thermodynamics is consistent with the hypothesis that, for μl > 3, the warped AdS 3 ground state of TMG is holographically dual to a 2D boundary CFT with central charges c R -formula and c L -formula.

  9. AdS solutions through transgression

    International Nuclear Information System (INIS)

    Donos, Aristomenis; Gauntlett, Jerome P.; Kim, Nakwoo

    2008-01-01

    We present new classes of explicit supersymmetric AdS 3 solutions of type IIB supergravity with non-vanishing five-form flux and AdS 2 solutions of D = 11 supergravity with electric four-form flux. The former are dual to two-dimensional SCFTs with (0,2) supersymmetry and the latter to supersymmetric quantum mechanics with two supercharges. We also investigate more general classes of AdS 3 solutions of type IIB supergravity and AdS 2 solutions of D = 11 supergravity which in addition have non-vanishing three-form flux and magnetic four-form flux, respectively. The construction of these more general solutions makes essential use of the Chern-Simons or 'transgression' terms in the Bianchi identity or the equation of motion of the field strengths in the supergravity theories. We construct infinite new classes of explicit examples and for some of the type IIB solutions determine the central charge of the dual SCFTs. The type IIB solutions with non-vanishing three-form flux that we construct include a two-torus, and after two T-dualities and an S-duality, we obtain new AdS 3 solutions with only the NS fields being non-trivial.

  10. Polarised Black Holes in AdS

    CERN Document Server

    Costa, Miguel S.; Oliveira, Miguel; Penedones, João; Santos, Jorge E.

    2016-05-03

    We consider solutions in Einstein-Maxwell theory with a negative cosmological constant that asymptote to global $AdS_{4}$ with conformal boundary $S^{2}\\times\\mathbb{R}_{t}$. At the sphere at infinity we turn on a space-dependent electrostatic potential, which does not destroy the asymptotic $AdS$ behaviour. For simplicity we focus on the case of a dipolar electrostatic potential. We find two new geometries: (i) an $AdS$ soliton that includes the full backreaction of the electric field on the $AdS$ geometry; (ii) a polarised neutral black hole that is deformed by the electric field, accumulating opposite charges in each hemisphere. For both geometries we study boundary data such as the charge density and the stress tensor. For the black hole we also study the horizon charge density and area, and further verify a Smarr formula. Then we consider this system at finite temperature and compute the Gibbs free energy for both $AdS$ soliton and black hole phases. The corresponding phase diagram generalizes the Hawkin...

  11. Current status of AdS instability

    CERN Multimedia

    CERN. Geneva

    2016-01-01

    arXiv:1403.6471 and thoroughly developed in arXiv:1407.6273. On the other hand the negative cosmological constant allows for the existence of stable, time-periodic, asymptotically AdS solutions of Einstein equations [arXiv:1303.3186].

  12. AdS. Klein-Gordon equation

    OpenAIRE

    Bel, Ll.

    2014-01-01

    I propose a generalization of the Klein-Gordon equation in the framework of AdS space-time and exhibit a four parameter family of solutions among which there is a two parameter family of time-dependent bound states.

  13. Lorentzian AdS, Wormholes and Holography

    CERN Document Server

    Arias, Raul E; Silva, Guillermo A

    2011-01-01

    We investigate the structure of two point functions for the QFT dual to an asymptotically Lorentzian AdS-wormhole. The bulk geometry is a solution of 5-dimensional second order Einstein Gauss Bonnet gravity and causally connects two asymptotically AdS space times. We revisit the GKPW prescription for computing two-point correlation functions for dual QFT operators O in Lorentzian signature and we propose to express the bulk fields in terms of the independent boundary values phi_0^\\pm at each of the two asymptotic AdS regions, along the way we exhibit how the ambiguity of normalizable modes in the bulk, related to initial and final states, show up in the computations. The independent boundary values are interpreted as sources for dual operators O^\\pm and we argue that, apart from the possibility of entanglement, there exists a coupling between the degrees of freedom leaving at each boundary. The AdS_(1+1) geometry is also discussed in view of its similar boundary structure. Based on the analysis, we propose a ...

  14. Baby Skyrmions in AdS

    Energy Technology Data Exchange (ETDEWEB)

    Elliot-Ripley, Matthew; Winyard, Thomas [Department of Mathematical Sciences, Durham University,South Rd, Durham (United Kingdom)

    2015-09-01

    We study the baby Skyrme model in a pure AdS background without a mass term. The tail decays and scalings of massless radial solutions are demonstrated to take a similar form to those of the massive flat space model, with the AdS curvature playing a similar role to the flat space pion mass. We also numerically find minimal energy solutions for a range of higher topological charges and find that they form concentric ring-like solutions. Popcorn transitions (named in analogy with studies of toy models of holographic QCD) from an n layer to an n+1-layer configuration are observed at topological charges 9 and 27 and further popcorn transitions for higher charges are predicted. Finally, a point-particle approximation for the model is derived and used to successfully predict the ring structures and popcorn transitions for higher charge solitons.

  15. Supersymmetric AdS3, AdS2 and bubble solutions

    International Nuclear Information System (INIS)

    Gauntlett, Jerome P.; Waldram, Daniel; Kim, Nakwoo

    2007-01-01

    We present new supersymmetric AdS 3 solutions of type IIB supergravity and AdS 2 solutions of D = 11 supergravity. The former are dual to conformal field theories in two dimensions with N = (0, 2) supersymmetry while the latter are dual to conformal quantum mechanics with two supercharges. Our construction also includes AdS 2 solutions of D = 11 supergravity that have non-compact internal spaces which are dual to three-dimensional N = 2 superconformal field theories coupled to point-like defects. We also present some new bubble-type solutions, corresponding to BPS states in conformal theories, that preserve four supersymmetries

  16. (99m)Tc HYNIC-TOC imaging and 177Lu DOTA-octreotate treatment in non-iodine-concentrating dedifferentiated thyroid carcinoma metastases: an unusual alternative diagnosis.

    Science.gov (United States)

    Basu, Sandip; Joshi, Amit

    2014-07-01

    The value of Tc HYNIC-TOC scintigraphy clarifying skeletal and hepatic-predominant metastatic disease in a 55-year-old woman (diagnosed earlier to have papillary carcinoma thyroid and had undergone total thyroidectomy and radioiodine ablation) is illustrated. The whole-body radioiodine scan and battery of serum tumor markers were normal. Multiple metastatic foci in the liver and skeleton were Tc HYNIC-TOC avid. Serum chromogranin A level was substantially elevated (1771.60 ng/mL). This represents an unusual alternative diagnosis signified by a highly positive scan in the setting of apparent non-iodine-concentrating metastatic disease in a patient of differentiated thyroid carcinoma.

  17. Peptide Receptor Radionuclide Therapy with (90)Y-DOTATOC and (177)Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland

    DEFF Research Database (Denmark)

    Pfeifer, Andreas Klaus; Gregersen, Tine; Grønbæk, Henning

    2011-01-01

    Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this t...

  18. Peptide receptor radionuclide therapy with Y-DOTATOC and (177)Lu-DOTATOC in advanced neuroendocrine tumors: results from a Danish cohort treated in Switzerland

    DEFF Research Database (Denmark)

    Pfeifer, Andreas Klaus; Gregersen, Tine; Grønbæk, Henning

    2011-01-01

    Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this t...

  19. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2012-09-01

    2010 and 2011 annual scientific meeting of the American Society of Clinical Oncologists  Manuscript detailing background and rationale for the...noncancerous causes, and 6.6% died from unknown causes [15]. A pooled analysis of salvage cryoablation demonstrated 54.5% 5-year actuarial biochemical

  20. Effectiveness of quenchers to reduce radiolysis of (111)In- or (177)Lu-labelled methionine-containing regulatory peptides. Maintaining radiochemical purity as measured by HPLC.

    Science.gov (United States)

    de Blois, Erik; Chan, Ho Sze; Konijnenberg, Mark; de Zanger, Rory; Breeman, Wouter A P

    2012-01-01

    An overview how to measure and to quantify radiolysis by the addition of quenchers and to maintain Radio-Chemical Purity (RCP) of vulnerable methionine-containing regulatory peptides is presented. High RCP was only achieved with a combination of quenchers. However, quantification of RCP is not standardized, and therefore comparison of radiolabelling and RCP of regulatory peptides between different HPLC-systems and between laboratories is cumbersome. Therefore we suggest a set of standardized requirements to quantify RCP by HPLC for radiolabelled DTPA- or DOTA-peptides. Moreover, a dosimetry model was developed to calculate the doses in the reaction vials during radiolabelling and storage of the radiopeptides, and to predict RCP in the presence and absence of quenchers. RCP was measured by HPLC, and a relation between radiation dose and radiolysis of RCP was established. The here described quenchers are tested individually as ƒ(concentration) to investigate efficacy to reduce radiolysis of radiolabelled methionine-containing regulatory peptides.

  1. Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with {sup 177}Lu-D OTATATE

    Energy Technology Data Exchange (ETDEWEB)

    Sansovini, Maddalena; Severi, Stefano; Ianniello, Annarita; Nicolini, Silvia; Fantini, Lorenzo; Paganelli, Giovanni [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine Unit, Meldola (Italy); Mezzenga, Emilio [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Medical Physics Unit, Meldola (Italy); Ferroni, Fabio [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Radiology Unit, Meldola (Italy); Scarpi, Emanuela; Monti, Manuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy); Bongiovanni, Alberto [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Osteoncology and Rare Tumors Center, Meldola (Italy); Cingarlini, Sara [University of Verona, Department of Oncology, Verona Comprehensive Cancer Network, G.B. Rossi Hospital, Verona (Italy); Grana, Chiara Maria; Bodei, Lisa [European Institute of Oncology Milan (IEO), Division of Nuclear Medicine, Milan (Italy)

    2017-03-15

    Lu-DOTATATE (Lu-PRRT) is a valid therapeutic option in differentiated pancreatic neuroendocrine tumors (P-NETs). FDG PET seems to be an important prognostic factor in P-NETs. We evaluated the efficacy of Lu-PRRT and the role of FDG PET in 60 patients with advanced P-NETs. From March 2008 to June 2011, 60 consecutive patients with P-NETs were enrolled in the study. Follow-up lasted until March 2016. Eligible patients were treated with two different total cumulative activities (18.5 or 27.8 GBq in 5 cycles every 6-8 weeks), according to kidney and bone marrow parameters. Twenty-eight patients received a mean full activity (FA) of 25.9 GBq and 32 a mean reduced activity (RA) of 18.5 GBq. The disease control rate (DCR), defined as the sum of CR+PR+SD was 85.7 % in the FA group and 78.1 % in the RA group. Median progression-free survival (mPFS) was 53.4 months in the FA group and 21.7 months in the RA group (P = 0.353). Median overall survival (mOS) was not reached (nr) in FA patients and was 63.8 months in the RA group (P = 0.007). Fifty-five patients underwent an FDG PET scan before Lu-PRRT, 32 (58 %) showing an increased FDG uptake in tumor sites. mPFS was 21.1 months in FDG PET-positive patients and 68.7 months in the FDG PET-negative group (P < 0.0002), regardless of the total activity administered. Both FA and RA are active in patients undergoing Lu-PRRT. However, an FA of 27.8 GBq of Lu-PRRT prolongs PFS and OS compared to an RA of 18.5 GBq. Our results indicate that FDG PET is an independent prognostic factor in this patient setting. (orig.)

  2. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients With High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2016-09-01

    agents Not applicable. 7  PRODUCTS:  Publications, conference papers , and presentations:  Journal publications. Nothing to report...Books or other non-periodical, one-time publications. Nothing to report.  Other publications, conference papers , and presentations. Nothing to...phosphate buffered saline containing not more than 1% Human Serum Albumin (HSA). All reagents used in the conjugation and purification of J591 are made

  3. Comparison of tumour and whole body absorbed doses of 177-Lu-DOTA-TATE and Lu-177-DOTA-NOC treatment in the same patient group

    International Nuclear Information System (INIS)

    Yeyin, N.; Kabasakal, L.; Akyel, R.; Demir, M.; Kanmaz, B.; Ocak, M.; Toklu, T.; Selcuk, N.

    2015-01-01

    Full text of publication follows. Peptide Receptor Radionuclide Therapy (PRRT) with Lu-177 labelled peptides in patients with neuroendocrine tumours (NETs) aroused great interest. An estimation of actual radiation doses to tumours is very important for therapy planning. There are several radiolabelled peptides, which can be used for PRRT with different biological behaviour. Aim: the aim of the study was to compare the tumour and normal organ absorbed doses in patients who have received Lu-177-DOTA-TATE and Lu-177 DOTA-NOC. Materials and methods: study was composed of 20 patients (M/F: 10/10, mean age: 51.5 ± 14.9) with histologically proven inoperable NETs. All patients received Lu-177-DOTA-NOC treatment 6 to 12 weeks after last Lu-177-DOTA-TATE treatment. Dosimetric calculations were performed using MIRD scheme and lesion doses were calculated using post therapy whole body images obtained at 4, 20, 44, and 68 hours after injection. Tumour volumes were determined from CT images. Thirteen blood samples beginning from time zero to 4 days after injection were obtained for bone marrow and whole body dosimetry. Results: There were 53 lesions in Lu-177-DOTA-TATE post-therapy whole body images and 49 lesions in Lu-177 DOTA-NOC post therapy images. Lesions were selected according to lesion delineation and superimposed lesions were excluded. Mean lesion absorbed dose is calculated to be 47.4 ± 53.4 and 42.9 ± 52.8 Gy per 370 MBq for Lu-177-DOTA-TATE and DOTA-NOC respectively (p>0.5). There were significantly higher absorbed doses for kidney and bone marrow after Lu-177-DOTA-NOC treatment as compared to Lu-177-DOTA-TATE treatment, which were 6.9 ± 2.7 vs 3.9 ± 1.7 (p<0.05) and 0.12 ± 0.0 vs 0.10 ± 0.0 (p<0.05) Gy, respectively. There was not any difference in plasma elimination times between two tracers. On the other hand the whole body absorbed dose was significantly higher after Lu-177-DOTA-NOC treatment, which was 0.24 ± 0.07 vs 0.20 ± 0.06 Gy (p<0.05), respectively. Conclusion: the radiation absorbed doses to kidney, bone marrow and whole body after Lu-177-DOTA-NOC treatment are significantly higher than those of Lu-177-DOTA-TATE so it should be performed carefully and with patient dosimetric calculations. (authors)

  4. Dynamic and static small-animal SPECT in rats for monitoring renal function after 177Lu-labeled Tyr3-octreotate radionuclide therapy.

    NARCIS (Netherlands)

    Melis, M.; Swart, J.; Visser, M. de; Berndsen, S.C.; Koelewijn, S.; Valkema, R.; Boerman, O.C.; Krenning, E.P.; Jong, M. de

    2010-01-01

    High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with beta-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal

  5. Predicting AD conversion

    DEFF Research Database (Denmark)

    Liu, Yawu; Mattila, Jussi; Ruiz, Miguel �ngel Mu�oz

    2013-01-01

    To compare the accuracies of predicting AD conversion by using a decision support system (PredictAD tool) and current research criteria of prodromal AD as identified by combinations of episodic memory impairment of hippocampal type and visual assessment of medial temporal lobe atrophy (MTA) on MRI...

  6. Winding strings in AdS3

    International Nuclear Information System (INIS)

    Herscovich, Estanislao; Minces, Pablo; Nunez, Carmen

    2006-01-01

    Correlation functions of one-unit spectral flowed states in string theory on AdS 3 are considered. We present the modified Knizhnik-Zamolodchikov and null vector equations to be satisfied by amplitudes containing states in winding sector one and study their solution corresponding to the four point function including one w = 1 field. We compute the three point function involving two one-unit spectral flowed operators and find expressions for amplitudes of three w = 1 states satisfying certain particular relations among the spins of the fields. Several consistency checks are performed

  7. The political attack ad

    Directory of Open Access Journals (Sweden)

    Palma Peña-Jiménez, Ph.D.

    2011-01-01

    Full Text Available During election campaigns the political spot has a clear objective: to win votes. This message is communicated to the electorate through television and Internet, and usually presents a negative approach, which includes a direct critical message against the opponent, rather than an exposition of proposals. This article is focused on the analysis of the campaign attack video ad purposely created to encourage the disapproval of the political opponent among voters. These ads focus on discrediting the opponent, many times, through the transmission of ad hominem messages, instead of disseminating the potential of the political party and the virtues and manifesto of its candidate. The article reviews the development of the attack ad since its first appearance, which in Spain dates back to 1996, when the famous Doberman ad was broadcast, and examines the most memorable campaign attack ads.

  8. AdS2 holographic dictionary

    International Nuclear Information System (INIS)

    Cvetič, Mirjam; Papadimitriou, Ioannis

    2016-01-01

    We construct the holographic dictionary for both running and constant dilaton solutions of the two dimensional Einstein-Maxwell-Dilaton theory that is obtained by a circle reduction from Einstein-Hilbert gravity with negative cosmological constant in three dimensions. This specific model ensures that the dual theory has a well defined ultraviolet completion in terms of a two dimensional conformal field theory, but our results apply qualitatively to a wider class of two dimensional dilaton gravity theories. For each type of solutions we perform holographic renormalization, compute the exact renormalized one-point functions in the presence of arbitrary sources, and derive the asymptotic symmetries and the corresponding conserved charges. In both cases we find that the scalar operator dual to the dilaton plays a crucial role in the description of the dynamics. Its source gives rise to a matter conformal anomaly for the running dilaton solutions, while its expectation value is the only non trivial observable for constant dilaton solutions. The role of this operator has been largely overlooked in the literature. We further show that the only non trivial conserved charges for running dilaton solutions are the mass and the electric charge, while for constant dilaton solutions only the electric charge is non zero. However, by uplifting the solutions to three dimensions we show that constant dilaton solutions can support non trivial extended symmetry algebras, including the one found by Compère, Song and Strominger http://dx.doi.org/10.1007/JHEP05(2013)152, in agreement with the results of Castro and Song http://arxiv.org/abs/1411.1948. Finally, we demonstrate that any solution of this specific dilaton gravity model can be uplifted to a family of asymptotically AdS 2 ×S 2 or conformally AdS 2 ×S 2 solutions of the STU model in four dimensions, including non extremal black holes. The four dimensional solutions obtained by uplifting the running dilaton solutions coincide

  9. Complexity of the AdS soliton

    Science.gov (United States)

    Reynolds, Alan P.; Ross, Simon F.

    2018-05-01

    We consider the holographic complexity conjectures in the context of the AdS soliton, which is the holographic dual of the ground state of a field theory on a torus with antiperiodic boundary conditions for fermions on one cycle. The complexity is a non-trivial function of the size of the circle with antiperiodic boundary conditions, which sets an IR scale in the dual geometry. We find qualitative differences between the calculations of complexity from spatial volume and action (CV and CA). In the CV calculation, the complexity for antiperiodic boundary conditions is smaller than for periodic, and decreases monotonically with increasing IR scale. In the CA calculation, the complexity for antiperiodic boundary conditions is larger than for periodic, and initially increases with increasing IR scale, eventually decreasing to zero as the IR scale becomes of order the UV cutoff. We compare these results to a simple calculation for free fermions on a lattice, where we find the complexity for antiperiodic boundary conditions is larger than for periodic.

  10. AdS2 models in an embedding superspace

    International Nuclear Information System (INIS)

    McKeon, D.G.C.; Sherry, T.N.

    2003-01-01

    An embedding superspace, whose bosonic part is the flat (2+1)-dimensional embedding space for AdS 2 , is introduced. Superfields and several supersymmetric models are examined in the embedded AdS 2 superspace

  11. Mobile ad hoc networking

    CERN Document Server

    John Wiley & Sons

    2004-01-01

    "Assimilating the most up-to-date information on research and development activities in this rapidly growing area, Mobile Ad Hoc Networking covers physical, data link, network, and transport layers, as well as application, security, simulation, and power management issues in sensor, local area, personal, and mobile ad hoc networks. Each of the book's sixteen chapters has been written by a top expert and discusses in-depth the most important topics in the field. Mobile Ad Hoc Networking is an excellent reference and guide for professionals seeking an in-depth examination of topics that also provides a comprehensive overview of the current state-of-the-art."--Jacket.

  12. AdS3: the NHEK generation

    International Nuclear Information System (INIS)

    Bena, Iosif; Heurtier, Lucien; Puhm, Andrea

    2016-01-01

    It was argued in http://dx.doi.org/10.1007/JHEP03(2013)028 that the five-dimensional near-horizon extremal Kerr (NHEK) geometry can be embedded in String Theory as the infrared region of an infinite family of non-supersymmetric geometries that have D1, D5, momentum and KK monopole charges. We show that there exists a method to embed these geometries into asymptotically-AdS 3 ×S 3 /ℤ N solutions, and hence to obtain infinite families of flows whose infrared is NHEK. This indicates that the CFT dual to the NHEK geometry is the IR fixed point of a Renormalization Group flow from a known local UV CFT and opens the door to its explicit construction.

  13. Hadronization at the AdS wall

    International Nuclear Information System (INIS)

    Evans, Nick; French, James; Threlfall, Ed; Jensen, Kristan

    2010-01-01

    We describe hadronization events, using the AdS/CFT Correspondence, which display many of the qualitative features expected in QCD. In particular we study the motion of strings with separating end points in a back-reacted hard wall geometry. The solutions show the development of a linear QCD-like string. The end points oscillate in the absence of string breaking. We introduce string breaking by hand and evolve the new state forward in time to observe the separation of two string segments. A kink associated with this breaking evolves to the end points of the string inducing rho meson production. We explicitly compute the rho meson production at the end point.

  14. Management job ads

    DEFF Research Database (Denmark)

    Holmgreen, Lise-Lotte

    2014-01-01

    jobs by discursively constructing job ads that appeal to both sexes. This argument is part of the broader field of corporate social responsibility, corporate citizenship, and stakeholder management, which involves discussions of the obligations of corporations to acknowledge and mitigate...... the increasingly widespread impact that their activities have on communities and social structures. The article emphasises the need for more active engagement on the part of corporations by analysing the discursive construction of preferred candidates in a small sample of Danish management job ads. By means...... that this agreement reflects a high degree of conservatism in the system where men enjoy a considerable advantage and where procedures that ensure male dominance are perpetuated even in the linguistic and discursive construction of job ads....

  15. ADS National Programmes: China

    International Nuclear Information System (INIS)

    2015-01-01

    In China the conceptual study of an ADS concept which lasted for about five years ended in 1999. As one project of the National Basic Research Programme of China (973 Programme) in energy domain, which is sponsored by the China Ministry of Science and Technology (MOST), a five year programme of fundamental research of ADS physics and related technology was launched in 2000 and passed national review at the end of 2005. From 2007, another five year 973 Programme Key Technology Research of Accelerator Driven Subcritical System for Nuclear waste Transmutation started. The research activities were focused on HPPA physics and technology, reactor physics of external source driven subcritical assembly, nuclear data base and material study. For HPPA, a high current injector consisting of an ECR ion source, LEBT and an RFQ accelerating structure of 3.5 MeV has been built and were being improved. In reactor physics study, a series of neutron multiplication experimental study has been carrying out. The VENUS I facility has been constructed as the basic experimental platform for neutronics study in ADS blanket. VENUS I a zero power subcritical neutron multiplying assembly driven by external neutron produced by a pulsed neutron generator or 252Cf neutron source. The theoretical, experimental and simulation studies on nuclear data, material properties and nuclear fuel circulation related to ADS are carried out in order to provide the database for ADS system analysis. China Institute of Atomic Energy (CIAE), Institute of High Energy Physics (IHEP) and other Chinese institutes carried out the MOST project together. Besides CIAE, China Academy of Science (CAS) pays more and more attention to Advanced Nuclear Fuel Cycles (ANFC). A large programme of ANFC, including ADS and Th based nuclear fuel cycle, has been launched by CAS

  16. Dynamic ad hoc networks

    CERN Document Server

    Rashvand, Habib

    2013-01-01

    Motivated by the exciting new application paradigm of using amalgamated technologies of the Internet and wireless, the next generation communication networks (also called 'ubiquitous', 'complex' and 'unstructured' networking) are changing the way we develop and apply our future systems and services at home and on local, national and global scales. Whatever the interconnection - a WiMAX enabled networked mobile vehicle, MEMS or nanotechnology enabled distributed sensor systems, Vehicular Ad hoc Networking (VANET) or Mobile Ad hoc Networking (MANET) - all can be classified under new networking s

  17. Adding an extra storey

    DEFF Research Database (Denmark)

    Engelmark, Jesper; Dahl, Torben; Melgaard, Ebbe

    2007-01-01

    of them had to be renovated after a shorter period. In stead of just replacing the original roof with a new one, it is now a days rather common to ad an extra storey where that is possible according to local planning. The reason is as a rule based on economical benefits, but very often this extra storey...

  18. Globally regular instability of AdS_3

    OpenAIRE

    Bizon, P.; Jałmużna, J.

    2013-01-01

    We consider three-dimensional AdS gravity minimally coupled to a massless scalar field and study numerically the evolution of small smooth circularly symmetric perturbations of the $AdS_3$ spacetime. As in higher dimensions, for a large class of perturbations, we observe a turbulent cascade of energy to high frequencies which entails instability of $AdS_3$. However, in contrast to higher dimensions, the cascade cannot be terminated by black hole formation because small perturbations have ener...

  19. Nonlinear realization of supersymmetric AdS space isometries

    International Nuclear Information System (INIS)

    Clark, T. E.; Love, S. T.

    2006-01-01

    The isometries of AdS 5 space and supersymmetric AdS 5 xS 1 space are nonlinearly realized on four-dimensional Minkowski space. The resultant effective actions in terms of the Nambu-Goldstone modes are constructed. The dilatonic mode governing the motion of the Minkowski space probe brane into the covolume of supersymmetric AdS 5 space is found to be unstable and the bulk of the AdS 5 space is unable to sustain the brane. No such instability appears in the nonsupersymmetric case

  20. Ads in Indonesia

    Directory of Open Access Journals (Sweden)

    Wulan Roro Retno

    2017-01-01

    Full Text Available Cosmetics industry created the beauty myth for women through advertising. A cosmetic ad in Indonesia has spread a new concept of white skin: East Asia beauty myth. The white concept of Asia white skin basically derived from colonial legacy. The purpose of the research was analyzing the beauty myth in Indonesia ads using postcolonial perspective. The principal result brought the discourse analysis and postcolonial perspective a new insight in communication research. Particularly on media and cultural studies. Major conclusions showed that the beauty myth since the Dutch colonial period never been change. The main concept is always in colonialism’s idea: “white is better”. The West is better than the East.

  1. Philosophia ad bellum

    Directory of Open Access Journals (Sweden)

    Yu. O. Loboda

    2014-06-01

    Full Text Available In the paper «Philosophia ad bellum» is being realized an attempt to classify philosophic approaches to the study of phenomenon of war by the analogy with the structure of «Just war theory» – 1. Philosophia ad bellum – «philosophy for war», where are investigated ways of using of philosophic methods of cognition in applied military sciences; 2. Philosophia supra bello – «philosophy above war», which investigates world­view, historic­philosophic, existential, logic­epistemological aspects of war; 3. Philosophia contra belli – «philosophy against war», where research of the essence of war gets its logical conclusion in grounding of the absurdity of thinking schemes which justify war as an act of violence. In the article was made historic­philosophic overview of the part «Philosophia ad bellum», where were showed tangent questions, which are considered by philosophic logic and theory of strategic intelligence. It was stated, that specialists if military intelligence admit the important role of researches in logic and theory of cognition in their professional work; were defined basic questions, which have the most essential interest for military professionals. There were analyzed ways of using of philosophic methods in developing military strategies, was made a conclusion that philosophy can be a basis of strategic failures and victories as well.

  2. The group approach to AdS space propagators

    International Nuclear Information System (INIS)

    Leonhardt, Thorsten; Manvelyan, Ruben; Ruehl, Werner

    2003-01-01

    We show that AdS two-point functions can be obtained by connecting two points in the interior of AdS space with one point on its boundary by a dual pair of Dobrev's boundary-to-bulk intertwiners and integrating over the boundary point

  3. Manifestly T-dual formulation of AdS space

    International Nuclear Information System (INIS)

    Hatsuda, Machiko; Kamimura, Kiyoshi; Siegel, Warren

    2017-01-01

    We present a manifestly T-dual formulation of curved spaces such as an AdS space. For group manifolds related by the orthogonal vielbein fields the three form H=dB in the doubled space is universal at least locally. We construct an affine nondegenerate doubled bosonic AdS algebra to define the AdS space with the Ramond-Ramond flux. The non-zero commutator of the left and right momenta leads to that the left momentum is in an AdS space while the right momentum is in a dS space. Dimensional reduction constraints and the physical AdS algebra are shown to preserve all the doubled coordinates.

  4. Evaporation of large black holes in AdS

    International Nuclear Information System (INIS)

    Rocha, Jorge V

    2010-01-01

    The AdS/CFT correspondence offers a new perspective on the long-standing black hole information paradox. However, to be able to use the available gauge/gravity machinery one is forced to consider so-called 'large' black holes in AdS, and these objects are thermodynamically stable - they do not evaporate. We describe a simple toy model that allows large AdS black holes to decay, by coupling the emitted radiation to an external scalar field propagating in an auxiliary space. This effectively changes the properties of the boundary of AdS, making it partly absorbing. We demonstrate that the evaporation process never ceases by explicitly presenting (a) the transmission coefficient for a wave scattering from the bulk into auxiliary space and (b) the greybody factor for a black 3-brane in an AdS background. Therefore, the model provides an interesting framework to address the information paradox using AdS/CFT techniques.

  5. Manifestly T-dual formulation of AdS space

    Energy Technology Data Exchange (ETDEWEB)

    Hatsuda, Machiko [Physics Division, Faculty of Medicine, Juntendo University,Chiba 270-1695 (Japan); KEK Theory Center, High Energy Accelerator Research Organization,Tsukuba, Ibaraki 305-0801 (Japan); Kamimura, Kiyoshi [Physics Division, Faculty of Medicine, Juntendo University,Chiba 270-1695 (Japan); Siegel, Warren [C.N. Yang Institute for Theoretical Physics, Stony Brook University,Stony Brook, NY 11794-3840 (United States)

    2017-05-12

    We present a manifestly T-dual formulation of curved spaces such as an AdS space. For group manifolds related by the orthogonal vielbein fields the three form H=dB in the doubled space is universal at least locally. We construct an affine nondegenerate doubled bosonic AdS algebra to define the AdS space with the Ramond-Ramond flux. The non-zero commutator of the left and right momenta leads to that the left momentum is in an AdS space while the right momentum is in a dS space. Dimensional reduction constraints and the physical AdS algebra are shown to preserve all the doubled coordinates.

  6. Open strings on AdS2 branes

    International Nuclear Information System (INIS)

    Lee, Peter; Ooguri, Hirosi.; Park, Jongwon; Tannenhauser, Jonathan

    2001-01-01

    We study the spectrum of open strings on AdS 2 branes in AdS 3 in an NS-NS background, using the SL(2,R) WZW model. When the brane carries no fundamental string charge, the open string spectrum is the holomorphic square root of the spectrum of closed strings in AdS 3 . It contains short and long strings, and is invariant under spectral flow. When the brane carries fundamental string charge, the open string spectrum again contains short and long strings in all winding sectors. However, branes with fundamental string charge break half the spectral flow symmetry. This has different implications for short and long strings. As the fundamental string charge increases, the brane approaches the boundary of AdS 3 . In this limit, the induced electric field on the worldvolume reaches its critical value, producing noncommutative open string theory on AdS 2

  7. Leading Change, Adding Value.

    Science.gov (United States)

    Evans, Nick

    2016-09-12

    Essential facts Leading Change, Adding Value is NHS England's new nursing and midwifery framework. It is designed to build on Compassion in Practice (CiP), which was published 3 years ago and set out the 6Cs: compassion, care, commitment, courage, competence and communication. CiP established the values at the heart of nursing and midwifery, while the new framework sets out how staff can help transform the health and care sectors to meet the aims of the NHS England's Five Year Forward View.

  8. Conical singularities in AdS space time

    International Nuclear Information System (INIS)

    Ferreira, Cristine Nunes

    2011-01-01

    Full text: In recent years, the study of conformal gauge theories from 10-D has been motivated by the AdS d+1 /CFT d correspondence, first conjectured by J. Maldacena. The aim of this work is to consider the d = 4 case by analysing the configuration of the N coincident D3 branes. In this context, the work shows that there is a duality between type IIB string theory in AdS 5 x S 5 and N = 4 SU(N) Super Yang-Mills Theory in the IR. The AdS 5 /CFT 4 correspondence brought also new approaches to the strong coupling problem in QCD. Nowadays, there is a whole line of works that focus on the low dimensional correspondence AdS 4 /CFT 3 , like the application to graphene and topological insulators, and the AdS 3 /CFT 2 correspondence, related with the entanglement entropy. In this work, we consider the vortex configuration solution to the AdS 4 and AdS 3 space-time. The most important motivation is to discuss the boundary theory resulting from these solutions. We have examined a straightforward approach to a holographic computation of the graphene and entanglement entropy in the presence of the conical singularity. After this analysis, we consider the scalar field in the bulk in the presence of this metrics and work out the compactification modes. Taking the holographic point of view, we study and discuss the resulting Green function. (author)

  9. Hawking radiation from AdS black holes

    International Nuclear Information System (INIS)

    Hubeny, Veronika E; Rangamani, Mukund; Marolf, Donald

    2010-01-01

    We study Hartle-Hawking-like states of quantum field theories on asymptotically AdS black hole backgrounds, with particular regard to the phase structure of interacting theories. By a suitable analytic continuation we show that the equilibrium dynamics of field theories on large asymptotically AdS black holes can be related to the low-temperature states of the same field theory on the AdS soliton (or pure AdS) background. This allows us to gain insight into Hartle-Hawking-like states on large-radius Schwarzschild- or rotating-AdS black holes. Furthermore, we exploit the AdS/CFT correspondence to explore the physics of strongly coupled large N theories on asymptotically AdS black holes. In particular, we exhibit a plausibly complete set of phases for the M2-brane world-volume superconformal field theory on a BTZ black hole background. Our analysis partially resolves puzzles previously raised in connection with Hawking radiation on large AdS black holes.

  10. Wireless Ad Hoc Networks

    Directory of Open Access Journals (Sweden)

    Hong-Chuan Yang

    2007-01-01

    Full Text Available We study the energy-efficient configuration of multihop paths with automatic repeat request (ARQ mechanism in wireless ad hoc networks. We adopt a cross-layer design approach and take both the quality of each radio hop and the battery capacity of each transmitting node into consideration. Under certain constraints on the maximum tolerable transmission delay and the required packet delivery ratio, we solve optimization problems to jointly schedule the transmitting power of each transmitting node and the retransmission limit over each hop. Numerical results demonstrate that the path configuration methods can either significantly reduce the average energy consumption per packet delivery or considerably extend the average lifetime of the multihop route.

  11. AdS Branes from Partial Breaking of Superconformal Symmetries

    International Nuclear Information System (INIS)

    Ivanov, E.A.

    2005-01-01

    It is shown how the static-gauge world-volume superfield actions of diverse superbranes on the AdS d+1 superbackgrounds can be systematically derived from nonlinear realizations of the appropriate AdS supersymmetries. The latter are treated as superconformal symmetries of flat Minkowski superspaces of the bosonic dimension d. Examples include the N = 1 AdS 4 supermembrane, which is associated with the 1/2 partial breaking of the OSp(1|4) supersymmetry down to the N = 1, d = 3 Poincare supersymmetry, and the T-duality related L3-brane on AdS 5 and scalar 3-brane on AdS 5 x S 1 , which are associated with two different patterns of 1/2 breaking of the SU(2, 2|1) supersymmetry. Another (closely related) topic is the AdS/CFT equivalence transformation. It maps the world-volume actions of the codimension-one AdS d+1 (super)branes onto the actions of the appropriate Minkowski (super)conformal field theories in the dimension d

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

    Directory of Open Access Journals (Sweden)

    Ada H V Repetto-Llamazares

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

  13. Supersymmetric warped AdS in extended topologically massive supergravity

    International Nuclear Information System (INIS)

    Deger, N.S.; Kaya, A.; Samtleben, H.; Sezgin, E.

    2014-01-01

    We determine the most general form of off-shell N=(1,1) supergravity field configurations in three dimensions by requiring that at least one off-shell Killing spinor exists. We then impose the field equations of the topologically massive off-shell supergravity and find a class of solutions whose properties crucially depend on the norm of the auxiliary vector field. These are spacelike-squashed and timelike-stretched AdS 3 for the spacelike and timelike norms, respectively. At the transition point where the norm vanishes, the solution is null warped AdS 3 . This occurs when the coefficient of the Lorentz–Chern–Simons term is related to the AdS radius by μℓ=2. We find that the spacelike-squashed AdS 3 can be modded out by a suitable discrete subgroup of the isometry group, yielding an extremal black hole solution which avoids closed timelike curves

  14. Ad gist : Ad communication in a single eye fixation

    NARCIS (Netherlands)

    Pieters, R.; Wedel, M.

    2012-01-01

    Most ads in practice receive no more than a single eye fixation. This study investigates the limits of what ads can communicate under such adverse exposure conditions. We find that consumers already know at maximum levels of accuracy and with high degree of certainty whether something is an ad or is

  15. Added masses of ship structures

    CERN Document Server

    Korotkin, Alexandr I

    2008-01-01

    This essentially self-contained reference book contains data on added masses of ships and various ship and marine engineering structures. Theoretical and experimental methods for determining added masses of these objects are described.

  16. AdS5 black holes with fermionic hair

    International Nuclear Information System (INIS)

    Burrington, Benjamin A.; Liu, James T.; Sabra, W. A.

    2005-01-01

    The study of new Bogomol'nyi-Prasad-Sommerfield (BPS) objects in AdS 5 has led to a deeper understanding of AdS/CFT. To help complete this picture, and to fully explore the consequences of the supersymmetry algebra, it is also important to obtain new solutions with bulk fermions turned on. In this paper we construct superpartners of the 1/2 BPS black hole in AdS 5 using a natural set of fermion zero modes. We demonstrate that these superpartners, carrying fermionic hair, have conserved charges differing from the original bosonic counterpart. To do so, we find the R-charge and dipole moment of the new system, as well as the mass and angular momentum, defined through the boundary stress tensor. The complete set of superpartners fits nicely into a chiral representation of AdS 5 supersymmetry, and the spinning solutions have the expected gyromagnetic ratio, g=1

  17. AdS Black Hole with Phantom Scalar Field

    Directory of Open Access Journals (Sweden)

    Limei Zhang

    2017-01-01

    Full Text Available We present an AdS black hole solution with Ricci flat horizon in Einstein-phantom scalar theory. The phantom scalar fields just depend on the transverse coordinates x and y, which are parameterized by the parameter α. We study the thermodynamics of the AdS phantom black hole. Although its horizon is a Ricci flat Euclidean space, we find that the thermodynamical properties of the black hole solution are qualitatively the same as those of AdS Schwarzschild black hole. Namely, there exists a minimal temperature and the large black hole is thermodynamically stable, while the smaller one is unstable, so there is a so-called Hawking-Page phase transition between the large black hole and the thermal gas solution in the AdS space-time in Poincare coordinates. We also calculate the entanglement entropy for a strip geometry dual to the AdS phantom black holes and find that the behavior of the entanglement entropy is qualitatively the same as that of the black hole thermodynamical entropy.

  18. Universal regularization prescription for Lovelock AdS gravity

    International Nuclear Information System (INIS)

    Kofinas, Georgios; Olea, Rodrigo

    2007-01-01

    A definite form for the boundary term that produces the finiteness of both the conserved quantities and Euclidean action for any Lovelock gravity with AdS asymptotics is presented. This prescription merely tells even from odd bulk dimensions, regardless the particular theory considered, what is valid even for Einstein-Hilbert and Einstein-Gauss-Bonnet AdS gravity. The boundary term is a given polynomial of the boundary extrinsic and intrinsic curvatures (also referred to as Kounterterms series). Only the coupling constant of the boundary term changes accordingly, such that it always preserves a well-posed variational principle for boundary conditions suitable for asymptotically AdS spaces. The background-independent conserved charges associated to asymptotic symmetries are found. In odd bulk dimensions, this regularization produces a generalized formula for the vacuum energy in Lovelock AdS gravity. The standard entropy for asymptotically AdS black holes is recovered directly from the regularization of the Euclidean action, and not only from the first law of thermodynamics associated to the conserved quantities

  19. New Massive Gravity and AdS4 Counterterms

    International Nuclear Information System (INIS)

    Jatkar, Dileep P.; Sinha, Aninda

    2011-01-01

    We show that the recently proposed Dirac-Born-Infeld extension of new massive gravity emerges naturally as a counterterm in four-dimensional anti-de Sitter space (AdS 4 ). The resulting on-shell Euclidean action is independent of the cutoff at zero temperature. We also find that the same choice of counterterm gives the usual area law for the AdS 4 Schwarzschild black hole entropy in a cutoff-independent manner. The parameter values of the resulting counterterm action correspond to a c=0 theory in the context of the duality between AdS 3 gravity and two-dimensional conformal field theory. We rewrite this theory in terms of the gauge field that is used to recast 3D gravity as a Chern-Simons theory.

  20. Constrained supermanifolds for AdS M-theory backgrounds

    International Nuclear Information System (INIS)

    Fre, Pietro; Grassi, Pietro Antonio

    2008-01-01

    A long standing problem is the supergauge completion of AdS 4 x ({G/H}) 7 or AdS 5 x ({G/H}) 5 backgrounds which preserve less then maximal supersymmetry. In parallel with the supersolvable realization of the AdS 4 x S 7 background based on κ-symmetry, we develop a technique which amounts to solving the above-mentioned problem in a way useful for pure spinor quantization for supermembranes and superstrings. Instead of gauge fixing some of the superspace coordinates using κ-symmetry, we impose an additional constraint on them reproducing the simplifications of the supersolvable representations. The constraints are quadratic, homogeneous, Sp(4,R)-covariant, and consistent from the quantum point of view in the pure spinor approach. Here we provide the geometrical solution which, in a subsequent work, will be applied to the membrane and the superstring sigma models

  1. Asymptotically AdS spacetimes with a timelike Kasner singularity

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Jie [Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem 91904 (Israel)

    2016-07-21

    Exact solutions to Einstein’s equations for holographic models are presented and studied. The IR geometry has a timelike cousin of the Kasner singularity, which is the less generic case of the BKL (Belinski-Khalatnikov-Lifshitz) singularity, and the UV is asymptotically AdS. This solution describes a holographic RG flow between them. The solution’s appearance is an interpolation between the planar AdS black hole and the AdS soliton. The causality constraint is always satisfied. The entanglement entropy and Wilson loops are discussed. The boundary condition for the current-current correlation function and the Laplacian in the IR is examined. There is no infalling wave in the IR, but instead, there is a normalizable solution in the IR. In a special case, a hyperscaling-violating geometry is obtained after a dimensional reduction.

  2. Holographic description of AdS2 black holes

    International Nuclear Information System (INIS)

    Castro, Alejandra; Larsen, Finn; Grumiller, Daniel; McNees, Robert

    2008-01-01

    We develop the holographic renormalization of AdS 2 gravity systematically. We find that a bulk Maxwell term necessitates a boundary mass term for the gauge field and verify that this unusual term is invariant under gauge transformations that preserve the boundary conditions. We determine the energy-momentum tensor and the central charge, recovering recent results by Hartman and Strominger. We show that our expressions are consistent with dimensional reduction of the AdS 3 energy-momentum tensor and the Brown-Henneaux central charge. As an application of our results we interpret the entropy of AdS 2 black holes as the ground state entropy of a dual CFT.

  3. Central charge for AdS2 quantum gravity

    International Nuclear Information System (INIS)

    Hartman, Thomas; Strominger, Andrew

    2009-01-01

    Two-dimensional Maxwell-dilaton quantum gravity on AdS 2 with radius l and a constant electric field E is studied. In conformal gauge, this is equivalent to a CFT on a strip. In order to maintain consistent boundary conditions, the usual conformal diffeomorphisms must be accompanied by a certain U(1) gauge transformation. The resulting conformal transformations are generated by a twisted stress tensor, which has a central charge c = 3kE 2 l 4 /4 where k is the level of the U(1) current. This is an AdS 2 analog of the Brown-Henneaux formula c = 3l/2G for the central charge of quantum gravity on AdS 3 .

  4. New supersymmetric AdS4 type II vacua

    International Nuclear Information System (INIS)

    Tsimpis, D.

    2010-01-01

    We review the supersymmetric AdS 4 x w M 6 backgrounds of type IIA/IIB supergravity constructed in[1]. In type IIA the supersymmetry is N=2, and the six-dimensional internal space is locally an S 2 bundle over a four-dimensional Kaehler-Einstein base; in IIB the internal space is the direct product of a circle and a five-dimensional squashed Sasaki-Einstein manifold. These backgrounds do not contain any sources, all fluxes (including the Romans mass in IIA) are generally non-zero, and the dilaton and warp factor are non-constant. The IIA solutions include the massive deformations of the IIA reduction of the eleven-dimensional AdS 4 x Y p,q solutions, and had been predicted to exist on the basis of the AdS 4 /CFT 3 correspondence. (Abstract Copyright [2010], Wiley Periodicals, Inc.)

  5. Instantons from geodesics in AdS moduli spaces

    Science.gov (United States)

    Ruggeri, Daniele; Trigiante, Mario; Van Riet, Thomas

    2018-03-01

    We investigate supergravity instantons in Euclidean AdS5 × S5/ℤk. These solutions are expected to be dual to instantons of N = 2 quiver gauge theories. On the supergravity side the (extremal) instanton solutions are neatly described by the (lightlike) geodesics on the AdS moduli space for which we find the explicit expression and compute the on-shell actions in terms of the quantised charges. The lightlike geodesics fall into two categories depending on the degree of nilpotency of the Noether charge matrix carried by the geodesic: for degree 2 the instantons preserve 8 supercharges and for degree 3 they are non-SUSY. We expect that these findings should apply to more general situations in the sense that there is a map between geodesics on moduli-spaces of Euclidean AdS vacua and instantons with holographic counterparts.

  6. Loops in AdS from conformal field theory

    Science.gov (United States)

    Aharony, Ofer; Alday, Luis F.; Bissi, Agnese; Perlmutter, Eric

    2017-07-01

    We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1 /N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1 /N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for finite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case of ϕ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an infinite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.

  7. Phases of global AdS black holes

    International Nuclear Information System (INIS)

    Basu, Pallab; Krishnan, Chethan; Subramanian, P.N. Bala

    2016-01-01

    We study the phases of gravity coupled to a charged scalar and gauge field in an asymptotically Anti-de Sitter spacetime (AdS_4) in the grand canonical ensemble. For the conformally coupled scalar, an intricate phase diagram is charted out between the four relevant solutions: global AdS, boson star, Reissner-Nordstrom black hole and the hairy black hole. The nature of the phase diagram undergoes qualitative changes as the charge of the scalar is changed, which we discuss. We also discuss the new features that arise in the extremal limit.

  8. Minimal surfaces in AdS space and integrable systems

    Science.gov (United States)

    Burrington, Benjamin A.; Gao, Peng

    2010-04-01

    We consider the Pohlmeyer reduction for spacelike minimal area worldsheets in AdS5. The Lax pair for the reduced theory is found, and written entirely in terms of the A3 = D3 root system, generalizing the B2 affine Toda system which appears for the AdS4 string. For the B2 affine Toda system, we show that the area of the worlsheet is obtainable from the moduli space Kähler potential of a related Hitchin system. We also explore the Saveliev-Leznov construction for solutions of the B2 affine Toda system, and recover the rotationally symmetric solution associated to Painleve transcendent.

  9. AdS5 magnetized solutions in minimal gauged supergravity

    Directory of Open Access Journals (Sweden)

    Jose Luis Blázquez-Salcedo

    2017-08-01

    Full Text Available We construct a generalization of the AdS charged rotating black holes with two equal magnitude angular momenta in five-dimensional minimal gauged supergravity. In addition to the mass, electric charge and angular momentum, the new solutions possess an extra-parameter associated with a non-zero magnitude of the magnetic potential at infinity. In contrast with the known cases, these new black holes possess a non-trivial zero-horizon size limit which describes a one parameter family of spinning charged solitons. All configurations reported in this work approach asymptotically an AdS5 spacetime in global coordinates and are free of pathologies.

  10. Twistor description of spinning particles in AdS

    Science.gov (United States)

    Arvanitakis, Alex S.; Barns-Graham, Alec E.; Townsend, Paul K.

    2018-01-01

    The two-twistor formulation of particle mechanics in D-dimensional anti-de Sitter space for D = 4 , 5 , 7, which linearises invariance under the AdS isometry group Sp(4; K ) for K=R,C,H, is generalized to the massless N -extended "spinning particle". The twistor variables are gauge invariant with respect to the initial N local worldline supersymmetries; this simplifies aspects of the quantum theory such as implications of global gauge anomalies. We also give details of the two-supertwistor form of the superparticle, in particular the massive superparticle on AdS5.

  11. Holography in Lovelock Chern-Simons AdS gravity

    Science.gov (United States)

    Cvetković, Branislav; Miskovic, Olivera; Simić, Dejan

    2017-08-01

    We analyze holographic field theory dual to Lovelock Chern-Simons anti-de Sitter (AdS) gravity in higher dimensions using first order formalism. We first find asymptotic symmetries in the AdS sector showing that they consist of local translations, local Lorentz rotations, dilatations and non-Abelian gauge transformations. Then, we compute 1-point functions of energy-momentum and spin currents in a dual conformal field theory and write Ward identities. We find that the holographic theory possesses Weyl anomaly and also breaks non-Abelian gauge symmetry at the quantum level.

  12. The forecaster's added value

    Science.gov (United States)

    Turco, M.; Milelli, M.

    2009-09-01

    skill scores of two competitive forecast. It is important to underline that the conclusions refer to the analysis of the Piemonte operational alert system, so they cannot be directly taken as universally true. But we think that some of the main lessons that can be derived from this study could be useful for the meteorological community. In details, the main conclusions are the following: - despite the overall improvement in global scale and the fact that the resolution of the limited area models has increased considerably over recent years, the QPF produced by the meteorological models involved in this study has not improved enough to allow its direct use, that is, the subjective HQPF continues to offer the best performance; - in the forecast process, the step where humans have the largest added value with respect to mathematical models, is the communication. In fact the human characterisation and communication of the forecast uncertainty to end users cannot be replaced by any computer code; - eventually, although there is no novelty in this study, we would like to show that the correct application of appropriated statistical techniques permits a better definition and quantification of the errors and, mostly important, allows a correct (unbiased) communication between forecasters and decision makers.

  13. Mixed-symmetry fields in AdS(5), conformal fields, and AdS/CFT

    Energy Technology Data Exchange (ETDEWEB)

    Metsaev, R.R. [Department of Theoretical Physics, P.N. Lebedev Physical Institute,Leninsky prospect 53, Moscow 119991 (Russian Federation)

    2015-01-15

    Mixed-symmetry arbitrary spin massive, massless, and self-dual massive fields in AdS(5) are studied. Light-cone gauge actions for such fields leading to decoupled equations of motion are constructed. Light-cone gauge formulation of mixed-symmetry anomalous conformal currents and shadows in 4d flat space is also developed. AdS/CFT correspondence for normalizable and non-normalizable modes of mixed-symmetry AdS fields and the respective boundary mixed-symmetry anomalous conformal currents and shadows is studied. We demonstrate that the light-cone gauge action for massive mixed-symmetry AdS field evaluated on solution of the Dirichlet problem amounts to the light-cone gauge 2-point vertex of mixed-symmetry anomalous shadow. Also we show that UV divergence of the action for mixed-symmetry massive AdS field with some particular value of mass parameter evaluated on the Dirichlet problem amounts to the action of long mixed-symmetry conformal field, while UV divergence of the action for mixed-symmetry massless AdS field evaluated on the Dirichlet problem amounts to the action of short mixed-symmetry conformal field. We speculate on string theory interpretation of a model which involves short low-spin conformal fields and long higher-spin conformal fields.

  14. No-carrier-added (NCA) synthesis of 6-[{sup 18}F]fluoro-L-DOPA using 3,5,6,7,8,8a-hexahydro-7,7,8a-trimethyl-[6S-(6{alpha}, 8{alpha}, 8{alpha}{beta})]-6,8-methano-2H-1,4-benzoxazin-2-one

    Energy Technology Data Exchange (ETDEWEB)

    Horti, A. [Yale Univ., New Haven, CT (United States). School of Medicine]|[Yale Univ., West Haven, CT (United States). PET Center; Redmond, D.E. Jr. [Yale Univ., New Haven, CT (United States). School of Medicine; Soufer, R. [Yale Univ., West Haven, CT (United States). PET Center

    1995-12-31

    3,5,6,7,8,8a-Hexahydro-7,7,8a-trimethyl-[6S-(6{alpha},8{alpha} , 8{alpha}{beta})]-6,8-methano-2H-1,4-benzoxazino-2-one (2) was investigated as chiral auxiliary for asymmetric NCA nucleophilic synthesis of 6-[{sup 18}F]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[{sup 18}F]fluorobenzaldehyde (1a) or 6-[{sup 18}F]fluoro-piperonal (1b) in the presence of NaH with 2 gave the corresponding [{sup 18}F]-3-[(2-fluorophenyl)methylene]-3,5,6,7,8,8a-hexahydro-7,7,8 a-trimethyl-[6S-(3Z,3{alpha},6{alpha},8{alpha},8{alpha}{beta})]-6, 8-methano-2H-1,4-benzoxazin-2-one derivative 3a or 3b as a single stereoisomer. L-Selectride promoted hydrogenation of the olefinic double bond of these derivatives, in presence of tertbutyl alcohol, afforded the corresponding [{sup 18}F]-3-[(2-fluorophenyl) methyl]-3,5,6,7,8,8a-hexahydro-7,7,8a-trimethyl-[3S-(3{alpha}, 6{alpha}, 8{alpha}8{alpha}{beta})]-6,8-methano-2H-1,4-benzoxazin-2-one derivatives (4a,b) without affecting the orientation of diasterofacial discrimination. Deprotection of the derivatives 4a,b yielded 6-[{sup 18}F]fluoro-L-DOPA (e.e. >90%, 3% radiochemical yield (EOB), total synthesis time 125 min, specific activity >2000 mCi/{mu}mol). Direct deprotection/reduction of the compounds 3a,b provides the enantiomeric mixture of 6-[{sup 18}F]fluoro-D,L-DOPA (10-12% radiochemical yield) and, after chiral separation, 6-[{sup 18}F]fluoro-L-DOPA (e.e. 98%, 4-5% radiochemical yield). (author).

  15. No-carrier-added (NCA) synthesis of 6-[18F]fluoro-L-DOPA using 3,5,6,7,8,8a-hexahydro-7,7,8a-trimethyl-[6S-(6α, 8α, 8αβ)]-6,8-methano-2H-1,4-benzoxazin-2-one

    International Nuclear Information System (INIS)

    Horti, A.; Yale Univ., West Haven, CT; Redmond, D.E. Jr.; Soufer, R.

    1995-01-01

    3,5,6,7,8,8a-Hexahydro-7,7,8a-trimethyl-[6S-(6α,8α , 8αβ)]-6,8-methano-2H-1,4-benzoxazino-2-one (2) was investigated as chiral auxiliary for asymmetric NCA nucleophilic synthesis of 6-[ 18 F]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[ 18 F]fluorobenzaldehyde (1a) or 6-[ 18 F]fluoro-piperonal (1b) in the presence of NaH with 2 gave the corresponding [ 18 F]-3-[(2-fluorophenyl)methylene]-3,5,6,7,8,8a-hexahydro-7,7,8 a-trimethyl-[6S-(3Z,3α,6α,8α,8αβ)]-6, 8-methano-2H-1,4-benzoxazin-2-one derivative 3a or 3b as a single stereoisomer. L-Selectride promoted hydrogenation of the olefinic double bond of these derivatives, in presence of tertbutyl alcohol, afforded the corresponding [ 18 F]-3-[(2-fluorophenyl) methyl]-3,5,6,7,8,8a-hexahydro-7,7,8a-trimethyl-[3S-(3α, 6α, 8α8αβ)]-6,8-methano-2H-1,4-benzoxazin-2-one derivatives (4a,b) without affecting the orientation of diasterofacial discrimination. Deprotection of the derivatives 4a,b yielded 6-[ 18 F]fluoro-L-DOPA (e.e. >90%, 3% radiochemical yield (EOB), total synthesis time 125 min, specific activity >2000 mCi/μmol). Direct deprotection/reduction of the compounds 3a,b provides the enantiomeric mixture of 6-[ 18 F]fluoro-D,L-DOPA (10-12% radiochemical yield) and, after chiral separation, 6-[ 18 F]fluoro-L-DOPA (e.e. 98%, 4-5% radiochemical yield). (author)

  16. AdS pure spinor superstring in constant backgrounds

    International Nuclear Information System (INIS)

    Chandia, Osvaldo; Bevilaqua, L. Ibiapina; Vallilo, Brenno Carlini

    2014-01-01

    In this paper we study the pure spinor formulation of the superstring in AdS_5×S"5 around point particle solutions of the classical equations of motion. As a particular example we quantize the pure spinor string in the BMN background

  17. Internet Advertising. Google AdWords versus Facebook Ads

    OpenAIRE

    Paul PAŞCU

    2014-01-01

    This article describes how to use the applications for Internet advertising, Google AdWords and Facebook Ads. Our attempt is to present the advantages and disadvantages of each of them, the costs and benefits, a useful aspect for companies that plan to start advertising campaigns on the Internet.

  18. Internet Advertising. Google AdWords versus Facebook Ads

    Directory of Open Access Journals (Sweden)

    Paul PAŞCU

    2014-05-01

    Full Text Available This article describes how to use the applications for Internet advertising, Google AdWords and Facebook Ads. Our attempt is to present the advantages and disadvantages of each of them, the costs and benefits, a useful aspect for companies that plan to start advertising campaigns on the Internet.

  19. Penrose inequality for asymptotically AdS spaces

    International Nuclear Information System (INIS)

    Itkin, Igor; Oz, Yaron

    2012-01-01

    In general relativity, the Penrose inequality relates the mass and the entropy associated with a gravitational background. If the inequality is violated by an initial Cauchy data, it suggests a creation of a naked singularity, thus providing means to consider the cosmic censorship hypothesis. We propose a general form of Penrose inequality for asymptotically locally AdS spaces.

  20. Penrose inequality for asymptotically AdS spaces

    Energy Technology Data Exchange (ETDEWEB)

    Itkin, Igor [Raymond and Beverly Sackler School of Physics and Astronomy, Tel-Aviv University, Tel-Aviv 69978 (Israel); Oz, Yaron, E-mail: yaronoz@post.tau.ac.il [Raymond and Beverly Sackler School of Physics and Astronomy, Tel-Aviv University, Tel-Aviv 69978 (Israel)

    2012-02-28

    In general relativity, the Penrose inequality relates the mass and the entropy associated with a gravitational background. If the inequality is violated by an initial Cauchy data, it suggests a creation of a naked singularity, thus providing means to consider the cosmic censorship hypothesis. We propose a general form of Penrose inequality for asymptotically locally AdS spaces.

  1. Confinement, glueballs and strings from deformed AdS

    International Nuclear Information System (INIS)

    Apreda, Riccardo; Crooks, David E.; Evans, Nick; Petrini, Michela

    2004-01-01

    We study aspects of confinement in two deformed versions of the AdS/CFT correspondence - the GPPZ dual of N = 1* Yang Mills, and the Yang Mills* N 0 dual. Both geometries describe discrete glueball spectra which we calculate numerically. The results agree at the 10% level with previous AdS/CFT computations in the Klebanov Strassler background and AdS Schwarzchild respectively. We also calculate the spectra of bound states of the massive fermions in these geometries and show that they are light, so not decoupled from the dynamics. We then study the behaviour of Wilson loops in the 10d lifts of these geometries. We find a transition from AdS-like strings in the UV to strings that interact with the unknown physics of the central singularity of the space in the IR. (author)

  2. Supersymmetric AdS6 solutions of type IIB supergravity

    International Nuclear Information System (INIS)

    Kim, Hyojoong; Kim, Nakwoo; Suh, Minwoo

    2015-01-01

    We study the general requirement for supersymmetric AdS 6 solutions in type IIB supergravity. We employ the Killing spinor technique and study the differential and algebraic relations among various Killing spinor bilinears to find the canonical form of the solutions. Our result agrees precisely with the work of Apruzzi et al. (JHEP 1411:099, 2014), which used the pure spinor technique. Hoping to identify the geometry of the problem, we also computed four-dimensional theory through the dimensional reduction of type IIB supergravity on AdS 6 . This effective action is essentially a non-linear sigma model with five scalar fields parametrizing SL(3,ℝ)/SO(2,1), modified by a scalar potential and coupled to Einstein gravity in Euclidean signature. We argue that the scalar potential can be explained by a subgroup CSO(1,1,1) ⊂SL(3,ℝ) in a way analogous to gauged supergravity

  3. AdS gravity and the scalar glueball spectrum

    Energy Technology Data Exchange (ETDEWEB)

    Vento, Vicente [Departament de Fisica Teorica, Universitat de Valencia y Institut de Fisica Corpuscular, Consejo Superior de Investigaciones Cientificas, Burjassot (Valencia) (Spain)

    2017-09-15

    The scalar glueball spectrum has attracted much attention since the formulation of Quantum Chromodynamics. Different approaches give very different results for the glueball masses. We revisit the problem from the perspective of the AdS/CFT correspondence. (orig.)

  4. Smoothed transitions in higher spin AdS gravity

    International Nuclear Information System (INIS)

    Banerjee, Shamik; Shenker, Stephen; Castro, Alejandra; Hellerman, Simeon; Hijano, Eliot; Lepage-Jutier, Arnaud; Maloney, Alexander

    2013-01-01

    We consider CFTs conjectured to be dual to higher spin theories of gravity in AdS 3 and AdS 4 . Two-dimensional CFTs with W N symmetry are considered in the λ = 0 (k → ∞) limit where they are conjectured to be described by continuous orbifolds. The torus partition function is computed, using reasonable assumptions, and equals that of a free-field theory. We find no phase transition at temperatures of order 1; the usual Hawking–Page phase transition is removed by the highly degenerate light states associated with conical defect states in the bulk. Three-dimensional Chern–Simons matter CFTs with vector-like matter are considered on T 3 , where the dynamics is described by an effective theory for the eigenvalues of the holonomies. Likewise, we find no evidence for a Hawking–Page phase transition at a large level k. (paper)

  5. Winding strings and AdS3 black holes

    International Nuclear Information System (INIS)

    Troost, Jan

    2002-01-01

    We start a systematic study of string theory in AdS 3 black hole backgrounds. Firstly, we analyse in detail the geodesic structure of the BTZ black hole, including spacelike geodesics. Secondly, we study the spectrum for massive and massless scalar fields, paying particular attention to the connection between Sl(2,R) subgroups, the theory of special functions and global properties of the BTZ black holes. We construct classical strings that wind the black holes. Finally, we apply the general formalism to the vacuum black hole background, and formulate the boundary spacetime Virasoro algebra in terms of worldsheet operators. We moreover establish the link between a proposal for a ghost free spectrum for Sl(2,R) string propagation and the massless black hole background, thereby claryfing aspects of the AdS 3 /CFT correspondence. (author)

  6. AdS strings with torsion: Noncomplex heterotic compactifications

    International Nuclear Information System (INIS)

    Frey, Andrew R.; Lippert, Matthew

    2005-01-01

    Combining the effects of fluxes and gaugino condensation in heterotic supergravity, we use a ten-dimensional approach to find a new class of four-dimensional supersymmetric AdS 4 compactifications on almost-Hermitian manifolds of SU(3) structure. Computation of the torsion allows a classification of the internal geometry, which for a particular combination of fluxes and condensate, is nearly Kaehler. We argue that all moduli are fixed, and we show that the Kaehler potential and superpotential proposed in the literature yield the correct AdS 4 radius. In the nearly Kaehler case, we are able to solve the H Bianchi identity using a nonstandard embedding. Finally, we point out subtleties in deriving the effective superpotential and understanding the heterotic supergravity in the presence of a gaugino condensate

  7. The Mixed Phase of Charged AdS Black Holes

    Directory of Open Access Journals (Sweden)

    Piyabut Burikham

    2016-01-01

    Full Text Available We study the mixed phase of charged AdS black hole and radiation when the total energy is fixed below the threshold to produce a stable charged black hole branch. The coexistence conditions for the charged AdS black hole and radiation are derived for the generic case when radiation particles carry charge. The phase diagram of the mixed phase is demonstrated for both fixed potential and charge ensemble. In the dual gauge picture, they correspond to the mixed phase of quark-gluon plasma (QGP and hadron gas in the fixed chemical potential and density ensemble, respectively. In the nuclei and heavy-ion collisions at intermediate energies, the mixed phase of exotic QGP and hadron gas could be produced. The mixed phase will condense and evaporate into the hadron gas as the fireball expands.

  8. Perturbative entanglement thermodynamics for AdS spacetime: renormalization

    International Nuclear Information System (INIS)

    Mishra, Rohit; Singh, Harvendra

    2015-01-01

    We study the effect of charged excitations in the AdS spacetime on the first law of entanglement thermodynamics. It is found that ‘boosted’ AdS black holes give rise to a more general form of first law which includes chemical potential and charge density. To obtain this result we have to resort to a second order perturbative calculation of entanglement entropy for small size subsystems. At first order the form of entanglement law remains unchanged even in the presence of charged excitations. But the thermodynamic quantities have to be appropriately ‘renormalized’ at the second order due to the corrections. We work in the perturbative regime where T thermal ≪T E .

  9. Generalised structures for N=1 AdS backgrounds

    Energy Technology Data Exchange (ETDEWEB)

    Coimbra, André [Institut für Theoretische Physik & Center for Quantum Engineering and Spacetime Research,Leibniz Universität Hannover,Appelstraße 2, 30167 Hannover (Germany); Strickland-Constable, Charles [Institut de physique théorique, Université Paris Saclay, CEA, CNRS, Orme des Merisiers, F-91191 Gif-sur-Yvette (France)

    2016-11-16

    We expand upon a claim made in a recent paper [http://arxiv.org/abs/1411.5721] that generic minimally supersymmetric AdS backgrounds of warped flux compactifications of Type II and M theory can be understood as satisfying a straightforward weak integrability condition in the language of E{sub d(d)}×ℝ{sup +} generalised geometry. Namely, they are spaces admitting a generalised G-structure set by the Killing spinor and with constant singlet generalised intrinsic torsion.

  10. ADS Bumblebee comes of age

    Science.gov (United States)

    Accomazzi, Alberto; Kurtz, Michael J.; Henneken, Edwin; Grant, Carolyn S.; Thompson, Donna M.; Chyla, Roman; McDonald, Steven; Shaulis, Taylor J.; Blanco-Cuaresma, Sergi; Shapurian, Golnaz; Hostetler, Timothy W.; Templeton, Matthew R.; Lockhart, Kelly E.

    2018-01-01

    The ADS Team has been working on a new system architecture and user interface named “ADS Bumblebee” since 2015. The new system presents many advantages over the traditional ADS interface and search engine (“ADS Classic”). A new, state of the art search engine features a number of new capabilities such as full-text search, advanced citation queries, filtering of results and scalable analytics for any search results. Its services are built on a cloud computing platform which can be easily scaled to match user demand. The Bumblebee user interface is a rich javascript application which leverages the features of the search engine and integrates a number of additional visualizations such as co-author and co-citation networks which provide a hierarchical view of research groups and research topics, respectively. Displays of paper analytics provide views of the basic article metrics (citations, reads, and age). All visualizations are interactive and provide ways to further refine search results. This new search system, which has been in beta for the past three years, has now matured to the point that it provides feature and content parity with ADS Classic, and has become the recommended way to access ADS content and services. Following a successful transition to Bumblebee, the use of ADS Classic will be discouraged starting in 2018 and phased out in 2019. You can access our new interface at https://ui.adsabs.harvard.edu

  11. Noncommutative D-branes from covariant AdS superstring

    International Nuclear Information System (INIS)

    Sakaguchi, Makoto; Yoshida, Kentaroh

    2008-01-01

    We study noncommutative (NC) D-branes on AdS 5 xS 5 from κ-invariance of covariant Green-Schwarz action of an open string with a non-trivial world-volume flux. Finding boundary conditions to ensure the κ-invariance, we can see possible configurations of the NC D-branes. With this method 1/4 BPS NC D-branes are discussed. The resulting NC Dp-branes are 1/4 BPS at arbitrary position other than the p=1 case. The exceptional D-string is 1/2 BPS at the origin and 1/4 BPS outside the origin. Those are reduced to possible 1/4 BPS or 1/2 BPS AdS D-branes in the commutative limit. The same analysis is applied to an open superstring in a pp-wave and leads to 1/4 BPS configurations of NC D-branes. These D-branes are consistently obtained from AdS D-branes via the Penrose limit

  12. Supersymmetric giant graviton solutions in AdS3

    International Nuclear Information System (INIS)

    Mandal, Gautam; Raju, Suvrat; Smedbaeck, Mikael

    2008-01-01

    We parametrize all classical probe brane configurations that preserve four supersymmetries in (a) the extremal D1-D5 geometry, (b) the extremal D1-D5-P geometry, (c) the smooth D1-D5 solutions proposed by Lunin and Mathur, and (d) global AdS 3 xS 3 xT 4 /K3. These configurations consist of D1 branes, D5 branes, and bound states of D5 and D1 branes with the property that a particular Killing vector is tangent to the brane world volume at each point. We show that the supersymmetric sector of the D5-brane world volume theory may be analyzed in an effective 1+1 dimensional framework that places it on the same footing as D1 branes. In global AdS and the corresponding Lunin-Mathur solution, the solutions we describe are ''bound'' to the center of AdS for generic parameters and cannot escape to infinity. We show that these probes only exist on the submanifold of moduli space where the background B NS field and theta angle vanish. We quantize these probes in the near-horizon region of the extremal D1-D5 geometry and obtain the theory of long strings discussed by Seiberg and Witten

  13. Exploring AdS waves via nonminimal coupling

    International Nuclear Information System (INIS)

    Ayon-Beato, Eloy; Hassaiene, Mokhtar

    2006-01-01

    We consider nonminimally coupled scalar fields to explore the Siklos spacetimes in three dimensions. Their interpretation as exact gravitational waves propagating on AdS space restrict the source to behave as a pure radiation field. We show that the related pure radiation constraints single out a unique self-interaction potential depending on one coupling constant. For a vanishing coupling constant, this potential reduces to a mass term with a mass fixed in terms of the nonminimal-coupling parameter. This mass dependence allows the existence of several free cases including massless and tachyonic sources. There even exists a particular value of the nonminimal-coupling parameter for which the corresponding mass exactly compensates the contribution generated by the negative scalar curvature, producing a genuinely massless field in this curved background. The self-interacting case is studied in detail for the conformal coupling. The resulting gravitational wave is formed by the superposition of the free and the self-interaction contributions, except for a critical value of the coupling constant where a nonperturbative effect relating the strong and weak regimes of the source appears. We establish a correspondence between the scalar source supporting an AdS wave and a pp wave by showing that their respective pure radiation constraints are conformally related, while their involved backgrounds are not. Finally, we consider the AdS waves for topologically massive gravity and its limit to conformal gravity

  14. Enthalpy and the mechanics of AdS black holes

    International Nuclear Information System (INIS)

    Kastor, David; Traschen, Jennie; Ray, Sourya

    2009-01-01

    We present geometric derivations of the Smarr formula for static AdS black holes and an expanded first law that includes variations in the cosmological constant. These two results are further related by a scaling argument based on Euler's theorem. The key new ingredient in the constructions is a two-form potential for the static Killing field. Surface integrals of the Killing potential determine the coefficient of the variation of Λ in the first law. This coefficient is proportional to a finite, effective volume for the region outside the AdS black hole horizon, which can also be interpreted as minus the volume excluded from a spatial slice by the black hole horizon. This effective volume also contributes to the Smarr formula. Since Λ is naturally thought of as a pressure, the new term in the first law has the form of effective volume times change in pressure that arises in the variation of the enthalpy in classical thermodynamics. This and related arguments suggest that the mass of an AdS black hole should be interpreted as the enthalpy of the spacetime.

  15. Shock wave collisions and thermalization in AdS5

    International Nuclear Information System (INIS)

    Kovchegov, Yuri V.

    2011-01-01

    We study heavy ion collisions at strong 't Hooft coupling using AdS/CFT correspondence. According to the AdS/CFT dictionary heavy ion collisions correspond to gravitational shock wave collisions in AdS 5 . We construct the metric in the forward light cone after the collision perturbatively through expansion of Einstein equations in graviton exchanges. We obtain an analytic expression for the metric including all-order graviton exchanges with one shock wave, while keeping the exchanges with another shock wave at the lowest order. We read off the corresponding energy-momentum tensor of the produced medium. Unfortunately this energy-momentum tensor does not correspond to ideal hydrodynamics, indicating that higher order graviton exchanges are needed to construct the full solution of the problem. We also show that shock waves must completely stop almost immediately after the collision in AdS 5 , which, on the field theory side, corresponds to complete nuclear stopping due to strong coupling effects, likely leading to Landau hydrodynamics. Finally, we perform trapped surface analysis of the shock wave collisions demonstrating that a bulk black hole, corresponding to ideal hydrodynamics on the boundary, has to be created in such collisions, thus constructing a proof of thermalization in heavy ion collisions at strong coupling. (author)

  16. Ad skepticisms: Antecedents and consequences

    Directory of Open Access Journals (Sweden)

    Rafique Ahmed

    2016-11-01

    Full Text Available Engaging customer is the burning issue for companies especially the service sector, either online or offline. Minimizing the customer disengagement is the same like reducing dissatisfaction or churn. Customer disengagement may be caused by many factors, ad skepticism is one of them; ad skepticism has two main antecedents personality variable and consumption/influencing varia-bles. This research explores the relationship of ad skepticism with customer disengagement through personality variables which are cynicism, reactance and self-esteem. The unit of analysis is the telecom and banking industry of Pakistan which is foreseeing an era of virtual currency and both are customer oriented industries. Only offline disengagement is researched and data is collected from the Business centers of telecom and banking branches dealing with virtual curren-cy in Pakistan. Hypothetical model is given after digging the relevant literature; model is tested through confirmatory factor analysis and structural equation modeling. Eight hypotheses were purposed from the connections of model, all hypotheses are accepted except the cynicism posi-tive effect on social ad skepticism. This can be due to commonality of social and charity in Paki-stani society, Muslims consider charity as a pious act and they do not think for cynic behavior in charity or social related works. The results manifest that customers in telecom industry are hav-ing ad skepticism and that is becoming the cause of their disengagement. Further, social ad skep-ticism has more impact on the customer disengagement than the general ad skepticism. While the reactance has more effect on general ad skepticism than other antecedents and cynicism has the lowest impact on social ad skepticism than other antecedents.

  17. ADS-B in space

    DEFF Research Database (Denmark)

    Knudsen, Bjarke Gosvig; Jensen, Morten; Birklykke, Alex

    2014-01-01

    ADS-B is increasingly used for air traffic control in areas covered by terrestrial receivers; however, its limited range makes it unsuitable for other areas such as the oceans. To overcome this limitation, it has been proposed to receive ADS-B signals from low earth orbit nano-satellites and relay...... them to the terrestrial receivers. This paper gives an overview of the GATOSS mission and of its highly-sensitive ADS-B software-defined radio receiver payload. Details of the design and implementation of the receiver's decoder are introduced. The first real-life, space-based results show that ADS......-B signals are indeed successfully received in space and retransmitted to a terrestrial station by the GATOSS nano-satellite orbiting at 700+ km altitudes, thus showing that GATOSS is capable of tracking flights, including transoceanic ones, from space....

  18. Virginia ADS consortium - thorium utilization

    International Nuclear Information System (INIS)

    Myneni, Ganapati

    2015-01-01

    A Virginia ADS consortium, consisting of Virginia Universities (UVa, VCU, VT), Industry (Casting Analysis Corporation, GEM*STAR, MuPlus Inc.), Jefferson Lab and not-for-profit ISOHIM, has been organizing International Accelerator-Driven Sub-Critical Systems (ADS) and Thorium Utilization (ThU) workshops. The third workshop of this series was hosted by VCU in Richmond, Virginia, USA Oct 2014 with CBMM and IAEA sponsorship and was endorsed by International Thorium Energy Committee (IThEC), Geneva and Virginia Nuclear Energy Consortium Authority. In this presentation a brief summary of the successful 3 rd International ADS and ThU workshop proceedings and review the worldwide ADS plans and/or programs is given. Additionally, a report on new start-ups on Molten Salt Reactor (MSR) systems is presented. Further, a discussion on potential simplistic fertile 232 Th to fissile 233 U conversion is made

  19. A closer look at two AdS4 branes in an AdS5 bulk

    International Nuclear Information System (INIS)

    Thambyahpillai, Shiyamala

    2005-01-01

    We investigate a scenario with two AdS 4 branes in an AdS 5 bulk. In this scenario there are two gravitons and we investigate the role played by each of them for different positions of the second brane. We show that both gravitons play a significant role only when the turn-around point in the warp factor is approximately equidistant from both branes. We find that the ultralight mode becomes heavy as the second brane approaches the turn-around point, and the physics begins to resemble that of the RS model. Thus we demonstrate the crucial role played by the turn-around in the warp factor in enabling the presence of both gravitons. (author)

  20. ADS/CFT and QCD

    International Nuclear Information System (INIS)

    Brodsky, Stanley J.; de Teramond, Guy F.

    2007-01-01

    The AdS/CFT correspondence between string theory in AdS space and conformal .eld theories in physical spacetime leads to an analytic, semi-classical model for strongly-coupled QCD which has scale invariance and dimensional counting at short distances and color confinement at large distances. Although QCD is not conformally invariant, one can nevertheless use the mathematical representation of the conformal group in five-dimensional anti-de Sitter space to construct a first approximation to the theory. The AdS/CFT correspondence also provides insights into the inherently non-perturbative aspects of QCD, such as the orbital and radial spectra of hadrons and the form of hadronic wavefunctions. In particular, we show that there is an exact correspondence between the fifth-dimensional coordinate of AdS space z and a specific impact variable ζ which measures the separation of the quark and gluonic constituents within the hadron in ordinary space-time. This connection allows one to compute the analytic form of the frame-independent light-front wavefunctions, the fundamental entities which encode hadron properties and allow the computation of decay constants, form factors, and other exclusive scattering amplitudes. New relativistic lightfront equations in ordinary space-time are found which reproduce the results obtained using the 5-dimensional theory. The effective light-front equations possess remarkable algebraic structures and integrability properties. Since they are complete and orthonormal, the AdS/CFT model wavefunctions can also be used as a basis for the diagonalization of the full light-front QCD Hamiltonian, thus systematically improving the AdS/CFT approximation

  1. Wilson lines for AdS5 black strings

    International Nuclear Information System (INIS)

    Hristov, Kiril; Katmadas, Stefanos

    2015-01-01

    We describe a simple method of extending AdS 5 black string solutions of 5d gauged supergravity in a supersymmetric way by addition of Wilson lines along a circular direction in space. When this direction is chosen along the string, and due to the specific form of 5d supergravity that features Chern-Simons terms, the existence of magnetic charges automatically generates conserved electric charges in a 5d analogue of the Witten effect. Therefore we find a rather generic, model-independent way of adding electric charges to already existing solutions with no backreaction from the geometry or breaking of any symmetry. We use this method to explicitly write down more general versions of the Benini-Bobev black strings (http://dx.doi.org/10.1103/PhysRevLett.110.061601, http://dx.doi.org/10.1007/JHEP06(2013)005) and comment on the implications for the dual field theory and the similarities with generalizations of the Cacciatori-Klemm black holes (http://dx.doi.org/10.1007/JHEP01(2010)085) in AdS 4 .

  2. An AdS3 dual for minimal model CFTs

    International Nuclear Information System (INIS)

    Gaberdiel, Matthias R.; Gopakumar, Rajesh

    2011-01-01

    We propose a duality between the 2d W N minimal models in the large N't Hooft limit, and a family of higher spin theories on AdS 3 . The 2d conformal field theories (CFTs) can be described as Wess-Zumino-Witten coset models, and include, for N=2, the usual Virasoro unitary series. The dual bulk theory contains, in addition to the massless higher spin fields, two complex scalars (of equal mass). The mass is directly related to the 't Hooft coupling constant of the dual CFT. We give convincing evidence that the spectra of the two theories match precisely for all values of the 't Hooft coupling. We also show that the renormalization group flows in the 2d CFT agree exactly with the usual AdS/CFT prediction of the gravity theory. Our proposal is in many ways analogous to the Klebanov-Polyakov conjecture for an AdS 4 dual for the singlet sector of large N vector models.

  3. Heavy ion collisions in AdS5

    International Nuclear Information System (INIS)

    Kovchegov, Yuri V.

    2011-01-01

    We study heavy ion collisions at strong 't Hooft coupling using AdS/CFT correspondence. Heavy ion collisions correspond to gravitational shock wave collisions in AdS 5 . We construct the metric in the forward light cone after the collision perturbatively through expansion of Einstein equations in graviton exchanges. We obtain an analytic expression for the metric including all-order graviton exchanges with one shock wave, while keeping the exchanges with another shock wave at the lowest order. We read off the corresponding energy-momentum tensor of the produced medium. Unfortunately this energy-momentum tensor does not correspond to ideal hydrodynamics, indicating that higher order graviton exchanges are needed to construct the full solution of the problem. We also show that shock waves must completely stop almost immediately after the collision in AdS 5 , which, on the field theory side, corresponds to complete nuclear stopping due to strong coupling effects, likely leading to Landau hydrodynamics. Finally, we perform trapped surface analysis of the shock wave collisions demonstrating that a bulk black hole, corresponding to ideal hydrodynamics on the boundary, has to be created in such collisions, thus constructing a proof of thermalization in heavy ion collisions at strong coupling.

  4. Supergravity one-loop corrections on AdS7 and AdS3, higher spins and AdS/CFT

    Directory of Open Access Journals (Sweden)

    Matteo Beccaria

    2015-03-01

    Full Text Available As was shown earlier, the one-loop correction in 10d supergravity on AdS5×S5 corresponds to the contributions to the vacuum energy and 4d boundary conformal anomaly which are minus the values for one N=4 Maxwell supermultiplet, thus reproducing the subleading term in the N2−1 coefficient in the dual SU(N SYM theory. We perform similar one-loop computations in 11d supergravity on AdS7×S4 and 10d supergravity on AdS3×S3×T4. In the AdS7 case we find that the corrections to the 6d conformal anomaly a-coefficient and the vacuum energy are again minus the ones for one (2,0 tensor multiplet, suggesting that the total a-anomaly coefficient for the dual (2,0 theory is 4N3−9/4N−7/4 and thus vanishes for N=1. In the AdS3 case the one-loop correction to the vacuum energy or 2d central charge turns out to be equal to that of one free (4,4 scalar multiplet, i.e. is c=+6. This reproduces the subleading term in the central charge c=6(Q1Q5+1 of the dual 2d CFT describing decoupling limit of D5–D1 system. We also present the expressions for the 6d a-anomaly coefficient and vacuum energy contributions of general-symmetry higher spin field in AdS7 and consider their application to tests of vectorial AdS/CFT with the boundary conformal 6d theory represented by free scalars, spinors or rank-2 antisymmetric tensors.

  5. Small AdS black holes from SYM

    International Nuclear Information System (INIS)

    Asplund, Curtis; Berenstein, David

    2009-01-01

    We provide a characterization of the set of configurations in N=4 SYM theory that are dual to small AdS black holes. Our construction shows that the black hole dual states are approximately thermal on a SU(M) subset of degrees of freedom of a SU(N) gauge theory. M is determined dynamically and the black hole degrees of freedom are dynamically insulated from the rest. These states are localized on the S 5 and have dynamical processes that correspond to matter absorption that make them behave as black objects

  6. On attractor mechanism of AdS4 black holes

    International Nuclear Information System (INIS)

    Anabalón, Andrés; Astefanesei, Dumitru

    2013-01-01

    We construct a general family of exact non-extremal 4-dimensional black holes in AdS gravity with U(1) gauge fields non-minimally coupled to a dilaton and a non-trivial dilaton potential. These black holes can have spherical, toroidal, and hyperbolic horizon topologies. We use the entropy function formalism to obtain the near horizon data in the extremal limit. Due to the non-trivial self-interaction of the scalar field, the zero temperature black holes can have a finite horizon area even if only the electric field is turned on

  7. Small black holes in global AdS spacetime

    Science.gov (United States)

    Jokela, Niko; Pönni, Arttu; Vuorinen, Aleksi

    2016-04-01

    We study the properties of two-point functions and quasinormal modes in a strongly coupled field theory holographically dual to a small black hole in global anti-de Sitter spacetime. Our results are seen to smoothly interpolate between known limits corresponding to large black holes and thermal AdS space, demonstrating that the Son-Starinets prescription works even when there is no black hole in the spacetime. Omitting issues related to the internal space, the results can be given a field theory interpretation in terms of the microcanonical ensemble, which provides access to energy densities forbidden in the canonical description.

  8. Configurational entropy of charged AdS black holes

    Directory of Open Access Journals (Sweden)

    Chong Oh Lee

    2017-09-01

    Full Text Available When we consider charged AdS black holes in higher dimensional spacetime and a molecule number density along coexistence curves is numerically extended to higher dimensional cases. It is found that a number density difference of a small and large black holes decrease as a total dimension grows up. In particular, we find that a configurational entropy is a concave function of a reduced temperature and reaches a maximum value at a critical (second-order phase transition point. Furthermore, the bigger a total dimension becomes, the more concave function in a configurational entropy while the more convex function in a reduced pressure.

  9. Gravitational charges of transverse asymptotically AdS spacetimes

    International Nuclear Information System (INIS)

    Cebeci, Hakan; Sarioglu, Oezguer; Tekin, Bayram

    2006-01-01

    Using Killing-Yano symmetries, we construct conserved charges of spacetimes that asymptotically approach to the flat or anti-de Sitter spaces only in certain directions. In D dimensions, this allows one to define gravitational charges (such as mass and angular momenta densities) of p-dimensional branes/solitons or any other extended objects that curve the transverse space into an asymptotically flat or AdS one. Our construction answers the question of what kind of charges the antisymmetric Killing-Yano tensors lead to

  10. Entanglement entropy and duality in AdS4

    Directory of Open Access Journals (Sweden)

    Ioannis Bakas

    2015-07-01

    Full Text Available Small variations of the entanglement entropy δS and the expectation value of the modular Hamiltonian δE are computed holographically for circular entangling curves in the boundary of AdS4, using gravitational perturbations with general boundary conditions in spherical coordinates. Agreement with the first law of thermodynamics, δS=δE, requires that the line element of the entangling curve remains constant. In this context, we also find a manifestation of electric–magnetic duality for the entanglement entropy and the corresponding modular Hamiltonian, following from the holographic energy–momentum/Cotton tensor duality.

  11. The AdS3 central charge in string theory

    International Nuclear Information System (INIS)

    Troost, Jan

    2011-01-01

    We evaluate the vacuum expectation value of the central charge operator in string theory in an AdS 3 vacuum. Our calculation provides a rare non-zero one-point function on a spherical worldsheet. The evaluation involves the regularization both of a worldsheet ultraviolet divergence (associated to the infinite volume of the conformal Killing group), and a space-time infrared divergence (corresponding to the infinite volume of space-time). The two divergences conspire to give a finite result, which is the classical general relativity value for the central charge, corrected in bosonic string theory by an infinite series of tree level higher derivative terms.

  12. Introducing ADS 2.0

    Science.gov (United States)

    Accomazzi, Alberto; Kurtz, M. J.; Henneken, E. A.; Grant, C. S.; Thompson, D.; Luker, J.; Chyla, R.; Murray, S. S.

    2014-01-01

    In the spring of 1993, the Smithsonian/NASA Astrophysics Data System (ADS) first launched its bibliographic search system. It was known then as the ADS Abstract Service, a component of the larger Astrophysics Data System effort which had developed an interoperable data system now seen as a precursor of the Virtual Observatory. As a result of the massive technological and sociological changes in the field of scholarly communication, the ADS is now completing the most ambitious technological upgrade in its twenty-year history. Code-named ADS 2.0, the new system features: an IT platform built on web and digital library standards; a new, extensible, industrial strength search engine; a public API with various access control capabilities; a set of applications supporting search, export, visualization, analysis; a collaborative, open source development model; and enhanced indexing of content which includes the full-text of astronomy and physics publications. The changes in the ADS platform affect all aspects of the system and its operations, including: the process through which data and metadata are harvested, curated and indexed; the interface and paradigm used for searching the database; and the follow-up analysis capabilities available to the users. This poster describes the choices behind the technical overhaul of the system, the technology stack used, and the opportunities which the upgrade is providing us with, namely gains in productivity and enhancements in our system capabilities.

  13. Methods for chemical recovery of non-carrier-added radioactive tin from irradiated intermetallic Ti-Sb targets

    Science.gov (United States)

    Lapshina, Elena V [Troitsk, RU; Zhuikov, Boris L [Troitsk, RU; Srivastava, Suresh C [Setauket, NY; Ermolaev, Stanislav V [Obninsk, RU; Togaeva, Natalia R [Obninsk, RU

    2012-01-17

    The invention provides a method of chemical recovery of no-carrier-added radioactive tin (NCA radiotin) from intermetallide TiSb irradiated with accelerated charged particles. An irradiated sample of TiSb can be dissolved in acidic solutions. Antimony can be removed from the solution by extraction with dibutyl ether. Titanium in the form of peroxide can be separated from tin using chromatography on strong anion-exchange resin. In another embodiment NCA radiotin can be separated from iodide solution containing titanium by extraction with benzene, toluene or chloroform. NCA radiotin can be finally purified from the remaining antimony and other impurities using chromatography on silica gel. NCA tin-117m can be obtained from this process. NCA tin-117m can be used for labeling organic compounds and biological objects to be applied in medicine for imaging and therapy of various diseases.

  14. Critical gravity on AdS2 spacetimes

    International Nuclear Information System (INIS)

    Myung, Yun Soo; Kim, Yong-Wan; Park, Young-Jai

    2011-01-01

    We study the critical gravity in two-dimensional anti-de Sitter (AdS 2 ) spacetimes, which was obtained from the cosmological topologically massive gravity (TMG Λ ) in three dimensions by using the Kaluza-Klein dimensional reduction. We perform the perturbation analysis around AdS 2 , which may correspond to the near-horizon geometry of the extremal Banados, Teitelboim, and Zanelli (BTZ) black hole obtained from the TMG Λ with identification upon uplifting three dimensions. A massive propagating scalar mode δF satisfies the second-order differential equation away from the critical point of K=l, whose solution is given by the Bessel functions. On the other hand, δF satisfies the fourth-order equation at the critical point. We exactly solve the fourth-order equation, and compare it with the log gravity in two dimensions. Consequently, the critical gravity in two dimensions could not be described by a massless scalar δF ml and its logarithmic partner δF log 4th .

  15. AdS pure spinor superstring in constant backgrounds

    Energy Technology Data Exchange (ETDEWEB)

    Chandia, Osvaldo [Departamento de Ciencias, Facultad de Artes Liberales, Universidad Adolfo Ibáñez,Facultad de Ingeniería y Ciencias, Universidad Adolfo Ibáñez,Diagonal Las Torres 2640, Peñalolén, Santiago (Chile); Bevilaqua, L. Ibiapina [Escola de Ciências e Tecnologia, Universidade Federal do Rio Grande do Norte,Caixa Postal 1524, 59072-970, Natal, RN (Brazil); Vallilo, Brenno Carlini [Facultad de Ciencias Exactas, Departamento de Ciencias Físicas, Universidad Andres Bello,Republica 220, Santiago (Chile)

    2014-06-05

    In this paper we study the pure spinor formulation of the superstring in AdS{sub 5}×S{sup 5} around point particle solutions of the classical equations of motion. As a particular example we quantize the pure spinor string in the BMN background.

  16. Crystal manyfold universes in /AdS space

    Science.gov (United States)

    Kaloper, N.

    2000-02-01

    We derive crystal braneworld solutions, comprising of intersecting families of parallel /n+2-branes in a /4+n-dimensional /AdS space. Each family consists of alternating positive and negative tension branes. In the simplest case of exactly orthogonal families, there arise different crystals with unbroken /4D Poincaré invariance on the intersections, where our world can reside. A crystal can be finite along some direction, either because that direction is compact, or because it ends on a segment of /AdS bulk, or infinite, where the branes continue forever. If the crystal is interlaced by connected /3-branes directed both along the intersections and orthogonal to them, it can be viewed as an example of a Manyfold universe proposed recently by Arkani-Hamed, Dimopoulos, Dvali and the author. There are new ways for generating hierarchies, since the bulk volume of the crystal and the lattice spacing affect the /4D Planck mass. The low energy physics is sensitive to the boundary conditions in the bulk, and has to satisfy the same constraints discussed in the Manyfold universe. Phenomenological considerations favor either finite crystals, or crystals which are infinite but have broken translational invariance in the bulk. The most distinctive signature of the bulk structure is that the bulk gravitons are Bloch waves, with a band spectrum, which we explicitly construct in the case of a /5-dimensional theory.

  17. The PredictAD project

    DEFF Research Database (Denmark)

    Antila, Kari; Lötjönen, Jyrki; Thurfjell, Lennart

    2013-01-01

    Alzheimer's disease (AD) is the most common cause of dementia affecting 36 million people worldwide. As the demographic transition in the developed countries progresses towards older population, the worsening ratio of workers per retirees and the growing number of patients with age-related illnes...... candidates and implement the framework in software. The results are currently used in several research projects, licensed to commercial use and being tested for clinical use in several trials....... objective of the PredictAD project was to find and integrate efficient biomarkers from heterogeneous patient data to make early diagnosis and to monitor the progress of AD in a more efficient, reliable and objective manner. The project focused on discovering biomarkers from biomolecular data...

  18. Facilities Management and Added Value

    DEFF Research Database (Denmark)

    Jensen, Per Anker

    2010-01-01

    Aim: This paper aims to present different models of the concept of the added value of Facilities Management (FM), including the FM Value Map, which forms the basis of research group in EuroFM, and to present some of the results of this research collaboration. Approach and methodology: The paper...... is based on literature reviews of the most influential journals within the academic fields of FM, Corporate Real Estate Management and Business to Business Marketing and discussions between participants of the research group working on a further exploration and testing of the FM Value Map. Conclusions......: The research shows a number of different definitions and focus points of Added Value of FM, dependent on the academic field and the area of application. The different research perspectives explored a holistic view on the added value of FM by the integration of an external market based view (with a focus...

  19. Smooth causal patches for AdS black holes

    Science.gov (United States)

    Raju, Suvrat

    2017-06-01

    We review the paradox of low energy excitations of a black hole in anti-de Sitter space (AdS). An appropriately chosen unitary operator in the boundary theory can create a locally strong excitation near the black hole horizon, whose global energy is small as a result of the gravitational redshift. The paradox is that this seems to violate a general rule of statistical mechanics, which states that an operator with energy parametrically smaller than k T cannot create a significant excitation in a thermal system. When we carefully examine the position dependence of the boundary unitary operator that produces the excitation and the bulk observable necessary to detect the anomalously large effect, we find that they do not both fit in a single causal patch. This follows from a remarkable property of position-space AdS correlators that we establish explicitly and resolves the paradox in a generic state of the system, since no combination of observers can both create the excitation and observe its effect. As a special case of our analysis, we show how this resolves the "Born rule" paradox of Marolf and Polchinski [J. High Energy Phys. 01 (2016) 008, 10.1007/JHEP01(2016)008] and we verify our solution using an independent calculation. We then consider boundary states that are finely tuned to display a spontaneous excitation outside the causal patch of the infalling observer, and we propose a version of causal patch complementarity in AdS/CFT that resolves the paradox for such states as well.

  20. Smart AD and DA Converters

    NARCIS (Netherlands)

    Roermund, van A.H.M.; Hegt, J.A.; Harpe, P.J.A.; Radulov, G.I.; Zanikopoulos, A.; Doris, K.; Quinn, P.J.

    2005-01-01

    In this paper, a concept is proposed to solve the problems related to the embedding of AD and DA converters in system-on-chips, FPGAs or other VLSI solutions. Problems like embedded testing, yield, reliability and reduced design space become crucial bottlenecks in the integration of high-performance

  1. agradecimento aos consultores ad hoc

    Directory of Open Access Journals (Sweden)

    REA Editor

    2012-02-01

    Full Text Available Agradecemos aos professores Nildo Viana (UFG e Flavio Sofiati (UFG, organizadores do DOSSIÊ JUVENTUDE & SOCIEDADE, e aos Consultores Ad hoc pela leitura e apreciação crítica dos artigos submetidos e publicados nesta edição.

  2. An investigation of AdS2 backreaction and holography

    International Nuclear Information System (INIS)

    Engelsöy, Julius; Mertens, Thomas G.; Verlinde, Herman

    2016-01-01

    We investigate a dilaton gravity model in AdS 2 proposed by Almheiri and Polchinski http://dx.doi.org/10.1007/JHEP11(2015)014 and develop a 1d effective description in terms of a dynamical boundary time with a Schwarzian derivative action. We show that the effective model is equivalent to a 1d version of Liouville theory, and investigate its dynamics and symmetries via a standard canonical framework. We include the coupling to arbitrary conformal matter and analyze the effective action in the presence of possible sources. We compute commutators of local operators at large time separation, and match the result with the time shift due to a gravitational shockwave interaction. We study a black hole evaporation process and comment on the role of entropy in this model.

  3. Chiral gauge theory on AdS domain wall

    International Nuclear Information System (INIS)

    Shirman, Yuri

    2005-01-01

    We describe a realization of chiral gauge theories based on the domaim wall fermion construction implemented on an interval in five dimensional AdS spacetime. At semi-classical level deconstructed description of the theory is given in terms of 4-dimensional Minkowski slices supporting chiral zero modes at the ends. Energy scales warp down along the fifth dimension. When the theory is augmented by 4-dimensional neutral Majorana spinors together with the Higgs mechanism at the low energy end, we can arrange for a theory where the lightest gauge boson mode as well as chiral zero mode at the high energy end are parametrically lighter than other states. Triangle anomalies and instanton effects are expected to make gauge bosons heavy if the resulting effective theory i