Science.gov

Sample records for 177lu 51cr 153sm

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

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

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

    NASA Astrophysics Data System (ADS)

    Ranjbar, Hassan; Ghannadi-Maragheh, Mohammad; Bahrami-Samani, Ali; Beiki, Davood

    2015-03-01

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

  3. Rhabdoid papillary meningioma treated with 177Lu DOTATATE PRRT.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-03-01

    An 18-year-old girl presented with a 3-year history of a recurrent skull base mass confirmed to be a rhabdoid papillary meningioma. The tumor was octreotide avid and metastatic to the lungs, thoracic lymph nodes, and bones, and she was referred for PRRT (peptide receptor radionuclide therapy) with 177Lu DOTATATE. After 3 induction treatment cycles of 177Lu DOTATATE, she experienced significant improvements in her symptoms; however, just before the fourth treatment, she developed cervical spinal cord compression and passed away shortly thereafter. The use of 177Lu DOTATATE therapy in the management of rhabdoid papillary meningioma warrants further research. PMID:25608146

  4. Prospects of medium specific activity (177) Lu in targeted therapy of prostate cancer using (177) Lu-labeled PSMA inhibitor.

    PubMed

    Chakraborty, Sudipta; Chakravarty, Rubel; Shetty, Priyalata; Vimalnath, K V; Sen, Ishita B; Dash, Ashutosh

    2016-07-01

    Targeted radionuclide therapy using (177) Lu-labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA-617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of (177) Lu-PSMA-617 at hospital radiopharmacy using moderate specific activity (177) Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA-617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of (177) Lu-PSMA-617. Based on these, 7.4 GBq therapeutic dose of (177) Lu-PSMA-617 was formulated by incubating 160 µg of PSMA-617 with indigenously produced (177) LuCl3 (555 GBq/µg specific activity of (177) Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% (n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic (68) Ga-PSMA-11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of (177) Lu-PSMA-617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity (177) Lu at an affordable cost. PMID:27264278

  5. Method for preparing high specific activity 177Lu

    SciTech Connect

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

    2004-04-06

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

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

    PubMed Central

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

    2013-01-01

    The biodistribution of the anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab (177Lu-DOTA-HH1) was evaluated. Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-tetraxetan-rituximab and free 177Lu in nude mice implanted with Daudi lymphoma xenografts. The data showed that 177Lu-tetulomab had a relevant stability and tumor targeting properties in the human lymphoma model. The half-life of 177Lu allowed significant tumor to normal tissue ratios to be obtained indicating that 177Lu-tetraxetan-tetulomab could be suitable for clinical testing. The biological and effective half-life in blood was higher for 177Lu-tetraxetan-tetulomab than for 177Lu-tetraxetan-rituximab. The biodistribution of 177Lu-tetraxetan-tetulomab did not change significantly when the protein dose was varied from 0.01 to 1 mg/kg. Dosimetry calculations showed that the absorbed radiation doses to normal tissues and tumor in mice were not significantly different for 177Lu-tetraxetan-tetuloma b and 177Lu-tetraxetan-rituximab. The absorbed radiation doses were extrapolated to human absorbed radiation doses. These extrapolated absorbed radiation doses to normal tissues for 177Lu-tetraxetan-tetulomab at an injection of 40 MBq/kg were significantly lower than the absorbed radiation doses for 15 MBq/kg Zevalin, suggesting that higher tumor radiation dose can be reached with 177Lu-tetraxetan-tetulomab in the clinic. PMID:23256748

  7. Consequences of meta-stable (177m)Lu admixture in (177)Lu for patient dosimetry.

    PubMed

    Konijnenberg, Mark W

    2015-01-01

    Lutetium-177 ((177)Lu) is a rare earth metal in the lanthanides series which decays by beta emission with a half life of 6.647 days to three excited states and the ground state of (177)Hf. When (177)Lu is produced by neutron capture in (176)Lu, inevitably an admixture is formed of the long-lived isomer (177)mLu. As its half-life of 160.4 days is so much longer than that of (177)Lu, concerns are raised on its possible enhancement in radiation dose to the patient treated with (177)Lu-DOTA-octreotate. This report evaluates this possible enhancement of the absorbed dose, based on the published pharmacokinetic profile of (177)Lu-DOTA-octreotate and assuming an admixture of 1 kBq (177)mLu /MBq (177)Lu (0.1%). PMID:25771362

  8. Optimization of irradiation conditions for {sup 177}Lu production at the LVR-15 research reactor

    SciTech Connect

    Lahodova, Z.; Viererbl, L.; Klupak, V.; Srank, J.

    2012-07-01

    The use of lutetium in medicine has been increasing over the last few years. The {sup 177}Lu radionuclide is commercially available for research and test purposes as a diagnostic and radiotherapy agent in the treatment of several malignant tumours. The yield of {sup 177}Lu from the {sup 176}Lu(n,{gamma}){sup 177}Lu nuclear reaction depends significantly on the thermal neutron fluence rate. The capture cross-sections of both reaction {sup 176}Lu(n,{gamma}){sup 177}Lu and reaction {sup 177}Lu(n,{gamma}){sup 178}Lu are very high. Therefore a burn-up of target and product nuclides should be taken into account when calculating {sup 177}Lu activity. The maximum irradiation time, when the activity of the {sup 177}Lu radionuclide begins to decline, was found for different fluence rates. Two vertical irradiation channels at the LVR-15 nuclear research reactor were compared in order to choose the channel with better irradiation conditions, such as a higher thermal neutron fluence rate in the irradiation volume. In this experiment, lutetium was irradiated in a titanium capsule. The influence of the Ti capsule on the neutron spectrum was monitored using activation detectors. The choice of detectors was based on requirements for irradiation time and accurate determination of thermal neutrons. The following activation detectors were selected for measurement of the neutron spectrum: Ti, Fe, Ni, Co, Ag and W. (authors)

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

  10. Thermal neutron capture cross section for the K isomer {sup 177}Lu{sup m}

    SciTech Connect

    Belier, G.; Roig, O.; Daugas, J.-M.; Giarmana, O.; Meot, V.; Letourneau, A.; Marie, F.; Foucher, Y.; Aupiais, J.; Abt, D.; Jutier, Ch.; Le Petit, G.; Bettoni, C.; Gaudry, A.; Veyssiere, Ch.; Barat, E.; Dautremer, T.; Trama, J.-Ch.

    2006-01-15

    The thermal neutron radiative capture cross section for the K isomeric state in {sup 177}Lu has been measured for the first time. Several {sup 177}Lu{sup m} targets have been prepared and irradiated in various neutron fluxes at the Lauee Langevin Institute in Grenoble and at the CEA reactors OSIRIS and ORPHEE in Saclay. The method consists of measuring the {sup 178}Lu activity by {gamma}-ray spectroscopy. The values obtained in four different neutron spectra have been used to calculate the resonance integral of the radiative capture cross section for {sup 177}Lu{sup m}. In addition, an indirect method leads to the determination of the {sup 177}Lu{sup g} neutron radiative capture cross section.

  11. Tumoral fibrosis effect on the radiation absorbed dose of (177)Lu-Tyr(3)-octreotate and (177)Lu-Tyr(3)-octreotate conjugated to gold nanoparticles.

    PubMed

    Azorín-Vega, E P; Zambrano-Ramírez, O D; Rojas-Calderón, E L; Ocampo-García, B E; Ferro-Flores, G

    2015-06-01

    The aim of this work was to evaluate the tumoral fibrosis effect on the radiation absorbed dose of the radiopharmaceuticals (177)Lu-Tyr(3)-octreotate (monomeric) and (177)Lu-Tyr(3)-octreotate-gold nanoparticles (multimeric) using an experimental HeLa cells tumoral model and the Monte Carlo PENELOPE code. Experimental and computer micro-environment models with or without fibrosis were constructed. Results showed that fibrosis increases up to 33% the tumor radiation absorbed dose, although the major effect on the dose was produced by the type of radiopharmaceutical (112Gy-multimeric vs. 43Gy-monomeric). PMID:25305748

  12. A potencial theranostic agent for EGF-R expression tumors: (177)Lu-DOTA-nimotuzumab.

    PubMed

    Calzada, Victoria; Zhang, Xiuli; Fernandez, Marcelo; Diaz-Miqueli, Arlhee; Iznaga-Escobar, Normando; Deutscher, Susan L; Balter, Henia; Quinn, Thomas P; Cabral, Pablo

    2012-10-01

    In this work Nimotuzumab (monoclonal antibody, recognizes the EGF-R) was radiolabeled with (177)Lu as a potential cancer therapy radiopharmaceutical. In-vitro cell binding studies and in-vivo biodistribution and imaging studies were performed to determine the radiochemical stability, targeting specificity and pharmacokinetics of the (177)Lu-labeled antibody. Nimotuzumab was derivatized with DOTA-NHS at room temperature for 2 hours. DOTA-Nimotuzumab was radiolabeled with (177)LuCl3 (15 MBq/mg) at 37°C for 1 h. The radiochemical purity was assessed by ITLC, silica gel and by RP-HPLC. Binding specificity studies were performed with EGF-R positive A431 human epithelial carcinoma and EGF-R negative MDA-MB-435 breast carcinoma cells. Biodistribution studies were performed in healthy female CD-1 mice at 1 h, 4 h, 24 h, and A431 xenografted nude mice at 10 min, 1 h, 4 h, 24 h, 48 h, and 96 h. SPECT-CT imaging studies were performed in A431 xenografted mice at 24 h post injection. DOTA-Nimotuzumab was efficiently labeled with (177) LuCl(3) at 37°C. The in vitro stability of labeled product was optimal over 24 h in buffered saline and mouse serum. Specific recognition of EGF-R by (177)Lu-DOTA-Nimotuzumab was observed in A431 cell binding studies. Biodistribution studies demonstrated increasing tumor uptake of (177)Lu-DOTA-Nimotuzumab over time, with tumor to muscle ratios of 6.26, 10.68, and 18.82 at 4 h, 24 h, and 96 h post injection. Imaging of A431 xenografted mice showed high uptake in the tumor. (177)Lu-DOTA-Nimotuzumab has the potential to be a promising therapy agent, which may be useful in the treatment of patients with EGF-R positive cancer. PMID:22280117

  13. Theranostic Radiopharmaceuticals Based on Gold Nanoparticles Labeled with (177)Lu and Conjugated to Peptides.

    PubMed

    Ferro-Flores, Guillermina; Ocampo-García, Blanca E; Santos-Cuevas, Clara L; de María Ramírez, Flor; Azorín-Vega, Erika P; Meléndez-Alafort, Laura

    2015-01-01

    Gold nanoparticles (AuNPs) have been proposed for a variety of medical applications such as localized heat sources for cancer treatment and drug delivery systems. The conjugation of peptides to AuNPs produces stable multimeric systems with target-specific molecular recognition. Lutetium- 177 ((177)Lu) has been successfully used in peptide radionuclide therapy. Recently, (177)Lu-AuNPs conjugated to different peptides have been proposed as a new class of theranostic radiopharmaceuticals. These radioconjugates may function simultaneously as molecular imaging agents, radiotherapy systems and thermal-ablation systems. This article covers advancements in the design, synthesis, physicochemical characterization, molecular recognition assessment and preclinical therapeutic efficacy of gold nanoparticles radiolabeled with (177)Lu and conjugated to RGD (-Arg-Gly-Asp-), Lys(3)-Bombesin and Tat(49-57) peptides. PMID:25771363

  14. (177) Lu-5-Fluorouracil a potential theranostic radiopharmaceutical: radiosynthesis, quality control, biodistribution, and scintigraphy.

    PubMed

    Rasheed, Rashid; Tariq, Saleha; Naqvi, Syed Ali Raza; Gillani, Syed Jawad Hussain; Rizvi, Faheem Askari; Sajid, Muhammad; Rasheed, Shahid

    2016-08-01

    The aim of this study is to develop (177) Lu-5-Flourouracil as a potential cancer therapeutic radiopharmaceutical. 5-Flourouracil (5-FU) is widely accepted as an anticancer drug of broad spectrum fame. The labeling of 5-FU was carried out at different set of experimental conditions using high specific activity of (177) LuCl3 . The optimum conditions for maximum radiochemical yield was set: 5-FU (5 mg), (177) LuCl3 (185 MBq), diethylenetriaminepentaacetic acid (10 µg), reaction volume (2 mL), pH (5.5), temperature (80°C), and reaction time (20 min). The radiochemical labeling was assessed with Whatman No. 2 paper, instant thin layer chromatographic, and radio-HPLC, which revealed >94% labeling results with sufficient stability up to 6 h. Serum stability study also showed (177) Lu-5-FU promising stability. Biodistribution study in normal rats and rabbits showed liver, stomach, kidney, and heart as area of increased tracer accumulation just after injection, which decreased to 1.4%, 0.4%, 0.2%, and 0.39% ID/g, respectively, after 72 h. Glomerular filtration rate and cytotoxicity study results of (177) Lu-5-FU showed it had no adverse effect on renal function and nontoxic to blood cells. The promising characteristics of (177) Lu-5-FU, that is, clever elimination from kidney and nontoxic nature toward blood cells make it the radiopharmaceutical for further testing in patients for therapeutic purposes. PMID:27444959

  15. Predicting the yield of (177)Lu radionuclide produced by the cyclic irradiation technique.

    PubMed

    Odame Duodu, Godfred; Akaho, Edward H K; Serfor-Armah, Yaw; Nyarko, Benjamin J B; Afi Achoribo, Elom

    2011-03-01

    The feasibility study on the production of (177)Lu radioisotope using a low power research reactor has been conducted. A reliable method for predicting the yield of (177)Lu produced using the cyclic activation technique based on the Westcott formalism has been established. A specific activity of 243.24 mCi/g was obtained when a (176)Lu(2)O(3) of natural abundance was irradiated for 4 h and decayed for 20 h for four cycles at GHARR-1 with a neutron flux of 5.0×10(11) ncm(-2)s(-1). PMID:21177113

  16. Esthesioneuroblastoma (olfactory neuroblastoma) treated with 111In-octreotide and 177Lu-DOTATATE PRRT.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-04-01

    A 51-year-old man with a recurrent metastatic esthesioneuroblastoma (olfactory neuroblastoma) was referred for peptide receptor radionuclide therapy (PRRT). He received 4 treatments of 111In-octreotide over 8 months and 3 treatments of 177Lu-DOTATATE over 4 months, which helped alleviate his symptoms and improved his quality of life; however, the tumor ultimately progressed and he passed away shortly thereafter. PRRT with 111In-octreotide or 177Lu-DOTATATE could play a role in the management of esthesioneuroblastoma. PMID:25674857

  17. Extraventricular neurocytoma treated with 177Lu DOTATATE PRRT induction and maintenance therapies.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-03-01

    A 64-year-old woman with a 30-year history of recurrent sellar masses presented with severe headache and rapidly progressive visual field loss in the left eye. She was diagnosed with an extraventricular neurocytoma, which was octreotide positive, and was referred for PRRT (peptide receptor radionuclide therapy) with 177Lu [DOTA0,Tyr3]octreotate (DOTATATE). After 4 induction and 4 maintenance treatment cycles, her headaches resolved, her vision improved, and her sellar mass stabilized. The use of 177Lu DOTATATE PRRT in the management of extraventricular neurocytoma warrants further research. PMID:25608145

  18. Single vial kit formulation of DOTATATE for preparation of (177) Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy.

    PubMed

    Mukherjee, Archana; Lohar, Sharad; Dash, Ashutosh; Sarma, Haladhar Dev; Samuel, Grace; Korde, Aruna

    2015-04-01

    The clinical applications of radiolabeled somatostatin analogue (177) Lu-DOTA-Tyr(3) -Thr(8) -Octreotide ((177) Lu-DOTATATE) constitute a promising treatment option for patients with disseminated and inoperable neuroendocrine (NET) tumors. Formulation of (177) Lu-DOTATATE in hospital radiopharmacy under aseptic conditions in a safe and reliable manner is a major constraint for its extensive use. The present work was intended to develop a kit for the safe preparation of the therapeutic radiopharmaceutical, viz. (177) Lu-DOTATATE of high quality that can be easily adapted at conventional hospital radiopharmacies. Single vial kits of DOTATATE were formulated and evaluated for suitability for radiolabeling as well as stability on its storage. Patient dose of (177) Lu-DOTATATE (7.4 GBq) could be successfully prepared using semi-automated in-house setup that assures safe handling and high yields of product of pharmaceutical purity suitable for clinical use. Fast clearance of activity via renal route was observed in preclinical biodistribution studies of (177) Lu-DOTATATE carried out in normal Swiss mice. Deployment of in-house produced (177) LuCl3 , cold kits and easy adaptability of synthesis setup at hospital radiopharmacy for preparation is likely to expand applications of peptide receptor radionuclide therapy. PMID:25765604

  19. Reducing renal uptake of 90Y- and 177Lu-labeled alpha-melanocyte stimulating hormone peptide analogues

    SciTech Connect

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

    2006-06-15

    The purpose of this study was to improve the tumor-to-kidney uptake ratios of 90Y- and 177Lu-[1,2,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Re-Cys,D-Phe,Arg]alpha-melanocyte stimulating hormone (DOTA-RE(Arg)CCMSH), through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. A new peptide of DOTA-Re(Glu,Arg)CCMSH was designed, synthesized and labeled with 90Y and 177Lu. Pharmacokinetics of 90Y- and 177Lu-DOTA-RE(Glu,Arg)CCNSH were determined in B16/F1 murine melanoma-bearing C57 mice. Both exhibited significantly less renal uptake than 90Y- and 177Lu-DOTA-Re(Arg)CCMSH at 30 min and at 2, 3, and 24 h after dose administration. The renal uptake values of 90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH were 28.16% and 28.81% of those of 90Y- and 177Lu-DOTA-RE(Arg)CCMSH, respectively, at 4 hr post-injection. We also showed higher tumor-to-kidney uptake ratios 2.28 and 1.69 times that of 90Y- and 177Lu-DOTA-Re(Arg)CCMSH, respectively, at 4 h post-injection. The90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH activity accumulation was low in normal organs except for kidneys. 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 90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma.

  20. Direct evidence for inelastic neutron 'acceleration' by {sup 177}Lu{sup m}

    SciTech Connect

    Roig, O.; Meot, V.; Rosse, B.; Belier, G.; Daugas, J.-M.; Morel, P.; Letourneau, A.; Menelle, A.

    2011-06-15

    The inelastic neutron acceleration cross section on the long-lived metastable state of {sup 177}Lu has been measured using a direct method. High-energy neutrons have been detected using a specially designed setup placed on a cold neutron beam extracted from the ORPHEE reactor in Saclay. The 146{+-}19 b inelastic neutron acceleration cross section in the ORPHEE cold neutron flux confirms the high cross section for this process on the {sup 177}Lu{sup m} isomer. The deviation from the 258{+-}58 b previously published obtained for a Maxwellian neutron flux at a 323 K temperature could be explained by the presence of a low energy resonance. Resonance parameters are deduced and discussed.

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

    PubMed

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

    2016-04-11

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

  2. [177Lu-PSMA-617 therapy, dosimetry and follow-up in patients with metastatic castration-resistant prostate cancer].

    PubMed

    Fendler, Wolfgang P; Kratochwil, Clemens; Ahmadzadehfar, Hojjat; Rahbar, Kambiz; Baum, Richard P; Schmidt, Matthias; Pfestroff, Andreas; Lützen, Ulf; Prasad, Vikas; Heinzel, Alexander; Heuschkel, Martin; Ruf, Juri; Bartenstein, Peter; Krause, Bernd J

    2016-06-28

    Radioligand therapy (RLT) using 177Lu labelled inhibitors of the prostate-specific membrane antigen (177Lu-PSMA) is performed in patients with metastatic castration-resistant prostate cancer (mCRPC) after exhaustion of other options. German University Clinics offer RLT since 2013 on a compassionate use basis. The present consensus document includes recommendations for RLT with 177Lu-PSMA-617. These consensus statements were developed by an expert panel formed by the German Society of Nuclear Medicine (DGN) in December 2015. Statements include recommendations for indication, baseline tests, therapy protocol, concomitant therapy, dosimetry, and follow-up. Consensus recommendations aim to inform the attending medical staff, standardize 177Lu-PSMA-617 RLT, and improve quality of individual patient care. PMID:27350005

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

    NASA Astrophysics Data System (ADS)

    Wang, Hsin-Ell; Yu, Hung-Man; Lu, Yi-Ching; Heish, Ning-Ning; Tseng, Yun-Long; Huang, Kuang-Liang; Chuang, Kuo-Tang; Chen, Chin-Hsiung; Hwang, Jeng-Jong; Lin, Wuu-Jyh; Wang, Shyh-Jen; Ting, Gann; Whang-Peng, Jacqueline; Deng, Win-Ping

    2006-12-01

    In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. MethodsThe DTPA/PEG-liposomes were synthesized with a medium size of 110 nm, conjugated with 111In/ 177Lu-(oxine) 3 to afford 111In/ 177Lu-liposome. The stability of 111In/ 177Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of 111In/ 177Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. ResultsThe incorporation efficiency of 111In/ 177Lu into liposomes was 95%. After incubation at 37 °C for 72 h in serum, more than 83% of radioactivity was still retained in the intact 111In/ 177Lu-liposomes. The biodistribution of 111In-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 177Lu-liposomes. Scintigraphic imaging with 111In-liposomes showed unambiguous tumor images at 48 h p.i. Dose estimation showed that the absorbed dose in tumor from 177Lu-liposomes was 5.74×10 -5 Gy/MBq. ConclusionsThis 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.

  4. (177)Lu-Labeled Cerasomes Encapsulating Indocyanine Green for Cancer Theranostics.

    PubMed

    Jing, Lijia; Shi, Jiyun; Fan, Di; Li, Yaqian; Liu, Renfa; Dai, Zhifei; Wang, Fan; Tian, Jie

    2015-10-01

    This Article reported the fabrication of a robust theranostic cerasome encapsulating indocyanine green (ICG) by incorporating 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DSPE-PEG2000-DOTA), followed by chelating radioisotope of (177)Lu. Its applications in optical and nuclear imaging of tumor uptake and biodistribution, as well as photothermal killing of cancer cells, were investigated. It was found that the obtained cerasome could act efficiently as fluorescence contrast agent as well as nuclear imaging tracer. Encapsulating ICG into cerasome could protect ICG from degradation, aggregation, and fast elimination from body, resulting in remarkable improvement in near-infrared fluorescence imaging, photothermal stability, and in vivo pharmacokinetic profile. Both fluorescence and nuclear imaging showed that such agent could selectively accumulate in tumor site after intravenous injection of the cerasome agent into Lewis lung carcinoma tumor bearing mice, resulting in efficient photothermal ablation of tumor through a one-time NIR laser irradiation at the best time window. The ability to track the uptake of cerasomes on a whole body basis could provide researchers with an excellent tool for developing cerasome-based drug delivery agents, especially the strategy of labeling cerasomes with theranostic radionuclide (177)Lu, enabling the ability of the (177)Lu-labeled cerasomes for radionuclide cancer therapy and even the combined therapy. PMID:26398723

  5. Specific radioactivity of neutron induced radioisotopes: assessment methods and application for medically useful 177Lu production as a case.

    PubMed

    Le, Van So

    2011-01-01

    The conventional reaction yield evaluation for radioisotope production is not sufficient to set up the optimal conditions for producing radionuclide products of the desired radiochemical quality. Alternatively, the specific radioactivity (SA) assessment, dealing with the relationship between the affecting factors and the inherent properties of the target and impurities, offers a way to optimally perform the irradiation for production of the best quality radioisotopes for various applications, especially for targeting radiopharmaceutical preparation. Neutron-capture characteristics, target impurity, side nuclear reactions, target burn-up and post-irradiation processing/cooling time are the main parameters affecting the SA of the radioisotope product. These parameters have been incorporated into the format of mathematical equations for the reaction yield and SA assessment. As a method demonstration, the SA assessment of 177Lu produced based on two different reactions, 176Lu (n,γ)177Lu and 176Yb (n,γ) 177Yb (β- decay) 177Lu, were performed. The irradiation time required for achieving a maximum yield and maximum SA value was evaluated for production based on the 176Lu (n,γ)177Lu reaction. The effect of several factors (such as elemental Lu and isotopic impurities) on the 177Lu SA degradation was evaluated for production based on the 176Yb (n,γ) 177Yb (β- decay) 177Lu reaction. The method of SA assessment of a mixture of several radioactive sources was developed for the radioisotope produced in a reactor from different targets. PMID:21248665

  6. Production, biodistribution assessment and dosimetric evaluation of 177Lu-TTHMP as an agent for bone pain palliation

    PubMed Central

    Zolghadri, Samaneh; Yousefnia, Hassan; Jalilian, Amir Reza; Ghannadi-Maragheh, Mohammad

    2015-01-01

    Objective(s): Recently, bone-avid radiopharmaceuticals have been shown to have potential benefits for the treatment of widespread bone metastases. Although 177Lu-triethylene tetramine hexa methylene phosphonic acid (abbreviated as 177Lu-TTHMP), as an agent for bone pain palliation, has been evaluated in previous studies, there are large discrepancies between the obtained results. In this study, production, quality control, biodistribution, and dose evaluation of 177Lu-TTHMP have been investigated and compared with the previously reported data. Methods: TTHMP was synthesized and characterized, using spectroscopic methods. Radiochemical purity of the 177Lu-TTHMP complex was determined using instant thin-layer chromatography (ITLC) and high performance liquid chromatography (HPLC) methods. The complex was injected to wild-type rats and biodistribution was studied for 7 days. Preliminary dose evaluation was investigated based on biodistribution data in rats. Results: 177Lu was prepared with 2.6-3 GBq/mg specific activity and radionuclide purity of 99.98%. 177Lu-TTHMP was successfully prepared with high radiochemical purity (>99%). The complex showed rapid bone uptake, while accumulation in other organs was insignificant. Dosimetric results showed that all tissues received almost insignificant absorbed doses in comparison with bone tissues. Conclusion: Based on the obtained results, this radiopharmaceutical can be a good candidate for bone pain palliation therapy in skeletal metastases.

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

    PubMed Central

    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

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

    PubMed

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

    2016-06-01

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

  9. 177Lu-labeled HPMA Copolymers Utilizing Cathepsin B and S Cleavable Linkers: Synthesis, Characterization and Preliminary In Vivo Investigation in a Pancreatic Cancer Model

    PubMed Central

    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 177Lu, the peptide-polymer conjugates were renamed 177Lu- metabolically active copolymers (177Lu-MACs) with the corresponding designation 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. Results In vivo evaluation of the 177Lu-MACs was performed in a HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72 h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72 h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. Conclusions While further studies are needed to optimize the pharmacokinetics of the 177Lu

  10. 177Lu-DOTA-HH1, a Novel Anti-CD37 Radio-Immunoconjugate: A Study of Toxicity in Nude Mice

    PubMed Central

    Repetto-Llamazares, Ada H. V.; Larsen, Roy H.; Giusti, Anna Maria; Riccardi, Elena; Bruland, Øyvind S.; Selbo, Pål Kristian; Dahle, Jostein

    2014-01-01

    Background 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 studieswith 177Lu-HH1. Methodology/Principal Findings 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. Conclusions/Significance 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. PMID:25068508

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

    DOE PAGESBeta

    Frost, Sofia H. L.; Frayo, Shani L.; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark D.; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; et al

    2015-03-18

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Lagerburg, Vera; Klausen, Thomas L.; Holm, Søren

    2014-01-01

    Purpose Patient-specific dosimetry of lutetium-177 (177Lu)-DOTATATE treatment in neuroendocrine tumours is important, because uptake differs across patients. Single photon emission computer tomography (SPECT)-based dosimetry requires a conversion factor between the obtained counts and the activity, which depends on the collimator type, the utilized energy windows and the applied scatter correction techniques. In this study, energy window subtraction-based scatter correction methods are compared experimentally and quantitatively. Materials and methods 177Lu SPECT images of a phantom with known activity concentration ratio between the uniform background and filled hollow spheres were acquired for three different collimators: low-energy high resolution (LEHR), low-energy general purpose (LEGP) and medium-energy general purpose (MEGP). Counts were collected in several energy windows, and scatter correction was performed by applying different methods such as effective scatter source estimation (ESSE), triple-energy and dual-energy window, double-photopeak window and downscatter correction. The intensity ratio between the spheres and the background was measured and corrected for the partial volume effect and used to compare the performance of the methods. Results Low-energy collimators combined with 208 keV energy windows give rise to artefacts. For the 113 keV energy window, large differences were observed in the ratios for the spheres. For MEGP collimators with the ESSE correction technique, the measured ratio was close to the real ratio, and the differences between spheres were small. Conclusion For quantitative 177Lu imaging MEGP collimators are advised. Both energy peaks can be utilized when the ESSE correction technique is applied. The difference between the calculated and the real ratio is less than 10% for both energy windows. PMID:24525900

  14. (90) Y/(177) Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation.

    PubMed

    Chakravarty, Rubel; Chakraborty, Sudipta; Sarma, Haladhar Dev; Nair, K V Vimalnath; Rajeswari, Ardhi; Dash, Ashutosh

    2016-07-01

    Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation. PMID:27264196

  15. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F.; Ramogida, Caterina F.; Ramos, Nicholas

    2013-01-01

    A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCNBn- H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator DOTA. The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C ~50–88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapatrastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. PMID:23901833

  16. Development of (177)Lu-DOTA-Dendrimer and Determination of Its Effect on Metal and Ion Levels in Tumor Tissue.

    PubMed

    Kovacs, Luciana; Tassano, Marcos; Cabrera, Mirel; Zamboni, Cibele B; Fernández, Marcelo; Anjos, Roberto M; Cabral, Pablo

    2015-12-01

    Dendrimers are synthetic nanomolecules with well-defined chemical structures. Different strategies have been used for radiolabeling dendrimers with different radioisotopes. In this study, the aim was to conjugate dendrimers with (177)Lu, to observe the in vivo behavior of the labeled compound and to measure the elementary changes in tumor tissue that could be caused by ionizing radiation. PAMAM G4 dendrimers conjugated with DOTA were labeled with (177)Lu. The radiolabeled compound was characterized and its stability was evaluated by reverse phase high performance liquid chromatography. Radiolabeling yield was >98% and stable for 24 hours. Biodistribution studies of (177)Lu-DOTA-dendrimers in C57BL/6 melanoma-bearing mice showed blood clearance with hepatic and renal depuration and tumor uptake. The concentrations of Br, Ca, Cl, Fe, K, Mg, Na, Rb, S, and Zn were determined in tumor tissues of C57BL/6 mice treated with (177)Lu-DOTA-dendrimers and in untreated mice. The results showed decreased concentrations of Br (62%), Ca (24%), Cl (51%), K (12%) and Na (60%) and increased concentrations of Fe (8%), Mg (28%), Rb (100%), S (6%) and Zn (4%) in tumor tissues of mice treated with (177)Lu-DOTA-dendrimers. These data may be useful to evaluate changes in tumor tissues as indicators of damage that could be caused by ionizing radiation. PMID:26625257

  17. Evaluation of (177)Lu-CHX-A''-DTPA-Bevacizumab as a radioimmunotherapy agent targeting VEGF expressing cancers.

    PubMed

    Kameswaran, Mythili; Pandey, Usha; Gamre, Naresh; Vimalnath, K V; Sarma, Haladhar Dev; Dash, Ashutosh

    2016-08-01

    This study aimed at the preparation and evaluation of (177)Lu-CHX-A''-DTPA-Bevacizumab for targeting VEGF over-expressing cancers. Bevacizumab conjugated to p-NCS-Bn-CHX-A''-DTPA was radiolabeled with (177)Lu. The radioimmunoconjugate characterized by SE-HPLC exhibited radiochemical purity of 98.0±0.6%. In vitro stability was retained upto 4 days at 37°C. In vitro cell binding studies showed good uptake by VEGF expressing U937 tumor cells. Biodistribution studies in melanoma model showed significant uptake and retention of (177)Lu-CHX-A''-DTPA-Bevacizumab in tumor with reduction in uptake in presence of cold Bevacizumab confirming its specificity to VEGF. PMID:27258216

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

    SciTech Connect

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

    2015-03-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

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

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

    PubMed

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

    2015-11-01

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

  1. Complete Resolution of Neuroendocrine Tumor Soft Tissue Metastases After 177Lu DOTATATE PRRT Induction and Maintenance Therapy.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-08-01

    A 60-year-old woman diagnosed with a well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes was treated with 4 induction cycles and 2 maintenance cycles of (177)Lu [DOTA,(0)Tyr(3)]octreotate (DOTATATE) peptide receptor radionuclide therapy. Her posttreatment imaging showed partial response after 4 induction cycles and complete response after 2 additional maintenance cycles. This case highlights the need for further research into maintenance (177)Lu DOTATATE therapy to improve outcomes in neuroendocrine tumor patients. PMID:25546219

  2. Therapeutic efficacy of 177Lu-CHX-A″-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy

    PubMed Central

    Kelly, Marcus P; Lee, Sze Ting; Lee, F-T; Smyth, Fiona E; Davis, Ian D.; Brechbiel, Martin W; Scott, Andrew M

    2008-01-01

    Background This study investigated the biodistribution and therapeutic efficacy of Lutetium-177 (177Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo. Methods The in vitro cytotoxicity of 177Lu labeled hu3S193 on Ley positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo. Results 177Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 ± 3.9 %ID/g observed at 120 hr post injection. In RIT studies, 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350μCi was determined for 177Lu-hu3S193. Combination of 177Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy. Conclusions 177Lu-hu3S193 RIT is effective as a single agent in the treatment of Ley positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies. PMID:18942092

  3. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice

    PubMed Central

    Schüler, Emil; Larsson, Maria; Parris, Toshima Z.; Johansson, Martin E.; Helou, Khalil; Forssell-Aronsson, Eva

    2015-01-01

    The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity. Methods C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy. Results In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months. Conclusion Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm

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

    PubMed

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

    2016-06-01

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

  5. 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

    NASA Astrophysics Data System (ADS)

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

    2012-07-01

    Clinical trials on 177Lu-90Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace 90Y. 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 93Y, 90Y and 125Sn in combination with 177Lu 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 177Lu and 90Y activity. However, 125Sn-177Lu 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. 125Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics 125Sn is the best RN for combination with 177Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of 125Sn-labelled somatostatin analogues.

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

    PubMed

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

    2016-06-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. Radiation Nanomedicine for EGFR-Positive Breast Cancer: Panitumumab-Modified Gold Nanoparticles Complexed to the β-Particle-Emitter, (177)Lu.

    PubMed

    Yook, Simmyung; Cai, Zhongli; Lu, Yijie; Winnik, Mitchell A; Pignol, Jean-Philippe; Reilly, Raymond M

    2015-11-01

    Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triple-negative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-emitter, (177)Lu and with PEG chains (5 kDa) linked to panitumumab for targeting BC cells expressing EGFR. The AuNP were further coated with PEG chains (2 kDa) to stabilize the particles to aggregation. The binding and internalization of EGFR-targeted AuNP ((177)Lu-T-AuNP) into BC cells was studied and compared to nontargeted (177)Lu-NT-AuNP. The cytotoxicity of (177)Lu-T-AuNP and (177)Lu-NT-AuNP was measured in clonogenic assays using BC cells with widely different EGFR densities: MDA-MB-468 (10(6) receptors/cell), MDA-MB-231 (10(5) receptors/cell), and MCF-7 cells (10(4) receptors/cell). Radiation absorbed doses to the cell nucleus of MDA-MB-468 cells were estimated based on subcellular distribution. Darkfield and fluorescence microscopy as well as radioligand binding assays revealed that (177)Lu-T-AuNP were specifically bound by BC cells dependent on their EGFR density whereas the binding and internalization of (177)Lu-NT-AuNP was significantly lower. The affinity of binding of (177)Lu-T-AuNP to MDA-MB-468 cells was reduced by 2-fold compared to (123)I-labeled panitumumab (KD = 1.3 ± 0.2 nM vs 0.7 ± 0.4 nM, respectively). The cytotoxicity of (177)Lu-T-AuNP was dependent on the amount of radioactivity incubated with BC cells, their EGFR density and the radiosensitivity of the cells. The clonogenic survival (CS) of MDA-MB-468 cells overexpressing EGFR was reduced to <0.001% at the highest amount of (177)Lu-T-AuNP tested (4.5 MBq; 6 × 10(11) AuNP per 2.5 × 10(4)-1.2 × 10(5) cells). (177)Lu-T-AuNP were less effective for killing MDA-MB-231 cells or MCF-7 cells with

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

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Zhao, Xiao-Guang; Bigner, Darell D.; Zalutsky, Michael R.

    2010-01-01

    Introduction Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with177Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. Materials and Methods L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine- pentaacetic acid (CHX-A″-DTPA) and 2-(4-Isothiocyanatobenzyl)-6-methyldiethylene- triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4- Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.)EGFR glioma xenografts over a period of 1 to 8 days to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). Results Except with C-DOTA, tumor uptake for the 177Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor:normal tissue ratios for 177Lu-1B4M-DTPA-L8A4 and to an even greater extent, 177Lu-MeO-DOTA-L8A4, were higher than those for [125I]SGMIB-L8A4 in most other tissues. Conclusions Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for 177Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application. PMID:20870149

  10. Photon strength functions in 177Lu: Study of scissors resonance in high-spin region

    NASA Astrophysics Data System (ADS)

    Bečvář, F.; Krtička, M.; Tomandl, I.; Valenta, S.

    2015-05-01

    The nucleus 177Lu is characteristic by an unusually high value of the thermal-neutron capturing state spin, J = 13/2, and by distinct low-energy rotational bands built on the 7/2+ ground state and the 9/2- level at 150 keV. The γ cascades connecting the capturing state with the members of these bands carry unique information about the role of identical M1 scissors-mode resonances, built according to Brink hypothesis assumingly on each energy level, even in conditions of fast nuclear rotation. With this motivation we measured a set of spectra of two-step γ cascades following the thermal neutron capture in 176Lu. The measurement was performed at neutron beam of the LWR-15 Reactor in Řež. From the analysis of these spectra the common parameters of the scissors resonances were deduced. The obtained results are discussed.

  11. Targeted Radionuclide Therapy with A 177Lu-labeled Anti-HER2 Nanobody

    PubMed Central

    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 (MW < 15 kDa) functional antigen-binding fragments that are derived from heavy chain-only camelid antibodies. Here, we show that the extend of kidney retention of nanobodies 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

  12. Aminocarboxylate complexes and octreotide complexes with no carrier added 177Lu, 166Ho and 149Pm.

    PubMed

    Li, Wen Ping; Smith, C Jeff; Cutler, Cathy S; Hoffman, Timothy J; Ketring, Alan R; Jurisson, Silvia S

    2003-04-01

    Several aminocarboxylate complexes of the "no carrier added" (NCA) radiolanthanides (149)Pm, (166)Ho and (177)Lu were evaluated using our in vitro hydroxyapatite and serum stability model and in vivo in normal CF-1 mice [10]. The aminocarboxylate chelates evaluated with the NCA radiolanthanides for in vitro stability were EDTA, CDTA, DTPA, MA-DTPA and DOTA. In addition, the NCA radiolanthanide complexes with DTPA-octreotide (DTPA-OCT) were synthesized and evaluated, as a model for a peptide conjugated aminocarboxylate complex. The biodistribution studies of the NCA complexes with DTPA, DOTA and DTPA-OCT showed that the in vitro model correctly predicted the in vivo stability of the radiolanthanide complexes, with Ln-DOTA > Ln-DTPA > Ln-DTPA-OCT. PMID:12745015

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

    NASA Astrophysics Data System (ADS)

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

    2016-06-01

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

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

    PubMed

    Cho, Eun-Ha; Lim, Jae Cheong; Lee, So-Young; Jung, Sung-Hee

    2016-07-01

    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 (177)Lu, 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 (177)Lu-labeling, in which the peptides were radiolabeled with (177)Lu by a high radiolabeling yield. A competitive displacement of (125)I-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 (177)Lu-DOTA-[Nle]-cCCK has higher binding affinity than (177)Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors. PMID:27430985

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

    PubMed

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

    2015-01-01

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

  16. Development of (153) Sm-folate-polyethyleneimine-conjugated chitosan nanoparticles for targeted therapy.

    PubMed

    Mollarazi, Esmail; Jalilian, Amir R; Johari-Daha, Fariba; Atyabi, Fatemeh

    2015-06-30

    The aim of this study was to develop biocompatible, water-soluble (153) Sm-labeled chitosan nanoparticles (NPs) containing folate and polyethyleneimine functionalities i.e. chitosan-graft-PEI-folate (CHI-DTPA-g-PEI-FA), suitable for targeted therapy. The physicochemical properties of the obtained NPs were characterized by dynamic light-scattering analysis for their mean size, size distribution, and zeta potential; scanning electron microscopy for surface morphology; and (1) H-NMR, FT-IR analyses for molecular dispersity of folate in the NPs. NPs were spherical with mean diameter below 250 nm, polydispersity of below 0.15, and positive zeta potential values. The NP complex ((153) Sm-CHI-DTPA-g-PEI-FA) was stable at 25 °C (6-8 h, >90% radiochemical purity, instant thin layer chromatography (ITLC)). Binding studies using fluorescent NPs for internalization also demonstrated significant uptake in MCF-7 cells. MCF-7 cell internalization was significantly greater for 4T1. In blocking studies, both MCF-7 and 4T1 cell lines demonstrated specific folate receptor (FR) binding (decreasing 45%). In vivo biodistribution studies indicated major excretion of NPs metabolites and/or free (153) Sm through the kidneys. The preliminary imaging studies in 4T1 tumor-bearing mice showed minor uptake up to 96 h. The present folic acid that functionalized chitosan NP is a candidate material for folate receptor therapy. PMID:26036233

  17. Fast voxel-level dosimetry for (177)Lu labelled peptide treatments.

    PubMed

    Hippeläinen, E; Tenhunen, M; Sohlberg, A

    2015-09-01

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for (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

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

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

  19. Formation of medical radioisotopes 111In, 117 m Sn, 124Sb, and 177Lu in photonuclear reactions

    NASA Astrophysics Data System (ADS)

    Danagulyan, A. S.; Hovhannisyan, G. H.; Bakhshiyan, T. M.; Avagyan, R. H.; Avetisyan, A. E.; Kerobyan, I. A.; Dallakyan, R. K.

    2015-06-01

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

  20. Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

    PubMed Central

    Schüler, Emil; Parris, Toshima Z.; Helou, Khalil; Forssell-Aronsson, Eva

    2014-01-01

    Aim The aim of this study was to investigate the variation of the miRNA expression levels in normal renal cortical tissue after 177Lu-octreotate administration, a radiopharmaceutical used for treatment of neuroendocrine cancers. Methods Female BALB/c nude mice were i.v. injected with 1.3, 3.6, 14, 45, or 140 MBq 177Lu-octreotate, while control animals received saline. The animals were killed at 24 h after injection and total RNA, including miRNA, was extracted from the renal cortical tissue and hybridized to the Mouse miRNA Oligo chip 4plex to identify differentially regulated miRNAs between exposed and control samples. Results In total, 57 specific miRNAs were differentially regulated in the exposed renal cortical tissues with 1, 29, 21, 27, and 31 miRNAs identified per dose-level (0.13, 0.34, 1.3, 4.3, and 13 Gy, respectively). No miRNAs were commonly regulated at all dose levels. miR-194, miR-107, miR-3090, and miR-3077 were commonly regulated at 0.34, 1.3, 4.3, and 13 Gy. Strong effects on cellular mechanisms ranging from immune response to p53 signaling and cancer-related pathways were observed at the highest absorbed dose. Thirty-nine of the 57 differentially regulated miRNAs identified in the present study have previously been associated with response to ionizing radiation, indicating common radiation responsive pathways. Conclusion In conclusion, the 177Lu-octreotate associated miRNA signatures were generally dose-specific, thereby illustrating transcriptional regulation of radiation responsive miRNAs. Taken together, these results imply the importance of miRNAs in early immunological responses in the kidneys following 177Lu-octreotate administration. PMID:25386939

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

    NASA Astrophysics Data System (ADS)

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-08-01

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

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

    PubMed

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

    2015-08-01

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with (177)Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for (177)Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in (177)Lu PRRT. PMID:26215085

  4. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in individuals with neck or mediastinal paraganglioma (PGL).

    PubMed

    Zovato, S; Kumanova, A; Demattè, S; Sansovini, M; Bodei, L; Di Sarra, D; Casagranda, E; Severi, S; Ambrosetti, A; Schiavi, F; Opocher, G; Paganelli, G

    2012-05-01

    Paragangliomas (PGLs) are neuroendocrine tum-ors that arise embryologically from the neural crest. Sympathetic PGLs can be located in the thoracic-abdominal region while parasympathetic PGLs are mainly situated in the head and neck region. Most PGLs are sporadic, but in 30% of cases they are hereditary (associated with mutations of SDHB, SDHC, SDHD, SDHAF2, SDHA, TMEM, MAX, and VHL); they can be classified into 4 different paraganglioma syndromes: PGL1, PGL2, PGL3, and PGL4. Surgery is the treatment of choice for both sympathetic and parasympathetic PGLs. Other types of treatment include medical agents (such as gemcitabine, cisplatin, or sunitinib) and radiotherapy (external-beam radiotherapy or stereotactic surgery). Surgery and radiotherapy, however, can cause important side effects such as vascular complications and peripheral nerve damage (hypoglossal, recurrent laryngeal, glossopharyngeal, and vagus). Another possible treatment option is the use of peptide receptor radionuclide therapy (PRRT), including PRRT with 177Lu-DOTATATE. We studied 4 patients with hereditary nonmetastatic paraganglioma syndrome type 1 (PGL1), with progressive disease, in whom surgical excision was not possible. They were treated with 177Lu-DOTATATE (3-5 cycles) and all had a partial response (PR) or a stable disease (SD) to the treatment. In conclusion, a good alternative treatment when surgical or radiation therapy are contraindicated could be radiometabolic therapy with 177Lu-DOTATATE. PMID:22566197

  5. [177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

    PubMed Central

    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

  6. Indirect Production of No Carrier Added (NCA) (177)Lu from Irradiation of Enriched (176)Yb: Options for Ytterbium/Lutetium Separation.

    PubMed

    Dash, Ashutosh; Chakravarty, Rubel; Knapp, Furn F Russ; Pillai, Ambikalmajan M R

    2015-01-01

    This article presents a concise review of the production of no-carrier-added (NCA) (177)Lu by the 'indirect' route by irradiating ytterbium-176 ((176)Yb)-enriched targets. The success of this production method depends on the ability to separate the microscopic amounts of NCA (177)Lu from bulk irradiated ytterbium targets. The presence of Yb(+3) from the target in the final processed (177)Lu will adversely affect the quality of (177)Lu by decreasing the specific activity and competing with Lu(+3) complexation since ytterbium will follow the same coordination chemistry. Ytterbium and lutetium are adjacent members of the lanthanide family with very similar chemical properties which makes the separation of one from the other a challenging task. This review provides a summary of the methods developed for the separation and purification of NCA (177)Lu from neutron irradiated (176)Yb-enriched targets, a critical assessment of recent developments and a discussion of the current status of this (177)Lu production method. PMID:25771377

  7. Precision electron-gamma spectroscopic data from the beta decay of 153Sm

    NASA Astrophysics Data System (ADS)

    Deepa, S.; Rani Rao, Dwaraka; Venkataramaniah, K.

    2016-02-01

    The decay of 153Sm was studied with a HPGe detector and a Si(Li) detector based electron transporter. Forty four gamma transitions belonging to sixteen excited levels in the daughter nucleus 153Eu were analyzed for their energies, emission intensities, conversion electron intensities and conversion coefficients. These values have resulted in the determination of precise beta emission intensities to the levels in 153Eu and in the construction of an internally consistent decay scheme. The present study will add to the decay data available on this radionuclide for reliable dose estimations for medical applications.

  8. Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu.

    PubMed

    Mohsin, Huma; Jia, Fang; Sivaguru, Geethapriya; Hudson, Michael J; Shelton, Tiffani D; Hoffman, Timothy J; Cutler, Cathy S; Ketring, Alan R; Athey, Phillip S; Simón, Jaime; Frank, R Keith; Jurisson, Silvia S; Lewis, Michael R

    2006-01-01

    The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas. PMID:16536481

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

    PubMed

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

    2007-03-15

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

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

    PubMed

    Poorbaygi, Hosein; Reza Aghamiri, Seyed Mahmoud; Sheibani, Shahab; Kamali-Asl, Alireza; Mohagheghpoor, Elham

    2011-10-01

    Our objective was to determine if glass microspheres impregnated with two radionuclides, (90)Y as source of therapeutic beta emissions and (177)Lu as source of diagnostic gamma emissions can be useful for SPECT imaging during or after application of the (90)Y microspheres for treating of hepatic tumors. The glass-based microspheres labeled with (89)Y and lutetium (YAS (Lu)) or (89)Y and ytterbium (YAS (Yb)) were prepared by the sol-gel process where sol droplets directly were formed to gel microspheres. Results of the neutron activation indicate that such a combination of glass, microspheres allow bio-distribution studies by SPECT imaging with high resolution. PMID:21723135

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β(-)-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes (177)Lu (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 (177)Lu-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 (177)Lu-trastuzumab comparatively to animals treated with a non-specific control, (177)Lu-HuIgG, and then to prior published results obtained using (212)Pb-trastuzumab, an α-particle RIT agent. (177)Lu-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 (212)Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. (177)Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β(-)- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β(-)-particle RIT for the management of intraperitoneal disease. PMID:27196891

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

    PubMed Central

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

    2011-01-01

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

  15. Labeling Internalizing Anti-Epidermal Growth Factor Receptor Variant III Monoclonal Antibody with 177Lu: In Vitro Comparison of Acyclic and Macrocyclic Ligands

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Welsh, Phil; Zalutsky, Michael R.

    2009-01-01

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

  16. Pretargeted Radioimmunotherapy of Prostate Cancer with an Anti-TROP-2×Anti-HSG Bispecific Antibody and a 177Lu-Labeled Peptide

    PubMed Central

    Frielink, Cathelijne; Goldenberg, David M.; Sharkey, Robert M.; Lütje, Susanne; McBride, William J.; Oyen, Wim J.G.; Boerman, Otto C.

    2014-01-01

    Abstract TROP-2 is a pancarcinoma marker that is expressed at high levels in many epithelial cancers, including prostate cancer (PC). The trivalent bispecific antibody TF12 (anti-TROP2×anti-HSG [histamine-succinyl-glycine]) has shown to effectively target PC. In this study, the efficacy of pretargeted radioimmunotherapy (PRIT) with multiple cycles of TF12 and 177Lu-labeled diHSG-peptide (IMP288) in mice with s.c. PC3 tumors was investigated and compared with that of conventional RIT with 177Lu-labeled anti-TROP-2 mAb hRS7. Methods: The potential of one, two, and three cycles of PRIT using the TF12 pretargeted 177Lu-IMP288 (41 MBq per cycle) was determined in mice with s.c. PC3 tumors, and compared with the efficacy and toxicity of RIT with 177Lu-hRS7 dosed at the maximum tolerated dose (11 MBq). Results: PRIT of two and three cycles showed significantly higher median survival (>150 days) compared with PRIT of one cycle of TF12 and 177Lu-IMP288 (111 days, p<0.001) or the controls (76 days, p<0.0001). All mice treated with the mAb 177Lu-hRS7 survived at the end of the experiment (150 days), compared with 80% in the mice that were treated with three cycles of PRIT and 70% in the group that received two cycles of PRIT. Clinically significant hematologic toxicity was found only in the groups that received either three cycles of PRIT (p<0.0009) or RIT (p<0.0001). Conclusions: TROP-2-expressing PC can be targeted efficiently with TF12 and radiolabeled IMP288. 177Lu-IMP288 accumulated rapidly in the tumors. PRIT of multiple cycles inhibited the growth of s.c. PC3 tumors. Clinically relevant hematological toxicity was observed in the group that received three cycles of PRIT; however, conventional RIT with the parent mAb 177Lu-hRS7 was at least as effective with similar toxicity. PMID:25226447

  17. Monte Carlo calculated TG-60 dosimetry parameters for the {beta}{sup -} emitter {sup 153}Sm brachytherapy source

    SciTech Connect

    Sadeghi, Mahdi; Taghdiri, Fatemeh; Hamed Hosseini, S.; Tenreiro, Claudio

    2010-10-15

    Purpose: The formalism recommended by Task Group 60 (TG-60) of the American Association of Physicists in Medicine (AAPM) is applicable for {beta} sources. Radioactive biocompatible and biodegradable {sup 153}Sm glass seed without encapsulation is a {beta}{sup -} emitter radionuclide with a short half-life and delivers a high dose rate to the tumor in the millimeter range. This study presents the results of Monte Carlo calculations of the dosimetric parameters for the {sup 153}Sm brachytherapy source. Methods: Version 5 of the (MCNP) Monte Carlo radiation transport code was used to calculate two-dimensional dose distributions around the source. The dosimetric parameters of AAPM TG-60 recommendations including the reference dose rate, the radial dose function, the anisotropy function, and the one-dimensional anisotropy function were obtained. Results: The dose rate value at the reference point was estimated to be 9.21{+-}0.6 cGy h{sup -1} {mu}Ci{sup -1}. Due to the low energy beta emitted from {sup 153}Sm sources, the dose fall-off profile is sharper than the other beta emitter sources. The calculated dosimetric parameters in this study are compared to several beta and photon emitting seeds. Conclusions: The results show the advantage of the {sup 153}Sm source in comparison with the other sources because of the rapid dose fall-off of beta ray and high dose rate at the short distances of the seed. The results would be helpful in the development of the radioactive implants using {sup 153}Sm seeds for the brachytherapy treatment.

  18. Kidney Dosimetry in 177Lu and 90Y Peptide Receptor Radionuclide Therapy: Influence of Image Timing, Time-Activity Integration Method, and Risk Factors

    PubMed Central

    Guerriero, F.; Ferrari, M. E.; Botta, F.; Fioroni, F.; Grassi, E.; Versari, A.; Sarnelli, A.; Pacilio, M.; Amato, E.; Strigari, L.; Bodei, L.; Paganelli, G.; Iori, M.; Pedroli, G.; Cremonesi, M.

    2013-01-01

    Kidney dosimetry in 177Lu and 90Y PRRT requires 3 to 6 whole-body/SPECT scans to extrapolate the peptide kinetics, and it is considered time and resource consuming. We investigated the most adequate timing for imaging and time-activity interpolating curve, as well as the performance of a simplified dosimetry, by means of just 1-2 scans. Finally the influence of risk factors and of the peptide (DOTATOC versus DOTATATE) is considered. 28 patients treated at first cycle with 177Lu DOTATATE and 30 with 177Lu DOTATOC underwent SPECT scans at 2 and 6 hours, 1, 2, and 3 days after the radiopharmaceutical injection. Dose was calculated with our simplified method, as well as the ones most used in the clinic, that is, trapezoids, monoexponential, and biexponential functions. The same was done skipping the 6 h and the 3 d points. We found that data should be collected until 100 h for 177Lu therapy and 70 h for 90Y therapy, otherwise the dose calculation is strongly influenced by the curve interpolating the data and should be carefully chosen. Risk factors (hypertension, diabetes) cause a rather statistically significant 20% increase in dose (t-test, P < 0.10), with DOTATATE affecting an increase of 25% compared to DOTATOC (t-test, P < 0.05). PMID:23865075

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

    Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine 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. PMID:25460570

  1. 142-Sm - a suitable positron emitter for uptake monitoring in 153-Sm EDTMP therapy

    SciTech Connect

    Beyer, G.J.; Donath, A.; Morel, C.

    1996-05-01

    The positron emitting isotopes {sup 86}Y and 83Sr are favoured candidates for monitoring the individual nuclide uptake in bone metastases with PET when {sup 90}Y or {sup 89}Sr are used in the therapy. It therefore seemed to be logical to propose the short-lived positron emitter {sup 142}Sm to perform the in vivo dosimetry in case cf {sup 153}Sm EDTMP therapy. {sup 142}Sm (72 min, 50 % positron branching) forms the 40 sec {sup 142}Pm with 95% positron decay rate. Three aspects will be discussed in the paper: the production of several GBq of the {sup 142}Sm in the required high quality, systematic studies of the biokinetic behaviour of radio-lanthanides with EDTMP as ligand and first dynamic PET studies using rabbits as animal model. Spallation reaction of 1 GeV protons interacting with a 100/g/cm{sup 2} Ta target in combination with an on line isotope separation process was used for the production of the radionuclides. The on line isotope separator facility ISOLDE at CERN provides excellent possibilities to produce {sup 142}Sm in multi GBq quantities, isotopically clean and carrier free. All other radio-lanthanides used in the study were produced at the ISOLDE facility as well. Using a number of long-lived radio-lanthanides we studied systematically the biokinetics of the lanthanides at different EDTMP concentrations and established clear relationships between biokinetics, EDTMP concentration and the ionic radius of the radioisotope used.

  2. 177Lu-DO3A-HSA-Z EGFR:1907: characterization as a potential radiopharmaceutical for radionuclide therapy of EGFR-expressing head and neck carcinomas.

    PubMed

    Hoppmann, Susan; Qi, Shibo; Miao, Zheng; Liu, Hongguang; Jiang, Han; Cutler, Cathy S; Bao, Ande; Cheng, Zhen

    2012-06-01

    Epidermal growth factor receptor 1 (EGFR) is an attractive target for radionuclide therapy of head and neck carcinomas. Affibody molecules against EGFR (Z(EGFR)) show excellent tumor localizations in imaging studies. However, one major drawback is that radiometal-labeled Affibody molecules display extremely high uptakes in the radiosensitive kidneys which may impact their use as radiotherapeutic agents. The purpose of this study is to further explore whether radiometal-labeled human serum albumin (HSA)-Z(EFGR) bioconjugates display desirable profiles for the use in radionuclide therapy of EGFR-positive head and neck carcinomas. The Z(EFGR) analog, Ac-Cys-Z(EGFR:1907), was site-specifically conjugated with HSA. The resulting bioconjugate 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A)-HSA-Z(EGFR:1907) was then radiolabeled with either (64)Cu or (177)Lu and subjected to in vitro cell uptake and internalization studies using the human oral squamous carcinoma cell line SAS. Positron emission tomography (PET), single photon emission computed tomography (SPECT), and biodistribution studies were conducted using SAS-tumor-bearing mice. Cell studies revealed a high (8.43 ± 0.55 % at 4 h) and specific (0.95 ± 0.09 % at 4 h) uptake of (177)Lu-DO3A-HSA-Z(EGFR:1907) as determined by blocking with nonradioactive Z(EGFR:1907). The internalization of (177)Lu-DO3A-HSA-Z(EGFR:1907) was verified in vitro and found to be significantly higher than that of (177)Lu-labeled Z(EFGR) at 2-24 h of incubation. PET and SPECT studies showed good tumor imaging contrasts. The biodistribution of (177)Lu-DO3A-HSA-Z(EGFR:1907) in SAS-tumor-bearing mice displayed high tumor uptake (5.1 ± 0.44 % ID/g) and liver uptake (31.5 ± 7.66 % ID/g) and moderate kidney uptake (8.5 ± 1.08 % ID/g) at 72 h after injection. (177)Lu-DO3A-HSA-Z(EGFR:1907) shows promising in vivo profiles and may be a potential radiopharmaceutical for radionuclide therapy of EGFR-expressing head and neck carcinomas

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

    SciTech Connect

    Montégiani, Jean-François; Gaudin, Émilie; Després, Philippe; Jackson, Price A.; Beauregard, Jean-Mathieu

    2014-08-15

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

    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. PMID:25919487

  6. Survival after somatostatin based radiopeptide therapy with 90Y-DOTATOC vs. 90Y-DOTATOC plus 177Lu-DOTATOC in metastasized gastrinoma

    PubMed Central

    Dumont, Rebecca A; Seiler, Daniela; Marincek, Nicolas; Brunner, Philippe; Radojewski, Piotr; Rochlitz, Christoph; Müller-Brand, Jan; Maecke, Helmut R; Briel, Matthias; Walter, Martin A

    2015-01-01

    We aimed to explore the effects of 90Y-DOTATOC and 90Y-DOTATOC plus 177Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of 90Y-DOTATOC or with cycles alternating between 90Y-DOTATOC and 177Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received 90Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received 90Y-DOTATOC plus 177Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with 90Y-DOTATOC plus 177Lu-DOTATOC as compared to 90Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to 90Y-DOTATOC and 90Y-DOTATOC plus 177Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma. PMID:25625026

  7. Accurate assessment of whole-body retention for PRRT with (177)Lu using paired measurements with external detectors.

    PubMed

    Liu, Boxue; de Blois, Erik; Breeman, Wouter A P; Konijnenberg, Mark W; Wolterbeek, Hubert T; Bode, Peter

    2015-01-01

    The aim of this study was to assess the accuracy of the results of whole-body measurements by comparison with the urine collection method in the PRRT with (177)Lu and furthermore to develop a more accurate method of paired measurements. Excreted samples were collected at given intervals and activities were measured by a dose calibrator. Traditionally, whole-body activities during subsequent measurements are normalized individually to the administered activity. In order to correct for the effects of the activity in the bladder during the baseline measurement before the first voiding and activity redistributions in the patient body during subsequent measurements, a series of paired measurements before and after each voiding were carried out. Time-dependent detector responses at given times were derived and time-activity retentions were then determined. Compared to the results of the urine collection, whole-body activities by traditional whole-body measurements were overestimated by ca. 14% at 1 h after administration and randomly varied from -29% to 49% at 24 h. Measurement uncertainties of whole-body activities were from ± 4% (the coverage factor k=2) at 1 h to >± 20% at 24 h by the urine collection and ± 7% by paired measurements, respectively. Whole-body activities at 1 h by paired measurements were validated using the results by measurements of the collected first urine. The new method of paired measurements has an equivalent measurement accuracy and even better during the later measurements with respect to the urine collection method and therefore can replace urine approach for assessing the time-activity remaining in the patient body. PMID:25771370

  8. Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

    PubMed Central

    2014-01-01

    Background Previously, we reported on the unexpected development of distant metastases in the subcutaneous rat pancreas CA20948 tumor model after 4.5 weeks of treatment with RAD001-only or in combination with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) (Cancer Res. 73:12-8, 2013). Moreover, the combination therapy was less effective compared to 177Lu-DOTATATE-only. In the current study, we address the following questions: (1) Why was the combination therapy less effective? Is 177Lu-DOTATATE tumor uptake affected by pretreatment with RAD001? (2) Could sudden cessation of RAD001 therapy cause the development of distant metastases? (3) Is 177Lu-DOTATATE an effective treatment option for these metastases? Methods Lewis rats (HanHsd or SsNHsd substrain with a slight difference in immune response) bearing subcutaneous CA20948 tumors were treated with either 125 or 275 MBq 177Lu-DOTATATE, RAD001, or their combination. RAD001 was given twice a week for 4.5 or 12 weeks, whereas 177Lu-DOTATATE was given as a single injection. When combined, RAD001 was started either 3 days prior to or 3 days post administration of 177Lu-DOTATATE. SPECT/CT was performed to quantify 177Lu-DOTATATE tumor uptake. Where indicated, primary tumors were surgically removed when tumor size is >6,000 mm3 to enable monitoring for possible metastasis. If metastases were suspected, an 111In-DTPA-octreotide SPECT/CT scan was performed. Seven rats with metastases were treated with 400 MBq 177Lu-DOTATATE. Results Lu-DOTATATE tumor uptake was not significantly affected by RAD001 pretreatment. The occurrence of metastases after RAD001 treatment was not dose dependent in the dose range tested, nor was it related to the duration of RAD001 treatment. In the experiment in which the LEW/SsNsd substrain was used, only 12.5% of RAD001-treated rats showed complete response (CR), compared to 50% tumor regression in the control group. Re-treatment with a high dose of 177Lu-DOTATATE resulted in CR in only two

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

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

    PubMed

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

    2002-07-25

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

  11. Multimodal Somatostatin Receptor Theranostics Using [(64)Cu]Cu-/[(177)Lu]Lu-DOTA-(Tyr(3))octreotate and AN-238 in a Mouse Pheochromocytoma Model.

    PubMed

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

    2016-01-01

    Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors. For metastatic disease, no effective therapy is available. Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [(177)Lu]Lu-DOTA-(Tyr(3))octreotate (DOTATATE) and AN-238. Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models. In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [(64)Cu]Cu-DOTATATE. Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14. Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [(177)Lu]Lu-DOTATATE compared to AN-238 and doxorubicin. Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies. This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo. Our findings highlight the therapeutic potential of somatostatin analogs, especially of [(177)Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs. Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome. PMID:27022413

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

    PubMed Central

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

    2016-01-01

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

  13. Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice.

    PubMed

    Oddstig, Jenny; Bernhardt, Peter; Lizana, Helena; Nilsson, Ola; Ahlman, Håkan; Kölby, Lars; Forssell-Aronsson, Eva

    2012-02-01

    The aim of this study was to investigate the activity distribution in neouroendocrine tumors after diagnostic, or therapeutic, amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate and to investigate how the activity distribution influences the absorbed dose. Furthermore, the activity distribution of a second administration of radiolabeled octreotate was studied. Nude mice with subcutaneously grown human midgut carcinoid (GOT1) were injected intravenously with different amounts of (177)Lu-octreotate. At different time points thereafter (4 h to 13 days), a second injection of [(111)In-DOTA(0)-Tyr(3)]-octreotate was given to estimate the somatostatin receptor (sstr) expression. The activity distribution in the tumors was then determined. Monte Carlo simulations with PENELOPE were performed for dosimetry. Fifty-one out of 58 investigated tumors showed a lower activity concentration in the peripheral part than in the central part of the tumor. The amount of activity injected, or time after administration, did neither influence the relative activity nor the sstr distribution in the tumor. After an initial down-regulation (at 4-24 h), there was an up-regulation of sstr (1.5-2 times, at 7-14 days). Monte Carlo simulations demonstrated an inhomogeneous absorbed dose distribution in the tumor using (177)Lu, with twice as high absorbed dose centrally than peripherally. The high activity concentration centrally and the up-regulation of sstr demonstrated will facilitate fractionated therapy using radiolabeled somatostatin analogues if similar results will be obtained also in patients. The inhomogeneous activity distribution in the tumor has to be taken into account when the absorbed dose distribution in tumor is calculated. PMID:22108870

  14. Metastatic Insulinoma Pancreatic Neuroendocrine Tumor Treated With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy: A Suggested Protocol.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2016-01-01

    A 70-year-old woman presented with frequent episodes of hypoglycemia. Imaging revealed a 6-cm pancreatic mass with several liver lesions. The pancreatic mass was resected and confirmed to be a well-differentiated insulinoma. Surgery improved but did not resolve her hypoglycemic episodes, and she was referred for peptide receptor radionuclide therapy with 177Lu-DOTATATE to treat her residual disease. A modified protocol with a continuous IV dextrose infusion was used, and the treatments were well tolerated. After 4 induction and 2 maintenance treatments, her hypoglycemic symptoms resolved completely and her disease stabilized. She has been progression free for 24 months. PMID:26562579

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

    PubMed

    Wrzesień, Małgorzata; Napolska, Katarzyna; Olszewski, Jerzy

    2016-03-01

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

  16. Biological comparison of 149Pm-, 166Ho-, and 177Lu-DOTA-biotin pretargeted by CC49 scFv-streptavidin fusion protein in xenograft-bearing nude mice.

    PubMed

    Lewis, Michael R; Zhang, Jiuli; Jia, Fang; Owen, Nellie K; Cutler, Cathy S; Embree, Mary F; Schultz, Jody; Theodore, Louis J; Ketring, Alan R; Jurisson, Silvia S; Axworthy, Donald B

    2004-02-01

    The radiolanthanides (149)Pm, (166)Ho, and (177)Lu possess a range of half-lives and alpha(-) beta(-) energies for targeted radiotherapy of cancer. (149)Pm-, (166)Ho-, and (177)Lu-DOTA-biotin were pretargeted to LS174T colorectal tumors in nude mice with CC49 scFvSA antibody-streptavidin fusion protein. Tumor uptakes of (149)Pm (22.9% ID/g), (166)Ho (30.2% ID/g), and (177)Lu (35.4% ID/g) peaked at 1-4 h. Rapid blood disappearance was accompanied by urinary excretion of 59-66% ID within 1 h. Biodistributions of these agents show promise for pretargeted radioimmunotherapy of cancer. PMID:15013487

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

    SciTech Connect

    Danagulyan, A. S.; Hovhannisyan, G. H. Bakhshiyan, T. M.; Avagyan, R. H.; Avetisyan, A. E.; Kerobyan, I. A.; Dallakyan, R. K.

    2015-06-15

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

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

    PubMed

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

    2014-02-01

    (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 24h. 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. PMID:24333746

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

    PubMed

    Kletting, Peter; 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 peptide

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

    PubMed Central

    Wu, Yin; Pfeifer, Andreas Klaus; Myschetzky, Rebecca; Garbyal, Rajendra Singh; Rasmussen, Palle; Knigge, Ulrich; Bzorek, Michael; Kristensen, Michael Holmsgaard; Kjaer, Andreas

    2013-01-01

    Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy. PMID:26824927

  1. In vivo Localization of 90Y- and 177Lu-Radioimmunoconjugates Using Cerenkov Luminescence Imaging in a Disseminated Murine Leukemia Model

    PubMed Central

    Balkin, Ethan R.; Kenoyer, Aimee; Orozco, Johnnie J.; Hernandez, Alexandra; Shadman, Mazyar; Fisher, Darrell R.; Green, Damian J.; Hylarides, Mark D.; Press, Oliver W.; Wilbur, D. Scott; Pagel, John M.

    2014-01-01

    Cerenkov radiation generated by positron-emitting radionuclides can be exploited for a molecular imaging technique known as Cerenkov Luminescence Imaging (CLI). Data have been limited, however, on the use of medium-to-high energy β-emitting radionuclides of interest for cancer imaging and treatment. We assessed the use of CLI as an adjunct to determine localization of radioimmunoconjugates to hematolymphoid tissues. Radiolabeled 177Lu- or 90Y-anti-CD45 antibody (Ab; DOTA-30F11) was administered by tail vein injection to athymic mice bearing disseminated murine myeloid leukemia with CLI images acquired at times afterward. Gamma counting of individual organs showed preferential uptake in CD45+ tissues with significant retention of radiolabeled Ab in sites of leukemia (spleen and bone marrow). This result was confirmed in CLI images with 1.35 × 105 ± 2.2 × 104 p/sec/cm2/sr and 3.45 × 103 ± 7.0 × 102 p/sec/cm2/sr for 90Y-DOTA-30F11 and 177Lu-DOTA-30F11, respectively, compared to undetectable signal for both radionuclides using the non-binding control Ab. Results showed that CLI allows for in vivo visualization of localized β-emissions. Pixel intensity variability resulted from differences in absorbed doses of the associated energies of the β-emitting radionuclide. Overall, our findings offer a preclinical proof of concept for the use of CLI techniques in tandem with currently available clinical diagnostic tools. PMID:25261237

  2. Evaluation of Beta-Absorbed Fractions in a Mouse Model for 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177Lu Radionuclides

    SciTech Connect

    Miller, William H.; Hartmann-Siantar, Christine; Fisher, Darrell R.; Descalle, Marie-Anne; Daly, Tom; Lehmann, Joerg; Lewis, Michael R.; Hoffman, Timothy J.; Smith, Jeff; Situ, Peter D.; Volkert, Wynn A.

    2005-08-01

    Several short-lived, high-energy beta emitters are being proposed as the radionuclide components for molecular-targeted potential cancer therapeutic agents. The laboratory mice used to determine the efficacy of these new agents have organs that are relatively small compared to the ranges of these high-energy particles. The dosimetry model developed by Hui et al. was extended to provide realistic beta-dose estimates for organs in mice that received therapeutic radiopharmaceuticals containing 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177 Lu. Major organs in this model included the liver, spleen, kidneys, lungs, heart, stomach, small and large bowel, thyroid, pancreas, bone, marrow, carcass, and a 0.025-g tumor. The study as reported in this paper verifies their results for 90Y and extends them by using their organ geometry factors combined with newly calculated organ self-absorbed fractions from PEREGRINE and MCNP. PEREGRINE and MCNP agree to within 8% for the worst-case organ with average differences (averaged over all organs) decreasing from 5% for 90Y to 1% for 177Lu. When used with typical biodistribution data, the three different models predict doses that are in agreement to within 5% for the worst-case organ. The beta-absorbed fractions and cross-organ-deposited energy provided in this paper can be used by researchers to predict mouse-organ doses and should contribute to an improved understanding of the relationship between dose and radiation toxicity in mouse models where use of these isotopes is favorable.

  3. Evaluation of beta-absorbed fractions in a mouse model for 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177Lu radionuclides.

    PubMed

    Miller, William H; Hartmann-Siantar, Christine; Fisher, Darrell; Descalle, Marie-Anne; Daly, Tom; Lehmann, Joerg; Lewis, Michael R; Hoffman, Timothy; Smith, Jeff; Situ, Peter D; Volkert, Wynn A

    2005-08-01

    Several short-lived, high-energy beta emitters are being proposed as the radionuclide components for molecular- targeted potential cancer therapeutic agents. The laboratory mice used to determine the efficacy of these new agents have organs that are relatively small compared to the ranges of these high-energy particles. The dosimetry model developed by Hui et al. was extended to provide realistic beta-dose estimates for organs in mice that received therapeutic radiopharmaceuticals containing (90)Y, (188)Re, (166)Ho, (149)Pm, (64)Cu, and (177)Lu. Major organs in this model included the liver, spleen, kidneys, lungs, heart, stomach, small and large bowel, thyroid, pancreas, bone, marrow, carcass, and a 0.025-g tumor. The study as reported in this paper verifies their results for (90)Y and extends them by using their organ geometry factors combined with newly calculated organ self-absorbed fractions from PEREGRINE and MCNP. PEREGRINE and MCNP agree to within 8% for the worst-case organ with average differences (averaged over all organs) decreasing from 5% for (90)Y to 1% for (177)Lu. When used with typical biodistribution data, the three different models predict doses that are in agreement to within 5% for the worst-case organ. The beta-absorbed fractions and cross-organ-deposited energy provided in this paper can be used by researchers to predict mouse-organ doses and should contribute to an improved understanding of the relationship between dose and radiation toxicity in mouse models where use of these isotopes is favorable. PMID:16114992

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

    PubMed Central

    Thakral, Parul; Singla, Suhas; Yadav, Madhav Prasad; Vasisht, Atul; Sharma, Atul; Gupta, Santosh Kumar; Bal, C.S.; Snehlata; Malhotra, Arun

    2014-01-01

    Background & objectives: The prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumour-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumour cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immunoconjugate of biosimilar Rituximab (Reditux™) and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab(BioSim) was desalted with sodium bicarbonate (0.1M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in vitro stability and sterility were studied. Immunoreactivity of 177Lu-DOTA-Rituximab (BioSim) was assessed using RAMOS cells. The radioimmunoconjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: An average of 4.25 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab (BioSim). The radiochemical purity of the labelled antibody was > 95 per cent with preserved affinity for CD20 antigen. The final preparation was stable up to about 120 h when tested under different conditions. A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177Lu-DOTA-antiCD20 antibody-Rituximab (BioSim) in patients of relapsed and refractory non Hodgkin's lymphoma can be considered. PMID:24927340

  5. The 51Cr neutrino source and Borexino: a desirable marriage

    NASA Astrophysics Data System (ADS)

    Ferrari, N.; Fiorentini, G.; Ricci, B.

    1996-02-01

    Exposure to a 51Cr neutrino source as that used in Gallex will provide an excellent overall performance test of Borexino, which should collect about 1400 source induced events, with an initial rate of about 35 counts per day. This will be particularly important if MSW-small-angle turns out to be the solution of the solar neutrino problem. In addition, if an independent, accurate calibration is available, one will have an interesting experiment on neutrino properties: as an example, a neutrino magnetic moment of the order 5 . 10-11 μB could be detected/excluded at the 90% C.L.

  6. sup 51 Cr release and oxidative stress in the lens

    SciTech Connect

    Stewart-DeHaan, P.J.; Sanwal, M.; Creighton, M.O.; Inch, W.R.; Trevithick, J.R. )

    1989-01-01

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

  7. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer

    PubMed Central

    Ahmadzadehfar, Hojjat; Eppard, Elisabeth; Kürpig, Stefan; Fimmers, Rolf; Yordanova, Anna; Schlenkhoff, Carl Diedrich; Gärtner, Florian; Rogenhofer, Sebastian; Essler, Markus

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64–82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17–2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients. PMID:26871285

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

    PubMed

    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. PMID:26471333

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

    PubMed

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

    2012-10-01

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

  10. Influence of cations on the complexation yield of DOTATATE with yttrium and lutetium: a perspective study for enhancing the 90Y and 177Lu labeling conditions.

    PubMed

    Asti, Mattia; Tegoni, Matteo; Farioli, Daniela; Iori, Michele; Guidotti, Claudio; Cutler, Cathy S; Mayer, Pat; Versari, Annibale; Salvo, Diana

    2012-05-01

    The DOTA macrocyclic ligand can form stable complexes with many cations besides yttrium and lutetium. For this reason, the presence of competing cationic metals in yttrium-90 and lutetium-177 chloride solutions can dramatically influence the radiolabeling yield. The aim of this study was to evaluate the coordination yield of yttrium- and lutetium-DOTATATE complexes when the reaction is performed in the presence of varying amounts of competing cationic impurities. In the first set of experiments, the preparation of the samples was performed by using natural yttrium and lutetium (20.4 nmol). The molar ratio between DOTATATE and these metals was 1 to 1. Metal competitors (Pb(2+), Zn(2+), Cu(2+), Fe(3+), Al(3+), Ni(2+), Co(2+), Cr(3+)) were added separately to obtain samples with varying molar ratio with respect to yttrium or lutetium (0.1, 0.5, 1, 2 and 10). The final solutions were analyzed through ultra high-performance liquid chromatography with an UV detector. In the second set of experiments, an amount of (90)Y or (177)Lu chloride (6 MBq corresponding to 3.3 and 45 pmol, respectively) was added to the samples, and a radio-thin layer chromatography analysis was carried out. The coordination of Y(3+) and Lu(3+) was dramatically influenced by low levels of Zn(2+), Cu(2+) and Co(2+). Pb(2+) and Ni(2+) were also shown to be strong competitors at higher concentrations. Fe(3+) was expected to be a strong competitor, but the effect on the incorporation was only partly dependent on its concentration. Al(3+) and Cr(3+) did not compete with Y(3+) and Lu(3+) in the formation of DOTATATE complexes. PMID:22172388

  11. 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.

    PubMed

    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 those

  12. 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

    PubMed Central

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

    2015-01-01

    The aim of this study is to assess the effectiveness of Radiosynovectomy (RSV) using 177Lu-labeled hydroxyapatite (177Lu-HA) in the treatment of painful synovitis and recurrent joint effusion of knee joints in rheumatoid arthritis (RA). Ten patients, diagnosed with RA and suffering from chronic painful resistant synovitis of the knee joints were referred for RSV. The joints were treated with 333 ± 46 MBq of 177Lu-HA particles administered intra-articularly. Monitoring of activity distribution was performed by static imaging of knee joint and whole-body gamma imaging. The patients were evaluated clinically before RSV and at 6 months after the treatment by considering the pain improvement from baseline values in terms of a 100-point visual analog scale (VAS), the improvement of knee flexibility and the pain remission during the night. RSV response was classified as poor (VAS < 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 177Lu-HA in the joints. All patients showed decreased joint swelling and pains, resulting in increased joint motion after 6 months. The percentage of VAS improvement from baseline values was 79.5 ± 20.0% 6 months after RS and found to be significantly related to patients' age (P = 0.01) and duration of the disease (P = 0.03). Knees with Steinbrocker's Grades 0 and I responded better than those with more

  13. [Radioprotection and environmental pollution by the use of the radionuclides 89Sr, 186Re, and 153Sm for pain palliation in metastatic bone diseases. Related calculations].

    PubMed

    Sbonias, Evangelos

    2005-01-01

    Due to the fact that the existing commercial analgesic drugs are not able to reduce effectively the pain caused by the metastatic bone disease, the use of radiopharmaceuticals with avidity to selectively localize in the metastatic skeletal sites, such as strondium-89 chloride (89Sr-Cl2), rhenium-186-hydroxy ethylene diphosphonate (186Re-HEDP), and samarium-153-ethylene diamine tetramethylene (153Sm-EDTMP), is widely accepted. However this medical application may be dangerous for the occupied personnel and more for general public, if radioactive waste is not properly disposed. In the following article we try to estimate the degree and the significance of that risk. For that reason we discuss the physical properties of these radionuclides and their distribution in the body of the patient. We conclude that 89Sr is not harmful for the physician, the attending personnel or those who live with the patient, because it radiates beta-radiation, while its gamma-radiation is negligeable. The radionuclides 186Re and 153Sm besides beta-radiation, also emit a perceptible amount of gamma-radiation. It has been shown that the exposure to gamma-radiation from these radionuclides of the physician, the attending personnel or those who live with the patient is very low as compared to the internationally accepted radioprotection limits. However the environmental contamination per treatment by either of these three radionuclides is not negligeable in comparison to the national and international accepted limits. Patients that are not in good clinical condition may pose an additional contamination danger to those attending them. For limiting radiocontamination, the annual number of treatments by the above three previous radionuclides, should be considered according to the ALARA principle in relation with the correct handling of these patients, and also considering the fundamentals of radioprotection. PMID:16142246

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

    PubMed

    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

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

    PubMed Central

    Basu, Sandip; Ranade, Rohit; Thapa, Pradeep

    2016-01-01

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

  16. Cross-sections for populating excited states in 150-153Sm via the (p,d) and (p,t) reactions

    NASA Astrophysics Data System (ADS)

    Humby, P.; Simon, A.; Beausang, C. W.; Gell, K.; Tarlow, T.; Vyas, G.; Ross, T. J.; Hughes, R. O.; Burke, J. T.; Casperson, R. J.; Koglin, J.; Ota, S.; Allmond, J. M.; McCleskey, M.; McCleskey, E.; Saastamoinen, A.; Chyzh, R.; Dag, M.

    2014-09-01

    Light ion transfer reactions were used to populate low/medium spin states in 150-154Sm via the (p,p' γ), (p,d γ) and (p,t γ) reactions. The 25 MeV proton beam, with an average current of 1 nA, was provided by the K-150 Cyclotron at the Cyclotron Institute of Texas A&M University. The outgoing charged particles and coincident gamma-rays were detected using the STARLiTeR arrays. STARs (Silicon Telescope Array for Reaction studies), a highly segmented ΔE-E silicon telescope, provides particle identification as well as the energies, times and angular distributions of the protons, deuterons and tritons in the exit channels. LiTeR (Livermore Texas Richmond array), an array of six BGO shielded HPGe clover detectors, records the energy, time and angular distribution of the coincident gamma rays, providing excellent selectivity of the states of interest. Preliminary results for the cross-sections for direct population of states in 150-153Sm will be presented. Light ion transfer reactions were used to populate low/medium spin states in 150-154Sm via the (p,p' γ), (p,d γ) and (p,t γ) reactions. The 25 MeV proton beam, with an average current of 1 nA, was provided by the K-150 Cyclotron at the Cyclotron Institute of Texas A&M University. The outgoing charged particles and coincident gamma-rays were detected using the STARLiTeR arrays. STARs (Silicon Telescope Array for Reaction studies), a highly segmented ΔE-E silicon telescope, provides particle identification as well as the energies, times and angular distributions of the protons, deuterons and tritons in the exit channels. LiTeR (Livermore Texas Richmond array), an array of six BGO shielded HPGe clover detectors, records the energy, time and angular distribution of the coincident gamma rays, providing excellent selectivity of the states of interest. Preliminary results for the cross-sections for direct population of states in 150-153Sm will be presented. This work was partly supported by the US Department of Energy

  17. Intestinal permeability to (/sup 51/Cr)EDTA in children with Crohn's disease and celiac disease

    SciTech Connect

    Turck, D.; Ythier, H.; Maquet, E.; Deveaux, M.; Marchandise, X.; Farriaux, J.P.; Fontaine, G.

    1987-07-01

    (/sup 51/Cr)EDTA was used as a probe molecule to assess intestinal permeability in 7 healthy control adults, 11 control children, 17 children with Crohn's disease, and 6 children with untreated celiac disease. After subjects fasted overnight, 75 kBq/kg (= 2 microCi/kg) /sup 51/Cr-labeled EDTA was given by mouth; 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the total oral dose. Mean and SD were as follows: control adults 1.47 +/- 0.62, control children 1.59 +/- 0.55, and patients with Crohn's disease or celiac disease 5.35 +/- 1.94. The difference between control children and patients was statistically significant (p less than 0.001). These results show that intestinal permeability to (/sup 51/Cr)EDTA is increased among children with active or inactive Crohn's disease affecting small bowel only or small bowel and colon, and with untreated celiac disease. The (/sup 51/Cr)EDTA permeability test could facilitate the decision to perform more extensive investigations in children suspected of small bowel disease who have atypical or poor clinical and biological symptomatology.

  18. (51Cr)EDTA intestinal permeability in children with cow's milk intolerance

    SciTech Connect

    Schrander, J.J.; Unsalan-Hooyen, R.W.; Forget, P.P.; Jansen, J. )

    1990-02-01

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

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

    PubMed Central

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

    2014-01-01

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

  20. May bone-targeted radionuclide therapy overcome PRRT-refractory osseous disease in NET? A pilot report on 188Re-HEDP treatment in progressive bone metastases after 177Lu-octreotate

    PubMed Central

    Sabet, Amir; Khalaf, Feras; Mahjoob, Soha; Al-Zreiqat, Abdullah; Biersack, Hans-Jürgen; Ezziddin, Samer

    2014-01-01

    Bone metastases (BM) of gastroenteropancreatic neuroendocrine tumours (GEP-NET) can be effectively controlled by peptide receptor radionuclide therapy (PRRT). Eventually, however, BM may become refractory and determine survival. We aimed to assess the clinical benefit of bone-targeted radionuclide therapy (BTRT) in this subgroup of patients failing PRRT. A small cohort of n=6 patients with progressive BM failing PRRT with 177Lu-octreotate (mean cumulative activity, 46.7 GBq) were treated with a total of 11 cycles BTRT using 2.6-3.3 GBq 188Re-HEDP per cycle and a median cumulative activity of 5.9 GBq. Pain palliation was quantified applying the visual analogue scale (VAS). The mean VAS decreased from 6.6 (range 5-8) to 3.7 (range 2-7). Five patients experienced partial resolution of bone pain (≥ 2 steps reduction on the VAS for at least 2 weeks) and one patient had no significant improvement. Flare phenomena occurred in 2 patients and lasted for 2-3 days. Tumor response consisted of stable disease in 2 and progressive disease in 4 patients. No regression of bone metastases has been observed. The median overall survival was 5 months (range 2-9). Relevant myelosuppression (grade 3-4; self-limited with no interventions or hospitalization), occurred 4-6 weeks post-treatment, and after 2 (18.1%) administrations or in 1 (16.7%) patient. No other relevant toxicities or treatment-related death was observed. 188Re-HEDP may be safely applied in patients with bone metastatic GEP-NET previously treated with 177Lu-octreotate. While acceptable pain relief may be expected, no tumor-regression or long-term disease stabilization with apparent survival benefit has been observed. This disputes the use of BTRT as salvage anti-tumor therapy in PRRT-refractory neuroendocrine bone metastases. PMID:24380048

  1. Biological evaluation of (177)Lu-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.

    PubMed

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

    2015-02-01

    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(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with (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 4hr. 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 1.5hr p.i., and was increased to 216.33±61.58 at 24hr 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. PMID:25457455

  2. Measuring the activity of a 51Cr neutrino source based on the gamma-radiation spectrum

    NASA Astrophysics Data System (ADS)

    Gorbachev, V. V.; Gavrin, V. N.; Ibragimova, T. V.; Kalikhov, A. V.; Malyshkin, Yu. M.; Shikhin, A. A.

    2015-12-01

    A technique for the measurement of activities of intense β sources by measuring the continuous gamma-radiation (internal bremsstrahlung) spectra is developed. A method for reconstructing the spectrum recorded by a germanium semiconductor detector is described. A method for the absolute measurement of the internal bremsstrahlung spectrum of 51Cr is presented.

  3. Monte Carlo characterization of biocompatible beta-emitting 90Y glass seed incorporated with the radionuclide 153Sm as a SPECT marker for brachytherapy applications.

    PubMed

    Hadadi, Asghar; Sadeghi, Mahdi; Sardari, Dariush; Khanchi, Alireza; Shirazi, Alireza

    2013-01-01

    A glass seed consisting of the β--emitting radionuclide 90Y incorporated with radionuclide 153Sm as SPECT marker is proposed for potential application in brachytherapy in order to reduce the undesirable dose to healthy adjacent organs. The aim of this work is to determine the dosimetric characteristics, as suggested in the AAPM TG-60/TG-149 reports, for this seed using Monte Carlo simulation. Monte Carlo codes MCNP5, EGSnrc, and FLUKA were used to calculate the absorbed dose distribution around the seed. Dosimetric parameters, such as reference absorbed dose rate, radial dose function, and one-dimensional (1D) and two-dimensional (2D) anisotropy functions, were obtained. The computational results from these three codes are in agreement within 5.4% difference on average. The absorbed dose rate at the reference point was estimated to be 5.01 cGy h-1 μCi-1 and self absorption of YAS glass seed amounted to 30.51%. The results showed that, with thermal neutron bombardment of 5 hours in a typical flux, sufficient activity for applications in brachytherapy may be achieved. With a 5 mCi initial activity, the total dose of a YAS glass seed was estimated to be 1.38 Gy at 1.0 cm from the seed center. Comparing with gamma emitting seeds, the 90Y seed could reduce undesirable doses to adjacent organs, because of the rapid dose falloff of beta ray. Because of the high R90 value of 5.5 mm, fewer number of 90Y seeds will be required for an interstitial brachytherapy treatment using permanent implant, in comparison with other beta-emitting seeds. The results would be helpful in the development of the radioactive implants using 90Y glass seeds for the brachytherapy treatment. PMID:24036862

  4. Intestinal permeability to (/sup 51/Cr)EDTA in children with cystic fibrosis

    SciTech Connect

    Leclercq-Foucart, J.; Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1986-05-01

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of (/sup 51/Cr)EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of (/sup 51/Cr)EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001).

  5. Studies with nonradioisotopic sodium chromate. II. Single- and double-label sup 52 Cr/ sup 51 Cr posttransfusion recovery estimations

    SciTech Connect

    Heaton, W.A.; Keegan, T.; Hanbury, C.M.; Holme, S.; Pleban, P. )

    1989-10-01

    A recently developed nonradioisotopic 52Cr technique was used to measure either red cell volume or posttransfusion recovery of stored red cells. The experimental method uses Zeeman electrothermal atomic absorption spectrophotometry to measure red cell chromium. Results from the 52Cr method were compared with those from 51Cr single-label and 125I-albumin/51Cr double-label procedures using 49-day AS-1 red cell concentrates drawn and prepared according to standard procedures. In the first group of five donors, red cell volume was estimated concurrently with both 52Cr-labeled fresh red cells and 125I-albumin. The latter measured plasma volume from which red cell volume was estimated on the basis of the hematocrit (125I red cell volume). 51Cr-labeled stored red cells were transfused to measure posttransfusion recoveries. The correlation between 52Cr and 125I red cell volumes was significant (r = 0.68, p less than 0.01), and, in this group, the differences were not significant (p less than 0.05). Twenty-four-hour posttransfusion recoveries of 51Cr-labeled stored red cells averaged 66 +/- 5 percent when measured with the 125I/51Cr technique and 69 +/- 8 percent when measured with the 52Cr/51Cr method. In the second group of five donors, red cell volume was estimated by the 125I-albumin technique, and the posttransfusion recovery of stored red cells was quantitated by 51Cr- and 52Cr-labeled stored cells simultaneously. In this group, posttransfusion recoveries with 125I/51Cr averaged 73 +/- 7 percent; with 125I/52Cr, they averaged 75 +/- 10 percent. Using the single-label method of calculation, recoveries averaged 76 +/- 7 and 75 +/- 10 percent for the 51Cr and 52Cr methods, respectively.

  6. Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I-, and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts

    PubMed Central

    Lucas, S.; Feron, O.; Gallez, B.; Masereel, B.; Michiels, C.; Vander Borght, T.

    2015-01-01

    Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like 131I or 90Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of 90Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as 90Y, 177Lu, 131I, 124I, and 188Re are used. Tumour control probability (TCP) and normal tissue complication probability (NTCP) curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody) distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC)). 90Y and 188Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases. PMID:26136812

  7. Thermal neutron capture cross sections for the 152Sm(n,γ) 153Sm and 154Sm(n,γ) 155Sm reactions at 0.0536 eV energy

    NASA Astrophysics Data System (ADS)

    Uddin, M. S.; Chowdhury, M. H.; Hossain, S. M.; Latif, Sk. A.; Islam, M. A.; Hafiz, M. A.; Mubin, S. H.; Zakaria, A. K. M.; Yunus, S. M.; Azharul Islam, S. M.

    2008-11-01

    The neutron capture cross sections for the 152Sm(n,γ) 153Sm and 154Sm(n,γ) 155Sm reactions at 0.0536 eV neutron energy were measured using an activation technique based on the TRIGA Mark-II research reactor, relative to the reference reaction 197Au(n,γ) 198Au. The activity was measured nondestructively using gamma-ray spectroscopy. Our measured values at this neutron energy are the first ones and are compared with 1/ v based evaluated cross sections reported in the ENDF/B-VII and JENDL-3.3 libraries. The measured value for the 152Sm(n,γ) 153Sm reaction is 0.28% lower than JENDL-3.3 and 0.48% higher than ENDF/B-VII. Our value for the production of 155Sm is about 3% and 2.3% higher than the evaluated value with ENDF/B-VII and JENDL-3.3 at 0.0536 eV, respectively.

  8. Current status of new SAGE project with 51Cr neutrino source

    NASA Astrophysics Data System (ADS)

    Gavrin, V.; Cleveland, B.; Danshin, S.; Elliott, S.; Gorbachev, V.; Ibragimova, T.; Kalikhov, A.; Knodel, T.; Kozlova, Yu.; Malyshkin, Yu.; Matveev, V.; Mirmov, I.; Nico, J.; Robertson, R. G. H.; Shikhin, A.; Sinclair, D.; Veretenkin, E.; Wilkerson, J.

    2015-03-01

    A very short-baseline neutrino oscillation experiment with an intense 51Cr neutrino source is currently under construction at the Baksan Neutrino Observatory of the Institute for Nuclear Research RAS (BNO). The experiment, which is based on the existing SAGE experiment, will use an upgraded Gallium-Germanium Neutrino Telescope (GGNT) and an artificial 51Cr neutrino source with activity ˜3 MCi to search for transitions of active neutrinos to sterile states with Δ m 2 ˜1 eV2. The neutrino source will be placed in the center of a liquid Ga metal target that is divided into two concentric zones, internal and external. The average path length of neutrinos in each zone will be the same and the neutrino capture rate will be measured separately in each zone. The oscillation signature, which comes from the ratio of events in the near and far gallium volumes, will be largely free of systematic errors, such as may occur from cross section and source strength uncertainties, and will provide a clean signal of electron neutrino disappearance into a sterile state at baselines of about 0.6 and 2.0 m. The sensitivity to the disappearance of electron neutrinos is expected to be a few percent. Construction of this set of new facilities, including a two-zone tank for irradiation of 50 tons of Ga metal with the intense 51Cr source, as well as additional modules of the GGNT counting and extraction systems, is close to completion. To check the new facilities they will first be used for SAGE solar neutrino measurements.

  9. Calorimetric method for determination of {sup 51}Cr neutrino source activity

    SciTech Connect

    Veretenkin, E. P. Gavrin, V. N.; Danshin, S. N.; Ibragimova, T. V.; Kozlova, Yu. P.; Mirmov, I. N.

    2015-12-15

    Experimental study of nonstandard neutrino properties using high-intensity artificial neutrino sources requires the activity of the sources to be determined with high accuracy. In the BEST project, a calorimetric system for measurement of the activity of high-intensity (a few MCi) neutrino sources based on {sup 51}Cr with an accuracy of 0.5–1% is created. In the paper, the main factors affecting the accuracy of determining the neutrino source activity are discussed. The calorimetric system design and the calibration results using a thermal simulator of the source are presented.

  10. Enhanced intestinal permeability to 51Cr-labeled EDTA in dogs with small intestinal disease.

    PubMed

    Hall, E J; Batt, R M

    1990-01-01

    Intestinal permeability in dogs with small intestinal disease was measured by quantitation of 24-hour urinary excretion of 51Cr-labeled EDTA following intragastric administration. Permeability was high in dogs with a variety of naturally acquired small intestinal diseases including wheat-sensitive enteropathy of Irish Setters, small intestinal bacterial over-growth, and giardiasis, and permeability was decreased after successful treatment. These findings indicate that the assessment of intestinal permeability may be a useful technique for detecting small intestinal disease and for monitoring the efficacy of treatment in dogs. PMID:2104825

  11. Use of a /sup 51/Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs

    SciTech Connect

    Lussier, A.; Arsenault, A.; Varady, J.; de Medicis, R.; Lussier, Y.; LeBel, E.

    1987-02-01

    Of techniques used to evaluate gastrointestinal (GI) bleeding, use of radiochromium (/sup 51/Cr)-tagged erythrocytes is the most quantitative and scientifically acceptable method. The value of this technique as well as systematic errors possible with its use are discussed. The medical literature concerning /sup 51/Cr evaluation of GI microbleeding with naproxen therapy is critically reviewed. We suggest that future studies using this technique be parallel, randomized, double-blind, and include a 1-week placebo baseline phase for all subjects. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) should last 3 to 4 weeks. A parallel group of subjects should receive placebo throughout the study. For valid statistical analyses, randomization must achieve baseline comparability of weight, height, age, and sex in the treatment groups. Data transformations may be necessary to satisfy the assumptions of the statistical model. Following these guidelines will enable investigators to better evaluate GI microbleeding during treatment with naproxen or other NSAIDs, and, hopefully, to establish the safety profiles of these drugs.37 references.

  12. Reversibility of increased intestinal permeability to 51Cr-EDTA in patients with gastrointestinal inflammatory diseases

    SciTech Connect

    Jenkins, R.T.; Jones, D.B.; Goodacre, R.L.; Collins, S.M.; Coates, G.; Hunt, R.H.; Bienenstock, J.

    1987-11-01

    Intestinal permeability in adults with inflammatory gastrointestinal diseases was investigated by measuring the 24-h urinary excretion of orally administered /sup 51/Cr-EDTA. Eighty controls along with 100 patients with Crohn's disease, 46 patients with ulcerative colitis, 20 patients with gluten-sensitive enteropathy, and 18 patients with other diseases were studied. In controls, the median 24-h excretion was 1.34%/24 h of the oral dose. Patients with Crohn's disease (median 2.96%/24 h), ulcerative colitis (median 2.12%/24 h), and untreated gluten-sensitive enteropathy (median 3.56%/24 h) had significantly elevated urinary excretion of the probe compared to controls (p less than 0.0001). Increased 24-h urinary excretion of /sup 51/Cr-EDTA had a high association with intestinal inflammation (p less than 0.0001). Test specificity and sensitivity were 96% and 57%, respectively. A positive test has a 96% probability of correctly diagnosing the presence of intestinal inflammation, whereas a negative test has a 50% probability of predicting the absence of disease.

  13. A Monte Carlo approach to small-scale dosimetry of solid tumour microvasculature for nuclear medicine therapies with (223)Ra-, (131)I-, (177)Lu- and (111)In-labelled radiopharmaceuticals.

    PubMed

    Amato, Ernesto; Leotta, Salvatore; Italiano, Antonio; Baldari, Sergio

    2015-07-01

    The small-scale dosimetry of radionuclides in solid-tumours is directly related to the intra-tumoral distribution of the administered radiopharmaceutical, which is affected by its egress from the vasculature and dispersion within the tumour. The aim of the present study was to evaluate the combined dosimetric effects of radiopharmaceutical distribution and range of the emitted radiation in a model of tumour microvasculature. We developed a computational model of solid-tumour microenvironment around a blood capillary vessel, and we simulated the transport of radiation emitted by (223)Ra, (111)In, (131)I and (177)Lu using the GEANT4 Monte Carlo. For each nuclide, several models of radiopharmaceutical dispersion throughout the capillary vessel were considered. Radial dose profiles around the capillary vessel, the Initial Radioactivity (IR) necessary to deposit 100 Gy of dose at the edge of the viable tumour-cell region, the Endothelial Cell Mean Dose (ECMD) and the Tumour Edge Mean Dose (TEMD), i.e. the mean dose imparted at the 250-μm layer of tissue, were computed. The results for beta and Auger emitters demonstrate that the photon dose is about three to four orders of magnitude lower than that deposited by electrons. For (223)Ra, the beta emissions of its progeny deliver a dose about three orders of magnitude lower than that delivered by the alpha emissions. Such results may help to characterize the dose inhomogeneities in solid tumour therapies with radiopharmaceuticals, taking into account the interplay between drug distribution from vasculature and range of ionizing radiations. PMID:25979209

  14. Relationship between intestinal permeability to ( sup 51 Cr)EDTA and inflammatory activity in asymptomatic patients with Crohn's disease

    SciTech Connect

    Pironi, L.; Miglioli, M.; Ruggeri, E.; Levorato, M.; Dallasta, M.A.; Corbelli, C.; Nibali, M.G.; Barbara, L. )

    1990-05-01

    The relationship between intestinal permeability to an oral dose (100 mu Ci) of (51CR)EDTA and the inflammatory activity of Crohn's disease was studied in 63 adult patients (32 unresected and 31 resected) who underwent 162 evaluations. The results of the (51CR)EDTA test were compared with the serum levels of the acute-phase reactant proteins (APRP) and with the result of the (111In)leukocyte scanning, respectively, as an indirect and direct method to assess intestinal inflammation. In a group of healthy adult controls, the upper normal value for the 24-hr urinary (51CR)EDTA excretion was 3.61 (97.5% percentile) and the mean coefficient of variation was 21%. Sensitivity and specificity of the (51CR)EDTA test in identifying active inflammation expressed by increased serum levels of APRP were, respectively, 97% and 54% in the unresected group and 68% and 52% in the resected group of patients. The low specificity of the test was due to the presence of increased (51CR)EDTA urinary excretion in about half the cases with normal serum levels of APRP. The (111In)leukocyte scanning was performed in a subgroup of 11 patients (three unresected and eight resected) with normal serum levels of APRP, six with increased and five with normal (51CR)EDTA urinary excretion. All six patients with increased intestinal permeability had a positive 111In image of mild to moderate degree of activity. A positive 111In scan was present in two of the five patients with normal permeability; these were two resected patients.

  15. Preliminary results from the {sup 51}Cr neutrino source experiment in GALLEX

    SciTech Connect

    Hampel, W.; Heusser, G.; Kiko, J.

    1996-09-01

    The GALLEX collaboration performed a second {sup 51}Cr neutrino source experiment during fall 1995. The full results from this second source experiment will not be available before the end of 1996. Meanwhile, we present a short description and preliminary results in this informal note. The (preliminary) value of the activity obtained form direct measurements has been found equal to (68.7 {+-}0.7) PBq (with 1-sigma error). This value, which is about 10% higher than the activity of the first source, was achieved by optimizing the irradiation conditions in the Silo{acute e} reactor and doing a longer irradiation of the enriched chromium. Preliminary results show that the ratio, R, of the radiochemically determined activity from {sup 71}Ge counting (57.1 {+-} PBq) to the directly measured activity is (0.83 {+-} 0.10). The combined value of R for the two source experiments is (0.92 {+-} 0.08).

  16. Use of 125I- and 51Cr-Labeled Albumin for the Measurement of Gastrointestinal and Total Albumin Catabolism*

    PubMed Central

    Kerr, Robert M.; Bois, John J. Du; Holt, Peter R.

    1967-01-01

    A method for the simultaneous measurement of gastrointestinal protein loss and total albumin turnover entailing the use of a combination of 125iodine- and 51chromium-labeled albumin is described. Albumin turnover was calculated by the measurement of albumin-125I plasma decay and cumulative urinary excretion, and the results obtained agreed closely with previous studies utilizing albumin-131I. Gastrointestinal catabolism was calculated from the rate of fecal excretion of 51Cr and the specific activity of plasma albumin-51Cr, and these data were related to the calculated albumin turnover results. During the period of 6-14 days after administration, the ratio of specific activties of albumin-125I and -51Cr in plasma and in extravascular spaces or gastric and biliary secretions remained almost identical. Fecal excretion of 51Cr was also quite stable at this time. In six normal subjects gastrointestinal catabolism accounted for less than 10% of total albumin catabolism. Excessive gastrointestinal protein losses did not contribute to the low serum albumin in three patients with cirrhosis or in two adults with the nephrotic syndrome. Multiple mechanisms leading to hypoalbuminemia were demonstrated in other subjects with a variety of gastrointestinal disorders. Images PMID:5630419

  17. Measuring the activity of a {sup 51}Cr neutrino source based on the gamma-radiation spectrum

    SciTech Connect

    Gorbachev, V. V. Gavrin, V. N.; Ibragimova, T. V.; Kalikhov, A. V.; Malyshkin, Yu. M.; Shikhin, A. A.

    2015-12-15

    A technique for the measurement of activities of intense β sources by measuring the continuous gamma-radiation (internal bremsstrahlung) spectra is developed. A method for reconstructing the spectrum recorded by a germanium semiconductor detector is described. A method for the absolute measurement of the internal bremsstrahlung spectrum of {sup 51}Cr is presented.

  18. Permeability of the small intestine to (/sup 51/Cr)EDTA in children with acute gastroenteritis or eczema

    SciTech Connect

    Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1985-06-01

    Increased gut permeability to macromolecules is thought to be an important factor in the development of food hypersensitivity. The latter can develop in the course of acute gastroenteritis and could play a role in infantile eczema. The authors studied gut permeability in 10 normal adults, 11 control children, 7 children with acute gastroenteritis, and 8 patients with infantile eczema, making use of (/sup 51/Cr)EDTA as probe molecule. (/sup 51/Cr)EDTA was given orally (50-100 microCi); 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the oral dose. Mean and standard error were 2.35 +/- 0.24, 2.51 +/- 0.21, 9.96 +/- 3.44, and 10.90 +/- 2.05 in normal adults, control children, and gastroenteritis and eczema patients, respectively. Differences between controls and either gastroenteritis (p less than 0.001) or eczema (p less than 0.001) patients are significant. The results support the hypothesis that increased gut permeability could play a role in food hypersensitivity.

  19. 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.

    PubMed

    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. PMID:25190735

  20. Radiolabeled red cell viability. I. Comparison of /sup 51/Cr, /sup 99m/Tc, and /sup 111/In for measuring the viability of autologous stored red cells

    SciTech Connect

    Marcus, C.S.; Myhre, B.A.; Angulo, M.C.; Salk, R.D.; Essex, C.E.; Demianew, S.H.

    1987-09-01

    The simultaneous determination of autologous /sup 99m/Tc red cell (RBC) and /sup 51/Cr RBC viability at 24 hours was measured in 19 normal volunteers whose RBCs had been stored in additive media (Nutracel) for 42 or 49 days. The ratio of the /sup 51/Cr:/sup 99m/Tc value was 1.23. In this experiment we also calculated /sup 51/Cr RBC viability by both the single-isotope method (extrapolation) and the double-isotope method (using /sup 125/I human serum albumin for an independent plasma volume) in the same volunteers. The corresponding viability values were not significantly different. The simultaneous determination of autologous /sup 111/In-oxine RBC and /sup 51/Cr RBC viability at 24 hours was measured in 19 other normal volunteers whose RBCs had been stored in citrate-phosphate-dextrose-adenine (CPDA-1) for 1 or 15 days. The ratio of the /sup 51/Cr:/sup 111/In value was 1.1. Use of these 24-hour viability ratios as conversion factors permits direct comparison of /sup 99m/Tc or /sup 111/In RBC viability with a /sup 51/Cr standard, and therefore expands the application of these newer RBC radiolabels.

  1. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ

    SciTech Connect

    Heyns A du, P.; Badenhorst, P.N.; Loetter, M.G.P.; Pieters, H.; Wessels, P.; Kotze, H.F.

    1986-01-01

    Mean platelet survival and turnover were simultaneously determined with autologous 111In-labeled platelets (111In-AP) and homologous 51Cr-labeled platelets (51Cr-HP) in ten patients with chronic immune thrombocytopenic purpura (ITP). In vivo redistribution of the 111In-AP was quantitated with a scintillation camera and computer-assisted image analysis. The patients were divided into two groups: those with splenic platelet sequestration (spleen-liver 111In activity ratio greater than 1.4), and those with diffuse sequestration in the reticuloendothelial system. The latter patients had more severe ITP reflected by pronounced thrombocytopenia, decreased platelet turnover, and prominent early hepatic platelet sequestration. Mean platelet life span estimated with 51Cr-HP was consistently shorter than that of 111In-AP. Platelet turnover determined with 51Cr-HP was thus over-estimated. The difference in results with the two isotope labels was apparently due to greater in vivo elution of 51Cr. Although the limitations of the techniques should be taken into account, these findings indicate that platelet turnover is not always normal or increased in ITP, but is low in severe disease. We suggest that this may be ascribed to damage to megakaryocytes by antiplatelet antibody. The physical characteristics in 111In clearly make this radionuclide superior to 51Cr for the study of platelet kinetics in ITP.

  2. Measurement of glomerular filtration rate in homozygous sickle cell disease: a comparison of 51Cr-EDTA clearance, creatinine clearance, serum creatinine and beta 2 microglobulin.

    PubMed Central

    Aparicio, S A; Mojiminiyi, S; Kay, J D; Shepstone, B J; de Ceulaer, K; Serjeant, G R

    1990-01-01

    Glomerular filtration rates (GFR) were measured with 51Cr-EDTA in 38 patients (aged 40-75 years) with homozygous sickle cell disease and compared with serum beta 2 microglobulin concentrations in 38 patients and with creatinine clearance in 21 patients. GFR estimated with 51Cr-EDTA was closely correlated with single serum creatinine measurements and the inverse of serum beta 2 microglobulin. Creatinine clearance was also found to be correlated, but values were, on average, 32% below those obtained by the 51Cr-EDTA method, and this difference was significant. It is concluded that measurements of beta 2 microglobulin, single serum creatinine, and creatinine clearance are valuable indicators of GFR in homozygous sickle cell disease. Measurement of beta 2 microglobulin was a useful and reliable method of estimating GFR from single plasma measurements and is therefore a useful means of screening the population. PMID:2115049

  3. Comparison of whole body and tissue blood volumes in rainbow trout (Salmo gairdneri) with 125I bovine serum albumin and 51Cr-erythrocyte tracers

    USGS Publications Warehouse

    Gingerich, W.H.; Pityer, R.A.

    1989-01-01

    Total, packed cell and, plasma volume estimates were made for the whole body and selected tissues of rainbow trout by the simultaneous injection of radiolabelled trout erythrocyte (51Cr-RBC) and radioiodinated bovine serum albumin (125I-BSA) tracers. Blood volumes were estimated with both markers separately by the tracer-hematocrit method and as the combination of the 51Cr-RBC packed cell and 125I-BSA plasma volumes. Mean whole body blood volume was significantly less when calculated from the 51Cr-RBC tracer data (3.52±0.78 ml/100 g; ±SD) than when calculated with the 125I-BSA tracer (5.06±0.86 ml/100 g) or as the sum of the two volumes combined (4.49±0.60 ml/100 g). The whole body hematocrit (28±5%), estimated as the quotient of the 51Cr-RBC volume divided by the sum of the 125I-BSA and the 51Cr-RBC volumes, also was significantly less than the dorsal aortic microhematocrit (36±4%). Estimates of total blood volumes in most tissues were significantly smaller when calculated from the51Cr-RBC data than when calculated by the other two methods. Tissue blood volumes were greatest in highly vascularized and well perfused tissues and least in poorly vascularized tissues. The relative degree of vascularization among tissues generally remained the same regardless of whether the red cell or the plasma tracer was used to calculated blood volume. It is not clear whether the expanded plasma volume is the result of the distribution of erythrocyte-poor blood into the secondary circulation or the result of extravascular exchange of plasma proteins.

  4. Comparative gastrointestinal blood loss associated with placebo, aspirin, and nabumetone as assessed by radiochromium (/sup 51/Cr)

    SciTech Connect

    Lussier, A.; Davis, A.; Lussier, Y.; Lebel, E.

    1989-03-01

    Nabumetone differs from most other nonsteroidal anti-inflammatory drugs. It is presented to the gut as a nonacidic prodrug, and is metabolized to its active form after absorption. Studies in animals and humans suggest it is less irritating to the gastrointestinal mucosa. This study compared the gastrointestinal microbleeding induced by nabumetone to aspirin (acetylsalicylic acid, ASA), and placebo in a double blind parallel study using chromium /sup 51/Cr labelled red cells to quantitate fecal blood loss (FBL) in healthy volunteers. Thirty subjects were randomized to treatment with nabumetone (2000 mg), ASA (3.6 g) or placebo for 21 days following a 7 day placebo period. Six subjects served as untreated controls. FBL in nabumetone treated subjects was not significantly different to placebo or untreated subjects. In contrast, ASA-treated subjects exhibited significantly increased FBL than the other 3 groups (P less than .0001).

  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

    SciTech Connect

    Larsson, Erik; Ljungberg, Michael; Martensson, Linda; Nilsson, Rune; Tennvall, Jan; Strand, Sven-Erik; Joensson, Bo-Anders

    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. Simultaneous measurement of 59Fe and 51Cr in iron absorption studies using a whole-body scanner with mobile shielding.

    PubMed

    Marx, J J; van den Beld, B; van Dongen, R; Strackee, L H

    1980-07-01

    A whole-body scanner is described with a mobile shadow shield which affords a considerable reduction in space. The scanner has two NaI(T1) scintillation crystals of 4 x 6", placed at opposite sites of the subject. Background radiation, efficiency and geometric qualities made the scanner very useful for clinical whole-body counting. The equipment was used in iron absorption studies using a double isotope technique with 59Fe and 51Cr. After ingestion of an oral test dose total body kinetics of 59Fe and 51Cr was followed up to 60 days in 4 volunteers. Between days 3 and 10 the 51Cr, which was used as an non-absorbable indicator, had left the body completely. The 59Fe reached a constant value not before day 10, indicating that iron retention cannot be measured before that time. From repeated measurement of 59Fe and 51Cr directly after ingestion until the first defaecation it could be deduced that the coefficient of variation for 59Fe was less than 1.5% with a scanning time of 600 sec, and for 51Cr less than 5%. Extreme variations in geometry, such as measurement of the activity in a beaker and of the same amount after ingestion in the body, yielded practically the same value for 59Fe. The double isotope technique made it possible to measure not only iron retention but also mucosal uptake and mucosal transfer of iron. It is pointed out that measurement of the last two parameters of iron absorption is not possible in patients with serious obstipation or with very low mucosal uptake values. PMID:6780983

  7. Determination of optimal sampling times for a two blood sample clearance method using (51)Cr-EDTA in cats.

    PubMed

    Vandermeulen, Eva; De Sadeleer, Carlos; Piepsz, Amy; Ham, Hamphrey R; Dobbeleir, André A; Vermeire, Simon T; Van Hoek, Ingrid M; Daminet, Sylvie; Slegers, Guido; Peremans, Kathelijne Y

    2010-08-01

    Estimation of the glomerular filtration rate (GFR) is a useful tool in the evaluation of kidney function in feline medicine. GFR can be determined by measuring the rate of tracer disappearance from the blood, and although these measurements are generally performed by multi-sampling techniques, simplified methods are more convenient in clinical practice. The optimal times for a simplified sampling strategy with two blood samples (2BS) for GFR measurement in cats using plasma (51)chromium ethylene diamine tetra-acetic acid ((51)Cr-EDTA) clearance were investigated. After intravenous administration of (51)Cr-EDTA, seven blood samples were obtained in 46 cats (19 euthyroid and 27 hyperthyroid cats, none with previously diagnosed chronic kidney disease (CKD)). The plasma clearance was then calculated from the seven point blood kinetics (7BS) and used for comparison to define the optimal sampling strategy by correlating different pairs of time points to the reference method. Mean GFR estimation for the reference method was 3.7+/-2.5 ml/min/kg (mean+/-standard deviation (SD)). Several pairs of sampling times were highly correlated with this reference method (r(2) > or = 0.980), with the best results when the first sample was taken 30 min after tracer injection and the second sample between 198 and 222 min after injection; or with the first sample at 36 min and the second at 234 or 240 min (r(2) for both combinations=0.984). Because of the similarity of GFR values obtained with the 2BS method in comparison to the values obtained with the 7BS reference method, the simplified method may offer an alternative for GFR estimation. Although a wide range of GFR values was found in the included group of cats, the applicability should be confirmed in cats suspected of renal disease and with confirmed CKD. Furthermore, although no indications of age-related effect were found in this study, a possible influence of age should be included in future studies. PMID:20452793

  8. Experimental and theoretical study for the production of 51Cr using p, d, 3He and 4He projectiles on V, Ti and Cr targets

    NASA Astrophysics Data System (ADS)

    Solieman, A. H. M.; Al-Abyad, M.; Ditroi, F.; Saleh, Z. A.

    2016-01-01

    Production of 51Cr (T1/2 = 27.7 d) have been studied experimentally through the reaction of proton and 3He on natV and natTi targets respectively by using a variable energy cyclotrons. Reaction cross sections were obtained at different energies using the stacked-foil technique. High resolution gamma ray spectrometers were used for measuring the γ-ray spectra. Comparison between the present experimental results and the previously reported data has been carried out and discussed. The possibility of producing 51Cr with reasonable yield using different projectiles and different natural targets was studied and reported. Excitation functions for the reactions of proton, deuteron, 3He and 4He particles on natural vanadium, titanium and chromium targets have been evaluated using two theoretical codes TALYS-1.6 and EMPIRE-3.1. The recommended cross-sections and the integral yields as well were obtained.

  9. Increased 177Lu-DOTATATE uptake in Paget disease.

    PubMed

    Minutoli, Fabio; Sindoni, Alessandro; Cardile, Davide; Pecorella, Giorgio Restifo; Baldari, Sergio

    2013-10-01

    A 45-year-old female patient was referred for peptide receptor radionuclide therapy of liver metastases of neuroendocrine origin; the patient had undergone 2 years earlier surgical resection of a grade 2 neuroendocrine neoplasm of ampulla of Vater infiltrating the duodenal submucosa and muscular layers and the neighboring pancreatic tissue. Post-therapy whole-body scan performed to evaluate in vivo radiopharmaceutical distribution confirmed high accumulation in liver lesions and revealed increased uptake in the hip bone. Bone scan and corresponding CT images demonstrated changes of Paget disease in the same district. PMID:23877528

  10. Thymoma treated with 177Lu DOTATATE induction and maintenance PRRT.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-05-01

    A 47-year-old man presented with a recurrent thymoma World Health Organization type A of the anterior chest wall with pleural metastases after failing chemotherapy. The tumor was positive on In-octreotide, and he was referred for peptide receptor radionuclide therapy (PRRT) with Lu DOTATATE. He received 4 induction and 2 maintenance Lu DOTATATE treatments (total dose, 1000 mCi) and reported significant improvement in symptoms. Before the seventh treatment, mild progression was diagnosed on CT, and PRRT was terminated. The use of induction and maintenance Lu DOTATATE PRRT therapy in the management of thymoma warrants further research. PMID:25783505

  11. Bioelimination of /sup 51/Cr and /sup 85/Sr by cockroaches, Gromphadorhina portentosa (Orthoptera: Blaberidae), as affected by mites, Gromphadorholaelaps schaeferi (parasitiformes: laelapidae)

    SciTech Connect

    Schowalter, T.D.; Crossley, D.A. Jr.

    1982-03-01

    This paper describes rates of Chromium-51 and Strontium-85 assimilation and bioelimination by the hissing cockroach, Gromphadorhina portentosa (Schaum), when the symbiotic mite, Gromphadorholaelaps schaeferi Till, was present or removed. Mite-infested cockroaches had significantly higher rates of /sup 51/Cr elimination relative to mite-free cockroaches, implying more rapid gut clearance times. We did not find a significant mite effect on /sup 85/Sr elimination by the host, but mite effects could have been masked by the apparently unique process of nutrient assimilation and elimination by G. portentosa. Conventional models of radioactive tracer bioelimination predict a rapid initial loss of tracer due to gut clearance, followed by a slower loss due to excretion of assimilated tracer. Our results indicated that assimilated /sup 85/Sr was eliminated earlier than unassimilated /sup 85/Sr was lost by defecation.

  12. Bioelimination of /sup 51/Cr and /sup 85/Sr by cockroaches, Gromphadorhina portentosa (orthoptera: blaberidae), as affected by mites, Gromphadorholaelaps schaeferi (parasitiformes: laelapidae)

    SciTech Connect

    Schowalter, T.D.; Crossley, D.A. Jr.

    1982-03-01

    The rates of Chromium-51 and Strontium-85 assimilation and bioelimination by the hissing cockroach, Gromphadorhina portentosa (Schaum) are described when the symbiotic mite, Gromphadorholaelaps schaeferi Till, was present or removed. Mite-infested cockroaches had significantly higher rates of /sup 51/Cr elimination relative to mite-free cockroaches, implying more rapid gut clearance times. The authors did not find a significant mite effect on /sup 85/Sr elimination by the host, but mite effects could have been masked by the apparently unique process of nutrient assimilation and elimination by G. portentosa. Conventional models of radioactive tracer bioelimination predict a rapid initial loss of tracer due to gut clearance, followed by a slower loss due to excretion of assimilated tracer. The results indicated that assimilated /sup 85/Sr was eliminated earlier than unassimilated /sup 85/Sr, which was lost by defecation.

  13. Radiokinetic study on nucleation process of 65Zn(OH)2, 65Zn3(PO4)2 and 51CrPO4 crystals in gelatin and agar

    NASA Astrophysics Data System (ADS)

    Cecal, Al; Palamaru, M.; Chisca, S.; Balan, A.

    1999-01-01

    The nucleation process of 65Zn(OH)2, 65Zn3(PO4)2, and 51CrPO4 crystals in gelatin and agar was studied by using radioactive tracers. The diffusion rate, constants for 65Zn2+ and 51Cr3+ cations through gel, and the reaction rate constants of nucleation process as well as the beginning time of crystal appearance were established. It was found that the reaction rate constant of the low-soluble crystal is higher, and consequently, in a given colloidal medium this parameter varies as follows: k * Zn(PO4)2> k * Zn(OH) 2> k * CrPO 4

  14. Radiokinetic study on nucleation process of 65Zn(OH)2, 65Zn3(PO4)2 and 51CrPO4 crystals in gelatin and agar

    NASA Astrophysics Data System (ADS)

    Cecal, Al; Palamaru, M.; Chisca, S.; Balan, A.

    1999-01-01

    The nucleation process of 65Zn(OH)2, 65Zn3(PO4)2, and 51CrPO4 crystals in gelatin and agar was studied by using radioactive tracers. The diffusion rate, constants for 65Zn2+ and 51Cr3+ cations through gel, and the reaction rate constants of nucleation process as well as the beginning time of crystal appearance were established. It was found that the reaction rate constant of the low-soluble crystal is higher, and consequently, in a given colloidal medium this parameter varies as follows: k * Zn(PO4)2>k * Zn(OH) 2>k * CrPO 4

  15. Survival of density subpopulations of rabbit platelets: use of /sup 51/Cr-or /sup 111/In-labeled platelets to measure survival of least dense and most dense platelets concurrently

    SciTech Connect

    Rand, M.L.; Packham, M.A.; Mustard, J.F.

    1983-02-01

    The origin of the density heterogeneity of platelets was studied by measuring the survival of density subpopulations of rabbit platelets separated by discontinuous Stractan density gradient centrifugation. When a total population of /sup 51/Cr-labelled platelets was injected into recipient rabbits, the relative specific radioactivity of the most dense platelets decreased rapidly. In contrast, that of the least dense platelets had not changed 24 hr after injection, and then decreased slowly. To distinguish between the possibilities that most dense platelets are cleared from the circulation more quickly than least dense platelets or that platelets decrease in density as they age in the circulation, the concurrent survival of least dense and most dense platelets, labelled with either /sup 51/Cr or /sup 111/In-labelled total platelet populations, determined concurrently in the same rabbits, are identical, calculated from 1 hr values as 100%. However, the 1-hr recovery of /sup 111/In-labelled platelets was slightly but significantly less than that of /sup 51/Cr-labelled platelets. Therefore, researchers studied the survival of /sup 51/Cr-labelled least dense and /sup 111/In-labelled most dense platelets as well as that of /sup 111/In-labelled least dense and /sup 51/Cr-labelled most dense platelets. Mean 1-hr recovery of least dense platelets, labelled with either isotope (78% +/- 7%, SD) was similar to that of most dense platelets, labelled with either isotope (77% +/- 8%; SD). Mean survival of least dense platelets was 47.3 +/- 18.7 hr (SD), which was significantly less than that of most dense platelets (76.1 +/- 21.6 hr; SD) (p less than 0.0025). These results indicate that platelets decrease in buoyant density as they age in the circulation and that most dense platelets are enriched in young platelets, and least dense in old.

  16. Cross sections of the 56Fe(n ,α ) 53Cr and 54Fe(n ,α ) 51Cr reactions in the MeV region

    NASA Astrophysics Data System (ADS)

    Wang, Zhimin; Fan, Xiao; Zhang, Luyu; Bai, Huaiyong; Chen, Jinxiang; Zhang, Guohui; Gledenov, Yu. M.; Sedysheva, M. V.; Krupa, L.; Khuukhenkhuu, G.

    2015-10-01

    Cross sections of the 56Fe(n ,α ) 53Cr and 54Fe(n ,α )51Cr reactions were measured at En=5.5 and 6.5 MeV and En=4.0 ,4.5 ,5.5 ,and 6.5 MeV , respectively, using a double-section gridded ionization chamber as the α -particle detector. Natural iron and enriched 56Fe and 54Fe foil samples were prepared. A deuterium gas target was used to produce monoenergetic neutrons through the 2H(d ,n )3He reaction. Two rounds of experiments were performed at the 4.5-MV Van de Graaff Accelerator of Peking University. The foreground and background were measured in separate runs. The neutron flux was monitored by a B F3 long counter, and the cross sections of the 238U(n ,f ) reaction were used as the standard. Present results are compared with those of the talys-1.6 code calculations, existing measurements, and evaluations.

  17. Maternal immunocompetence. I. The graft-versus-host reactivity of lymphocytes from pregnant rats and the distribution pattern of 51Cr-labeled lymphocytes in pregnant mice.

    PubMed

    Harrison, M R

    1976-01-01

    Lymphocytes from the peripheral blood, spleen, or para-aortic lymph nodes of prrimigravida L rats carrying (L X BN) F1 (LBN) fetuses are fully capable of mounting graft-versus-host (GVH) reactions in LBN F1 recipients. The reactivity of lymphocytes from interstrain pregnant (L X BN) or intrastrain pregnant (L X L) rats, or from rats postpartum from these pregnancies, is equivalent to that of normal virgin females over a full dose-response curve, ruling out both specific and nonspecific effects of pregnancy on the intrinsic GVH competence of the maternal thymus-derived (T) lymphocyte. Attempts to block GVH reactivity with serum from pregnant rats were unsuccessful. In addition, when the distribution pattern of 51Cr-labeled syngeneic and semiallogeneic lymphocytes was studied in intact primigravida mice, there was no difference between interstrain and intrastrain pregnant mice, and there was no evidence of immunologically specific 'trapping' in the para-aortic lymph nodes draining the interstrain pregnant uterus. PMID:8832

  18. Renal Distribution Volumes of Indocyanine Green, [51Cr]EDTA, and 24Na in Man during Acute Renal Failure after Shock. IMPLICATIONS FOR THE PATHOGENESIS OF ANURIA

    PubMed Central

    Reubi, F. C.; Vorburger, C.; Tuckman, J.

    1973-01-01

    The mechanism responsible for the anuria in acute renal failure after shock is still controversial. Suppressed glomerular filtration and/or tubular back-diffusion of the filtrate are major possible causes. In the present investigation, seven patients with acute anuria, three of these seven again in the polyuric phase, six patients with moderate renal impairment, four patients with chronic renal failure, and eight subjects with normal renal function were studied by a multiple indicator-dilution method in which the total renal blood flow and renal distribution volumes of indocyanine green, [51Cr]EDTA, and 24Na were determined. In normal subjects the average values for one kidney were 582 ml/min, 42 ml, 92 ml, and 139 ml, respectively. The measurements in the patients with moderate renal impairment were similar to those in the normal subjects, but were decreased in chronic renal failure. In acute anuria, the average values were 269 ml/min, 40 ml, 101 ml, and 114 ml and the kidney volume, estimated radiographically, was increased by 40%. When expressed as milliliters per milliliters kidney, the average distribution volume of 24Na was decreased from 0.64 to 0.38. This decrease is consistent with the hypothesis that suppressed filtration is largely responsible for the anuria and that back-diffusion is, at most, a contributory factor. The apparent contradiction between the relatively well-preserved total blood flow and the suppressed filtration may be due to a combination of afferent vasoconstriction and efferent vasodilatation. This view is supported by the observation that low filtration fractions were found in clearance measurements performed during the polyuric phase. PMID:4630601

  19. Investigation of the neutron activation of endohedral rare earth metallofullerenes

    SciTech Connect

    Shilin, V. A. Lebedev, V. T.; Kolesnik, S. G.; Kozlov, V. S.; Grushko, Yu. S.; Sedov, V. P.; Kukorenko, V. V.

    2011-12-15

    Endohedral lanthanide metallofullerenes and their water-soluble biocompatible derivatives have been synthesized. The effect that fast-neutron irradiation has on the stability and nuclear physical properties of endohedral metallofullerenes that are used as magnetocontrast materials ({sup 46}Sc, {sup 140}La, {sup 141}Nd, {sup 153}Sm, {sup 152}Eu, {sup 154}Eu, {sup 153}Sm, {sup 160}Tb, {sup 169}Yb, {sup 170}Tm (isomers I and III), and {sup 177}Lu) is studied. Our hypothesis, according to which carbon-shell relaxation is based on the fast nonradiative processes of an electron shake-off type, is confirmed.

  20. Cocktail Therapy of 177Lu-PSMA-617 and 177Lu-EDTMP in Patients With mCRPC: A Proof-of-Principle Application.

    PubMed

    Bal, Chandrasekhar; Yadav, Madhav Prasad; Ballal, Sanjana

    2016-08-01

    Prostate cancer is the second most common primary tumor affecting men worldwide. Among them, 10-20% develop castration resistant prostate cancer (CRPC). Ga-PSMA-PET/CT is an important theranostic agent for the evaluation of CRPC to assess the feasibility of treatment with Lu-PSMA-617 which is a novel therapeutic agent. Interestingly, in certain cases, we have observed non-PSMA-avid lesions despite raised sPSA levels. In this regard, we present a case of cocktail therapy applied using Lu-PSMA-617 and Lu-EDTMP therapy in a 38-year-old male CRPC patient with both soft tissue and extensive skeletal metastases. PMID:27187728

  1. Excretion of radionuclides in human breast milk following administration of /sup 125/I-fibrinogen, /sup 99/Tc/sup m/-MAA and /sup 51/Cr-EDTA

    SciTech Connect

    Mattsson, S.; Johansson, L.; Nosslin, B.; Ahlgren, L.

    1981-06-01

    Very few biokinetic and dosimetric data for estimating the absorbed dose to a breast-feeding child are available in the literature. The few available are usually case reports. We have measured the activity concentration in breast milk from one patient after administration of /sup 125/I-fibrinogen, from two patients after administration of /sup 99/Tc/sup m/-macroaggregated albumin, and from one patient after administration of /sup 51/Cr-EDTA. We have compared our data with earlier published results and estimated the absorbed dose to the breast-feeding child using biokinetic data presented in this work and recently published S-values for new-born children.

  2. Effect of background region of interest and time-interval selection on glomerular filtration ratio estimation by percentage dose uptake of (99m)Tc-DTPA in comparison with (51)Cr-EDTA clearance in healthy cats.

    PubMed

    Debruyn, Katrien; Vandermeulen, Eva; Saunders, Jimmy H; Dobbeleir, André A; Ham, Hamphrey R; Peremans, Kathelijne

    2013-08-01

    Evaluation of glomerular function is a useful part of the diagnostic approach in animals suspected of having renal disease. Time-interval and background region of interest (bg ROI) selection are determining factors when calculating the glomerular filtration ratio (GFR) based on percentage uptake of (99m)technetium-labelled diethylene triamine penta-acetic acid ((99m)Tc-DTPA). Therefore, three different time intervals (60-120 s, 120-180 s, 60-180 s) and three different bg ROIs (C-shape, caudolateral, cranial + caudal) were investigated. In addition, global GFRs based on percentage dose uptake of (99m)Tc-DTPA for the different time-intervals and bg ROIs were compared with the global GFR based on (51)chromium-ethylene diaminic tetra-acetic acid ((51)Cr-EDTA) plasma clearance in nine healthy European domestic shorthair cats. Paired Student's t-tests and linear regression analysis were used to analyse the data. Different time intervals seemed to cause significant variation (P <0.01) in absolute GFR values, regardless of the choice of bg ROI. Significant differences (P <0.01) between bg ROIs were only observed in the 120-180s time interval between the C-shape and cranial + caudal bg ROI, and between the caudolateral and cranial + caudal bg ROI. The caudolateral bg ROI in the 60-180 s time interval showed the highest correlation coefficient (r = 0.882) between (99m)Tc-DTPA and (51)Cr-EDTA, although a significant difference (P <0.05) was present between both techniques. PMID:23349527

  3. Production of {sup 177}Lu, a potential radionuclide for diagnostic and therapeutic applications

    SciTech Connect

    Khandaker, Mayeen Uddin; Kassim, Hasan Abu; Haba, Hiromitsu

    2015-04-24

    {sup 177g}Lu (T{sub 1/2}=6.647d; E{sub β{sup −max}}=498.3KeV, I{sub β{sup −total}}=100%; E{sub γ} = 112.9498 keV, I{sub γ} = 6.17%; E{sub γ} = 208.3662 keV, I {sub γ} = 10.36%) is widely used in many clinical procedures due to its excellent decay characteristics. Production cross-sections of the {sup nat}Yb(d,x){sup 177g}Lu reactions have been measured from a 24-MeV deuteron energy down to the threshold by using a stacked-foil activation technique combined with high resolution γ-ray spectrometry. An overall good agreement is found with some of the earlier measurements, whereas a partial agreement is obtained with the theoretical data extracted from the TENDL-2013 library. Physical thick target yield for the {sup 177g}Lu radionuclide was deduced using the measured cross-sections. The deduced yield curves indicate that a low energy (<11 MeV) cyclotron and a highly enriched {sup 176}Yb target could be used to obtain {sup 177g}Lu with negligible impurity from {sup 177m}Lu.

  4. Medullary thyroid carcinoma (MTC) treated with 177Lu-DOTATATE PRRT: a report of two cases.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-05-01

    Two patients diagnosed with metastatic medullary thyroid carcinoma (MTC) were referred for peptide receptor radionuclide therapy (PRRT) with Lu-[DOTA,Tyr]octreotate (DOTATATE). Each patient was treated with 4 doses of Lu-DOTATATE given 2 months apart. One patient achieved stable disease for 10 months then chose to pursue surgery, and the other achieved stable disease for 9 months on imaging; however, calcitonin continued to rise. The use of Lu-DOTATATE PRRT therapy in the management of MTC warrants further research. PMID:25674858

  5. Glucagonoma Pancreatic Neuroendocrine Tumor Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

    PubMed

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

    2015-11-01

    A 56-year-old man presented with a history of 2 prior resections of a recurrent pancreatic glucagonoma in the past 4 years. Workup revealed new liver and abdominal nodal metastases with a rising serum glucagon level. He was started on peptide receptor radionuclide therapy with Lu DOTATATE, and his disease stabilized, while his glucagon levels decreased and also stabilized. After 4 induction and 2 maintenance cycles, he remains progression free for 23 months. PMID:26204206

  6. Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

    SciTech Connect

    Guerra Liberal, Francisco D. C. E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S. E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S.

    2014-11-01

    Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all

  7. Treatment efficacy of 153Sm-EDTMP for painful bone metastasis

    PubMed Central

    Ayati, Narjess; Aryana, Kamran; Jalilian, Amir; Hoseinnejad, Toktam; Samani, Ali Bahrami; Ayati, Zahra; Shariati, Farzane; Zakavi, S. Rasoul

    2013-01-01

    Introduction: Involvement of the skeleton can cause an excruciating pain in two-thirds of terminal patients with a history of malignancy. Due to several limitations of other therapies, such as analgesics, bisphosphonates, chemotherapy, hormonal therapy and external beam radiotherapy; bone-seeking radiopharmaceuticals have an important role in palliation of pain from bone metastases. Although these kinds of therapies have many advantages including the ability to treat multiple sites of tumoral involvement simultaneously, no significant confliction with other treatments, ease of administration and the potential to be used repetitively; in Iran using of this modality is not widely practiced. In this study we evaluated the clinical usefulness of Sm-153 lexidronamfor pain management of bone metastases. Methods: 28 patients (14 males and 14 females) aged 38-77 years with a history of painful bone metastases caused by different cancers, not responding to conventional treatments were included in the study. All patients had a recent whole body bone scan indicating multiple bone metastases. 1 mCi/Kg Sm-153 lexidronam was injected intravenously to the patients. Whole body scintigraphy was done 3 or 18 hours post injection. Pain relief and quality of life have been evaluated by analog pain scale and Karnofsky index every week, respectively. Also, all patients were evaluated for hematological toxicity every two weeks. Active follow ups were performed. Results: 43% of patients showed the presence of the flare phenomenon during the first three days after Sm injection with a mean duration of 2.2 days. The pain relief began between 2 and 16 days post injection and the duration of pain palliation was in the range of 4 to 32 weeks (mean±SD=15.22±7.8). 64.3% of patients showed complete relief of pain and 21.4% achieved partial response to therapy. (Over all response to therapy was 85.7%). The lowest amount of peripheral blood cells was detected in the fourth week for RBCs and in the 6th week for WBCs and PLTs. No one experienced hematological toxicity induced problems. Conclusion: Sm-153 lexidronam is an effective treatment for painful bone metastases. The complication rate is low and the quality of life of the patients after treatment would be significantly improved.

  8. Metastatic Prostate Cancer With Restored Hormone-Response After Radioligand Therapy With 177Lu-PSMA-617.

    PubMed

    Schlenkhoff, Carl Diedrich; Knüpfer, Eberhard; Essler, Markus; Ahmadzadehfar, Hojjat

    2016-07-01

    An 80-year-old patient with castrate-resistant prostate cancer presented to our department for PSMA imaging because of a rising prostate-specific antigen (PSA) level. The tumor was diagnosed in 2004. GnRh analog was the only treatment the patient received. Two cycles of Lu-PSMA-617 were performed with a 2-month interval in between. Ten months after finishing with 2 cycles of Lu-PSMA therapy, we noticed a continuous falling PSA level and a decreasing tumor spread in the PET/CT imaging just under the hormone therapy. PMID:26909718

  9. Positive Influence of 177Lu PSMA-617 Therapy on Bone Marrow Depression Caused by Metastatic Prostate Cancer.

    PubMed

    Schlenkhoff, Carl Diedrich; Gaertner, Florian; Essler, Markus; Schmidt, Matthias; Ahmadzadehfar, Hojjat

    2016-06-01

    A 75-year-old man with castrate-resistant prostate cancer and increasing prostate-specific antigen (PSA) level developed severe bone marrow depression during Ra radionuclide therapy. Because of this, he was treated with Lu-PSMA in compassionate use for this not-yet-approved therapy. At the beginning of Lu-PSMA therapy, repeated blood transfusions (BT) were necessary. Six months after the last BT, after 3 cycles of Lu-PSMA, his blood count stabilized. He required no further BTs and his PSA level remained lowered. PMID:26909716

  10. Cardiac metastases of neuroendocrine tumors treated with 177Lu DOTATATE peptide receptor radionuclide therapy or 131I-MIBG therapy.

    PubMed

    Makis, William; McCann, Karey; Bryanton, Mark; McEwan, Alexander J B

    2015-12-01

    Neuroendocrine tumors have a propensity to metastasize to the heart, although the reason for this remains unknown. A review of 251 neuroendocrine tumor patients treated with Lu DOTATATE peptide receptor radionuclide therapy or I-MIBG therapy at our institution since 2003 revealed 2 patients with cardiac metastases (incidence, 0.8%), one treated with Lu DOTATATE and one with I-MIBG. We present the imaging findings of these 2 patients, as well as their management and responses to therapy. PMID:26359563

  11. Peptide receptor radionuclide therapy with (177)Lu DOTATATE in a case of recurrent carotid body paraganglioma with spinal metastases.

    PubMed

    Gupta, Santosh Kumar; Singla, Suhas; Karunanithi, Sellam; Damle, Nishikant; Bal, Chandrasekhar

    2014-05-01

    Paragangliomas are rare benign neuroendocrine tumors, and 80% of all paragangliomas are either carotid body tumors or glomus jugulare tumors. We present a case of recurrent unresectable carotid body paraganglioma with nodal and T7 vertebral metastases in a 30-year-old man 6 years postsurgery detected with Ga DOTANOC PET/CT and was administered with peptide receptor radionuclide therapy using Lu DOTATATE. After 5 cycles of Lu DOTATATE (total cumulative activity of 750 mCi [27 GBq]), significant response at the primary site on Ga DOTANOC PET/CT and complete disappearance of nodal and T7 vertebral metastases were noted. PMID:24217545

  12. Liver and bone metastases from small bowel neuroendocrine tumor respond to 177Lu-DOTATATE induction and maintenance therapies.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-02-01

    A 73-year-old man diagnosed with small bowel neuroendocrine tumor (NET) with liver and bone metastases was treated with 4 induction cycles and 2 maintenance cycles of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). His symptoms and mobility improved significantly following induction as well as maintenance treatments, and posttherapy imaging studies showed significant improvement in metastatic liver and bone disease. Current protocols consisting of 4 induction cycles of Lu-DOTATATE only may not be sufficient to optimally treat neuroendocrine liver and bone metastases, and further research into maintenance Lu-DOTATATE therapy is warranted. PMID:25243941

  13. 68Ga-PSMA PET/CT Imaging and 153Sm-EDTMP Bone Pain Palliation Therapy.

    PubMed

    Sasikumar, Arun; Joy, Ajith; Nanabala, Raviteja; Pillai, M R A; Thomas, Boben

    2016-07-01

    Ga-labeled prostate-specific membrane antigen (PSMA) is a potential tool in the imaging of recurrent prostate cancer. Ga-PSMA imaging is also useful for radiotherapy planning and in targeted therapy with Lu-PSMA. A few case reports regarding the use of Ga-PSMA in nonprostate cancer malignancies are also reported. We describe the use of Ga-PSMA imaging before Sm-EDTMP bone pain palliation therapy in a 58-year-old hormone refractory prostate cancer patient with extensive bone metastases. PMID:27055142

  14. Semi-automatic 3D-volumetry of liver metastases from neuroendocrine tumors to improve combination therapy with 177Lu-DOTATOC and 90Y-DOTATOC

    PubMed Central

    Cieciera, Matthaeus; Kratochwil, Clemens; Moltz, Jan; Kauczor, Hans-Ulrich; Holland-Letz, Tim; Choyke, Peter; Mier, Walter; Haberkorn, Uwe; Giesel, Frederik L.

    2016-01-01

    PURPOSE Patients with neuroendocrine tumors (NET) often present with disseminated liver metastases and can be treated with a number of different nuclides or nuclide combinations in peptide receptor radionuclide therapy (PRRT) depending on tumor load and lesion diameter. For quantification of disseminated liver lesions, semi-automatic lesion detection is helpful to determine tumor burden and tumor diameter in a time efficient manner. Here, we aimed to evaluate semi-automated measurement of total metastatic burden for therapy stratification. METHODS Nineteen patients with liver metastasized NET underwent contrast-enhanced 1.5 T MRI using gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid. Liver metastases (n=1537) were segmented using Fraunhofer MEVIS Software for three-dimensional (3D) segmentation. All lesions were stratified according to longest 3D diameter >20 mm or ≤20 mm and relative contribution to tumor load was used for therapy stratification. RESULTS Mean count of lesions ≤20 mm was 67.5 and mean count of lesions >20 mm was 13.4. However, mean contribution to total tumor volume of lesions ≤20 mm was 24%, while contribution of lesions >20 mm was 76%. CONCLUSION Semi-automatic lesion analysis provides useful information about lesion distribution in predominantly liver metastasized NET patients prior to PRRT. As conventional manual lesion measurements are laborious, our study shows this new approach is more efficient and less operator-dependent and may prove to be useful in the decision making process selecting the best combination PRRT in each patient. PMID:27015320

  15. Reversal of Severe and Refractory Humoral Hypercalcemia With 177Lu-Octreotate Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor of the Pancreas.

    PubMed

    Iliuta, Ioan-Andrei; Beauregard, Jean-Mathieu; Couture, Félix; Douville, Pierre; Mac-Way, Fabrice

    2015-09-01

    A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor. PMID:26053724

  16. Resolution of Hyperreninemia, Secondary Hyperaldosteronism, and Hypokalemia With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy in a Patient With Pancreatic Neuroendocrine Tumor.

    PubMed

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

    2015-11-01

    A 54-year-old woman presented with a history of nausea, vomiting, diarrhea, and recurrent episodes of severe hypokalemia requiring hospitalization. Imaging revealed a pancreatic mass with liver metastases, histologically confirmed to be a neuroendocrine tumor. Elevated active renin and aldosterone levels were identified, and the patient was treated with 4 induction cycles of Lu-DOTATATE, which resolved the diarrhea, nausea, and hypokalemia, and normalized the renin and aldosterone levels. After 3 additional maintenance Lu-DOTATATE treatments, the pancreatic tumor had decreased in size, was deemed operable, and was resected. She remains on maintenance Lu-DOTATATE therapy with progression-free survival of 45 months thus far. PMID:26359564

  17. (99m)Tc HYNIC-TOC imaging and 177Lu DOTA-octreotate treatment in non-iodine-concentrating dedifferentiated thyroid carcinoma metastases: an unusual alternative diagnosis.

    PubMed

    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. PMID:24873792

  18. The use of (68)Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177)Lu DOTATATE therapy in pituitary carcinoma.

    PubMed

    Novruzov, Fuad; Aliyev, Jamil A; Jaunmuktane, Zane; Bomanji, Jamshed B; Kayani, Irfan

    2015-01-01

    A 68-year-old man, with a history of pituitary surgery and radiation therapy for pituitary macroadenoma 20 years earlier, presented with a pituitary mass and enlarging lesions within the posterior fossa and spinal canal. Biopsy revealed low-grade pituitary carcinoma. PET/CT scan showed multiple foci of increased Ga DOTATATE activity including pituitary and posterior fossa lesions. After 3 fractions of Lu DOTATATE therapy, the tumor remained stable over 4 years on MRI and Ga DOTATATE scans. This case illustrates the benefit of Ga DOTATATE PET/CT in malignant pituitary disease to assess potential for somatostatin receptor therapy with Lu DOTATATE and monitor treatment. PMID:25275413

  19. 4D SPECT/CT acquisition for 3D dose calculation and dose planning in (177)Lu-peptide receptor radionuclide therapy: applications for clinical routine.

    PubMed

    Kairemo, Kalevi; Kangasmäki, Aki

    2013-01-01

    Molecular radiotherapy combines the potential of a specific tracer (vector) targeting tumor cells with local radiotoxicity. Designing a specific tumor-targeting/killing combination is a tailoring process. Radionuclides with imaging capacity serve best in the selection of the targeting molecule. The potential of targeted therapy with radiolabeled peptides has been reported in many conditions; peptide receptor radionuclide therapy (PRRT) is already part of Scandinavian guidelines for treating neuroendocrine tumors. Lu-177- and Y-90-labeled somatostatin analogs, including DOTATOC, DOTANOC, and DOTATATE, are most the commonly used and have turned out to be effective. For routine use, an efficient, rapid, and reliable dose calculation tool is needed. In this chapter we describe how serial pre- and posttherapeutic scans can be used for dose calculation and for predicting therapy doses. Our software for radionuclide dose calculation is a three-dimensional, voxel-based system. The 3D dose calculation requires coregistered SPECT image sets from several time points after infusion to reconstruct time-activity curves for each voxel. Image registration is done directly by SPECT image registration using the first time point as a target. From the time-activity curves, initial activity and total half-life maps are calculated to produce a cumulated activity map. The cumulated activity map is then convoluted with a voxel-dose kernel to obtain a 3D dose map. We performed dose calculations similarly for both therapeutic and preplanning images. Preplanning dose was extrapolated to predict therapy dose using the ratio of administered activities. Our 3D dose calculation results are also compared with those of OLINDA. Our preliminary results indicate that dose planning using pretherapeutic scanning can predict critical organ and tumor doses. In some cases, the dose planning prediction resulted in slight, and slightly dose-dependent, overestimation of final therapy dose. Real tumor dose was similar in both pretherapeutic and posttherapeutic scans using our software. The OLINDA software and our program gave similar normal organ doses, whereas tumor doses could be calculated in a more detailed manner using the 3D program. PMID:22918781

  20. Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases.

    PubMed

    Lange, Rogier; Ter Heine, Rob; Knapp, Russ Ff; de Klerk, John M H; Bloemendal, Haiko J; Hendrikse, N Harry

    2016-10-01

    Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents. PMID:27496068

  1. Quantitative estimation of hemorrhage in chronic subdural hematoma using the /sup 51/Cr erythrocyte labeling method

    SciTech Connect

    Ito, H.; Yamamoto, S.; Saito, K.; Ikeda, K.; Hisada, K.

    1987-06-01

    Red cell survival studies using an infusion of chromium-51-labeled erythrocytes were performed to quantitatively estimate hemorrhage in the chronic subdural hematoma cavity of 50 patients. The amount of hemorrhage was determined during craniotomy. Between 6 and 24 hours after infusion of the labeled red cells, hemorrhage accounted for a mean of 6.7% of the hematoma content, indicating continuous or intermittent hemorrhage into the cavity. The clinical state of the patients and the density of the chronic subdural hematoma on computerized tomography scans were related to the amount of hemorrhage. Chronic subdural hematomas with a greater amount of hemorrhage frequently consisted of clots rather than fluid.

  2. Radioisotope research, production, and processing at the University of Missouri Research Reactor

    SciTech Connect

    Ehrhardt, G.J.; Ketring, A.R.; Ja, Wei; Ma, D.; Zinn, K.; Lanigan, J.

    1995-12-31

    The University of Missouri Research Reactor (MURR) is a 10 MW, light-water-cooled and moderated research reactor which first achieved criticality in 1996 and is currently the highest powered university-owned research reactor in the U.S. For many years a major supplier of reactor-produced isotopes for research and commercial purposes, in the last 15 years MURR has concentrated on development of reactor-produced beta-particle emitters for experimental use in nuclear medicine therapy of cancer and rheumatoid arthritis. MURR has played a major role in the development of bone cancer pain palliation with the agents {sup 153}Sm EDTMP and {sup 186}Re/{sup 188}Re HEDP, as well as in the use of {sup 186}Re, {sup 177}Lu, {sup 166}Ho, and {sup 105}Rh for radioimmunotherapy and receptor-agent-guided radiotherapy. MURR is also responsible for the development of therapeutic, {sup 90}Y-labeled glass microspheres for the treatment of liver tumors, a product ({sup 90}Y Therasphere{trademark}) which is currently an approved drug in Canada. MURR has also pioneered the development of {sup 188}W/{sup 188}Re and {sup 99}Mo/{sup 99m}Tc gel generators, which make the use of low specific activity {sup 188}W and {sup 99}Mo practical for such isotope generators.

  3. Pm-149 DOTA bombesin analogs for potential radiotherapy. in vivo comparison with Sm-153 and Lu-177 labeled DO3A-amide-betaAla-BBN(7-14)NH(2).

    PubMed

    Hu, Fang; Cutler, Cathy S; Hoffman, Timothy; Sieckman, Gary; Volkert, Wynn A; Jurisson, Silvia S

    2002-05-01

    Promethium-149 (149Pm) is one of only three radiolanthanides that can be prepared in no carrier added concentrations. This high specific activity radiolanthanide is thus suitable for targeting limited numbers of specific receptors found on many tumor cells. Promethium-149 is a moderate energy beta(-) emitter (1.07 MeV (95.9%)) with a half-life of 2.21 days. Pm-149 also emits a low abundance of an imageable gamma ray (286 keV (3%)) that may allow in vivo tracking of the therapeutic dose. The 149Pm and Sm complexes with the DO3A-amide chelator with zero and three carbon spacers to the bombesin peptide analog BBN(7-14)NH(2) were synthesized and characterized. The Sm complexes were synthesized for macroscopic characterization purposes (ESI-MS, in vitro cell binding) since no stable isotopes of Pm are known. The biological properties of the 149Pm, 153Sm and 177Lu-DO3A-amide-betaAla-BBN complexes were compared in normal mouse biodistribution studies. PMID:12031877

  4. Estimated human absorbed dose of ¹⁷⁷Lu-BPAMD based on mice data: Comparison with ¹⁷⁷Lu-EDTMP.

    PubMed

    Yousefnia, Hassan; Zolghadri, Samaneh; Shanehsazzadeh, Saeed

    2015-10-01

    In this work, the absorbed dose of human organs for (177)Lu-BPAMD was evaluated based on biodistribution studies into the Syrian mice by RADAR method and was compared with (177)Lu-EDTMP as the only clinically used Lu-177 bone-seeking agent. The highest absorbed dose for both (177)Lu-BPAMD and (177)Lu-EDTMP is observed on the bone surface with 8.007 and 4.802 mSv/MBq. Generally, (177)Lu-BPAMD has considerable characteristics compared with (177)Lu-EDTMP and can be considered as a promising agent for the bone pain palliation therapy. PMID:26163291

  5. 'Reverse discordance' between 68Ga-DOTA-NOC PET/CT and 177Lu-DOTA-TATE posttherapy scan: the plausible explanations and its implications for high-dose therapy with radiolabeled somatostatin receptor analogs.

    PubMed

    Basu, Sandip; Abhyankar, Amit; Kand, Purushottam; Kumar, Rakesh; Asopa, Ramesh; Rajan, Mysore Govinda Ramakrishna; Nayak, Uday; Shimpi, Hemant; Das, Tapas; Venkatesh, Meera; Chakrabarty, Sudipta; Banerjee, Sharmila

    2011-07-01

    In this technical note, an unusual discordance between diagnostic and posttherapeutic scan resulting from the use of different somatostatin receptor ligands in two settings is described. Such observation, we believe, is multifactorial, but most importantly arises due to different receptor affinity profile of the ligands and different somatostatin receptor subtype expression in different tumors. It is important for the treating physician to be aware of this phenomenon that would aid in improving our understanding of complex ligand-receptor interactions in various somatostatin receptor-positive tumors with its possible implications for therapeutic decision making with radiolabeled somatostatin receptor analogues. PMID:21654355

  6. Resolution of Malignant Ascites and Stabilization of Metastases in a Patient With Small Bowel Neuroendocrine Tumor With 177Lu-DOTATATE Following Progression After 17 131I-MIBG Treatments and Chemotherapy.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-07-01

    A 39-year-old man diagnosed with a small bowel neuroendocrine tumor metastatic to the liver, lymph nodes, and bones achieved stable disease with ¹³¹I-MIBG therapy totalling 17 treatments over 9 years (cumulative dose of 1.9 Ci). His disease progressed after the 17th ¹³¹I-MIBG treatment, and he went on to fail chemotherapy, developing severe ascites requiring up to 8 L of weekly paracentesis. He was referred for ¹⁷⁷Lu-[DOTA⁰,Tyr³]octreotate (DOTATATE) therapy, and after 4 induction cycles, his ascites resolved completely, and his metastatic disease stabilized. ¹⁷⁷Lu-DOTATATE may be useful in patients with an extensive history of radioisotope therapy with ¹³¹I-MIBG. PMID:25546192

  7. A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: Comparison with other Monte Carlo codes

    SciTech Connect

    Papadimitroulas, Panagiotis; Loudos, George; Nikiforidis, George C.; Kagadis, George C.

    2012-08-15

    , which allowed us to produce a unique DPKs dataset using GATE. The dataset contains the total DPKs for {sup 67}Ga, {sup 68}Ga, {sup 90}Y, {sup 99m}Tc, {sup 111}In, {sup 123}I, {sup 124}I, {sup 125}I, {sup 131}I, {sup 153}Sm, {sup 177}Lu {sup 186}Re, and {sup 188}Re generated in water, bone, and lung. Conclusions: In this study, the authors have checked GATE's reliability for absorbed dose calculation when transporting different kind of particles, which indicates its robustness for dosimetry applications. A novel dataset of DPKs is provided, which can be applied in patient-specific dosimetry using analytical point kernel convolution algorithms.

  8. Phagocytosis-induced 51Cr release from activated macrophages and blood mononuclears. Effect of colchicine and antioxidants

    SciTech Connect

    McGee, M.P.; Hale, A.H.

    1981-09-01

    The chromium-release test was adapted to the measurement of the cellular injury induced when activated macrophages phagocytose particulates. Macrophages obtained from rabbit lungs undergoing BCG-induced chronic inflammation released more chromium when incubated in the presence of phagocytosable particles than when incubated under resting conditions. Blood mononuclear cells, 40-60% monocytes, procured from the same BCG-injected animals, were less susceptible to phagocytosis-induced injury than the macrophages obtained from the lungs. The amount of chromium released by the activated macrophages was proportional to the number of particles present during incubation. In the presence of catalase, the amounts of chromium released by phagocytosing and resting macrophages were similar; in the presence of superoxide dismutase and cytochrome c, the amount of chromium released by phagocytosing macrophages was 13-35% less than the amount of chromium released by macrophages incubated without the antioxidants. In addition, colchicine, an inhibitor of degranulation also exerted partial inhibition of the chromium release. These results suggest that oxygen radicals and lysosomal contents contribute to the cellular injury that results from phagocytosis.

  9. Targeted radiotherapy of bone malignancies.

    PubMed

    Jansen, David R; Krijger, Gerard C; Kolar, Zvonimir I; Zonnenberg, Bernard A; Zeevaart, Jan Rijn

    2010-12-01

    The severe pain associated with many disorders affecting bone account for a large proportion of cases of patient morbidity, due to the encumbrance of mobility and therefore, compromised quality of life. Skeletal metastasis is one such condition, which generally complicates the treatment of the primary cancers such as that of the breast, prostate and lung - causing intense pain and eventually even mortality. This paper presents examples of various approaches explored and proposed in the ongoing search to identify better radiopharmaceuticals for the treatment of bone disorders such as metastases. The primary objective of these developments is to alleviate the debilitating pain commonly associated with bone lesions. The efficacy of a radiotherapeutic agent intended for the treatment of diseased bone is particularly dependent on the radiation dose to the tumor cells and on the extent to which suppression of bone marrow or other critical organs can be avoided. Therefore, the design rationale requires careful consideration of the choice radionuclide and especially ensuring that the drug selectively targets the lesion or tumor site. The options pursued include the use of radioisotopes with an intrinsic affinity for bone, such as (89)Sr or (223)Ra, or the design of bone-seeking ligands, such as phosphonates, to selectively deliver the radionuclide to the target, e.g. [(153)Sm]Sm-EDTMP. A combination of the above may too be possible, where the bone seeking ligand facilitates the selective accumulation of a radionuclide, which by itself is also bone homing. In terms of therapeutic application radionuclides with various decay modes are proposed, including beta (-) emitters: (153)Sm, (89)Sr, (186)Re, (188)Re, (32)P, (177)Lu and (170)Tm; alpha (α) emitters: (223)Ra and (225)Ra; and Auger or conversion electron emitter: (117)mSn. From a purely diagnostic perspective, the radioisotopes used for imaging include the well known photon emitting (99)mTc, and positron emitters (18)F

  10. Use of the GEANT4 Monte Carlo to determine three-dimensional dose factors for radionuclide dosimetry

    NASA Astrophysics Data System (ADS)

    Amato, Ernesto; Italiano, Antonio; Minutoli, Fabio; Baldari, Sergio

    2013-04-01

    The voxel-level dosimetry is the most simple and common approach to internal dosimetry of nonuniform distributions of activity within the human body. Aim of this work was to obtain the dose "S" factors (mGy/MBqs) at the voxel level for eight beta and beta-gamma emitting radionuclides commonly used in nuclear medicine diagnostic and therapeutic procedures. We developed a Monte Carlo simulation in GEANT4 of a region of soft tissue as defined by the ICRP, divided into 11×11×11 cubic voxels, 3 mm in side. The simulation used the parameterizations of the electromagnetic interaction optimized for low energy (EEDL, EPDL). The decay of each radionuclide (32P, 90Y, 99mTc, 177Lu, 131I, 153Sm, 186Re, 188Re) were simulated homogeneously distributed within the central voxel (0,0,0), and the energy deposited in the surrounding voxels was mediated on the 8 octants of the three dimensional space, for reasons of symmetry. The results obtained were compared with those available in the literature. While the iodine deviations remain within 16%, for phosphorus, a pure beta emitter, the agreement is very good for self-dose (0,0,0) and good for the dose to first neighbors, while differences are observed ranging from -60% to +100% for voxels far distant from the source. The existence of significant differences in the percentage calculation of the voxel S factors, especially for pure beta emitters such as 32P or 90Y, has already been highlighted by other authors. These data can usefully extend the dosimetric approach based on the voxel to other radionuclides not covered in the available literature.

  11. Nuclear oncology, a fast growing field of nuclear medicine

    NASA Astrophysics Data System (ADS)

    Olivier, Pierre

    2004-07-01

    Nuclear Medicine in oncology has been for a long time synonymous with bone scintigraphy, the first ever whole body imaging modality, and with treatment of thyroid cancer with iodine-131. More recently, somatostatin receptor scintigraphy (SRS) using peptides such as 111In-labelled octreotide became a reference imaging method in the detection and staging of neuroendocrine tumors while 131I- and 123I-MIBG remain the tracers of reference for pheochromocytomas and neuroblastomas. Lymphoscintigraphic imaging based on peritumoral injection of 99mTc-labelled colloids supports, in combination with per operative detection, the procedure of sentinel node identification in breast cancers and melanomas. Positron Emission Tomography (PET) is currently experiencing a considerable growth in oncology based on the use of 18F-FDG (fluorodeoxyglucose), a very sensitive, although non-specific, tumor tracer. Development of instrumentation is crucial in this expansion of PET imaging with new crystals being more sensitive and hybrid imagers that permit to reduce the acquisition time and offer fused PET-CT images. Current developments in therapy can be classified into three categories. Radioimmunotherapy (RIT) based on monoclonal antibodies (or fragments) labelled with beta-emitters. This technique has recently made its entrance in clinical practice with a 90Y-labelled anti-CD20 antibody ( 90Y-ibritumomab tiuxetan (Zevalin ®)) approved in US for the treatment of some subtypes of non-Hodgkin's lymphoma. Radionuclide-bone pain palliation has experienced developments with 153Sm-EDTMP, 186Re-HEDP or 89Sr, efficient in patients with widespread disease. Last, the same peptides, as those used in SRS, are being developed for therapy, labelled with 90Y, 111In or 177Lu in patients who failed to respond to other treatments. Overall, nuclear oncology is currently a fast growing field thanks to the combined developments of radiopharmaceuticals and instrumentation.

  12. Theranostic Applications of Lutetium-177 in Radionuclide Therapy.

    PubMed

    Das, Tapas; Banerjee, Sharmila

    2016-01-01

    Lutetium-177 has been widely discussed as a radioisotope of choice for targeted radionuclide therapy. The simultaneous emission of imageable gamma photons [208 keV (11%) and 113 keV (6.4%)] along with particulate β(-) emission [β(max) = 497 keV] makes it a theranostically desirable radioisotope. In the present article, the possibility of using two 177Lu-based agents viz. 177Lu-EDTMP and 177Lu-DOTATATE for theranostic applications in metastatic bone pain palliation (MBPP) and peptide receptor radionuclide therapy (PRRT), have been explored. In the case of 177Lu-EDTMP, the whole-body images obtained are compared with those recorded using 99mTc-MDP in the same patient. On the other hand, pre-therapy images acquired with 177Lu-DOTA-TATE are compared with similar images obtained with standard agents, such as 99mTc-HYNIC-TOC (SPECT) and 68Ga-DOTA-TOC (PET) in the same patient. The advantage of the long physical half-life (T1/2) of 177Lu has been utilized in mapping the pharmacokinetics of two additional agents, 177Lu-labeled hydroxyapatite (HA) in radiation synovectomy of knee joints and 177Lu-HA for therapy of hepatocellular carcinoma. Results of these multiple studies conclusively document the potential of 177Lu as a theranostic radioisotope. PMID:25771364

  13. Gastrointestinal absorption of metals (51Cr, 65Zn, 95mTc, 109Cd, 113Sn, 147Pm, and 238Pu) by rats and swine.

    PubMed

    Sullivan, M F; Miller, B M; Goebel, J C

    1984-12-01

    Adult and neonatal rats and neonatal pigs were gavaged with solutions of metal radionuclides to determine gastrointestinal absorption. Zinc-65 and technetium-95m were well-absorbed by both age groups; chromium-51, cadmium-109, tin-113, promethium-147, and plutonium-238 were not. The quantities of the poorly absorbed metals that were absorbed by neonates were between 4 and 100 times higher than those absorbed by adult rats. Autoradiograms prepared from the entire small intestine of the neonatal rat showed that 109Cd was retained in the duodenum. In contrast, measurements in the piglets showed much higher 109Cd retention in the ileum than in the duodenum. Autoradiograms and radiochemical measurements of 147Pm and 238Pu in both neonatal rats and swine showed the highest level of retention in the ileum. The results indicate that, for most of the metals studied, absorption from the gastrointestinal tract is substantially higher for neonatal than for adult rats. PMID:6510393

  14. Accuracy of blood volume estimations in critically ill children using 125I-labelled albumin and 51Cr-labelled red cells.

    PubMed

    Linderkamp, O; Holthausen, H; Seifert, J; Butenandt, I; Riegel, K P

    1977-06-01

    Blood volume was estimated using 51chromium labelled red cells and 125iodinated human serum albumin in 5 children with sepsis, in 6 burned children and 7 children with acute lymphoblastic leukaemia. Studies of the equilibration pattern demonstrated that the mixing time of labelled red cells was prolonged to 40 minutes or more in 5 children, indicating the existence of slowly circulating red cells. Mixing of labelled albumin was complete within 10 minutes in 15 patients and within 20 minutes in all the children studied. In a burned patient with severe sepsis, exchange transfusion improved the clinical state and normalized the equilibration pattern of labelled red cells. The mean body/venous haematocrit ratio was 0.893+/-0.018 (SD) in the children with sepsis, 0.859+/-0.052 in the burned patients, and 0.916+/-0.078 in the children with acute lymphoblastic leukaemia, increasing with spleen size in the latter group. PMID:267010

  15. A radio-theranostic nanoparticle with high specific drug loading for cancer therapy and imaging.

    PubMed

    Satterlee, Andrew B; Yuan, Hong; Huang, Leaf

    2015-11-10

    We have developed a theranostic nanoparticle delivering the model radionuclide (177)Lu based on the versatile lipid-calcium-phosphate (LCP) nanoparticle delivery platform. Characterization of (177)Lu-LCP has shown that radionuclide loading can be increased by several orders of magnitude without affecting the encapsulation efficiency or the morphology of (177)Lu-LCP, allowing consistency during fabrication and overcoming scale-up barriers typical of nanotherapeutics. The choice of (177)Lu as a model radionuclide has allowed in vivo anticancer therapy in addition to radiographic imaging via the dual decay modes of (177)Lu. Tumor accumulation of (177)Lu-LCP was measured using both SPECT and Cerenkov imaging modalities in live mice, and treatment with just one dose of (177)Lu-LCP showed significant in vivo tumor inhibition in two subcutaneous xenograft tumor models. Microenvironment and cytotoxicity studies suggest that (177)Lu-LCP inhibits tumor growth by causing apoptotic cell death via double-stranded DNA breaks while causing a remodeling of the tumor microenvironment to a more disordered and less malignant phenotype. PMID:26341695

  16. ¹⁷⁷Lu-Labeled Agents for Neuroendocrine Tumor Therapy and Bone Pain Palliation in Uruguay.

    PubMed

    Balter, Henia; Victoria, Trindade; Mariella, Terán; Javier, Gaudiano; Rodolfo, Ferrando; Andrea, Paolino; Graciela, Rodriguez; Juan, Hermida; Eugenia, De Marco; Patricia, Oliver

    2016-01-01

    Lutetium-177 is an emerging radionuclide due its convenient chemical and nuclear properties. In this paper we describe the development and evaluation in Uruguay of the targeted 177Lu labelled radiopharmaceuticals EDTMP (for bone pain palliation) and DOTA-TATE (neuroendocrine tumors). We optimized the preparation of these 177Lu radiopharmaceuticals including radiolabelling, quality control methods, in vitro and in vivo stability and their therapeutic application in patients. Radiation dosimetry aspects of 177Lu are also included. Nine male patients with prostate cancer and four female patients with breast carcinoma with multiple bone metastatic lesions were treated with 177Lu-EDTMP. Four patients with gastroentheropancreatic neuroendocrine tumors (GEP-NET) and one patient with bronchial NET were treated with 1- 3 cycles with a cumulative dose of 4.44-22.2 GBq of 177Lu-DOTA-TATE. Scintigraphic images of the patients treated with 177Lu-EDTMP evidenced high and rapid uptake in bone metastasis, remaining after 7 days post administration. Images allow skeletal visualization with high definition and demonstrate increased uptake in bone metastases. For 177Lu-DOTA-TATE, partial remissions were obtained in 4 patients and the remaining patient did not show significant progression 3 months after the second cycle. No serious adverse effects were registered, even in two patients with confirmed renal disease and high risk for renal disease Dosimetry assessments confirm the predictive value of the personalized therapy with radiolabelled peptides. We found it is possible to accumulate high therapeutic doses in tumours in sequential administrations of 177Lu-DOTA-TATE, increasing the probability of biological response without significant impairment of the renal function in patients with risk factors. These results demonstrate the attractive therapeutic properties of these two 177Lu labelled agents and the feasibility of this metabolic therapy in regions far away from 177Lu producing

  17. Melanoma targeting property of a Lu-177-labeled lactam bridge-cyclized alpha-MSH peptide.

    PubMed

    Guo, Haixun; Miao, Yubin

    2013-04-15

    The purpose of this study was to determine the melanoma targeting property of (177)Lu-DOTA-GGNle-CycMSHhex in B16/F1 melanoma-bearing C57 mice. (177)Lu-DOTA-GGNle-CycMSHhex exhibited high receptor-mediated melanoma uptake and fast urinary clearance. The tumor uptake of (177)Lu-DOTA-GGNle-CycMSHhex was 20.25 ± 4.59 and 21.63 ± 6.27% ID/g at 0.5 and 2h post-injection, respectively. Approximately 83% of injected dose cleared out the body via urinary system at 2h post-injection. (177)Lu-DOTA-GGNle-CycMSHhex showed high tumor to normal organ uptake ratios except for the kidneys. The tumor/kidney uptake ratios of (177)Lu-DOTA-GGNle-CycMSHhex were 2.76 and 1.74 at 2 and 24h post-injection. The melanoma lesions were clearly visualized by SPECT/CT using (177)Lu-DOTA-GGNle-CycMSHhex as an imaging probe at 2h post-injection. Overall, high melanoma uptake coupled with fast urinary clearance of (177)Lu-DOTA-GGNle-CycMSHhex underscored its potential for melanoma treatment in the future. PMID:23473679

  18. Lutetium-labelled peptides for therapy of neuroendocrine tumours.

    PubMed

    Kam, B L R; Teunissen, J J M; Krenning, E P; de Herder, W W; Khan, S; van Vliet, E I; Kwekkeboom, D J

    2012-02-01

    Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours. PMID:22388631

  19. Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate

    SciTech Connect

    Schlom, J.; Siler, K.; Milenic, D.E.; Eggensperger, D.; Colcher, D.; Miller, L.S.; Houchens, D.; Cheng, R.; Kaplan, D.; Goeckeler, W. )

    1991-06-01

    {sup 177}Lutetium ({sup 177}Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here the first use of a {sup 177}Lu-labeled immunoconjugate, {sup 177}Lu-CC49, in an experimental therapy model for human carcinoma. {sup 177}Lu-CC49 was shown to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Overt toxicity was observed with the administration of approximately 500 microCi of {sup 177}Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 microCi of {sup 177}Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 microCi of {sup 177}Lu-CC49 (250 microCi/week for 3 consecutive weeks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm3) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, {sup 177}Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the {sup 177}Lu-CC49 versus that of the {sup 177}Lu-control MAb. The merits and limitations of the use of {sup 177}Lu-labeled immunoconjugates (in particular, {sup 177}Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.

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

    PubMed

    Aranda-Lara, Liliana; Ferro-Flores, Guillermina; Azorín-Vega, Erika; Ramírez, Flor de María; Jiménez-Mancilla, Nallely; Ocampo-García, Blanca; Santos-Cuevas, Clara; Isaac-Olivé, Keila

    2016-01-01

    The aim of this work was to synthesize Lys(1)(α,γ-Folate)-Lys(3)((177)Lu-DOTA)-Bombesin (1-14) ((177)Lu-Folate-BN), as well as to assess its potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (FR) and gastrin-releasing peptide receptors (GRPR). Radiation absorbed doses of (177)Lu-Folate-BN (74 MBq, i.v.) estimated in athymic mice with T47D-induced breast tumors (positive to FR and GRPR), showed tumor doses of 23.9±2.1 Gy. T47D-tumors were clearly visible (Micro-SPECT/CT images). (177)Lu-Folate-BN demonstrated properties suitable as a theranostic radiopharmaceutical. PMID:26545016

  1. Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer.

    PubMed

    Phaeton, Rebecca; Jiang, Zewei; Revskaya, Ekaterina; Fisher, Darrell R; Goldberg, Gary L; Dadachova, Ekaterina

    2016-01-01

    Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer. PMID:26625938

  2. Studies on the Labeling of Ethylenediaminetetramethylene Phosphonic Acid, Methylene Diphosphonate, Sodium Pyrophosphate and Hydroxyapatite with Lutetium-177 for use in Nuclear Medicine.

    PubMed

    Abbasi, Imtiaz Ahmed

    2015-01-01

    For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various (177)Lu-labeled bone-seeking complexes such as (177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), (177)Lu-methylene diphosphonate (MDP) and (177)Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and (177)Lu-Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). (177)Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for (177)Lu-MDP, (177)Lu-EDTMP and (177)Lu-PYP at 3.37 ± 0.06 cm, 5.53 ± 0.15 cm and 7.03 ± 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with (177)Lu in injectable solution form. HA particulates could too be labeled with (177)Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and

  3. Studies on the Labeling of Ethylenediaminetetramethylene Phosphonic Acid, Methylene Diphosphonate, Sodium Pyrophosphate and Hydroxyapatite with Lutetium-177 for use in Nuclear Medicine

    PubMed Central

    Abbasi, Imtiaz Ahmed

    2015-01-01

    For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various 177Lu-labeled bone-seeking complexes such as 177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), 177Lu-methylene diphosphonate (MDP) and 177Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and 177Lu-Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). 177Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for 177Lu-MDP, 177Lu-EDTMP and 177Lu-PYP at 3.37 ± 0.06 cm, 5.53 ± 0.15 cm and 7.03 ± 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with 177Lu in injectable solution form. HA particulates could too be labeled with 177Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and the later could be

  4. T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the /sup 51/Cr-release assay

    SciTech Connect

    Zinkernagel, R.M.; Haenseler, E.; Leist, T.; Cerny, A.; Hengartner, H.; Althage, A.

    1986-10-01

    A model for immunologically T cell-mediated hepatitis was established in mice infected with lymphocytic choriomeningitis virus (LCMV). The severity of hepatitis was monitored histologically and by determination of changes in serum levels of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), and alkaline phosphatase (AP). Kinetics of histological disease manifestations, increases of liver enzyme levels in the serum, and cytotoxic T cell activities in livers and spleens all correlated and were dependent upon several parameters: LCMV-isolate; LCMV-WE caused extensive hepatitis, LCMV-Armstrong virtually none. Virus dose. Route of infection; i.v. or i.p. infection caused hepatitis, whereas infection into the footpad did not. The general genetic background of the murine host; of the strains tested, Swiss mice and A-strain mice were more susceptible than C57BL or CBA mice; BALB/c and DBA/2 mice were least susceptible. The degree of immunocompetence of the murine host; T cell deficient nu/nu mice never developed hepatitis, whereas nu/+ or +/+ mice always did. B cell-depleted anti-IgM-treated mice developed immune-mediated hepatitis comparably or even more extensively than control mice. Local cytotoxic T cell activity; mononuclear cells isolated from livers during the period of overt hepatitis were two to five times more active than equal numbers of spleen cells. Adoptive transfer of nylon wool-nonadherent anti-Thy-1.2 and anti-Lyt-2 plus C-sensitive, anti-L3T4 plus C-resistant lymphocytes into irradiated mice preinfected with LCMV-WE caused a rapid time- and dose-dependent linear increase of serum enzyme levels. This increase was caused by adoptive transfer of lymphocytes if immune cell donors and recipient mice shared class I, but not when they shared class II histocompatibility antigens.

  5. Current Status of Nuclear Medicine Practice in the Middle East.

    PubMed

    Paez, Diana; Becic, Tarik; Bhonsle, Uday; Jalilian, Amir R; Nuñez-Miller, Rodolfo; Osso, Joao Alberto

    2016-07-01

    availability of (68)Ge-(68)Ga generators is increasing and studies involving prostate-specific membrane antigen or DOTA-chelated peptides or both are performed in at least seven countries. Although therapeutic radionuclide agents are mostly imported from outside the region, this does not limit the availability of therapies with (90)Y, (153)Sm, (177)Lu, (131)I, (188)Re, and (89)Sr. Nevertheless, therapies based on alpha particle emitters are still largely not available in the region and are currently only available in Israel and Turkey. Regarding human resources, according to the data provided there are 1157 NM physicians, 1953 technologists, 586 medical physicists, and 173 radiopharmacists or radiochemists in the region. Approximately half of all available human resources are accounted for by Turkey. The region has great potential for expanding the applications of NM; this becomes especially important in view of the high prevalence of non-communicable diseases. Further increasing awareness of the clinical applications of NM in healthcare and strengthening technical and human capacities including the establishment of training programs for all professionals and disciplines in the field are recognized as key components in advancing the practice of NM in the Middle East. PMID:27237437

  6. Calculation of electron and isotopes dose point kernels with fluka Monte Carlo code for dosimetry in nuclear medicine therapy

    SciTech Connect

    Botta, F.; Mairani, A.; Battistoni, G.; Cremonesi, M.; Di Dia, A.; Fasso, A.; Ferrari, A.; Ferrari, M.; Paganelli, G.; Pedroli, G.; Valente, M.

    2011-07-15

    Purpose: The calculation of patient-specific dose distribution can be achieved by Monte Carlo simulations or by analytical methods. In this study, fluka Monte Carlo code has been considered for use in nuclear medicine dosimetry. Up to now, fluka has mainly been dedicated to other fields, namely high energy physics, radiation protection, and hadrontherapy. When first employing a Monte Carlo code for nuclear medicine dosimetry, its results concerning electron transport at energies typical of nuclear medicine applications need to be verified. This is commonly achieved by means of calculation of a representative parameter and comparison with reference data. Dose point kernel (DPK), quantifying the energy deposition all around a point isotropic source, is often the one. Methods: fluka DPKs have been calculated in both water and compact bone for monoenergetic electrons (10{sup -3} MeV) and for beta emitting isotopes commonly used for therapy ({sup 89}Sr, {sup 90}Y, {sup 131}I, {sup 153}Sm, {sup 177}Lu, {sup 186}Re, and {sup 188}Re). Point isotropic sources have been simulated at the center of a water (bone) sphere, and deposed energy has been tallied in concentric shells. fluka outcomes have been compared to penelope v.2008 results, calculated in this study as well. Moreover, in case of monoenergetic electrons in water, comparison with the data from the literature (etran, geant4, mcnpx) has been done. Maximum percentage differences within 0.8{center_dot}R{sub CSDA} and 0.9{center_dot}R{sub CSDA} for monoenergetic electrons (R{sub CSDA} being the continuous slowing down approximation range) and within 0.8{center_dot}X{sub 90} and 0.9{center_dot}X{sub 90} for isotopes (X{sub 90} being the radius of the sphere in which 90% of the emitted energy is absorbed) have been computed, together with the average percentage difference within 0.9{center_dot}R{sub CSDA} and 0.9{center_dot}X{sub 90} for electrons and isotopes, respectively. Results: Concerning monoenergetic electrons

  7. Calculation of electron and isotopes dose point kernels with fluka Monte Carlo code for dosimetry in nuclear medicine therapy

    SciTech Connect

    Botta, F; Di Dia, A; Pedroli, G; Mairani, A; Battistoni, G; Fasso, A; Ferrari, A; Ferrari, M; Paganelli, G; Valente, M

    2011-06-01

    The calculation of patient-specific dose distribution can be achieved by Monte Carlo simulations or by analytical methods. In this study, fluka Monte Carlo code has been considered for use in nuclear medicine dosimetry. Up to now, fluka has mainly been dedicated to other fields, namely high energy physics, radiation protection, and hadrontherapy. When first employing a Monte Carlo code for nuclear medicine dosimetry, its results concerning electron transport at energies typical of nuclear medicine applications need to be verified. This is commonly achieved by means of calculation of a representative parameter and comparison with reference data. Dose point kernel (DPK), quantifying the energy deposition all around a point isotropic source, is often the one.Methods: fluka DPKs have been calculated in both water and compact bone for monoenergetic electrons (10–3 MeV) and for beta emitting isotopes commonly used for therapy (89Sr, 90Y, 131I, 153Sm, 177Lu, 186Re, and 188Re). Point isotropic sources have been simulated at the center of a water (bone) sphere, and deposed energy has been tallied in concentric shells. fluka outcomes have been compared to penelope v.2008 results, calculated in this study as well. Moreover, in case of monoenergetic electrons in water, comparison with the data from the literature (etran, geant4, mcnpx) has been done. Maximum percentage differences within 0.8·RCSDA and 0.9·RCSDA for monoenergetic electrons (RCSDA being the continuous slowing down approximation range) and within 0.8·X90 and 0.9·X90 for isotopes (X90 being the radius of the sphere in which 90% of the emitted energy is absorbed) have been computed, together with the average percentage difference within 0.9·RCSDA and 0.9·X90 for electrons and isotopes, respectively.Results: Concerning monoenergetic electrons, within 0.8·RCSDA (where 90%–97% of the particle energy is deposed), fluka and penelope agree mostly within 7%, except for 10 and 20 keV electrons (12% in water, 8

  8. Production and Clinical Applications of Radiopharmaceuticals and Medical Radioisotopes in Iran.

    PubMed

    Jalilian, Amir Reza; Beiki, Davood; Hassanzadeh-Rad, Arman; Eftekhari, Arash; Geramifar, Parham; Eftekhari, Mohammad

    2016-07-01

    -meta-iodobenzylguanidine for treatment of neuroblastoma, pheochromocytoma, and other neuroendocrine tumors has been steadily increasing in major academic university hospitals. Also (153)Sm-EDTMP, (177)Lu-EDTMP, (90)Y-citrate, (90)Y-hydroxyapatite colloid, (188/186)Re-sulfur colloid, and (188/186)Re-HEDP have been locally developed and now routinely available for bone pain palliation and radiosynovectomy. Cu-64 has been available to the nuclear medicine community for some time. With recent reports in diagnostic and therapeutic applications of this agent especially in the field of oncology, we anticipate an expansion in production and availability. The initiation of the production line for gallium-68 generator is one of the latest exciting developments. We are proud that Iran would be joining the club of few nations with production lines for this type of generator. There are also quite a number of SPECT and PET tracers at research and preclinical stage of development preliminarily introduced for possible future clinical applications. Availability of fluorine-18 tracers and gallium-68 generators would no doubt allow rapid dissemination of PET/CT practices in various parts of our large country even far from a cyclotron facility. Also, local production and availability of therapeutic radiopharmaceuticals are going to open exciting horizons in the field of nuclear medicine therapy. Given the available manpower, local infrastructure of SPECT imaging, and rapidly growing population, the production of Tc-99m generators and cold kit would continue to flourish in Iran. PMID:27237443

  9. Pharmacokinetic, Dosimetry and Toxicity Study of ¹⁷⁷Lu-EDTMP in Patients: Phase 0/I study.

    PubMed

    Bal, Chandrasekhar; Arora, Geetanjali; Kumar, Praveen; Damle, Nishikant; Das, Tapas; Chakraborty, Sudipta; Banerjee, Sharmila; Venkatesh, Meera; Zaknun, John J; Pillai, M R A

    2016-01-01

    177Lu-EDTMP has been proposed as a potent bone pain palliation agent owing to theoretical advantage of reduced bone marrow suppression resulting from the low β(-) energy and a suitably long half-life facilitating its wider distribution with less loss from radioactive decay. Herein, we report the pharmacokinetics, dosimetry and toxicity analysis of 177Lu-EDTMP in patients (phase-0/I study). In a phase-0 study, the biokinetics of skeletal and non-skeletal uptake of 177Lu-EDTMP was assessed in 6 patients with metastatic prostate cancer using tracer doses (172.7-206.9MBq). Data of whole skeletal uptake, blood and fractionated urine samples were obtained and dosimetric calculations were performed using the OLINDA/EXM 1.0 software. Prolonged bone retention was observed in all patients. Excretion was mainly via the renal route and blood clearance was rapid and biphasic. Mean estimated red marrow dose was 0.80±0.15mGy/MBq while mean total-body dose was 0.16±0.04mGy/MBq. A maximum tolerated dose (MTD) of 2000-3250MBqfor 177Lu-EDTMP was calculated. For the phase-I study, 21 patients with metastatic prostate cancer were given a therapeutic dose of 177Lu- EDTMP (692-5550MBq). Toxiciy (WHO), evaluated by assessment of hemoglobin levels, platelet and leukocyte counts over 12 weeks, was mainly limited to anemia or thrombocytopenia. Only transient toxicity was observed in 14/21 patients, of which 6 had baseline toxicity. Beyond the MTD, a significantly higher number of patients displayed grade 3-4 toxicity. Pain relief, assessed by VAS pain score, was observed in 86% patients with median relief duration of 7 weeks. The results demonstrate that 177Lu-EDTMP has excellent pharmacokinetic and dosimetric properties, besides being safe and effective. Along with estimating radiation dose values to certain critical organs, we have also proposed an MTD for 177Lu-EDTMP that correlated well with toxicity data. The encouraging dosimetry and toxicity data of 177Lu-EDTMP reported provide the

  10. Lu-177 preparation for radiotherapy application.

    PubMed

    Park, Ul Jae; Lee, Jun-Sig; Choi, Kang Hyuk; Nam, Sung Soo; Yu, Kook Hyun

    2016-09-01

    A separation study using a (176)Yb target for the preparation of nca (177)Lu, which is a beta-emitting nuclide used not only in radioimmunotherapy applications but also in the treatment of various lesions, has been performed. A material having a better selectivity and separation efficiency for Lu than Yb was developed, and the separation conditions of (177)Lu were derived using this from a neutron irradiated (176)Yb target. The separation material was an organo-ceramic hybrid material containing a phosphate group. Adsorption behavior was determined through batch experiments, and (177)Lu separation from the Yb target was evaluated through column experiments. The Yb target, with a 99.72% in (176)Yb, was irradiated in the irradiation hole of HANARO, which has a thermal neutron flux of 1.6E+14ncm(-2)s(-1). The batch experiments revealed that the organo-ceramic hybrid material (Sol-POS) had a separation factor of 1.6 at 0.5M HCl. Separation was performed through extraction chromatography using a 5mg enriched Yb target, and the separation yield of the NCA (177)Lu was about 78%. If the amount of Yb target is increased to produce curies level (177)Lu, additional purification will be needed. PMID:27295512

  11. PLGA Nanoparticles for Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Novel Approach towards Reduction of Renal Radiation Dose

    PubMed Central

    Arora, Geetanjali; Shukla, Jaya; Ghosh, Sourabh; Maulik, Subir Kumar; Malhotra, Arun; Bandopadhyaya, Gurupad

    2012-01-01

    Background Peptide receptor radionuclide therapy (PRRT), employed for treatment of neuroendocrine tumors (NETs) is based on over-expression of Somatostatin Receptors (SSTRs) on NETs. It is, however, limited by high uptake and retention of radiolabeled peptide in kidneys resulting in unnecessary radiation exposure thus causing nephrotoxicity. Employing a nanocarrier to deliver PRRT drugs specifically to the tumor can reduce the associated nephrotoxicity. Based on this, 177Lu-DOTATATE loaded PLGA nanoparticles (NPs) were formulated in the present study, as a potential therapeutic model for NETs. Methodology and Findings DOTATATE was labeled with Lutetium-177 (177Lu) (labeling efficiency 98%; Rf∼0.8). Polyethylene Glycol (PEG) coated 177Lu-DOTATATE-PLGA NPs (50∶50 and 75∶25) formulated, were spherical with mean size of 304.5±80.8 and 733.4±101.3 nm (uncoated) and 303.8±67.2 and 494.3±71.8 nm (coated) for PLGA(50∶50) and PLGA(75∶25) respectively. Encapsulation efficiency (EE) and In-vitro release kinetics for uncoated and coated NPs of PLGA (50∶50 & 75∶25) were assessed and compared. Mean EE was 77.375±4.98% & 67.885±5.12% (uncoated) and 65.385±5.67% & 58.495±5.35% (coated). NPs showed initial burst release between 16.64–21.65% with total 42.83–44.79% over 21days. The release increased with coating to 20.4–23.95% initially and 60.97–69.12% over 21days. In-vivo studies were done in rats injected with 177Lu-DOTATATE and 177Lu-DOTATATE-NP (uncoated and PEG-coated) by imaging and organ counting after sacrificing rats at different time points over 24 hr post-injection. With 177Lu-DOTATATE, renal uptake of 37.89±10.2%ID/g was observed, which reduced to 4.6±1.97% and 5.27±1.66%ID/g with uncoated and coated 177Lu-DOTATATE-NP. The high liver uptake with uncoated 177Lu-DOTATATE-NP (13.68±3.08% ID/g), reduced to 7.20±2.04%ID/g (p = 0.02) with PEG coating. Conclusion PLGA NPs were easily formulated and modified for desired release properties

  12. A novel tetraazamacrocycle bearing a thiol pendant arm for labeling biomolecules with radiolanthanides.

    PubMed

    Lacerda, Sara; Campello, M Paula; Marques, Fernanda; Gano, Lurdes; Kubícek, Vojtech; Fousková, Petra; Tóth, Eva; Santos, Isabel

    2009-06-21

    The novel tetraazamacrocycle 10-(2-sulfanylethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H(4)DO3ASH) was synthesized and characterized by multinuclear NMR spectroscopy, 2D NMR techniques and mass spectrometry. The protonation constants of H(4)DO3ASH were determined by potentiometry at 25 degrees C in 0.1 M KCl ionic strength, and the protonation sequence was assigned based on (1)H- and (13)C-NMR titrations. The stability constants of the DO3ASH complexes with Ce(3+), Sm(3+) and Ho(3+) have been determined by potentiometry and UV-Vis spectroscopy. They are very similar, comprising a narrow range (logK(ML) = 21.0-22.0). UV-Vis spectrophotometric data on Ce(3+)-DO3ASH and relaxivity measurements on the Gd(3+)-DO3ASH complex suggest that the thiol group does not coordinate to the metal, even in its deprotonated form. For labeling with radioactive lanthanides(iii), various conditions were tested and both complexes, (153)Sm/(166)Ho-DO3ASH, were obtained in quantitative yield (> 98%) at pH = 6. At room temperature, formation kinetics were faster for the (153)Sm than for the (166)Ho complex (5 vs. 60 min, respectively, needed for complete labeling). The stability of these hydrophilic complexes ((153)Sm, logD = -2.1; (166)Ho, logD = -1.6) has been studied in different buffers, in human serum and in the presence of excess of cysteine and glutathione. (153)Sm-DO3ASH has shown a high stability under these conditions and a relatively low protein binding (2.1%), while (166)Ho-DO3ASH was less stable, including in the presence of cysteine and glutathione, and had a slightly higher protein binding (6.7%). In vivo studies have been performed only for the more stable (153)Sm-DO3ASH complex and its biological profile and in vivo stability has been compared to that of (153)Sm-DO3A in the same animal model. The biodistribution profile presents a similar trend with rapid total excretion from the whole animal body, mainly via the urinary pathway. The most striking difference

  13. Biokinetics and dosimetry of several radiolabelled peptides in cancer cells

    NASA Astrophysics Data System (ADS)

    Rodríguez-Cortés, J.; Ferro-Flores, G.; de Murphy, C. Arteaga; Pedraza-López, M.; Ramírez-Iglesias, M. A. T.

    Radiolabelled peptides have been used as target-specific radiopharmaceuticals. The goal of this research was the in vitro assessment of the uptake, internalization, externalization, and efflux of five radiolabelled peptides in cancer cells to estimate radiation-absorbed doses from experimental biokinetic data. 177Lu-DOTA-octreotate, 188Re-lanreotide, and 99mTc-HYNIC-octreotide were studied in the AR42J cell line. The PC3 and NCIH69 cells were used for 99mTc-HYNIC-bombesin and 177Lu-DOTA-minigastrin, respectively. The cumulated activities in the membrane and cytoplasm were calculated by integration of the experimental time-activity curves and used for dosimetry calculations according to the Medical Internal Radiation Dose (MIRD) cellular methodology. The mean absorbed dose to the cell nucleus were 0.69±0.09, 0.11±0.08, 0.55±0.09, 3.45±0.48, and 3.30±0.65 Gy/Bq for 99mTc-HYNIC-bombesin, 99mTc-HYNIC-octreotide, 177Lu-DOTA-minigastrin, 177Lu-DOTA-octreotate, and 188Re-lanreotide, respectively. If radiopharmaceutical cell kinetics were not used and only uptake data were considered, the calculated doses would be overestimated up to 25 times.

  14. Activity estimation in radioimmunotherapy using magnetic nanoparticles

    PubMed Central

    Rajabi, Hossein; Johari Daha, Fariba

    2015-01-01

    Objective Estimation of activity accumulated in tumor and organs is very important in predicting the response of radiopharmaceuticals treatment. In this study, we synthesized 177Lutetium (177Lu)-trastuzumab-iron oxide nanoparticles as a double radiopharmaceutical agent for treatment and better estimation of organ activity in a new way by magnetic resonance imaging (MRI). Methods 177Lu-trastuzumab-iron oxide nanoparticles were synthesized and all the quality control tests such as labeling yield, nanoparticle size determination, stability in buffer and blood serum up to 4 d, immunoreactivity and biodistribution in normal mice were determined. In mice bearing breast tumor, liver and tumor activities were calculated with three methods: single photon emission computed tomography (SPECT), MRI and organ extraction, which were compared with each other. Results The good results of quality control tests (labeling yield: 61%±2%, mean nanoparticle hydrodynamic size: 41±15 nm, stability in buffer: 86%±5%, stability in blood serum: 80%±3%, immunoreactivity: 80%±2%) indicated that 177Lu-trastuzumab-iron oxide nanoparticles could be used as a double radiopharmaceutical agent in mice bearing tumor. Results showed that 177Lu-trastuzumab-iron oxide nanoparticles with MRI had the ability to measure organ activities more accurate than SPECT. Conclusions Co-conjugating radiopharmaceutical to MRI contrast agents such as iron oxide nanoparticles may be a good way for better dosimetry in nuclear medicine treatment. PMID:25937783

  15. Kidney dosimetry in ¹⁷⁷Lu and ⁹⁰Y peptide receptor radionuclide therapy: influence of image timing, time-activity integration method, and risk factors.

    PubMed

    Guerriero, F; Ferrari, M E; Botta, F; Fioroni, F; Grassi, E; Versari, A; Sarnelli, A; Pacilio, M; Amato, E; Strigari, L; Bodei, L; Paganelli, G; Iori, M; Pedroli, G; Cremonesi, M

    2013-01-01

    Kidney dosimetry in (177)Lu and (90)Y PRRT requires 3 to 6 whole-body/SPECT scans to extrapolate the peptide kinetics, and it is considered time and resource consuming. We investigated the most adequate timing for imaging and time-activity interpolating curve, as well as the performance of a simplified dosimetry, by means of just 1-2 scans. Finally the influence of risk factors and of the peptide (DOTATOC versus DOTATATE) is considered. 28 patients treated at first cycle with (177)Lu DOTATATE and 30 with (177)Lu DOTATOC underwent SPECT scans at 2 and 6 hours, 1, 2, and 3 days after the radiopharmaceutical injection. Dose was calculated with our simplified method, as well as the ones most used in the clinic, that is, trapezoids, monoexponential, and biexponential functions. The same was done skipping the 6 h and the 3 d points. We found that data should be collected until 100 h for (177)Lu therapy and 70 h for (90)Y therapy, otherwise the dose calculation is strongly influenced by the curve interpolating the data and should be carefully chosen. Risk factors (hypertension, diabetes) cause a rather statistically significant 20% increase in dose (t-test, P < 0.10), with DOTATATE affecting an increase of 25% compared to DOTATOC (t-test, P < 0.05). PMID:23865075

  16. In vitro and in vivo evaluation of novel ligands for radioimmunotherapy.

    PubMed

    Chong, Hyun-Soon; Milenic, Diane E; Garmestani, Kayhan; Brady, Erik D; Arora, Hans; Pfiester, Candice; Brechbiel, Martin W

    2006-05-01

    Novel ligands cis-2,6-bis[N,N-bis(carboxymethyl)aminomethyl]-1-piperidineacetic acid (PIP-DTPA), cis-[(1R,11S)-6,9,15-Tris-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadec-3-yl]-acetic acid (PIP-DOTA), cis-{2,7-bis-[bis-carboxymethyl-amino)-methyl]-azepan-1-yl}-acetic acid (AZEP-DTPA), [2-(4,7-bis-carboxymethyl-[1,4,7]triazacyclononan-1-yl-ethyl]-2-carbonylmethyl-amino]-tetraacetic acid (NETA) and [{4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA) are investigated as potential chelators of 177Lu, 90Y, 212Pb and 213Bi for radioimmunotherapy (RIT). The new ligands are radiolabeled with 177Lu, 86/88/90Y, 203Pb and 205/6Bi, and in vitro stability and in vivo stability of the radiolabeled complexes are assessed in human serum and athymic mice, respectively. In vitro studies indicate that all radiolabeled complexes with the exception of 90Y-AZEP-DTPA are stable in serum for 5-11 days. All new ligands examined herein are found to tightly hold 177Lu in vivo. Piperidine-backboned DTPA (PIP-DTPA) complexes radiolabeled with all radioisotopes examined display excellent in vivo stability, that is, excretion without dissociation. The azepane-backboned DTPA derivative, AZEP-DTPA, appears ineffective in binding all but 177Lu in vivo. NETA and NPTA radiolabeled with 86Y or 177Lu exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with 203Pb-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both 203Pb-PIP-DOTA and 205/6Bi-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for 205/6Bi but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind 203Pb and 205/6Bi in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for 177Lu and 90Y. Serum stability and in vivo biodistribution

  17. In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies

    PubMed Central

    Chatalic, Kristell L.S.; Konijnenberg, Mark; Nonnekens, Julie; de Blois, Erik; Hoeben, Sander; de Ridder, Corrina; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean; van Gent, Dik C.; Nock, Berthold A.; Maina, Theodosia; van Weerden, Wytske M.; de Jong, Marion

    2016-01-01

    A single tool for early detection, accurate staging, and personalized treatment of prostate cancer (PCa) would be a major breakthrough in the field of PCa. Gastrin-releasing peptide receptor (GRPR) targeting peptides are promising probes for a theranostic approach for PCa overexpressing GRPR. However, the successful application of small peptides in a theranostic approach is often hampered by their fast in vivo degradation by proteolytic enzymes, such as neutral endopeptidase (NEP). Here we show for the first time that co-injection of a NEP inhibitor (phosphoramidon (PA)) can lead to an impressive enhancement of diagnostic sensitivity and therapeutic efficacy of the theranostic 68Ga-/177Lu-JMV4168 GRPR-antagonist. Co-injection of PA (300 µg) led to stabilization of 177Lu-JMV4168 in murine peripheral blood. In PC-3 tumor-bearing mice, PA co-injection led to a two-fold increase in tumor uptake of 68Ga-/177Lu-JMV4168, 1 h after injection. In positron emission tomography (PET) imaging with 68Ga-JMV4168, PA co-injection substantially enhanced PC-3 tumor signal intensity. Radionuclide therapy with 177Lu-JMV4168 resulted in significant regression of PC-3 tumor size. Radionuclide therapy efficacy was confirmed by production of DNA double strand breaks, decreased cell proliferation and increased apoptosis. Increased survival rates were observed in mice treated with 177Lu-JMV4168 plus PA as compared to those without PA. This data shows that co-injection of the enzyme inhibitor PA greatly enhances the theranostic potential of GRPR-radioantagonists for future application in PCa patients. PMID:26722377

  18. The La antigen is over-expressed in lung cancer and is a selective dead cancer cell target for radioimmunotherapy using the La-specific antibody APOMAB®

    PubMed Central

    2014-01-01

    Background The lupus-associated (La)-specific murine monoclonal antibody DAB4 (APOMAB®) specifically binds dead cancer cells. Using DAB4, we examined La expression in human lung cancer samples to assess its suitability as a cancer-selective therapeutic target. We evaluated the safety and effectiveness of radioimmunotherapy (RIT) using DAB4 radiolabeled with Lutetium-177 (177Lu) in the murine Lewis Lung (LL2) carcinoma model, and determined whether combining RIT with DNA-damaging cisplatin-based chemotherapy, a PARP inhibitor (PARPi), or both alters treatment responses. Methods The expression of La mRNA in human lung cancer samples was analysed using the online database Oncomine, and the protein expression of La was examined using a TissueFocus Cancer Survey Tissue Microarray. The binding of DAB4 to cisplatin-treated LL2 cells was assessed in vitro. LL2 tumour-bearing mice were administered escalating doses of 177Lu-DAB4 alone or in combination with chemotherapy, and tumour growth and survival measured. Biodistribution analysis was used to determine tissue uptake of 177Lu-DAB4 or its isotype control (177Lu-Sal5), when delivered alone or after chemotherapy. PARPi (rucaparib; AG-014699) was combined with chemotherapy and the effects of combined treatment on tumour growth, tumour cell DNA damage and death, and intratumoural DAB4 binding were also analysed. The effect of the triple combination of PARPi, chemotherapy and 177Lu-DAB4 on tumour growth and survival of LL2 tumour-bearing mice was tested. Results La was over-expressed at both mRNA and protein levels in surgical specimens of human lung cancer and the over-expression of La mRNA conferred a poorer prognosis. DAB4 bound specifically to cisplatin-induced dead LL2 cells in vitro. An anti-tumour dose response was observed when escalating doses of 177Lu-DAB4 were delivered in vivo, with supra-additive responses observed when chemotherapy was combined with 177Lu-DAB4. Combining PARPi with chemotherapy was more

  19. Neutron Activated Samarium-153 Microparticles for Transarterial Radioembolization of Liver Tumour with Post-Procedure Imaging Capabilities

    PubMed Central

    Hashikin, Nurul Ab. Aziz; Yeong, Chai-Hong; Abdullah, Basri Johan Jeet; Ng, Kwan-Hoong; Chung, Lip-Yong; Dahalan, Rehir; Perkins, Alan Christopher

    2015-01-01

    Introduction Samarium-153 (153Sm) styrene divinylbenzene microparticles were developed as a surrogate for Yttrium-90 (90Y) microspheres in liver radioembolization therapy. Unlike the pure beta emitter 90Y, 153Sm possess both therapeutic beta and diagnostic gamma radiations, making it possible for post-procedure imaging following therapy. Methods The microparticles were prepared using commercially available cation exchange resin, Amberlite IR-120 H+ (620–830 μm), which were reduced to 20–40 μm via ball mill grinding and sieve separation. The microparticles were labelled with 152Sm via ion exchange process with 152SmCl3, prior to neutron activation to produce radioactive 153Sm through 152Sm(n,γ)153Sm reaction. Therapeutic activity of 3 GBq was referred based on the recommended activity used in 90Y-microspheres therapy. The samples were irradiated in 1.494 x 1012 n.cm-2.s-1 neutron flux for 6 h to achieve the nominal activity of 3.1 GBq.g-1. Physicochemical characterisation of the microparticles, gamma spectrometry, and in vitro radiolabelling studies were carried out to study the performance and stability of the microparticles. Results Fourier Transform Infrared (FTIR) spectroscopy of the Amberlite IR-120 resins showed unaffected functional groups, following size reduction of the beads. However, as shown by the electron microscope, the microparticles were irregular in shape. The radioactivity achieved after 6 h neutron activation was 3.104 ± 0.029 GBq. The specific activity per microparticle was 53.855 ± 0.503 Bq. Gamma spectrometry and elemental analysis showed no radioactive impurities in the samples. Radiolabelling efficiencies of 153Sm-Amberlite in distilled water and blood plasma over 48 h were excellent and higher than 95%. Conclusion The laboratory work revealed that the 153Sm-Amberlite microparticles demonstrated superior characteristics for potential use in hepatic radioembolization. PMID:26382059

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

    PubMed Central

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

    2015-01-01

    Objective(s): Peptide Receptor Radionuclide Therapy (PRRT) with yttrium-90 (90Y) and lutetium-177 (177Lu)-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. Methods: 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) 177Lu 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. Results: A total of 17 [177Lu]-DOTATATE syntheses were performed between August 2013 and December 2014. The amount of radioactive [177Lu]-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. Conclusions: The automated synthesis of [177Lu]-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 177Lu and almost negligible radiation exposure of the operators. PMID:27408890

  1. Lutetium-177 Labeled Bombesin Peptides for Radionuclide Therapy.

    PubMed

    Reynolds, Tamila Stott; Bandari, Rajendra P; Jiang, Zongrun; Smith, Charles J

    2016-01-01

    The rare-earth radionuclides that decay by beta particle (β-) emission are considered to be ideal in the context of targeted radiotherapy. The rare-earth isotopes exist primarily in the 3+ oxidation state and are considered to be hard metal centers, requiring multidentate, hard donor ligands such as the poly(aminocarboxylates) for in vivo kinetic inertness. 177Lu is a rare-earth radionuclide that is produced in moderate specific activity (740 GBq/mg) by direct neutron capture of enriched 176Lu via the 176Lu(n,γ)177Lu nuclear reaction. 177Lu has a half-life of 6.71 d, decays by beta emission (Ebmax = 0.497 MeV), and emits two imagable photons (113keV, 3% and 208kev, 11%). High specific activity, no-carrier-added 177Lu can also be prepared by an indirect neutron capture nuclear reaction on a 176Yb target. Herein, we report upon bombesin (BBN) peptides radiolabeled with 177Lu. The impetus driving many of the research studies that we have described in this review is that the high-affinity gastrin releasing peptide receptor (GRPR, BBN receptor subtype 2, BB2) has been identified in tissue biopsy samples and immortalized cell lines of many human cancers and is an ideal biomarker for targeting early-stage disease. Early on, the ability of GRPR agonists to be rapidly internalized coupled with a high incidence of GRPR expression on various neoplasias was a driving force for the design and development of new diagnostic and therapeutic agents targeting GRP receptor-positive tumors. Recent reports, however, show compelling evidence that radiopharmaceutical design and development based upon antagonist-type ligand frameworks clearly bears reexamination. Last of all, the ability to target multiple biomarkers simultaneously via a heterodimeric targeting ligand has also provided a new avenue to investigate the dual targeting capacity of bivalent radioligands for improved in vivo molecular imaging and treatment of specific human cancers. In this report, we describe recent advances

  2. A Patient With Metastatic Sarcoma was Successfully Treated With Radiolabeled Somatostatin Analogs

    PubMed Central

    Crespo-Jara, Aurora; González Manzano, Ramón; Lopera Sierra, Maribel; Redal Peña, María Carmen; Brugarolas Masllorens, Antonio

    2016-01-01

    Abstract We present a sarcoma patient with a tumor reduction of more than 50% in lung metastasis after 2 single courses of the investigational medical product Lutathera (177Lu-DOTA0-Tyr3-octreotate). She was resistant to more than 6 lines of therapy including all the available active drugs in soft tissue sarcomas. The high expression of somatostatin receptors was shown by microarrays and Octreoscan. The overall duration of response exceeded 1 year. PMID:27355848

  3. Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody.

    PubMed

    Vallabhajosula, Shankar; Nikolopoulou, Anastasia; Jhanwar, Yuliya S; Kaur, Gurveen; Tagawa, Scott T; Nanus, David M; Bander, Neil H; Goldsmith, Stanley J

    2016-01-01

    Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa. PMID:25771365

  4. Phase II study of lutetium-177 labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer

    PubMed Central

    Tagawa, Scott T.; Milowsky, Matthew I.; Morris, Michael; Vallabhajosula, Shankar; Christos, Paul; Akhtar, Naveed H.; Osborne, Joseph; Goldsmith, Stanley J.; Larson, Steve; Taskar, Neeta Pandit; Scher, Howard I.; Bander, Neil H.; Nanus, David M.

    2013-01-01

    Purpose To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival. Experimental Design In this dual-center phase II study, 2 cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n=15) received 70 mCi/m2 to verify response rate and examine biomarkers. Results 47 patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. 10.6% experienced ≥ 50% decline in PSA, 36.2% experienced ≥ 30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. 25.5% experienced grade 4 neutropenia with 1 episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs 13.3%, p=0.048) and longer survival (21.8 vs 11.9 months, p=0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious non-hematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. Conclusion A single dose of 177Lu-J591 was well-tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose-response. Imaging biomarkers appear promising. PMID:23714732

  5. Nuclear medicine program progress report for quarter ending September 30, 1995

    SciTech Connect

    Knapp, F.F. Jr.; Ambrose, K.R.; Beets, A.L.; Luo, H.; McPherson, D.W.; Mirzadeh, S.

    1995-12-31

    In this report, we describe the results for study of the production of lutetium-177 ({sup 177}Lu) in the High Flux Isotope Reactor (HFIR). Two pathways for production of {sup 177}Lu were studied which involved both direct neutron capture on enriched {sup 176}Lu, {sup 176}Lu (n,{gamma}){sup 177}Lu, reaction and by decay of ytterbium-177 ({sup 177}Yb) produced by the {sup 176}Yb(n,{gamma}){sup 177}Yb ({beta}{sup {minus}} {sup {yields}}) reaction. Although the direct route is more straight forward and does not involve any separation steps, the indirect method via {beta}{sup {minus}}-decay of {sup 177}Yb has the advantage of providing carrier-free {sup 177}Lu, which would be required for antibody radiolabeling and other applications where very high specific activity is required.Substrates required for preparation of tissue-specific agents and several radioisotopes were also provided during this period through several Medical Cooperative Programs. These include the substrate for preparation of the ``BMIPP`` cardiac imaging which was developed in the ORNL Nuclear Medicine Program, which was provided to Dr. A. Giodamo, M.D. and colleagues at the Catholic University Hospital in Rome, Italy. Tungsten-188 produced in the ORNL HFIR was also provided to the Catholic University Hospital for fabrication of a tungsten-188/rhenium-188 generator to provide carrier-free rhenium-188 which will be used for preparation of rhenium-188 labeled methylenediphosphonate (MDP) for initial clinical evaluation for palliative treatment of bone pain (L. Troncone, M.D.). Samples of substrates for preparation of the new ORNL ``IQNP`` agent for imaging of muscarinic-cholinergic receptors were provided to the Karolinska Institute in Stockholm, Sweden, for preparation of radioiodinated IQNP for initial imaging studies with this new agent in monkeys and for tissue binding studies with human brain samples obtained from autopsy (C. Halldin, Ph.D.).

  6. Zebularine significantly sensitises MEC1 cells to external irradiation and radiopharmaceutical therapy when administered sequentially in vitro.

    PubMed

    Bryan, Jeffrey N; Kumar, Senthil R; Jia, Fang; Balkin, Ethan R; Lewis, Michael R

    2014-02-01

    Zebularine is a cytidine analogue incorporated into DNA during replication, inhibiting DNA methyltransferase 1 (DNMT1), resulting in demethylation and changes in gene expression. Such modification may improve radiosensitivity in resistant lymphoma cells. The hypothesis of this study was that zebularine and radiation would synergistically inhibit cell growth and viability. Human MEC1 malignant B cells were incubated with 0-200 µM zebularine for 48 h. Media containing zebularine was removed, and the cells were irradiated with 0-2 Gy of either external beam irradiation or (177) Lu-DOTA-TATE, a radiolabelled somatostatin analogue. Concentration and viability were measured over 48-72 h. The proportion of apoptotic cells was identified using an active Caspase 3/7 assay. Zebularine inhibited growth of cells in a dose-dependent manner during exposure. No residual growth inhibition occurred following removal of the drug. Zebularine and external irradiation inhibited cell proliferation in a dose-dependent, synergistic interaction, but the effect on viability was additive. Treatment with zebularine and (177) Lu-DOTA-TATE resulted in less inhibition of proliferation (P = 0.0135), but a synergistic decrease in viability. Apoptotic fraction was much higher in cells irradiated with (177) Lu-DOTA-TATE than external irradiation. External irradiation induces growth arrest rather than apoptosis. Apoptosis is the primary effect of radiopharmaceutical therapy on tumour cells. Treatment with the methylation inhibitor, zebularine, appears to synergistically augment these natural effects in vitro, which could be exploited clinically. PMID:24323360

  7. Zebularine Significantly Sensitizes MEC1 cells to External Irradiation and Radiopharmaceutical Therapy When Administered Sequentially in Vitro

    PubMed Central

    Bryan, Jeffrey N.; Kumar, Senthil R.; Jia, Fang; Balkin, Ethan R.; Lewis, Michael R.

    2014-01-01

    Zebularine is a cytidine analog incorporated into DNA during replication, inhibiting DNA methyltransferase 1 (DNMT1), resulting in demethylation and changes in gene expression. Such modification may improve radiosensitivity in resistant lymphoma cells. The hypothesis of this study was that zebularine and radiation would synergistically inhibit cell growth and viability. Human MEC1 malignant B cells were incubated with 0–200μM zebularine for 48h. Media containing zebularine was removed, and the cells were irradiated with 0–2 Gy of either external beam irradiation or 177Lu-DOTA-TATE, a radiolabeled somatostatin analogue. Concentration and viability were measured over 48-72h. The proportion of apoptotic cells was identified using an active Caspase 3/7 assay. Zebularine inhibited growth of cells in a dose-dependent manner during exposure. No residual growth inhibition occurred following removal of the drug. Zebularine and external irradiation inhibited cell proliferation in a dose-dependent, synergistic interaction, but the effect on viability was additive. Treatment with zebularine and 177Lu-DOTA-TATE resulted in less inhibition of proliferation (P=0.0135), but a synergistic decrease in viability. Apoptotic fraction was much higher in cells irradiated with 177Lu-DOTA-TATE than external irradiation. External irradiation arrests growth arrest rather than apoptosis. Apoptosis is the primary effect of radiopharmaceutical therapy on tumor cells. Treatment with the methylation inhibitor, zebularine, appears to synergistically augment these natural effects in vitro, which could be exploited clinically. PMID:24323360

  8. Predictors of Long-Term Outcome from Intraperitoneal Radioimmunotherapy for Ovarian Cancer

    PubMed Central

    You, Zhiying; Alvarez, Ronald; Partridge, Edward; Grizzle, William; LoBuglio, Albert

    2012-01-01

    Abstract Data was analyzed from 92 patients > 5 years after intraperitoneal (IP) radionuclide therapy (RIT) with 90Y- or 177Lu-CC49 to determine prognostic factors. Patients had CC49 antibody-reactive ovarian cancer confined to the abdominal cavity after primary debulking and chemotherapy. The first 27 patients received IP 177Lu-CC49 alone; the remainder received Interferon (IFN), to increase the expression of the tumor-associated glycoprotein-72 (TAG-72) antigen, +/− IP paclitaxel (25–100 mg/m2) 2 days before RIT. Factors assessed by univariate (and some multivariate) analysis included age, race, body size, interval between initial diagnosis and RIT, interval between 2nd look surgery and RIT, 90Y versus 177Lu, MBq dose, paclitaxel dose, grade of tumor, extent of initial surgery, size of disease deposits prior to RIT, intensity of TAG reactivity, the addition of unlabeled antibody, and the development of human anti-mouse antibody and/or serum sickness after murine antibody. A statistically significant improvement in progression-free survival (p≤0.05) was noted for less bulky disease and younger age. Administration of paclitaxel plus IFN, an immune response, and use of 90Y showed a favorable nonsignificant trend. Dose escalation of radionuclide did not change risk of progression; thus, this therapy may have therapeutic efficacy at modest dose levels. PMID:22239432

  9. Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer.

    PubMed

    Bodei, Lisa; Kwekkeboom, Dik J; Kidd, Mark; Modlin, Irvin M; Krenning, Eric P

    2016-05-01

    Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, (90)Y-octreotide and (177)Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with (177)Lu-octreotate vs high-dose octreotide long-acting release demonstrated that (177)Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs. PMID:27067503

  10. Samarium-153 therapy for prostate cancer: the evaluation of urine activity, staff exposure and dose rate from patients.

    PubMed

    Parlak, Yasemin; Gumuser, Gul; Sayit, Elvan

    2015-03-01

    The aim of this study was to determine the excretion of Samarium-153-ethylenediaminetetramethylphosphonic acid ((153)Sm-EDTMP) in urine and to calculate the dose rate of its retention in the body as a function of time and the dose received by the skin of laboratory staff's finger. Urine samples were collected from 11 patients after intravenous injection of (153)Sm-EDTMP. The measurements of dose rate were performed. Thermoluminescent dosemeters were used for absorbed dose measurements. Effective half-lives that were calculated from urine sample measurements were found as 7.1±3 h within the first 24 h. Whole body dose rates before collecting urine of patients were 60.0 ± 15.7 µSv h(-1) for within 1 h following (153)Sm-EDTMP administration. The highest finger radiation dose is to the right-hand thumb (3.8 ± 2 mGy). The results of the study imply that patients who recieved (153)Sm-EDTMP therapy should be kept a minumum of 8 h in an isolated room at hospital and that one staff should give therapy at most two patients per week. PMID:25063786

  11. The use of 185 MBq and 740 MBq of 153-samarium hydroxyapatite for knee synovectomy in haemophilia

    PubMed Central

    Calegaro, J U M; Machado, J; Furtado, R G; de Almeida, J S C; de Vasconcelos, A V P; de Barboza, M F; de Paula, A P

    2014-01-01

    The penetration of beta energy of 153-samarium (153Sm) (0.8 MeV) is not only appropriate for synovectomy of median articulations but is possible to improve the radiobiological effect using increased activities. The aim of this study was to assess the effectiveness of 185 MBq and 740 MBq of 153-samarium hydroxyapatite (153Sm-HA) in knees of haemophilic patients. Thirty-one patients – 36 knees, 30 males, were divided into two groups without coinjection of corticosteroid: A – 14 patients (17 knees) treated with intra-articular dose of 185 MBq of 153Sm-HA, average age 23 years; B – 17 patients (19 knees) with 740 MBq of 153Sm-HA, average age 21.3 years. The evaluation before and after 1 year of synovectomy used the following criteria: reduction in the number of haemarthroses and use of the coagulation factor and improvement in articular motility. Adverse-effects occurrence was considered too. Early and late scintigraphic studies were performed after synoviorthesis and no joint immobilization was recommended. The reduction in haemarthrosis and use of coagulation factor were: group 1 – 31.3% and 25%; group 2 – 81.5% and 79% with P < 0.001 respectively; no significant improvement in knees motility was noted for both groups. Four cases of mild reactional synovitis were observed in each group. The scintigraphic control showed homogenous distribution of the radiopharmaceuticals with no articular escape; the material was considered safe by its permanence in the articulation. We have significant improvement in the synovectomy of haemophilic knees with 740 MBq of 153Sm-HA; the less penetration of its beta radiation was compensated by the increased biological effect with the higher used activity. PMID:24330418

  12. Novel heterobimetallic radiotheranostic: preparation, activity, and biodistribution.

    PubMed

    Adriaenssens, Louis; Liu, Qiang; Chaux-Picquet, Fanny; Tasan, Semra; Picquet, Michel; Denat, Franck; Le Gendre, Pierre; Marques, Fernanda; Fernandes, Célia; Mendes, Filipa; Gano, Lurdes; Campello, Maria Paula Cabral; Bodio, Ewen

    2014-07-01

    A novel Ru(II) (arene) theranostic complex is presented. It is based on a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocycle bearing a triarylphosphine and can be tracked in vivo by using the γ emission of (153) Sm atoms. Notably, the heteroditopic ligand can be selectively metalated with ruthenium at the phosphorus atom despite the presence of other functionalities that are prone to metal coordination. Subsequent labeling with radionuclides such as (153) Sm can then be performed easily. The resulting heterobimetallic complex exhibits favorable solubility and stability properties in biologically relevant media. It also shows in vitro cytotoxicity in line with that expected for this type of metallodrug, and is nontoxic to the organism as a whole. As a proof of concept, initial studies in healthy mice were performed to obtain information about the uptake, biodistribution, and excretion of the radiolabeled complex. PMID:24449620

  13. Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent

    PubMed Central

    Chatalic, Kristell L.S.; Heskamp, Sandra; Konijnenberg, Mark; Molkenboer-Kuenen, Janneke D.M.; Franssen, Gerben M.; Clahsen-van Groningen, Marian C.; Schottelius, Margret; Wester, Hans-Jürgen; van Weerden, Wytske M.; Boerman, Otto C.; de Jong, Marion

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics—they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. 111In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of 111In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during 177Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA. PMID:27162555

  14. Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results

    PubMed Central

    Schoffelen, R; Boerman, O C; Goldenberg, D M; Sharkey, R M; van Herpen, C M L; Franssen, G M; McBride, W J; Chang, C-H; Rossi, E A; van der Graaf, W T A; Oyen, W J G

    2013-01-01

    Background: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). Methods: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 μg). After confirmation of tumour targeting by 111In-IMP288, patients were treated with a bsMAb/177Lu-IMP288 cycle. Results: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-μg peptide dose. High 177Lu-IMP288 doses (2.5–7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3–4 thrombocytopaenia in 10% of the patients who received 177Lu-IMP288. Conclusion: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted. PMID:23860529

  15. Influence of total-body mass on the scaling of S-factors for patient-specific, blood-based red-marrow dosimetry

    NASA Astrophysics Data System (ADS)

    Traino, A. C.; Ferrari, M.; Cremonesi, M.; Stabin, M. G.

    2007-09-01

    To perform patient-specific, blood-based red-marrow dosimetry, dose conversion factors (the S factors in the MIRD formalism) have to be scaled by patients' organ masses. The dose to red marrow includes both self-dose and cross-irradiation contributions. Linear mass scaling for the self-irradiation term only is usually applied as a first approximation, whereas the cross-irradiation term is considered to be mass independent. Recently, the need of a mass scaling correction on both terms, not necessarily linear and dependent on the radionuclide, has been highlighted in the literature. S-factors taking into account different mass adjustments of organs are available in the OLINDA/EXM code. In this paper, a general algorithm able to fit the mass-dependent factors Srm<--tb and Srm<--rm is suggested and included in a more general equation for red-marrow dose calculation. Moreover, parameters to be considered specifically for therapeutic radionuclides such as 131I, 90Y and 177Lu are reported. The red-marrow doses calculated by the traditional and new algorithms are compared for 131I in ablation therapy (14 pts), 177Lu- (13 pts) and 90Y- (11 pts) peptide therapy for neuroendocrine tumours, and 90Y-Zevalin therapy for NHL (21 pts). The range of differences observed is as follows: -36% to -10% for 131I ablation, -22% to 5% for 177Lu-DOTATATE, -9% to 11% for 90Y-DOTATOC and -8% to 6% for 90Y-Zevalin. All differences are mostly due to the activity in the remainder of the body contributing to cross-irradiation. This paper quantifies the influence of mass scaling adjustment on usually applied therapies and shows how to derive the appropriate parameters for other radionuclides and radiopharmaceuticals.

  16. Lu-177-Labeled Zirconia Particles for Radiation Synovectomy.

    PubMed

    Polyak, Andras; Nagy, Lívia Naszályi; Drotár, Eszter; Dabasi, Gabriella; Jóba, Róbert P; Pöstényi, Zita; Mikolajczak, Renata; Bóta, Attila; Balogh, Lajos

    2015-12-01

    The present article describes the preparation of β-emitter lutetium-177-labeled zirconia colloid and its preliminary physicochemical and biological evaluation of suitability for local radionuclide therapy. The new (177)Lu-labeled therapeutic radiopharmaceutical candidate was based on the synthesis mode of a previously described zirconia nanoparticle system. The size and shape of the developed radiopharmaceutical compound were observed through a scanning electron microscope and dynamic light scattering methods. The radiocolloid had a 1.7 μm mean diameter and showed high in vitro radiochemical and colloid size stability at room temperature and during the blood sera stability test. After the in vitro characterizations, the product was investigated in the course of the treatment of a spontaneously diseased dog veterinary patient's hock joint completed with single-photon emission computed tomography (SPECT) imaging follow-up measurements and a dual-isotope SPECT imaging tests with conventional (99m)Tc-methanediphosphonic acid bone scintigraphy. In the treated dog, no clinical side-effects or signs of histopathological changes of the joints were recorded during the treatment. SPECT follow-up studies clearly and conspicuously showed the localization of the (177)Lu-labeled colloid in the hock joint as well as detectable but negligible leakages of the radiocolloid in the nearest lymph node. On the basis of biological follow-up tests, the orthopedic team assumed that the (177)Lu-labeled zirconia colloid-based local radionuclide therapy resulted in a significant and long-term improvement in clinical signs of the patient without any remarkable side-effects. PMID:26683134

  17. Dosimetry and toxicity of Samarium-153-EDTMP administered for bone pain due to skeletal metastases

    SciTech Connect

    Bayouth, J.E.; Macey, D.J.; Kasi, L.P.

    1994-01-01

    Palliation of bone pain in patients with cancer metastatic to bone is being evaluated in several cancer centers by the administration of the bone-seeking phosphonate ethylenediaminetetramethylenephosphonic acid (EDTMP) chelated with the beta particle-emitting radionuclide {sup 153}Sm. In this study {sup 153}Sm-EDTMP was intravenously injected into 19 patients over a 1-min period. Patients received up to four injections of 18.5 MBq (0.5 mCi) or 37 MBq (1.0mCi) per kilogram of body weight. Skeletal retention was calculated from urinary excretion. No uptake of {sup 153}Sm-EDTMP in nonskeletal tissues was observed in whole-body gamma camera images. The mean skeletal uptake for all patients was 54% {plus_minus} 16% of the injected dose (%ID). This resulted in the bone marrow receiving 89 cGy/GBq {plus_minus} 27 cGy/GBq (3.28 cGy/mCi {plus_minus} 0.99 cGy/mCi), with calculated marrow doses ranging from 27 cGy to 338 cGy. For each patient, the estimated radiation absorbed dose to the marrow was correlated to the percent decrease in platelet number, ranging from 7.4% to 78.9%. Since the deviation of uptake between the four injections for a given patient (7.6% ID) was less than the deviation for all patients (16% ID), the initial dose may be used to estimate the skeletal uptake for the remaining doses. These radiation dose estimates permit patients at risk to be identified prior to reaching myelotoxicity and develop dose-response models. Thirteen patients (68%) reported significant pain relief from this radionuclide therapy. Bone pain appears to be alleviated by {sup 153}Sm-EDTMP with limited red marrow doses and no toxic effects in other organs. 15 refs., 8 figs., 2 figs.

  18. Phase I Trial of Vertebral Intracavitary Cement and Samarium (VICS): Novel Technique for Treatment of Painful Vertebral Metastasis

    SciTech Connect

    Ashamalla, Hani; Cardoso, Erico; Macedon, Mark; Guirguis, Adel; Weng Lijun; Ali, Shamsah; Mokhtar, Bahaa; Ashamalla, Michael; Panigrahi, Nokul

    2009-11-01

    Purpose: Kyphoplasty is an effective procedure to alleviate pain in vertebral metastases. However, it has no proven anticancer activity. Samarium-153-ethylene diamine tetramethylene phosphonate ({sup 153}Sm-EDTMP) is used for palliative treatment of bone metastases. A standard dose of 1 mCi/kg is administrated intravenously. The present study was conducted to determine the feasibility of intravertebral administration of {sup 153}Sm with kyphoplasty. Methods and Materials: A total of 33 procedures were performed in 26 patients. Of these 26 patients, 7 underwent procedures performed at two vertebral levels. The mean age of the cohort was 64 years (range, 33-86). The kyphoplasty procedure was performed using a known protocol; 1-4 mCi of {sup 153}Sm was admixed with the bone cement and administered under tight radiation safety measures. Serial nuclear body scans were obtained. Pain assessment was evaluated using a visual analog pain score. Results: All patients tolerated the procedure well. No procedure-related morbidities were noted. No significant change had occurred in the blood counts at 1 month after the procedure. One case was not technically satisfactory. Nuclear scans revealed clear radiotracer uptake in the other 32 vertebrae injected. Except for the first patient, no radiation leakage was encountered. The mean pain score using the visual analog scale improved from 8.6 before to 2.8 after the procedure (p < .0001). Follow-up bone scans demonstrated a 43% decrease in the tracer uptake. Conclusion: The results of our study have shown that the combination of intravertebral administration of {sup 153}Sm and kyphoplasty is well tolerated with adequate pain control. No hematologic adverse effects were found. A reduction of the bone scan tracer uptake was observed in the injected vertebrae. Longer follow-up is needed to study the antineoplastic effect of the procedure.

  19. Patient selection for personalized peptide receptor radionuclide therapy using Ga-68 somatostatin receptor PET/CT.

    PubMed

    Kulkarni, Harshad R; Baum, Richard P

    2014-01-01

    Neuroendocrine tumors are malignant solid tumors originating from neuroendocrine cells dispersed throughout the body. Differentiated neuroendocrine tumors overexpress somatostatin receptors (SSTRs), which enable the diagnosis using radiolabeled somatostatin analogues. Internalization and retention within the tumor cell are important for peptide receptor radionuclide therapy using the same peptide. The use of the same DOTA-peptide for SSTR PET/CT using (68)Ga and for peptide receptor radionuclide therapy using therapeutic radionuclides like (177)Lu and (90)Y offers a unique theranostic advantage. PMID:25029937

  20. Metastatic superscan in prostate carcinoma on gallium-68-prostate-specific membrane antigen positron emission tomography/computed tomography scan

    PubMed Central

    Agarwal, Krishan Kant; Tripathi, Madhavi; Kumar, Rajeev; Bal, Chandrasekhar

    2016-01-01

    We describe the imaging features of a metastatic superscan on gallium-68 Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68(HBED-CC)], abbreviated as gallium-68-prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) imaging. 68Ga-PSMA is novel radiotracer undergoing evaluation for PET/CT imaging of prostate carcinoma. This patient had a superscan of metastases on conventional bone scintigraphy and was referred for 68Ga-PSMA PET/CT to evaluate the feasibility of 177Lu-PSMA therapy. PMID:27095868

  1. Metallofullerene-based Nanoplatform for Brain Tumor Brachytherapy and Longitudinal Imaging in a Murine Orthotopic Xenograft Model

    PubMed Central

    Shultz, Michael D.; Wilson, John D.; Fuller, Christine E.; Zhang, Jianyuan; Dorn, Harry C.

    2011-01-01

    Purpose: To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd3N@C80) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (177Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (177Lu-DOTA-f-Gd3N@C80), provide an anchor to deliver effective brachytherapy. Materials and Methods: All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd3N@C80 alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of 177Lu-DOTA-f-Gd3N@C80. Survival data were evaluated by using Kaplan-Meier statistical methods. Results: MR imaging showed extended tumor retention (25.6% ± 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f-Gd3N@C80 nanoplatform, which enabled longitudinal imaging. Successful coupling of 177Lu to the f-Gd3N@C80 surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (>2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage. Conclusion: The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe

  2. Peptide Receptor Radionuclide Therapy (PRRT) of Medullary and Nonmedullary Thyroid Cancer Using Radiolabeled Somatostatin Analogues.

    PubMed

    Salavati, Ali; Puranik, Ameya; Kulkarni, Harshad R; Budiawan, Hendra; Baum, Richard P

    2016-05-01

    As therapeutic options in advanced medullary and non-iodine avid differentiated (nonmedullary) thyroid cancers are limited and associated with significant toxicity, targeting of somatostatin receptors (SSTRs) for internal radiation therapy provides a promising option. Theranostics (therapy and diagnosis) using radiolabeled somatostatin analogues has proved to be a milestone in the management of SSTR-expressing tumors. Peptide receptor radionuclide therapy using (177)Lu-labeled or (90)Y-labeled somatostatin analogues may have a significant role in the management of medullary and nonmedullary thyroid cancers in those patients where PET/CT with (68)Ga-labeled somatostatin analogues demonstrates significant SSTR expression. PMID:27067502

  3. Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using a IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex

    PubMed Central

    Cheal, Sarah M.; Xu, Hong; Guo, Hong-fen; Zanzonico, Pat B.; Larson, Steven M.; Cheung, Nai-Kong

    2014-01-01

    Bispecific antibodies (BsAb) have proven to be useful targeting vectors for pretargeted radioimmunotherapy (PRIT). We sought to overcome key PRIT limitations such as high renal radiation exposure and immunogenicity (e.g. of streptavidin-antibody fusions), to advance clinical translation of this PRIT strategy for diasialoganglioside GD2-positive (GD2(+)) tumors. For this purpose, a IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 (1) and C825, a murine scFv antibody with high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with beta-particle emitting radiometals such as 177Lu and 90Y (2, 3). A three-step regimen including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with 177Lu (as 177Lu-DOTA-Bn; t1/2 = 6.71 days (d)) was optimized in immunocompromised mice carrying subcutaneous (s.c.) human GD2(+) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were ∼85 cGy/MBq and ≤3.7 cGy/MBq, respectively, with therapeutic indicies (TI) of 142 for blood and 23 for kidney. A therapy study (n = 5 per group; tumor volume: 240 ± 160 mm3) with three successive PRIT cycles (total 177Lu: ∼33 MBq; tumor dose ∼3400 cGy), revealed complete tumor response in 5/5 animals, with no recurrence up to 28 d post-treatment. Tumor ablation was confirmed histologically in 4/5 mice, and normal organs showed minimal overall toxicities. All non-treated mice required sacrifice within 12 d (>1.0 cm3 tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate s.c. GD2(+)–NB in mice while sparing kidney and bone marrow. PMID:24944121

  4. Relaxometry, luminescence measurements, electrophoresis, and animal biodistribution of lanthanide(III) complexes of some polyaza macrocyclic acetates containing pyridine

    SciTech Connect

    Kim, W.D.; Sherry, A.D.; Kiefer, G.E.; McMillan, K.; Maton, F.; Muller, R.N.

    1995-04-12

    Four Gd{sup 3+} complexes [Gd(BP2A){sup +}, Gd(PC2A){sup +}, Gd(PCTA){sup 0}, and Gd(BPO4A){sup {minus}}] with polyazamacrocyclic ligands that contain a pyridine moiety were prepared and examined for possible use as MRI contrast enhancement agents. The authors estimated the number of inner sphere water molecules (q{sub Gd}) for the Gd{sup 3+} complexes from the values of q found for the Tb{sup 3+} and/or Eu{sup 3+} complexes by luminescence lifetime measurements. It was estimated that q{sub Gd} = 3.5, 3.3, 2.4, and 0.2 for Gd(BP2A){sup +}, Gd(PC2A){sup +}, Gd(PCTA){sup 0}, and Gd(BPO4A){sup {minus}}, respectively. The inner sphere relaxivities (r{sub 1,inner}) of these tetraaza macrocyclic complexes were higher than that of Gd(DOTA){sup {minus}} [i.e. 6.79 for Gd(BP2A){sup +}, 6.21 for Gd(PC2A){sup +}, and 4.60 for Gd(PCTA){sup 0} mM{sup {minus}1}s{sup {minus}1} at 40 MHz and 25{degrees}C], but the normalized relaxivities per q{sub Gd} (1.94, 1.88, and 1.92 mM{sup {minus}1}s{sup {minus}1}, respectively) were comparable to that of Gd(DOTA){sup {minus}}. A quantitative treatment of the NMRD profiles based on Solomon-Bloembergen-Morgan theory, using the NMRD profile of Gd(BPO4A){sup {minus}} to correct for an outer sphere contribution, showed that the complexes exhibit characteristics similar to that of Gd(DOTA){sup {minus}} but with shorter electronic relaxation times. Tissue biodistribution results using radioactive {sup 153}Sm and {sup 159}Gd complexes in rats indicate that the cationic [{sup 153}Sm-(BP2A){sup +} and {sup 153}Sm(PC2A){sup +}] complexes accumulate preferably in the bone tissue while the neutral [{sup 153}Sm-(PCTA){sup 0}] and anionic [{sup 153}Sm(BPO4A){sup {minus}}] complexes appear to have renal clearances similar to those of other low molecular weight contrast agents [i.e. Gd(DTPA){sup 2{minus}} and Gd(DOTA){sup {minus}}].

  5. A Phase I Trial of Samarium-153-Lexidronam Complex for Treatment of Clinically Nonmetastatic High-Risk Prostate Cancer: First Report of a Completed Study

    SciTech Connect

    Valicenti, Richard K.; Trabulsi, Edouard; Intenzo, Charles; Lavarino, Jorosali; Xu Yihuan; Chervoneva, Inna

    2011-03-01

    Purpose: We completed a Phase I trial to determine the maximum tolerated dose of samarium-153 EDTMP ({sup 153}Sm) with hormonal therapy (HT) and radiation therapy (RT) in high-risk clinically nonmetastatic prostate cancer. Methods and Materials: High-risk M0 prostate cancer patients (prostate-specific antigen >20 ng/mL, Gleason score >7, or >T3) were eligible for this prospective trial of dose-escalated radioactive {sup 153}Sm-EDTMP (.25-2.0 mCi/kg) as primary or postoperative therapy. After 1 month of HT, we administered {sup 153}Sm-EDTMP followed by 4 more months of HT, 46.8 Gy to the pelvic region and 23.4 Gy to the prostate target (TD = 70.2 Gy). The primary endpoint was Grade III toxicity or higher by the National Cancer Institute Common Toxicity Criteria. Results: Twenty-nine patients enrolled (median prostate-specific antigen = 8.2 ng/mL, 27/29 (93%) T stage {>=}T2b, 24/29 (83%) had Gleason >7) and received {sup 153}Sm-EDTMP (.25 mCi/kg, 4 patients; 0.5 mCi/kg, 4 patients; 0.75 mCi/kg, 6 patients; 1.0 mCi/kg, 6 patients; 1.5 mCi/kg, 5 patients; 2.0mCi/kg, 4 patients). Twenty-eight patients underwent all planned therapy without delays (1 patient required surgery before the start of RT). With a median follow-up time of 23 months, there were 2 patients (7 %) experiencing Grade III hematologic toxicity. There were no other Grade III or IV side effects. Conclusions: Our trial demonstrates that 2 mCi/kg {sup 153}Sm -EDTMP with HT and RT was safe and feasible in men with high-risk M0 prostate cancer. A Phase II study to test this treatment is currently underway by the Radiation Therapy Oncology Group.

  6. Radionuclide Therapy of Unresectable Tumors with AvidinOX and (90)Y-biotinDOTA: Tongue Cancer Paradigm.

    PubMed

    Albertoni, Claudio; Leoni, Barbara; Rosi, Antonio; D'Alessio, Valeria; Carollo, Valeria; Spagnoli, Luigi Giusto; van Echteld, Cees; De Santis, Rita

    2015-09-01

    Local treatment of unresectable tumors is challenging, particularly with radioactivity. Current practice relies on external beam irradiation or on a variety of medical devices for brachytherapy. Both approaches proved useful in controlling tumor growth, but are characterized by poor compliance of the patient, significant side-effects, high costs, and technological complexity, which hamper widespread use. The authors recently described a novel form of radionuclide therapy based on the oxidized form of avidin that, chemically reacting with tissue proteins, can secure radioactive biotin within the injected tissue, either when precomplexed or when taken from the blood stream after intravenous administration. AvidinOX-pretargeted (177)Lu-biotinDOTA ((177)Lu-ST2210) is currently under clinical investigation for the treatment of liver oligometastases from colorectal cancer (clinicaltrials.gov/NCT02053324). In the present work, the authors show that injected AvidinOX can link tissues of various natures such as prostate, kidney, breast, or brain and can react by contact with scraped tissues such as skin or urinary bladder. AvidinOX injected into human OSC19 tongue cancer masses orthotopically transplanted in nude mice takes up intravenously administered (90)Y-ST2210, which exerts significant antitumor activity, while preserving the integrity and functionality of the tongue. Present data confirm that AvidinOX-based radionuclide therapy is an innovative and promising approach for the local treatment of inoperable tumors. PMID:26167947

  7. Radionuclide Therapy of Unresectable Tumors with AvidinOX and 90Y-biotinDOTA: Tongue Cancer Paradigm

    PubMed Central

    Albertoni, Claudio; Leoni, Barbara; Rosi, Antonio; D'Alessio, Valeria; Carollo, Valeria; Spagnoli, Luigi Giusto; van Echteld, Cees

    2015-01-01

    Abstract Local treatment of unresectable tumors is challenging, particularly with radioactivity. Current practice relies on external beam irradiation or on a variety of medical devices for brachytherapy. Both approaches proved useful in controlling tumor growth, but are characterized by poor compliance of the patient, significant side-effects, high costs, and technological complexity, which hamper widespread use. The authors recently described a novel form of radionuclide therapy based on the oxidized form of avidin that, chemically reacting with tissue proteins, can secure radioactive biotin within the injected tissue, either when precomplexed or when taken from the blood stream after intravenous administration. AvidinOX-pretargeted 177Lu-biotinDOTA (177Lu-ST2210) is currently under clinical investigation for the treatment of liver oligometastases from colorectal cancer (clinicaltrials.gov/NCT02053324). In the present work, the authors show that injected AvidinOX can link tissues of various natures such as prostate, kidney, breast, or brain and can react by contact with scraped tissues such as skin or urinary bladder. AvidinOX injected into human OSC19 tongue cancer masses orthotopically transplanted in nude mice takes up intravenously administered 90Y-ST2210, which exerts significant antitumor activity, while preserving the integrity and functionality of the tongue. Present data confirm that AvidinOX-based radionuclide therapy is an innovative and promising approach for the local treatment of inoperable tumors. PMID:26167947

  8. Peptide receptor radionuclide therapy for metastatic paragangliomas.

    PubMed

    Pinato, David J; Black, James R M; Ramaswami, Ramya; Tan, Tricia M; Adjogatse, Delali; Sharma, Rohini

    2016-05-01

    There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with (177)Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16-47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0-78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL. PMID:27059363

  9. The determination of the rate of conjugation immunoglobuline with bifunctional chelator

    NASA Astrophysics Data System (ADS)

    Málek, Z.; Miler, V.; Budský, F.

    2006-01-01

    The work was performed under the GACR project: "Technology of preparation of radionuclides and their labelled compounds for nuclear medicine and pharmacy with the use of the reactor LVR-15" reg. no. 104/03/0499. Imaging of cell’s antigens with the use of labelled immunoglobulines allows imaging of specific receptors on cell membrane and specific tumours. It is necessary to carry out the labelling of the immunoglobulines with radionuclides of suitable physical properties, which form cations (e.g., 111In, 90Y, 177Lu) that form very strong chelates of sufficiently high stability constant preventing the dissociation of complexes or the radionuclide under “in-vivo” conditions. The immunoglobuline must be conjugated with the bifunctional chelator (BCH), which contains both chelating unit and reactive group for binding to the immunoglobuline. In our laboratory we have conjugated human IgG and monoclonal antibody CD20 with diethylenetriamine pentaacetic acid dianhydride (cDTPAA). Radionuclides 90Y and 177Lu prepared on the LVR-15 reactor in NRI Rez were used for labelling. After conjugation and labelling the yields in relation to the amount of isotopic carrier have been determined.

  10. Effects of thrombin on the integrity of monolayers of cultured human endothelial cells

    SciTech Connect

    Galdal, K.S.; Evensen, S.A.; Brosstad, F.

    1982-09-01

    /sup 51/Cr-prelabelled endothelial cells (EC) in confluent monolayers were incubated in RPMI 1640 + foetal calf serum 20% (v/v) to which purified thrombin was added. Thrombin (greater than or equal to 0.1 NIH U/ml) significantly accelerated /sup 51/Cr-release and caused extensive but reversible cell contraction. Thrombin-exposed EC reacted to a new dose of thrombin with no appreciable shape change, but /sup 51/Cr-efflux was again accelerated. EC exposed to thrombin pretreated with N-bromosuccinimide (modifying the macromolecular site) or phenylmethylsulfonyl fluoride (blocking the serine site) retained normal morphology and did not leak excess amounts of /sup 51/Cr. Antithrombin III also inhibited the effect of thrombin. Pretreatment of EC with either indomethacin, aspirin, sulfinpyrazone, pronase or neuraminidase did not influence the effect of subsequent thrombin exposure.