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Sample records for 90y 188re 177lu

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

    S. Lucas

    2015-01-01

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

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

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

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

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

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

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

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

    Sofia H L Frost

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

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

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

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

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

    2015-03-01

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

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

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

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

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

    2014-01-01

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

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

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

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

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

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

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

    2014-02-15

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

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

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

  14. Therapeutic Radionuclide Generators: 90Sr/90Y and 188W/188Re Generators

    Radionuclide therapy using radiopharmaceuticals has been in existence for over 60 years and offers substantial benefits to cancer patients, in particular, patients suffering from thyroid cancer. Numerous clinical trials for treating other types of cancer using therapeutic radiopharmaceuticals are in progress, and their success will increase the demand for therapeutic radionuclides in the coming years. Those radioisotopes having short physical half-lives ranging from a few hours to a few days are useful for radionuclide therapy. The use of short lived radioisotopes for radionuclide therapy involves important challenges including the transport of the radionuclides and the need for frequent shipments. Radionuclide generators represent an efficient means for making short lived therapeutic radionuclides more widely available throughout the world. To meet the requirements for sustained growth and future expansion of the application of therapeutic radiopharmaceuticals in nuclear medicine, particularly in oncology, it is important to develop and maintain a constant and reliable supply of therapeutic radionuclides of the required quality in the desired quantities. The IAEA has several activities to support programmes that foster the enhanced availability of therapeutic radionuclides and radiopharmaceuticals in Member States. One such activity was the coordinated research project (CRP) on the development of generator technologies for therapeutic radionuclides, which ran from 2004 to 2007, in which participants from 13 countries worked to develop generator technologies for the preparation of 90Y and 188Re usable for radionuclide therapy. The objectives of the CRP were: (a) To develop reproducible methodologies for the preparation of 90Sr/90Y and 188W/188Re generators; (b) To standardize quality control techniques for generator eluted therapeutic radionuclides; (c) To optimize technologies for post-elution concentration of 188Re; (d) To prepare chromatography adsorbents having

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

    Johnnie J Orozco

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

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

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

    2016-03-01

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

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

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

    2014-02-15

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

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

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

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

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

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

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

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

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

    2014-08-28

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

  2. Development of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy at BARC. Chapter 6

    During the last decade, the group at Bhabha Atomic Research Centre (BARC), India, has focused attention on the development of 90Y based radiopharmaceuticals for therapy. Because the 90Sr/90Y generator is the primary source of high specific activity 90Y, local availability of the generator is crucial in the successful development of 90Y radiopharmaceuticals. In this context, 90Sr/90Y generators based on SLM and electrochemical techniques were designed and deployed at BARC for the elution of 90Y to be used for preparation of 90Y labelled products. This work formed a part of the IAEA CRP entitled Development of Generator Technologies for Therapeutic Radionuclides: 90Y and 188Re. In this chapter, work on the development of 90Y labelled products for treatment of NHL and liver cancer is reported. In addition, validation of the EPC technique for determination of 90Sr contamination in 90Y eluates and its comparison with the United States Pharmacopeia recommended method is presented. (author)

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

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

  4. Country report: Brazil. Development of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy at IPEN-CNEN/SP

    The overall objective of this CRP is to develop radiopharmaceuticals for targeted therapy using 188Re and 90Y and to study the performance of generators with long lived parent radionuclides as well as to validate the QC control procedures for estimating the purity of generator eluents. The CRP is expected to enhance the capability in production of 90Y and 188Re radiopharmaceuticals to meet the increasing demand of therapeutic products for clinical applications, in particular in Brazil. In this period efforts were made towards the assembling of 90Sr-90Y generators, quality control of 90Y, the labelling of DMSA(V) and anti-CD20 with 188Re and the labelling of Hydroxiapatite(HA) with 90Y. (author)

  5. Country report: Cuba. Local Production of 90Y And 188Re Radionuclides and Development of Radiopharmaceuticals for Therapy

    During the first period of this CRP we could test an efficient and reliable generator system based on ion-chromatography to obtain 90Y from its parent radionuclide 90Sr. This production scheme for 90Y was outlined in the previous CRP related with the development of generator technologies. Quality parameters such as trace metals that can potentially interfere in the labeling of biomoléculas, 90Y recovery, 90Sr/90Y ratio and radiation dose to bed matrix were evaluated. The results showed that high recovery and radionuclidic purity could be obtained for 90Y during its repeated separation from the 90Sr cow. No replacement or treatment of the cow were necessary and low waste generation and 90Sr losses less that 0.1% after each run were also observed during the present study. A Fab’ fragment was enzimatically produced and purified from the monoclonal antibody h-R3 (Nimotuzumab®). The fragment and the parent antibody were successfully conjugated with DOTA and labeled with 90Y. The radioinmunoconjugate thus obtained also exhibited a good 24 h in-vitro stability in an excess of DTPA. A 90Y radiocoloid was prepared in a cromic phosphate particle for radiosynoviorthesis with promising results in animal models. Two alumina based 188W/188Re generators were prepared and their eluates were used in the labeling of hR3-DOTA conjugates. Quality control and in vivo evaluation in comparison with 99mTc-hR3 showed very good results and similar pattern of distribution and pharmacokinetic and will be used in clinical trials for cancer patients. (author)

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

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

    2011-10-15

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

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

    Radfar Edalat

    2012-01-01

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

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

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

    2009-10-15

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

  9. 177Lu- labeled MOv18 as compared to 131I- or 90Y-labeled MOv18 has the better therapeutic effect in eradication of alpha folate receptor-expressing tumor xenografts

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

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

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

    2015-12-15

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

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

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

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

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

    2015-07-15

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

  13. Report on the 2nd Research Coordination Meeting on The Development of Therapeutic Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide. Working Document

    Radionuclide therapy is practiced for the treatment of malignant disorders of various organs and tissues as well as for treating certain other diseases such as rheumatoid arthritis. Advances in understanding tumor biology as well as developments in peptide chemistry and monoclonal antibody technology are opening new opportunities for the development of therapeutic radiopharmaceuticals, thereby widening the scope of radionuclide therapy. In addition, particulate based radiopharmaceuticals are useful for treating hepatocarcinoma as well as in radiation synovectomy. With the establishment of new products the demand and application of therapeutic nuclear medicine is expected to grow rapidly. While there are a large number of radioisotopes proposed for targeted therapy, practical considerations had been limiting the number of usable isotopes. Generator-produced radionuclides are an attractive option for the large scale on-site availability of therapeutic isotopes. The IAEA’s CRP on the ‘Development of generator technologies for therapeutic radionuclides’ (2004-2007) was successful in developing technologies for the preparation of 188W/188Re and 90Sr/90Y generators for eluting 188Re and 90Y of high radionuclidic and chemical purity usable for research applications in the development of therapeutic radiopharmaceuticals. The IAEA’s CRP on ‘The development of therapeutic radiopharmaceuticals based on 188Re and 90Y for radionuclide therapy’ was formulated to focus on enhancing the capacity of the 90Sr/90Y generator; to develop and validate quality control methods for the generator eluate; and to develop therapeutic radiopharmaceuticals based on 188Re and 90Y. The first RCM of the CRP was held in Polatom, Warsaw, Poland from 30 June to 4 July 2008. The meeting reviewed the work going on in the different participating laboratories, and the facilities, expertise and capabilities of the different participating groups, and formulated the work plan of the CRP. The work

  14. 166Ho and 90Y labeled 6D2 monoclonal antibody for targeted radiotherapy of melanoma: Comparison with 188Re radiolabel

    Introduction: An approach to radioimmunotherapy (RIT) of metastatic melanoma is the targeting of melanin pigment with monoclonal antibodies (mAbs) to melanin radiolabeled with therapeutic radionuclides. The proof of principle experiments were performed using a melanin-binding antibody 6D2 of IgM isotype radiolabeled with a β emitter 188Re and demonstrated the inhibition of tumor growth. In this study we investigated the efficacy of 6D2 antibody radiolabeled with two other longer lived β emitters 90Y and 166Ho in treatment of experimental melanoma, with the objective to find a possible correlation between the efficacy and half-life of the radioisotopes which possess high energy β (Emax > 1.5 MeV) emission properties. Methods: 6D2 was radiolabeled with longer lived β emitters 90Y and 166Ho in treatment of experimental melanoma in A2058 melanoma tumor-bearing nude mice. The immunoreactivity of the radiolabeled 6D2 mAb, its in vitro binding to the MNT1 human melanoma cells, the biodistribution and therapy in A2058 human melanoma bearing nude mice as well as dosimetry calculations were performed. Results: When labeled with the longer lived 90Y radionuclide, the 6D2 mAb did not produce any therapeutic effect in tumor bearing mice while the reduction of the tumor growth by 166Ho-6D2 was very similar to the previously reported therapy results for 188Re-6D2. In addition, 166Ho-labeled mAb produced the therapeutic effect on the tumor without any toxic effects while the administration of the 90Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. Conclusions: 166Ho-labeled mAb to melanin produced some therapeutic effect on the tumor without any toxic effects while the administration of the 90Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. We concluded that the serum half-life of the 6D2 carrier antibody matched well the physical half-life of 166Ho to deliver the tumoricidal absorbed dose to the tumor. Further

  15. Evaluation of S-values and dose distributions for 90Y, 131I, 166Ho, and 188Re in seven lobes of the rat liver

    Purpose: Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver. Methods: The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for 90Y, 131I, 166Ho, and 188Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor. Results: The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. 166Ho and 188Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues. Conclusions: The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for preclinical therapy studies, from tissue

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

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

  17. Development, Preparation and Quality Assurance of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy: In House Production of Radioisotopes at Vinča Instute of Nuclear Sciences. Chapter 10

    The objective of the project described in this chapter was the development of different radiolabelled compounds with 188Re and 90Y and optimization of labelling procedures. Four different groups of compounds were evaluated as follows: different polyphosphonates (HEDP, MDP and (2-hydroxy-3,4-dioxopentyl) phosphate (DPD)) and DMSA; HA particles; colloids like antimony trisulphide and tin colloid for radiosynovectomy and/or HCC; and biodegradable microspheres of HSA for HCC. During the project, the work was focused on the development of a 90Sr/90Y electrochemical generator, quality control methods for radionuclidic purity of 90Y, use of 90Y for radiometallation of a DOTA conjugated somatostatin analogue, [DOTA, Tyr3] octreotate, and preparation of 90Y DOTATATE for peptide receptor radionuclide therapy (PRRT). In vitro and in vivo evaluation of the labelled molecules and collection of data of promising radiotracers for clinical trials were also carried out. (author)

  18. Country report: Serbia. Development, Preparing and Quality Assurance of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy: The Possibilities for their Production in Laboratory for Radioisotopes, Ins «Vinča»

    The main object of the research planed for this project was to optimize the procedures for the 90Y and 188Re labelling of different compounds as well as their in vitro and in vivo evaluation. The work has been involved setting up the facilities, standardization of preparing protocols, and improving existing quality assurance/quality control (QA/QC) procedures in order to supply reliable products to the national nuclear medicine community

  19. Evaluation of S-values and dose distributions for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re in seven lobes of the rat liver

    Xie Tianwu; Liu Qian; Zaidi, Habib [Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074 (China) and Key Laboratory of Biomedical Photonics of Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074 (China); Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074 (China); Key Laboratory of Biomedical Photonics of Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074 (China) and Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, CH-1211 Geneva (Switzerland); Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, CH-1211 Geneva (Switzerland); Geneva Neuroscience Center, Geneva University, CH-1211 Geneva (Switzerland) and Department of Nuclear Medicine and Molecular Imaging, University Medical Center Gronigen, University of Groningen, 9700 RB Groningen (Netherlands)

    2012-03-15

    Purpose: Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver. Methods: The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor. Results: The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. {sup 166}Ho and {sup 188}Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues. Conclusions: The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for

  20. Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with 177Lu- and 90Y-BR96 mAbs

    Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. Methods: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with 90Y- and 177Lu-labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow-up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. Results: A red marrow absorbed dose-dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for 177Lu and 12.5 Gy for 90Y. Conclusions: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom weight, ranging from

  1. Country report: Pakistan. Second Research Co-ordination Meeting on Development of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy, 22-26 March 2010, Vienna

    Various experiments were carried out for the separation of 90Y from 90Sr using colloid formation behavior of 90Y in basic pH range. When the acidic solution of 90Sr/90Y was treated with NaOH and passed through a small glass wool column, more than 95% 90Y was retained on glass wool, which was further washed with 0.1 M NaOH. The 90Y was extracted in 1 M HCl. Radionuclidic purity was determined by half life measurement. The contamination of parent was less than 0.0001%. Similarly when the colloid was passed through membrane filter more than 95% 90Y was retained which was recovered by 1 M HCl. The contamination of 90Sr was less than 0.0001%. The stock solution of 90Sr/90Y in NH4OH/NaOH was again passed through Millipore filter paper or glass wool after one week. The retention of 90Y was insignificant. The equilibrium mixture of 90Sr/90Y was acidified with HCl and again precipitated with addition of NH4OH or NaOH. The basic solution was passed through the Millipore filter or glass wool. More than 90% activity of 90Y was retained, which was finally extracted in 1 M HCl It was concluded that for recovery of 90Y from 90Sr by colloid formation, the acidic solution of 90Sr/90Y shall be freshly precipitated by NH4OH or NaOH. It was also observed that the adsorption of 90Y was quite high when the 90Sr solution was left in a glass vial for the growth of 90Y. However it can be easily extracted after keeping it in boiling water bath for few minutes. The separated 90Y via colloid formation was used for the labeling of EDTMP. Labeling efficiency of 90Y-EDTMP was more than 98%

  2. Biokinetic study of free 177Lu in NIH mice

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

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

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

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

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

    2015-01-01

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

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

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

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

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

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

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

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

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

  9. Production logistics and possible applications of 177Lu

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

  10. Production logistics of 177Lu for radionuclide therapy

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

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

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

  12. Production of 186Re and 188Re, and synthesis of 188Re-DTPA

    Production of radioactive rhenium isotopes 186Re and 188Re, and synthesis of 188Re-DTPA have been studied. For 186Re, a production method by the 185Re(n, γ) 186Re reaction in a reactor has been established. For 188Re, a production method by the double neuron capture reaction of 186W, which produces a 188W/188Re generator, has been established. For synthesis of 188Re-DTPA, the optimum conditions, including pH, the amounts of regents and so on, have been determined. (author)

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

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

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

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

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

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

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

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

    2001-09-01

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

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

    2011-01-01

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

  18. Development of a 188W/188Re Generator, Post-Elution Concentration of 99mTc and Evaluation of High Capacity Adsorbents

    The objective of the coordinated research project was the development of techniques for the preparation of 90Sr/90Y and 188W/188Re generators. The research at IPEN-CNEN/SP focused on developing a generator technology using high specific activity 188W imported from the Russian Federation. The development of a 188Re gel type generator, using the experience acquired by IPEN in recent years through the 99mTc gel generator project, is discussed. Quality control procedures were developed to ensure the purity of the eluted 188Re, and special attention was given to post-elution concentration of 188Re. (author)

  19. Studies of HEDP labelled with 188Re from different generators of 188W /188Re

    The widespread interest in 188Re for therapeutic applications, is due to its attractive 16,9 hours half-life, emission of a β- particle with maximum energy of 2.12 MeV and gamma-ray of 155 keV suitable for imaging. This work presents the radiolabelling of HEDP (etidronate) with 188Re eluted from alumina-based 188W/188Re generators and tungstate-based 188W/188Re gel generators. Dependence of the yield of the 18'8Re-HEDP on the concentration of the reduction agent, p H, reaction time, temperature and addition of carrier Re2O7 were evaluated. The radiolabelling of 188Re-HEDP procedure using the optimum conditions resulted a yield >= 98% for liquid and lyophilized kits. This basic formulation contains: 30 mg de HEDP, 7 mg de SnCl2, 3 mg de ascorbic acid and addition of 20 mug of Re2O7. The reactions were carried out with heating in boiling water for 30 minutes followed by 60 minutes of incubation. Another important aspect of this work was the radiochemical quality control comparing the results of PC, TLC and ion chromatography, along with the experiments with HPLC. The biological distribution proved the adequate bone uptake and in vivo stability of 188Re-HEDP complexes. (author)

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

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

    2013-01-01

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

  1. Method for preparing high specific activity 177Lu

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

    2004-04-06

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

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

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

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

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

  4. Preparation of 188Re complexes for nuclear medicine

    Synthesis conditions for 188Re complexes without carrier and with methylenediphosphonic, 1-hydroxyethylenediphosphonic and dimercaptosuccinic acids are studied 188Re is produced using 188W/188Re generator. Tin dichloride is used for rhenium reduction and ascorbic acid is taken as antioxidant. Effect of reducer concentration, p H, process duration, antioxidant nature, temperature and carrier introduction on the complex yield is investigated. Under the optimal conditions the yield makes up over 95% both for 188Re with and without carrier. The complex stability in relation to p H and salt background change is studied

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

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

    2015-06-15

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

  6. Synthesis of {sup 188}Re-DMSA complex using carrier-free {sup 188}Re

    Hashimoto, Kazuyuki; Izumo, Mishiroku [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Islam, M.S.

    1997-03-01

    The synthesis of rhenium-DMSA labelled compound using carrier-free {sup 188}Re from the {sup 188}W/{sup 188}Re generator has been carried out. Stannous chloride was used as the reducing agent for reduction of rhenium and ascorbic acid was used as an antioxidant in the reaction media. The dependence of the yield of Re-DMSA complex upon the concentration of reducing agent, pH, reaction time, anti-oxidant, carrier and temperature was investigated. Under optimum conditions, the yield of Re-DMSA complexes were more than 98% for the carrier-free as well as carrier-added {sup 188}Re. The stability of the Re-DMSA complexes at different pH and time were also investigated. It was found that the Re-DMSA complex was very stable and did not undergo any changes or decomposition with the changes of pH from its initial values even after 48 hours of pH change for carrier-free as well as carrier-added complexes. (author)

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

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

    2006-11-15

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

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

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

    2015-12-01

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

  9. 177Lu radiochemical separation from 176Yb irradiated in high-flux research reactor SM

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

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

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

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

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

  12. Development of 177Lu-phytate Complex for Radiosynovectomy

    Hassan Yousefnia

    2013-05-01

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

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

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

  14. 188W/188Re Generator System and Its Therapeutic Applications

    A. Boschi

    2014-01-01

    Full Text Available The 188Re radioisotope represents a useful radioisotope for the preparation of radiopharmaceuticals for therapeutic applications, particularly because of its favorable nuclear properties. The nuclide decay pattern is through the emission of a principle beta particle having 2.12 MeV maximum energy, which is enough to penetrate and destroy abnormal tissues, and principle gamma rays (Eγ=155 keV, which can efficiently be used for imaging and calculations of radiation dose. 188Re may be conveniently produced by 188W/188Re generator systems. The challenges related to the double neutron capture reaction route to provide only modest yield of the parent 188W radionuclide indeed have been one of the major issues about the use of 188Re in nuclear medicine. Since the specific activity of 188W used in the generator is relatively low (<185 GBq/g, the eluted Re188O4- can have a low radioactive concentration, often ineffective for radiopharmaceutical preparation. However, several efficient postelution concentration techniques have been developed, which yield clinically useful Re188O4- solutions. This review summarizes the technologies developed for the preparation of 188W/188Re generators, postelution concentration of the 188Re perrhenate eluate, and a brief discussion of new chemical strategies available for the very high yield preparation of 188Re radiopharmaceuticals.

  15. Labelling of Biotin with 188Re. Chapter 8

    Different chemical strategies have been employed for labelling biotin using 188Re with the aim to develop a sterile and pyrogen free kit formulation that is suitable for clinical use. A number of biotin conjugated 188Re complexes were prepared and evaluated to determine their affinity for avidin. The most difficult challenge was to devise an efficient reaction pathway that was able to obtain the final radiocompounds in a high radiochemical yield. This work describes the molecular design and the chemical strategy that were followed to obtain reliable preparation of the new radiopharmaceuticals starting from generator produced [188ReO4]–. (author)

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

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

    2013-07-01

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

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

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

  18. Extraction centrifugal W-188/Re-188 generator for radiotherapeutic applications

    188 Re extraction generator for medical purposes development results are presented. The main advantage of such generator is the possibility to use as starting material the tungsten oxide of natural isotope composition irradiated in react or with mean neutron flux (1.0– 1.4·10 14 n ⋅ cm-2 ⋅ s-1). The parent (188 W) and daughter radionuclides were separated using centrifugal semicounter -current extractor developed at Physical Chemistry and Electrochemistry Institute under RAS (Russian Academy of Sciences). In the course of simulated solution experiments, optimal operating conditions were established for 188 Re production process. For this purpose, it is proposed to recover 188 Re by methylethylketone from alkaline solution (2.5 M KON + 2.5 M K2CO3) containing up to 200 g/l of W element. Methylethylketone is subsequently evaporated to dryness and residue is dissolved in isotonic solution of NaCl. An extraction generator model was built in hot cell; the process developed was then tested on radioactive solutions. The test has shown that the yield is 89% in the average and the radiochemical purity of 188 Re solution is ~ 97%. The activity of 188 W was less than 1·10-3 relative to that of 188 Re. Activity of other radioisotopes was below 1·10-4 . The content of inorganic impurities in 188 Re solution is determined only by the purity of aqueous solutions used for 188 Re dissolution. The generator model may be recommended as a basis for creation of commercial prototype of 188 Re extraction generator. Key words: extraction, generator, methylethylketone, radiopharmaceutical, metastases, preclinical research

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

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

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

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

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

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

  2. Specific energy from Auger and conversion electrons of 131I, 188Re-anti-CD20 to a lymphocyte's nucleus

    Torres-García, E.; Carrillo-Cazares, T. A.

    2011-01-01

    The typical radionuclides used to label anti-CD20 in the treatment of non-Hodgkin's lymphoma are 90Y, 131I, and 188Re, with the emission of beta particles, Auger electrons, and conversion electrons for the latter two. The aim of the present work was to calculate the contribution of high linear energy transfer radiation as Auger electrons (AE) and conversion electrons (CE) of 131I and 188Re-anti-CD20 to mean specific energy into the cell nucleus by Monte Carlo simulation (MCS), so as to infer therapeutic effectiveness on a dosimetric basis. MCS was used to quantify the frequency-mean specific energy into the cell nucleus, where the cell was modeled by two concentric spheres, considering two cell models. The results showed that 10% and 33% of the mean-specific energies (z¯) per disintegration imparted to the cell nucleus for both geometries are due to AE and CE; on the other hand, if the hit of AE and CE occurs, the contribution to (z¯) is about 64% and 86% for 131I and 188Re, respectively. According to the amount of specific energy from AE and CE into the cell nucleus by positive event, they can cause catastrophic effects in the nuclear DNA in the treatment of non-Hodgkin's lymphoma with 131I, 188Re-anti-CD20.

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

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

    2014-01-01

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

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

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

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

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

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

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

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

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

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

    Edalat Radfar; Azim Arbabi; Dariush Sardari

    2010-01-01

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

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

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

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

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

  11. Development of a 188W/188Re Generator

    The fabrication of a 188W/188Re generator is described in detail, including the stability testing and quality control methods used. Studies of the elution profiles of four generators showed that about 90% of the available activity was contained in a 4 mL volume of saline solution with high radioactive concentration. The generators were usable for over 6 months, and the quality of the eluate was within the approved specifications. An illustration of a shielding container made of tungsten for a 188Re eluate vial is also included. (author)

  12. Production of carrier-free 188Re in the past ten years in Taiwan

    Twenty clinical scale alumina-based 188W/188Re generators and carrier-free 188Re has been produced at the Institute of Nuclear Energy Research (INER-Taiwan) for over ten years. 2845.6 GBq (76.9 Ci) of 188Re-perrhenate solution has been eluted from generators during the past ten years. We have used the harvesting 188Re solution for labeling radiopharmaceuticals, such as 188Re-HEDP, 188Re-MDP, 188Re-microsphere, 188Relipiodol, and 188Re-sulfur colloid, etc. The average eluting yield of 188Re is 78.6±5.8% that was investigated at 1115 harvesting times from 20 generators. Each generator can be used more than six months but the Millipore needs to be changed every two months for smooth harvesting and high yield of 188Re solution. (author)

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

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

    2012-01-01

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

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

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

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

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

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

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

  17. Labeling of MDP with 188Re for bone tumour therapy

    188Re is one of the most attractive radioisotopes for a variety of therapeutic applications in nuclear medicine, due to its physical decay properties, such as β- emission of 2.12 MeV, γ emission of 155 keV and half life of 16.9 hours. Biphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in several diseases that cause bone fragility and bone metastases. Because of these characteristics, labeled biphosphonates have been studied for bone pathologies, also acting as palliation of bone pain in case of metastasis.The aim of this study was to optimize the labeling of a phosphonate-MDP (Sodium Methylene Diphosphonate) with 188Re for use in bone pain palliation. 188Re was obtained by eluting a 188W-188Re generator from POLATOM. The labeling was performed at room temperature using MDP, SnCl2 as reducing agent and ascorbic acid. The variables studied were: Mass of ligand (3, 6 and 10 mg), reducing agent mass (5, 7, 10 and 11 mg), ascorbic acid mass (1, 3, 5 and 6 mg), pH (1 and 2) and time of reaction (15, 60, 120, 360 and 4320 minutes), that also reflected the stability of the radiopharmaceutical. The radiochemical control, that also measures the labeling efficiency was evaluated by paper chromatography using Whatman 3MM paper and the solvents acetone and 0.9%NaCl. The best formulation was the following: Mass of ligand MDP: 10 mg, mass of SnCl2: 5 mg, ascorbic acid mass: 3 mg, time of reaction: 30 minutes, pH: 1. Under optimum conditions, 188Re MDP radiolabeling yield was 98,07% and the radiopharmaceutical was stable up to 72 h. (author)

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

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

  19. A kit for preparation of 188Re sulfide suspension

    The 188Re sulfide suspension could be prepared quickly by a kit. The kit consists of three 10 mL vials. All the procedures were carried out in sterility circumstance. Vial A consisted of 1 mL KReO4 and Na2S2O3 (mole ratio 1:70) solution with excipient. Vial B was 5 mol/L HCl solution. Vial C consisted of 1.5 mL PVP and NaOH solution (mole ratio 1000:1). Vial B was sealed, Vial A and C were freeze-dried. Bacterium check, endotoxin check and security check were qualified. Kits were kept at ambient temperature and the Labelling efficiency of 188Re sulfide suspension was more than 98% with 2 months. The particle sizes were 1-5 μm (60.1 +- 12.7)%; 5-10 μm (30.9 +- 8.1)%; > 10 μm (9.0 +- 4.7)%. The radiochemical purity of 188Re sulfide suspension made by the kit was higher than 98% in 5 days with particle sizes 1-5 μm (49.9 +- 14.4%); 5-10 μm (41.1 +- 5.4)%; > 10μm (9.0 +- 3.3)%

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

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

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

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

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

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

    2016-04-11

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

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

    Dale Bailey

    2016-01-01

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

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

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

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

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

  6. 177Lu-DOTMP: a viable agent for palliative radiotherapy of painful bone metastasis

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

  7. [177Lu]-DOTA0-Tyr3-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma

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

    2010-01-01

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

  8. β-radiation exposure with 188Re-labelled pharmaceuticals

    Aim: The number of therapies with radiopharmaceuticals labelled with 188Re is increasing requiring the documentation of the beta radiation exposure Hp(0.07) of the staff at all working and production sites and during the application and follow-up of the patient according to the new German Radiation Protection Law (StrlSchV). However, data for β-radiation exposure are rare. Therefore, we determined the personal dose Hp(0.07) of the skin of the hands handling 188Re radiopharmaceuticals to identify steps of high radiation exposure and to optimize working conditions. Method: Thermoluminescence dosimeters (TLD 100) were fixed to the fingertips of the radiochemist, the physician and the nurse and compared to official ring dosimeters. In addition, to monitor radiation exposure continuously readable electronic beta- and gamma dosimeters EPD (Siemens) were used. At eight days in which therapies were performed these readings were evaluated. Results: Considering one therapy with a 188Re-labelled radiopharmaceutical the middle finger of the radiochemist (production) and the physician (application) showed a radiation burden of 894 and 664 μSv/GBq, respectively. The cumulative dose of the fingertips after eight days of therapy was 249 and 110 mSv for the radiochemist and physician, respectively. A cumulative finger dose after eight days of therapy of 17 and 39 μSv/GBq was found for physician and nurse leading to a Hp(0.07) of 3 and 6 mSv, respectively. Preparing the radiopharmaceutical labelled with 20 GBq of 188Re the reading of the personal electronic dosimeter of the radiochemist showed a γ-dose rate Hp(10) of 55 μSv/h and a β-dose rate Hp(0.07) of 663 μSv/h which are obviously not representative for the true radiation dose to the skin of the fingertips. Conclusion: During therapy with 188Re-labelled radiopharmaceuticals the true radiation dose to the skin of the finger tips exceeds by far the readings of the official ring dosimeters as well as the continuously

  9. 177Lu-DOTA-lanreotide: a novel tracer as a targeted agent for tumor therapy

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

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

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

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

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

  12. Labelling of aminomethylenephosphonate derivatives with generator-produced 188Re and their stability

    In this study, the labelling of aminomethylenephosphonate derivatives (EDTMP Ethylenediamine-N,N,N',N' -tetrakis(methylenephosphonic acid), EDBMP - Ethylenediamine- N,N'-bis(methylenephosphonic acid) and NTMP - nitrilotris(methylenephosphonic acid)) with carrier-free 188Re from the 188W/188Re generator was investigated in detail. Stannous chloride was used as the reducing agent for the reduction of rhenium. The labelling studies were carried out by mixing all the solutions (ligand, I-ascorbic acid, a solution for pH adjustment, 188Re and stannous chloride) in a vial. The dependence of the labelling yield upon the reaction conditions such as the concentrations of the reducing agent and the ligand (aminomethylenephosphonate), pH, temperature and the addition of a carrier was examined. The stability of the 188Re complex against pH change and dilution with saline was also studied. It was found that the formation condition of the 188Re complex, that is the temperature, pH and the addition of a carrier, influenced the stability of 188Re complex. The carrier-added 188Re complex was more stable than the carrier-free 188Re complex. Furthermore, the stability decreased in the order 188Re-EDTMP > 188Re-EDBMP > 188Re-NTMP for the carrier-free 188Re complex

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

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

    2016-03-15

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

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

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

    2016-06-01

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

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

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

  16. Study on the preparation and stability of 188Re biomolecules via EHDP

    A direct labelling technique via ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) as a weak competing ligand was developed for the preparation of several biomolecules: 188 Re-monoclonal antibody ior cea1 against carcinoembryonic antigen (188 Re-MoAb), biotinylated 188Re-MoAb (188 Re-MoAb-biotin), 188 Re-polyclonal IgG (188 Re-IgG), 188 Re-peptide (somatostatine analogue peptide b-(2-naphtyl)-D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-amide), 188 Re-MoAb fragments (188 Re-F(ab')2) and biotinylated 188 Re-F(ab')2 (188 Re-F(ab')2-biotin). The reaction conditions such as pH, temperature, weak ligand concentration and stannous chloride concentration were optimized during the radiolabelling of each biomolecule. Before the labelling procedure, disulphide bridge groups of the biomolecules were reduced with 2-mercaptoethanol (2-ME). To obtain 188 Re labelled antibodies and peptides in high radiochemical yields (>90%) via EHDP, it was necessary to use acidic conditions and a high concentration of stannous chloride to allow the redox reaction Re+7→Re+5:Re+4. The labelling of MoAb and F(ab')2 with 188Re via EHDP was also evaluated employing a pretargeted technique by avidin-biotin strategy in normal mice, demonstrating that the 188Re-labelled biotinylated antibodies are stable complexes in vivo. The 188Re-peptide complex prepared by this method, was stable for 24 h and no radiolytic degradation was observed. (author)

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

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

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

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

    2011-04-15

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

  19. Labelling of aminomethylenephosphonate derivatives with generator-produced {sup 188}Re and their stability

    Hashimoto, K. [Japan Atomic Energy Research Insttitute, Tokai-mura, Ibaraki-ken, (Japan). Department of Radioisotopes

    1997-10-01

    In this study, the labelling of aminomethylenephosphonate derivatives (EDTMP Ethylenediamine-N,N,N`,N` -tetrakis(methylenephosphonic acid), EDBMP - Ethylenediamine- N,N`-bis(methylenephosphonic acid) and NTMP - nitrilotris(methylenephosphonic acid)) with carrier-free {sup 188}Re from the {sup 188}W/{sup 1}8{sup 8R}e generator was investigated in detail. Stannous chloride was used as the reducing agent for the reduction of rhenium. The labelling studies were carried out by mixing all the solutions (ligand, I-ascorbic acid, a solution for pH adjustment, {sup 188}Re and stannous chloride) in a vial. The dependence of the labelling yield upon the reaction conditions such as the concentrations of the reducing agent and the ligand (aminomethylenephosphonate), pH, temperature and the addition of a carrier was examined. The stability of the {sup 188}Re complex against pH change and dilution with saline was also studied. It was found that the formation condition of the {sup 188}Re complex, that is the temperature, pH and the addition of a carrier, influenced the stability of {sup 188}Re complex. The carrier-added {sup 188}Re complex was more stable than the carrier-free {sup 188}Re complex. Furthermore, the stability decreased in the order {sup 188}Re-EDTMP > {sup 188}Re-EDBMP > {sup 188}Re-NTMP for the carrier-free {sup 188}Re complex 20 refs., 12 figs.

  20. Intratumoral injection of 188Re labeled cationic polyethylenimine conjugates: a preliminary report.

    Kim, Eun-Mi; Jeong, Hwan-Jeong; Heo, Young-Jun; Moon, Hyung-Bae; Bom, Hee-Seung; Kim, Chang-Guhn

    2004-10-01

    188Re (Rhenium) is easily obtained from an in-house 188W/188Re generator that is similar to the current 99Mo/99mTc generator, making it very convenient for clinical use. This characteristic makes this radionuclide a promising candidate as a therapeutic agent. Polyethylenimine (PEI) is a cationic polymer and has been used as a gene delivery vector. Positively charged materials interact with cellular blood components, vascular endothelium, and plasma proteins. In this study, the authors investigated whether intratumoral injection of 188Re labeled transferrin (Tf)-PEI conjugates exert the effect of radionuclide therapy against the tumor cells. When the diameters of the Ramos lymphoma (human Burkitt's lymphoma) xenografted tumors reached approximately 1 cm, 3 kinds of 188Re bound compounds (HYNIC-PEI-Tf, HYNIC-PEI, 188Re perrhenate) were injected directly into the tumors. There were increases in the retention of 188Re inside the tumor when PEI was incorporated with 188Re compared to the use of free 188Re. The 188Re HYNIC-Tf-PEI showed the most retention inside the tumor (retention rate=approximately 97%). H&E stain of isolated tumor tissues showed that 188Re labeled HYNIC-PEI-Tf caused extensive tumor necrosis. These results support 188Re HYNIC-PEI-Tf as being a useful radiopharmaceutical agent to treat tumors when delivered by intratumoral injection. PMID:15483337

  1. Experimental study of 188Re-BAC5 radioimmunotherapy on nasopharyngeal carcinoma

    The feasibility of radioimmunotherapy for NPC with 188Re-BAC5, a kind of monoclonal antibody to NPC, was investigated. The 188Re-BAC5 was prepared by direct labeling method and its biological activity was determined. The MTT method was used to determine the inhibition effect of the 188Re-BAC5 on CNE-2 cell line culture, and the destruction effect on CNE-2 multicellular spheroids model was also observed. The control group were 188Re-BSA and 188ReO4-. The biological activity of BAC5 was 1:780000 after purification. The labeling yield of 188Re-BAC5 was above 80%. The immuno-activity of 188Re-BAC5 was 61% ± 15%. The results of MTT showed that the inhibition effect of 188Re-BAC5 group was much stronger than the control group (P188Re-BAC5 had a obvious destruction effect on spheroids, and there was a significant difference between 188Re-BAC5 and the control group. In conclusion, 188Re-BAC5 may serve a possible way in the treatment of NPC in the near future

  2. Development of [90Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

    Introduction: Based on the concept of bifunctional radiopharmaceuticals, we have previously developed 186Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed 90Y-labeled radiopharmaceutical could be developed. Methods: In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [90Y]DOTA-complex-conjugated bisphosphonate ([90Y]DOTA-HBP) was prepared by coordination with 90Y, and its biodistribution was studied in comparison to [90Y]citrate. Results: In biodistribution experiments, [90Y]DOTA-HBP and [90Y]citrate rapidly accumulated and resided in the bone. Although [90Y]citrate showed a higher level of accumulation in the bone than [90Y]DOTA-HBP, the clearances of [90Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [90Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [90Y]DOTA-HBP were lower than those of [90Y]citrate. Conclusions: [90Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [90Y]citrate. Since the DOTA ligand forms a stable complex not only with 90Y but also with lutetium (177Lu), indium (111In), gallium (67/68Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging

  3. Labeling Lanreotide with 125I and 188Re

    Lanreotide is a new somatostatin analogue. It can bind to human somatostatin receptor (hSSTR) subtype 2 through 5 with high affinity and to hSSTR subtype I with low affinity. We investigate labeling condition, quality control and stability in vitro of 125I-Lanreotide and 188Re-lanreotide respectively. (A) Lanreotide is labeled with 125I using Chloramine T. The effect of reaction condition (such as reaction time, pH value, Lanreotide amount, quantity of Chloramine T and reaction volume) on labeling yield is investigated in detail. (B) The labeling yield and radiochemical purity (RP) is measured with paper chromatography (PC) and Sep-Pak C18 Cartridge. (C) The stability of 125I-Lanreotide in vitro is investigated by labeling compound incubating for 48 hours at 37 deg C in the 0.9% sodium chloride solution and RP is tested by PC at specific time intervals. (D) Lanreotide is labeled directly with 188Re via the mixture of citrate and tartate using stannous chloride as reduced agent. The influence of reaction conditions such as pH, temperature, amount of stannous chloride, amount of Lanreotide and reaction time on labeling yield is investigated in detail. At the time, the stability in vitro quality control and animal test are evaluated

  4. 177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

    Ada H V Repetto-Llamazares

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

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

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

    2015-10-15

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

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

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

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

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

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

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

    2008-07-01

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

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

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

    2010-01-01

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

  10. Experimental study of the biological properties of 188Re-Hepama-1 biologic superparamagnetic nanoparticles

    Objective: To investigate a new biologic-superparamagnetic nanoparticles's characteristics of immunological activity, biological distributing in vivo, targeting and inhibiting tumor effect. Methods: The experimental group 188Re-Hepama-l-superparamagnetic nanoparticles, and control groups, including 188ReO4-, 188Re-Hepama-1, and 188Re-superparamagnetic nanoparticles, were set up. The distributions were measured after injection 4 h and 24 h by caudal vein of Kuming mice. The magnetic targeting experiments in vivo were clone with and without magnetic field in liver after injection in New Zealand rabbit. The inhibiting tumor effect on hepatic cancer cell lines SMMC-7721 of the above four 188Re labeled products were measured by mono nuclear cell direct cytotoxicity assay method. Results: After injection 4 h and 24 h by vein, the liver taking was highest in group 188Re-Hepama-l-superparamagnetic nanoparticles. The radiative activity in liver in magnetism zoo was higher than in non magnetism zoo in 188Re- Hepama-1-superparamagnetic nanoparticles after applying magnetic field in left lobe of liver, and the ratio of in magnetism zoo to non magnetism zoo was 1.87. And the half effective inhibition radioactive concentrations (IC50) in 188Re-Hepama-l-superparamagnetic nanoparticles was one forth of 188ReO4-. Conclusion: 188Re- Hepama-l-superparamagnetic nanoparticles showed its fine stability in intro, good immunological activity and significant liver target. (authors)

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

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

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

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

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

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

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

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

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

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

    2015-11-01

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

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

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

    2015-11-01

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

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

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

    2014-05-15

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

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

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

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

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

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

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

  1. Preparation of 188W/188Re generator in a clinical-scale

    A 188W/188Re generator based on acid-treated alumina is prepared for medical application. 188Re can be eluted into vacuum vial with 0.9% NaCl solution in the presence or absence of ascorbic acid. The elution yield of 188Re is more than 70% during a period of three months. The 188W leakage is less than 10 - 4 %. Both the radiochemical purity and radionuclide purity are more than 99%

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

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

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

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

    2010-02-15

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

  4. Synthesis and primary biological evaluation of 188ReN-NEMPTDD

    A new nitrido-188Re complex, 188ReN-NEMPTDD, was synthesized through a modified method in high yield. This complex was stable in vitro. The biodistribution in normal mice showed that this ReN complex accumulated in the liver and was eliminated quickly from almost all organs. VX2 carcinoma was grown in the livers of rabbits. Transcatheter arterial embolization (TAE) was performed using 188ReN-NEMPTDD/lipiodol solution. The SPECT images showed that the lipiodol solution could be concentrated in the tumor for about 12 hours. These results indicated that 188ReN-NEMPTDD/lipiodol could be a potential radiopharmaceutical for liver cancer. (author)

  5. An alternative approach to the preparation of 188Re radiopharmaceuticals from generator-produced [188ReO4]-: efficient synthesis of 188Re(V)-meso-2,3-dimercaptosuccinic acid

    A new efficient approach for the preparation of 188Re radiopharmaceuticals starting from [188ReO4]-, produced at a carrier-free level through the 188W/188Re generator system, is described. The reaction procedure was based on the combined action of different reagents and has been applied in detail to the preparation of the therapeutic agent 188Re(V)-DMSA (H2DMSA [meso-2,3-dimercaptosuccinic acid]). The most efficient combination required the use of SnCl2, oxalate ions, and γ-cyclodextrin. These were reacted with [188ReO4]- and H2DMSA to afford the final radiopharmaceutical in high radiochemical purity, at room temperature, and in weakly acidic solution. The role played by the various reagents in the reaction was investigated. It was found that SnCl2 behaved as the actual reducing agent, whereas oxalate and γ-cyclodextrin greatly enhanced the ease of reduction of [188ReO4]- through the action of two hypothetical mechanisms. In the first step of the reaction, oxalate ions gave rise to the formation of Re(VII) complexes with the concomitant expansion of the coordination sphere of the metal. This process strongly favored the electron transfer between Sn2+ and Re+7 centers, giving rise to intermediate reduced rhenium complexes. These species were further stabilized by the formation of transient host-guest aggregates with γ-cyclodextrin and finally converted into 188Re(V)-DMSA through simple replacement of the coordinated ligands by H2DMSA

  6. Exploitation of nano alumina for the chromatographic separation of clinical grade 188Re from 188W: a renaissance of the 188W/188Re generator technology.

    Chakravarty, Rubel; Shukla, Rakesh; Ram, Ramu; Venkatesh, Meera; Tyagi, Avesh Kumar; Dash, Ashutosh

    2011-08-15

    The (188)W/(188)Re generator using an acidic alumina column for chromatographic separation of (188)Re has remained the most popular procedure world over. The capacity of bulk alumina for taking up tungstate ions is limited (∼50 mg W/g) necessitating the use of very high specific activity (188)W (185-370 GBq/g), which can be produced only in very few high flux reactors available in the world. In this context, the use of high-capacity sorbents would not only mitigate the requirement of high specific activity (188)W but also facilitate easy access to (188)Re. A solid state mechanochemical approach to synthesize nanocrystalline γ-Al(2)O(3) possessing very high W-sorption capacity (500 mg W/g) was developed. The structural and other investigations of the material were carried out using X-ray diffraction (XRD), transmission electron microscopy (TEM), Brunauer Emmett Teller (BET) surface area analysis, thermogravimetric-differential thermal analysis (TG-DTA), and dynamic light scattering (DLS) techniques. The synthesized material had an average crystallite size of ∼5 nm and surface area of 252 ± 10 m(2)/g. Sorption characteristics such as distribution ratios (K(d)), capacity, breakthrough profile, and elution behavior were investigated to ensure quantitative uptake of (188)W and selective elution of (188)Re. A 11.1 GBq (300 mCi) (188)W/(188)Re generator was developed using nanocrystalline γ-Al(2)O(3), and its performance was evaluated for a period of 6 months. The overall yield of (188)Re was >80%, with >99.999% radionuclidic purity and >99% radiochemical purity. The eluted (188)Re possessed appreciably high radioactive concentration and was compatible for the preparation of (188)Re labeled radiopharmaceuticals. PMID:21726091

  7. Labeling Lanreotide with 125I and 188Re. China

    Lanreotide (D-β-Nal-Cys-Try-D-Trp-Lys-Val-Cys-Thr-NH2) is a new somatostatin analogue. It can bind to human somatostatin receptor (hSSTR) subtype 2 through 5 with high affinity and to hSSTR subtype 1 with low affinity. We investigate labeling condition, quality control and stability in vitro of 125I-Lanreotide and 188Re-lanreotide respectively. (A) Lanreotide is labeled with 125I using Chloramine T. The effect of reaction condition (such as reaction time, pH value, Lanreotide amount, quantity of Chloramine T and reaction volume) on labeling yield is investigated in detail. (B) The labeling yield and radiochemical purity (RP) is measured with paper chromatography (PC) and Sep-Pak C18 Cartridge. For PC method, 125I-Lanreotide is spotted on the Whatman No.1 paper and developed in the mixture of CH3CH2CH2CH2OH and CH3CH2OH and NH4OH (v/v/v=5:2:1), the Rf value of every component in the mobile phase is given in table 1. For Sep-Pak C18 Cartridge methods each cartridge is washed with 10 ml of ethanol followed by 10 ml of iso-CH3CH2CH2OH solution. Aliquots of 0.1 mI sample is loaded onto the cartridge, unbound peptide (sodium iodine-125) is eluted with 5 ml of 0.5mol/L sodium acetate solution, 125I-Lanreotide is eluted with 5 mI of 95% aqueous ethanol solution. (C) The stability of 125I-Lanreotide in vitro is investigated by labeling compound incubating for 48 hours at 37 deg. C in the 0.9% sodium chloride solution and RP is tested by PC at specific time intervals. (D) Lanreotide is labeled directly with 188Re via the mixture of citrate and tartate using stannous chloride as reduced agent. The influence of reaction conditions such as pH, temperature, amount of stannous chloride, amount of Lanreotide and reaction time on labeling yield is investigated in detail. At the time, the stability in vitro quality control and animal test are evaluated

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

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

    2013-12-15

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

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

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

    2016-06-01

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

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

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

  11. A comparative study of {sup 188}Re(V)-meso-DMSA and {sup 188}Re(V)-rac-DMSA: preparation and in vivo evaluation in nude mice xenografted with a neuroendocrine tumor

    Park, Jun-Young [Department of Biomedical Laboratory Science, College of Health Science, Yonsei University, Wonju 220-710 (Korea, Republic of); Department of Nuclear Medicine, Yonsei University Health System, Seoul 120-752 (Korea, Republic of); Lee, Tae-Sup; Choi, Tae-Hyun; Cheon, Gi-Jeong; Choi, Chang-Woon [Laboratory of Nuclear Medicine, Korea Institute of Radiological and Medical Science, Seoul 139-706 (Korea, Republic of); Awh, Ok-Doo [Department of Nuclear Medicine, Yonsei University Health System, Seoul 120-752 (Korea, Republic of)], E-mail: immunoch@yonsei.ac.kr

    2007-11-15

    Dimercaptosuccinic acid (DMSA) exists in meso and racemic (rac) forms. Unlike a meso isomer, rac-2,3-DMSA is very soluble in water, strongly acidic solutions and organic solvents. Despite these differences, rac-2,3-DMSA has not been studied as a radiopharmaceutical. In this study, {sup 188}Re complexes with diastereomeric DMSA were prepared to compare the properties of {sup 188}Re(V)-rac-DMSA with those of {sup 188}Re(V)-meso-DMSA in in vitro and in vivo models. Methods: rac-2,3-DMSA was synthesized and radiolabeled with {sup 188}Re. The biodistribution and gamma camera imaging of {sup 188}Re(V)-meso-DMSA and {sup 188}Re(V)-rac-DMSA were performed in nude mice subcutaneously implanted with PC-12 cell lines. Results and conclusions: Both {sup 188}Re(V)-meso-DMSA and {sup 188}Re(V)-rac-DMSA showed excellent radiochemical purity and stability at room temperature. Compared with {sup 188}Re(V)-meso-DMSA, {sup 188}Re(V)-rac-DMSA needed a higher concentration of rac-DMSA and metabisulfite for maximum yields. {sup 188}Re(V)-meso-DMSA showed high labeling efficiency at pH 2, whereas {sup 188}Re(V)-rac-DMSA showed maximum yields at pH 5. The tumor uptake of {sup 188}Re(V)-rac-DMSA was 3.5 times higher than that of {sup 188}Re(V)-meso-DMSA at 1 h (P<.01). Gamma camera images showed that {sup 188}Re(V)-rac-DMSA was more selectively localized than {sup 188}Re(V)-meso-DMSA at the tumor region in a xenograft model. These results demonstrate that {sup 188}Re(V)-rac-DMSA may have better potential than {sup 188}Re(V)-meso-DMSA as a therapeutic agent against neuroendocrine tumors.

  12. A comparative study of 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA: preparation and in vivo evaluation in nude mice xenografted with a neuroendocrine tumor

    Dimercaptosuccinic acid (DMSA) exists in meso and racemic (rac) forms. Unlike a meso isomer, rac-2,3-DMSA is very soluble in water, strongly acidic solutions and organic solvents. Despite these differences, rac-2,3-DMSA has not been studied as a radiopharmaceutical. In this study, 188Re complexes with diastereomeric DMSA were prepared to compare the properties of 188Re(V)-rac-DMSA with those of 188Re(V)-meso-DMSA in in vitro and in vivo models. Methods: rac-2,3-DMSA was synthesized and radiolabeled with 188Re. The biodistribution and gamma camera imaging of 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA were performed in nude mice subcutaneously implanted with PC-12 cell lines. Results and conclusions: Both 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA showed excellent radiochemical purity and stability at room temperature. Compared with 188Re(V)-meso-DMSA, 188Re(V)-rac-DMSA needed a higher concentration of rac-DMSA and metabisulfite for maximum yields. 188Re(V)-meso-DMSA showed high labeling efficiency at pH 2, whereas 188Re(V)-rac-DMSA showed maximum yields at pH 5. The tumor uptake of 188Re(V)-rac-DMSA was 3.5 times higher than that of 188Re(V)-meso-DMSA at 1 h (P188Re(V)-rac-DMSA was more selectively localized than 188Re(V)-meso-DMSA at the tumor region in a xenograft model. These results demonstrate that 188Re(V)-rac-DMSA may have better potential than 188Re(V)-meso-DMSA as a therapeutic agent against neuroendocrine tumors

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

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

    2011-01-01

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

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

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

    2016-06-01

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

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

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

  16. 177Lu-DTPA-BIS-BIOTIN Binding of Octreotide-dextran-avidinated PANC-1 Cell Lines in Vitro

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

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

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

    2012-01-01

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

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

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

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

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

    2010-10-15

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

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

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

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

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

    2016-06-01

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

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

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

  3. Hydroxyapatite Based 99Mo-99mTc and 188W-188Re Generator Systems

    This paper describes studies evaluating the use of hydroxyapatite as the adsorbent material for both 99Mo-99mTc and 188W-188Re generator systems. Hydroxyapatite is an insoluble solid with anion exchange properties. A study of the sorption behaviour of 99Mo, 99mTc, 188W and 188Re on hydroxyapatite in NaCl medium was evaluated by batch experiments. The results demonstrated that while 99Mo, 99mTc and 188Re are not adsorbed by the hydroxyapatite in NaCl solutions (Kd 188W is strongly adsorbed (Kd >500). On the basis of these measurements, hydroxyapatite 188W-188Re generator systems were then constructed and eluted in NaCl solutions. The hydroxyapatite based 188W-188Re generator performances are presented

  4. Pharmacokinetics of radioimmunotherapeutic agent of direct labeling mAb 188Re-HAb18

    Chao Lou; Zhi-Nan Chen; Hui-Jie Bian; Jie Li; Shou-Bo Zhou

    2002-01-01

    AIM: To labed Anti-hepatoma monoclonal antibody (mAb)fragment HAb18 F (ab')2 was labeled with 188 Re for thepharmacokinetic model of 188 Re-HAb18 F (ab')2 and toevaluate its pharmacokinetic parameters in hepatoma-bearing nude mice.METHODS: HAb18 F(ab')2 was directly labeled with 188Reusing 2-mercaptoethanol (2-ME) as reducing agents.Labeling efficiency and immunoreactivity of 188 Re-HAb18 F( ab')2 were evaluated by Whatman 3MM paperchromatography and live cell assay, respectively.Biodiatribution analysis was also conducted in nude micebearing human hepatoma in which animals were sacrificed atdifferent time points(1, 4, 18, 24 and 24h) after 188Re-HAb18F(ab' )2 was injected through tail-vein into hepatoma-bearingnude mice. The blood and radioactivity of organs and masswere measured. The concentrations of 188 Re-HAb18 F(ab')2were evaluated with a pharmacokinetic 3P97 software.RESULTS: The optimum labeling efficiency andimmunoreactive fraction were 91.7% and 0.78%,respectively. The parameters of 188Re-HAb18 F(ab')2 were:T1/2, 2.29h; Vd, 1.49 × 10-9L@ Bq- 1; AUC, 20.49 × 109Bq@ h@L-1 ;CL, 0.45 × 10-3L@ h- 1. 188Re- HAb18 F(ab')2 could locatespecially in hepatoma with high selective reactivity of HAb18F(ab')2. 188 Re-HAb18 F(ab')2 was mainly eliminated bykidney. The maximal tumor to blood ratio was at 48h, andmaximal tumor to liver ratio was at 18h.CONCLUTION: The pharmacokinetics of 188Re-HAb18 F(ab')2fit a I-compartment model. 188 Re-HAb18 F(ab')2 can beuptaken selectively at the hepatoma site.

  5. Formulation of a freeze-dried kit for 188Re-MAG3 and its quality control

    The synthesis of 188Re-MAG3 is described using 188Re, which was obtained from the alumina based 188W/188Re generator. Dependence of the radiolabeling yields of 188Re-MAG3 on reducing agent concentration, Bz-MAG3 concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of 188Re-MAG3 was 98%. TLC and HPLC techniques were employed to monitor the different species formed. Biodistribution study of 188Re-MAG3 was carried out in rats and compared with behavior of 99mTc-MAG3. (author)

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

    Samaneh Zolghadri

    2015-06-01

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

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

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

    2015-01-01

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

  8. Extractive 90Y generator

    The generator for 90Y production is made up of two units - an extractive unit and a unit for deep purification. Contrary to the well-known methods of 90Y separation two mineral acids are used in the developed technology. The solutions of nitric acid are used for preliminary separation of 90Y and the solutions of hydrochloric acid are used for the deep purification of 90Y from 90Sr and stripping. The optimum conditions for carrying out this technology were found. The following results are reported: the carry-over of the stationary phase is excluded in this generator; the separation time is 30-60 minutes; the yield of the final product is not less than 95%; impurity of 90Sr is not more than 10-9---10%; the content of the chemical (nonactive) impurities is not more than the allowed one for radiopharmaceuticals

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

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

  10. 177Lu medical radioisotope separation from Yb-Lu matrix irradiated pass through ion exchanger resin by eluent of α-Hiba and HNO3 solution

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

  11. Stability of 188Re Labeled antibody for radioimmunotherapy and the effect of stabilizing agents

    For clinical application of beta-emitter labeled antibody, high specific activity is important. Carrier-free 188Re from 188W/ 188Re generator is an ideal radionuclide for this purpose. However, low stability of 188Re labeled antibody, especially in high specific activity, due to radiolytic decomposition by high energy (2.1 MeV) beta ray was problem. We studied the stability of 188Re labeled antibody, and stabilizing effect of several stabilizers. Pre-reduced monoclonal antibody (CEA79.4) was labeled with 188Re by incubating with generator-eluted 188Re-perrhenate in the presence of stannous tartrate for 2 hr at room temperature. Radiochemical purity of each preparation was determined by chromatography. Human serum albumin was added to the labeled antibodies (2%). Stability of 188Re-CEA79.4 was investigated in the presence of ascorbic acid, ethanol, or Tween 80 as stabilizing agents. Labeling efficiencies were 88±4% (n=12). Specific activities of 1.25 ∼4.77 MBq/μg were obtained. If stored after purging with N2, all the preparations were stable for 10 hr. However, stability decreased in the presence of air. Perrhenate and 188Re-tartrate was major impurity in declined preparation. Colloid-formation was not a significant problem in all cases. Addition of ascorbic acid stabilized the labeled antibodies either under N2 or under air by reducing the formation of perrhenate. High specific activity 188Re labeled antibody is unstable, especially, in the presence of oxygen. Addition of ascorbic acid increased the stability

  12. Rhenium-188: Availability from the W-188/Re-188 Generator and Status of Current Applications

    Pillai, M R A [Bhabha Atomic Research Centre, Mumbai, India; Dash, A [Bhabha Atomic Research Centre, Mumbai, India; Knapp Jr, Russ F [ORNL

    2012-01-01

    Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting - particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 KeV, 15.1%). The 188W/188Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) 188Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent 188W radionuclide have been a major impediment in the progress of application of 188Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade 188W/188Re generator. Since the specific activity of 188W used in the generator is relatively low (<5 Ci/g), the eluted 188ReO4- can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful 188ReO4-. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on 188Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability, and use of188Re including a discussion of why broader use of 188Re has not progressed as ecpected as a popular radionuclide for therapy.

  13. Preparation and biodistribution of 188Re-labeled folate conjugated human serum albumin magnetic cisplatin nanoparticles (188Re-folate-CDDP/HSA MNPs in vivo

    Tang QS

    2011-11-01

    Full Text Available Qiu-Sha Tang1,*, Dao-Zhen Chen2,*, Wen-Qun Xue2, Jing-Ying Xiang2, Yong-Chi Gong1, Li Zhang2, Cai-Qin Guo21Department of Pathology and Pathophysiology, Medical College, Southeast University, Nanjing, Jiangsu; 2Central Laboratory, Wuxi Hospital for Maternal and Child Health Care, Affiliated Medical School of Nanjin, Wuxi, Jiangsu, China *Authors contributed equally to this workBackground: The purpose of this study was to develop intraperitoneal hyperthermic therapy based on magnetic fluid hyperthermia, nanoparticle-wrapped cisplatin chemotherapy, and magnetic particles of albumin. In addition, to combine the multiple-killing effects of hyperthermal targeting therapy, chemotherapy, and radiotherapy, the albumin-nanoparticle surfaces were linked with radionuclide 188Re-labeled folic acid ligand (188Re-folate-CDDP/HSA.Methods: Human serum albumin was labeled with 188Re using the pre-tin method. Reaction time and optimal conditions of labeling were investigated. The particles were intravenously injected into mice, which were sacrificed at different time points. Radioactivity per gram of tissue of percent injected dose (% ID/g was measured in vital organs. The biodistribution of 188Re-folate-CDDP/HAS magnetic nanoparticles was assessed.Results: Optimal conditions for 188Re-labeled folate-conjugated albumin combined with cisplatin magnetic nanoparticles were: 0.1 mL of sodium gluconate solution (0.3 mol/L, 0.1 mL of concentrated hydrochloric acid with dissolved stannous chloride (10 mg/mL, 0.04 mL of acetic acid buffer solution (pH 5, 0.2 mol/L, 30 mg of folate-conjugated albumin combined with cisplatin magnetic nanoparticles, and 188ReO4 eluent (0.1 mL. The rate of 188Re-folate-CDDP-HSA magnetic nanoparticle formation exceeded 90%, and radiochemical purity exceeded 95%. The overall labeling rate was 83% in calf serum at 37°C. The major uptake tissues were the liver, kidney, intestine, and tumor after the 188Re-folate-CDDP/HSA magnetic nanoparticles

  14. Automation of the synthesis of highly concentrated 188Re-MAG3 for intracoronary radiation therapy

    We have developed an efficient method and an automated synthetic system for the preparation of highly concentrated 188Re-MAG3. Routine production of 188Re-MAG3 for use in intracoronary radiation therapy was performed by compressed air driven semi-automated shielded system. 188Re-MAG3 was prepared with a commercial kit and reducing agents, purified and concentrated by C18 Sep-Pak cartridges to desired radioactivity and volume. Using this automated system, reproducible radiolabeling yields of 80-85% were obtained

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

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

    2007-07-01

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

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

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

    2015-09-01

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

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

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

  18. MicroSPECT/CT imaging and pharmacokinetics of 188Re-(DXR)-liposome in human colorectal adenocarcinoma-bearing mice.

    Chen, Min-Hua; Chang, Chih-Hsien; Chang, Ya-Jen; Chen, Liang-Cheng; Yu, Chia-Yu; Wu, Yu-Hsien; Lee, Wan-Chi; Yeh, Chung-Hsin; Lin, Feng-Huei; Lee, Te-Wei; Yang, Chung-Shi; Ting, Gann

    2010-01-01

    Nanoliposome can be designed as a drug delivery carrier to improve the pharmacological and therapeutic properties of drug administration. (188)Re-labeled nanoliposomes are useful for diagnostic imaging as well as for targeted radionuclide therapy. In this study, the in vivo nuclear imaging, pharmacokinetics and biodistribution of administered nanoliposomes were investigated as drug and radionuclide carriers for targeting solid tumor via intravenous (i.v.) administration. The radiotherapeutics ((188)Re-liposome) and radiochemotherapeutics ((188)Re-DXR-liposome) were i.v. administered to nude mice bearing human HT-29 colorectal adenocarcinoma xenografts. (188)Re-liposome and (188)Re-DXR-liposomes show similar biodistribution profile; both have higher tumor uptake, higher blood retention time, and lower excretion rate than (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylenediamine (BMEDA). In contrast to tumor uptake, the area under the curve (AUC) value of tumor for (188)Re-liposome and (188)Re-DXR-liposome was 16.5- and 11.5-fold higher than that of free (188)Re-BMEDA, respectively. Additionally, (188)Re-liposome and (188)Re-DXR-liposome had a higher tumor-to-muscle ratio at 24 h (14.4+/-2 .7 and 17.14+/-4.1, respectively) than (188)Re-BMEDA (1.6+/-0.1). The tumor targeting and distribution of (188)Re-(DXR)-liposome (representing (188)Re-DXR-liposome and (188)Re-liposome) can also be acquired by signal photon-emission computed tomography/computed tomography images as well as whole body autoradiograph. These results suggest that (188)Re-(DXR)-liposomes are potentially promising agents for passive targeting treatment of malignant disease. PMID:20150618

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

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

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

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

  1. Preparation of 188 Re-lanreotide as a potential tumor therapeutic agent

    Radiolabeled peptides hold unlimited potential in diagnostic applications and therapy of malignant tumor. Somatostatin analogue peptide (Lanreotide) is labeled directly with 188Re via the mixture of citrate and tartrate. The influences of reaction conditions such as pH, temperature, amount of stannous chloride, Lanreotide quantity, reaction time on labeling yield are investigated in detail. At the same time, the stability in vitro, quality control and animal test are evaluated. The experimental results show that Lanreotide reacts with 188Re for 40 min at pH 2 - 3 and 60 degree C, the labeling yield is at range of 88% - 94%. After purification of 188Re-Lanreotide with Sep-Pak C18 reverse phase extraction cartridge, the radiochemical purity (RP) is more than 95%. 188Re-Lanreotide is eliminated rapidly from the blood and is excreted through liver, the uptake of lung and intestine is high

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

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

    2011-02-15

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

  3. 177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi

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

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

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

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

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

    2015-05-15

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

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

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

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

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

    2014-07-15

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

  8. Labeling procedures for the preparation of 188Re- DMSA(V)

    188Re has received a lot of attention in the past decade, due to its favorable nuclear characteristics [t1/2 16.9 h, Eβmax 2.12 MeV and Eγ 155 keV (15%) suitable for imaging], including the fact that it is carrier-free and can be obtained cost-effectively through the generator 188W-188Re. Besides the therapeutic usefulness of 188Re, the emission of the 155 keV gamma photon is an added advantage since the biodistribution of 188Re-labeled agents can be evaluated in vivo with a gamma camera. Biodistribution studies of 188Re-DMSA(V) have shown that its general pharmacokinetic properties are similar to that of 99mTc-DMSA(V), so this agent could be used for targeted radiotherapy of the same tumors, i.e., medullary thyroid carcinoma, bone metastases, soft tissue, head and neck tumors. The aim of this work is to evaluate two labeling procedures for the preparation of 188Re- DMSA(V). 188Re-DMSA(V) was prepared by two methods. The first method was prepared using a commercial kit of DMSA(III) for labeling with 99mTc, at high temperature (100 deg C). The second method was prepared in a vial containing 2.5 mg of DMSA, 1.00 mg of SnCl2.2H2O and 30 mg of sodium oxalate, in a total volume of 1.1 mL. The pH was adjusted to 5 with 37% HCl. After labeling the solution was stirred and incubated for 15 min at room temperature. The radiochemical purity was determined using TLC-SG developed with two different solvent systems. Preliminary results for both methods of labeling 188Re-DMSA(V) showed that the labeling yield was >90%. (author)

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

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

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

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

    2015-08-01

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

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

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

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

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

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

    2006-07-01

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

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

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

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

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

    2009-01-15

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

  15. [177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

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

    2016-01-01

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

  16. Intracoronary radionuclide therapy with liquid 188Re-filled balloons; radiopharmaceutical and dosimetric studies

    Percutaneous transluminal coronary angioplasty associated with radioactive liquid-filled balloons has demonstrated to be useful to inhibit the growth of neo intimal tissue. The present study pursued optimizing the relation risk/benefit during a procedure of brachytherapy with 188Re associated to angioplasty. Since the possibility of balloon rupture exists, to increase the security during the treatment different agents such as 188Re-DTPA, 188Re-Citrate and 188Re-EC vs 188ReO4 were evaluated. Dosimetric studies using Mirdose 3, after iv injection to Wistar rats, evaluation of a number of safety requirements in order to estimate radiation dose delivered to operating personnel and absorbed doses estimated by Monte Carlo method (PENELOPE). It is a safe procedure, both for the patient and the working staff; in case of ballon rupture the use of the above mentioned radiopharmaceuticals increases its security. 188Reβ emitor achieves a local dosis, diminishing the dose in healthy tissue (au)

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

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

    2015-09-15

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

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

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

  19. External beam radiotherapy synergizes 188Re-liposome against human esophageal cancer xenograft and modulates 188Re-liposome pharmacokinetics

    Chang CH

    2015-05-01

    Full Text Available Chih-Hsien Chang,1,2 Shin-Yi Liu,3 Chih-Wen Chi,3 Hsiang-Lin Yu,1 Tsui-Jung Chang,1 Tung-Hu Tsai,4 Te-Wei Lee,1 Yu-Jen Chen3–5 1Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan; 2Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, 3Department of Medical Research MacKay Memorial Hospital, 4Institute of Traditional Medicine, National Yang-Ming University, 5Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan Abstract: External beam radiotherapy (EBRT treats gross tumors and local microscopic diseases. Radionuclide therapy by radioisotopes can eradicate tumors systemically. Rhenium 188 (188Re-liposome, a nanoparticle undergoing clinical trials, emits gamma rays for imaging validation and beta rays for therapy, with biodistribution profiles preferential to tumors. We designed a combinatory treatment and examined its effects on human esophageal cancer xenografts, a malignancy with potential treatment resistance and poor prognosis. Human esophageal cancer cell lines BE-3 (adenocarcinoma and CE81T/VGH (squamous cell carcinoma were implanted and compared. The radiochemical purity of 188Re-liposome exceeded 95%. Molecular imaging by NanoSPECT/CT showed that BE-3, but not CE81T/VGH, xenografts could uptake the 188Re-liposome. The combination of EBRT and 188Re-liposome inhibited tumor regrowth greater than each treatment alone, as the tumor growth inhibition rate was 30% with EBRT, 25% with 188Re-liposome, and 53% with the combination treatment at 21 days postinjection. Combinatory treatment had no additive adverse effects and significant biological toxicities on white blood cell counts, body weight, or liver and renal functions. EBRT significantly enhanced the excretion of 188Re-liposome into feces and urine. In conclusion, the combination of EBRT with 188Re-liposome might be a potential treatment modality for esophageal cancer. Keywords: Radionuclide

  20. Imaging, Autoradiography, and Biodistribution of 188Re-Labeled PEGylated Nanoliposome in Orthotopic Glioma Bearing Rat Model

    Huang, Feng-Yun J.; LEE, TE-WEI; Kao, Chih-Hao K.; Chang, Chih-Hsien; Zhang, Xiaoning; Lee, Wan-Yu; Chen, Wan-Jou; Wang, Shu-Chi; Lo, Jem-Mau

    2011-01-01

    The 188Re-labeled pegylated nanoliposome (abbreviated as 188Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. 188Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce 188Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with 188Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT ima...

  1. Comparative studies of antibody anti-CD20 labeled with {sup 188}Re; Estudo comparativo da marcacao do anticorpo anti-CD20 com {sup 188}Re

    Dias, Carla Roberta de Barros Rodrigues

    2010-07-01

    Nuclear Medicine is an unique and important modality in oncology and the development of new tumor-targeted radiopharmaceuticals for both diagnosis and therapy is an area of interest for researchers. Rituximab (RTX) is a quimeric monoclonal antibody (mAb) (IgG 1) that specifically binds to CD20 antigen with high affinity and has been successfully used for the treatment of Non-Hodgkin Lymphoma (NHL) of cell B. The CD20 antigen is expressed over more than 90% of cell B NHL. Technetium-99m ({sup 99m}Tc) and rhenium-188 ({sup 188}Re) are an attractive radionuclide pair for clinical use due to their favorable decay properties for diagnosis ({sup 99m}Tc: T{sub 1/2} = 6 h, {gamma} radiation = 140 keV) and therapy ({sup 188}Re: T{sub 1/2} = 17 h, maximum {beta} energy = 2.12 MeV) and to their availability in the form of {sup 99}Mo/{sup 99}mTc and {sup 188}W/{sup 188}Re generators. The radionuclides can be conjugated to mAb using similar chemical procedures. The aim of this work was to study the labeling of anti-CD20 mAb (RTX) with {sup 188}Re using two techniques: the direct labeling method [{sup 188}Re(V)] and the labeling method via the carbonyl nucleus [{sup 188}Re(I)]. Besides the quality control, the radiolabeled mAb was submitted to in vivo, in vitro and ex vivo biological studies. For the direct labeling, RTX was reducing by incubation with 2-mercaptoethanol for generating sulphydryl groups (-SH) and further labeled with {sup 188}Re(V), in a study of several parameters in order to reach an optimized formulation. The labeling via the carbonyl nucleus both {sup 99}mTc and {sup 188}Re were employed through 2 different procedures: (1) labeling of intact RTX with {sup 99}mTc(I) and (2) reduced RTX (RTX{sub red}) labeled with {sup 99}mTc(I)/{sup 188}Re(I). Also a parameter study was performed to obtain an optimized formulation. The quality control method for evaluating the radiochemical purity showed a good labeling yield (93%) for the direct method. The labeling method

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

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

    2016-01-15

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

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

    Vilchis J, A.

    2013-07-01

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

  4. Evaluation of 188Re-MAG2-RGD-bombesin for potential prostate cancer therapy

    Glu-RGD-bombesin (RGD-BBN) is a heterodimeric peptide that contains motifs recognizing both integrin αvβ3 and gastrin releasing peptide receptor (GRPR). We evaluated here 188Re (t1/2 = 16.9 h) labeled RGD-BBN as a potential agent for radionuclide therapy of prostate cancer. RGD-BBN was conjugated with S-benzoylmercaptoacetylglycylglycyl (MAG2), and then labeled with 99mTc or 188Re, respectively. The dual-receptor binding affinity of MAG2-RGD-BBN was investigated by a radioligand competition binding assay. Biodistribution study of 188Re-MAG2-RGD-BBN was carried out in normal BALB/c mice and PC-3 human prostate tumor-bearing nude mice. Gamma imaging studies were performed in PC-3 tumor-bearing nude mice. Biodistribution in normal mice showed that both 99mTc and 188Re-labeled MAG2-RGD-BBN possessed high pancreas uptake due to the high GRPR expression of this organ. Gamma imaging with both 99mTc and 188Re-labeled RGD-BBN in PC-3 tumor-bearing nude mice demonstrated high tumor uptake. The PC-3 tumors were clearly visible at 1 postinjection, with high contrast to the contralateral background. The use of chelator MAG2 enables successful and high-yield 99mTc and 188Re radiolabeling of RGD-BBN with favorable tumor targeting specificity. Further optimization may allow potential clinical application of 188Re-MAG2-RGD-BBN for tumor-targeted radionuclide therapy

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

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

  6. Dosimetric evaluation of anti-CD20 labelled with 188Re

    Radioimmunotherapy has the potential to deliver lethal radiation energy directly to malignant cells via targeting of radioisotope-conjugated monoclonal antibodies (MAbs) to specific antigens. B-cell lymphoma is a particularly good candidate for radioimmunotherapy because the disease is inherently radiosensitive, malignant cells in the blood, bone marrow, spleen and lymphonodes are accessible, and MAbs have been developed to B-cell surface antigens that do not shed or modulate. Rituximab (RTX), the human IgG1-type chimeric form of the parent murine antibody ibritumomab, is specifically targeted against CD20, a surface antigen expressed by pre-B and mature human B lymphocytes. The use of rhenium-188 from a 188W/188Re generator system represents an attractive alternative radionuclide for therapy. 188Re is produced from beta decay of the 188W parent. In addition to the emission of high-energy electrons (Eβ= 2118 keV), 188Re also decays with emission of a gamma photon with an energy of 155 keV in 15% abundance. Besides the therapeutic usefulness of 188Re, the emission of gamma photon is an added advantage since the biodistribution of 188Re-labeled antibodies can be evaluated in vivo with a gamma camera. Also, rhenium has chemical properties similar to technetium. Thus, both can be conjugated to antibodies using similar chemistry methods. The objective of this work is to prove the usefulness of this radiopharmaceutical based on dosimetric studies, that are also required by the Brazilian Regulatory Agency (ANVISA). (author)

  7. A review on the current status and production technology for 188W-188Re generator system

    The current status of 188W-188Re generator production technology were reviewed in PART 1. Main interests were given to the aspects of 188W reactor production, irradiated targets reprocessing and generator loading technologies, such as alumina type and gel type generators. In order to develop the more convenient and advanced 188W-188Re generator, further studies must be carried out to get the precise evaluation of production and burn-up cross section of 188W, the more easily realizable generator loading procedure, and also to optimize the column and generator design to compensate the deterioration of generator performance because of parent radionuclide decay. By irradiation of 186W enriched sample, 188W-188Re generator production experiments were performed to evaluate the possibility of 188W-188Re generator production using HANARO, and PART 2 describes about the experiments. The experimental results shows the possibility of practical 188W-188Re generator production using of low-specific activity 188W produced in HANARO. (author). 79 refs., 4 tabs., 26 figs

  8. In vivo examination of 188Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer

    Introduction: Trastuzumab (Herceptin), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. Radiolabeled trastuzumab with β- or α emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect. Methods: In this study, trastuzumab was labeled with 188Re for radioimmunotherapy of HER2/neu-positive breast cancer. 188Re(I)-tricarbonyl ion, [188Re(OH2)3(CO)3]+, was employed as a precursor for directly labeling the monoclonal antibody with 188Re. The immunoreactivity of 188Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of 188Re(I)-trastuzumab within both tumor and normal tissues of athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressive) and similar mice bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressive) were investigated. Results: When incubated with human serum albumin and histidine at 25oC, 188Re(I)-trastuzumab was found to be stable within 24 h. The IC50 of 188Re(I)-trastuzumab was found to be 22.63±4.57 nM. 188Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of 188Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, 188Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the 188Re image at the localization of the tumor was dim. Conclusion: These results reveal that 188Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.

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

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

    2011-01-01

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

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

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

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

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

    2007-03-15

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

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

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

    2012-07-01

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

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

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

    2011-02-15

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

  14. Study of 188Re(V)-DMSA for treatment of cancer: radiolabeling and biodistribution

    The purpose of this study was to examine the radiolabeling and biodistribution of 188Re(V)-DMSA as a therapeutic cancer radiopharmaceutical. We made a DMSA kit(NaHCO3 1.5 mg, meso-2,3-dimercaptosuccinic acid 1.0 mg, L(+)-ascorbic acid 0.7 mg, SnCl2·2H2O 0.34 mg, pH 2.9) for labeling with 188Re. In this kit, 188ReO4 5 mCi/2 ml added and boiled at 100 .deg. C for 3 hr in water bath. The final pH adjusted to 7.5 with 7% NaHCO3 solution. We checked the labelling efficacy with TLC-SG(n-butanol : acetic acid : H2O= 3 : 2: 3) and examined the stability both in room temperature and in serum at 37 .deg. C. Biodistribution (1, 3, 13, 24, 48 hr) of 188Re(V)-DMSA compound was evaluated in Sarcoma 180 tumor-bearing mice. Each labeling efficiency and stability at room temperature for 48 hours was over 98% and 95%, respectively. The stability in serum were 82% (6 hr) and 85% (48 hr). Tumor uptake of 188Re(V)-DMSA in Sarcoma 180-bearing mice were 0.66±0.15% (1 hr), 0.51±0.10% (3 hr), 0.19±0.05%(24 hr) and 0.13±0.02%(48 hr). These result are consistent with those of 99mTc(V)-DMSA which were reported previously. In conclusion, 188Re(V)-DMSA may be a useful therapeutic radiopharmaceutical for treating some cancers and metastatic bone lesion

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

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

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

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

    2008-04-15

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

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

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

    2016-01-01

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

  18. Labeling procedures for the preparation of {sup 188}Re- DMSA(V)

    Brambilla, Tania P.; Osso Junior, Joao A., E-mail: taniabrambilla@yahoo.com.b, E-mail: jaosso@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2009-07-01

    {sup 188}Re has received a lot of attention in the past decade, due to its favorable nuclear characteristics [t{sub 1/2} 16.9 h, E{sub beta}{sub max} 2.12 MeV and E{sub gamma} 155 keV (15%) suitable for imaging], including the fact that it is carrier-free and can be obtained cost-effectively through the generator {sup 188}W-{sup 188}Re. Besides the therapeutic usefulness of {sup 188}Re, the emission of the 155 keV gamma photon is an added advantage since the biodistribution of {sup 188}Re-labeled agents can be evaluated in vivo with a gamma camera. Biodistribution studies of {sup 188}Re-DMSA(V) have shown that its general pharmacokinetic properties are similar to that of {sup 99}mTc-DMSA(V), so this agent could be used for targeted radiotherapy of the same tumors, i.e., medullary thyroid carcinoma, bone metastases, soft tissue, head and neck tumors. The aim of this work is to evaluate two labeling procedures for the preparation of {sup 188}Re- DMSA(V). {sup 188}Re-DMSA(V) was prepared by two methods. The first method was prepared using a commercial kit of DMSA(III) for labeling with {sup 99m}Tc, at high temperature (100 deg C). The second method was prepared in a vial containing 2.5 mg of DMSA, 1.00 mg of SnCl{sub 2}.2H2{sub O} and 30 mg of sodium oxalate, in a total volume of 1.1 mL. The pH was adjusted to 5 with 37% HCl. After labeling the solution was stirred and incubated for 15 min at room temperature. The radiochemical purity was determined using TLC-SG developed with two different solvent systems. Preliminary results for both methods of labeling {sup 188}Re-DMSA(V) showed that the labeling yield was >90%. (author)

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

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

    2014-01-01

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

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

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

    2006-07-01

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

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

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

    2016-01-01

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

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

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

    2011-01-01

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

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

    Diane E. Milenic

    2011-12-01

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

  4. Preliminary study of metabolic radiotherapy with 188Re via small animal imaging

    Baldazzi, G; Muciaccio, A; Navarria, Francesco Luigi; Pancaldi, G; Perrotta, A; Zuffa, M; Boccaccio, P; Uzunov, N; Bello, M; Bernardini, D; Mazzi, U; Moschini, G; Riondato, M; Rosato, A; Garibaldi, F; Pani, R; Antoccia, A; De Notaristefani, F; Hull, G; Cencelli, V O; Sgura, A; Tanzarella, C

    2006-01-01

    188Re is a beta- (Emax = 2.12 MeV) and gamma (155 keV) emitter. Since its chemistry is similar to that of the largely employed tracer, 99mTc, molecules of hyaluronic acid (HA) have been labelled with 188Re to produce a target specific radiopharmaceutical. The radiolabeled compound, i.v. injected in healthy mice, is able to accumulate into the liver after a few minutes. To study the effect of metabolic radiotherapy in mice, we have built a small gamma camera based on a matrix of YAP:Ce crystals, with 0.6x0.6x10 mm**3 pixels, read out by a R2486 Hamamatsu PSPMT. A high-sensitivity 20 mm thick lead parallel-hole collimator, with hole diameter 1.5 mm and septa of 0.18 mm, is placed in front of the YAP matrix. Preliminary results obtained with various phantoms containing a solution of 188Re and with C57 black mice injected with the 188Re-HA solution are presented. To increase the space resolution and to obtain two orthogonal projections simultaneously we are building in parallel two new cameras to be positioned at...

  5. Preliminary study of metabolic radiotherapy with {sup 188}Re via small animal imaging

    Antoccia, A. [Dept. of Biology, Univ. Roma3, V.le G. Marconi, I-00146 Rome (Italy); INFN, Sezione Roma3, Via della Vasca Navale 84, I-00146 Rome (Italy); Baldazzi, G. [Dept. of Physics, Univ. Bologna, V.le C. Berti-Pichat 6/2, I-40127 Bologna (Italy); INFN, Sezione Bologna, V.le C. Berti-Pichat 6/2, I-40127 Bologna (Italy); Bello, M. [Dept. of Physics, Univ. Padova, Via F. Marzolo 8, I-35131 Padova (Italy); INFN - LNL, V.le dell' Universita 2, I-35020 Legnaro(Italy)

    2006-01-15

    {sup 188}Re is a {beta}{sup -} (Emax=2.12 MeV) and {gamma} (155 keV) emitter. Since its chemistry is similar to that of the largely employed tracer, {sup 99m}Tc, molecules of hyaluronic acid (HA) have been labelled with {sup 188}Re to produce a target specific radiopharmaceutical. The radiolabeled compound, i.v. injected in healthy mice, is able to accumulate into the liver after a few minutes. To study the effect of metabolic radiotherapy in mice, we have built a small gamma camera based on a matrix of YAP:Ce crystals, with 0.6x0.6x10 mm{sup 3} pixels, read out by a R2486 Hamamatsu PSPMT. A high-sensitivity 20 mm thick lead parallel-hole collimator, with hole diameter 1.5 mm and septa of 0.18 mm, is placed in front of the YAP matrix. Preliminary results obtained with various phantoms containing a solution of {sup 188}Re and with C57 black mice injected with the {sup 188}Re-HA solution are presented. To increase the space resolution and to obtain two orthogonal projections simultaneously we are building in parallel two new cameras to be positioned at 90 degrees. They use a CsI(Tl) matrix with 1x1x5 mm{sup 3} pixels read out by H8500 Hamamatsu Flat panel PMT.

  6. Synthesis of polyacrylamide modified magnetic nanoparticles and radiolabeling with 188Re for magnetically targeted radiotherapy

    Magnetic nanoparticles were synthesized, modified with polyacrylamide, and then characterized by TEM, FTIR, VSM and PCS. Rhenium-188 (188Re) was bound to the nanoparticles by imidazolyl groups of histidine immobilized on the surface. The labeling yield was about 90% with good in vitro stability. Such nanoparticles might be useful for magnetically targeted radiotherapy

  7. 188Re-ethylene dicysteine: a novel agent for possible use in endovascular radiation therapy.

    Das, T; Banerjee, S; Samuel, G; Sarma, H D; Ramamoorthy, N; Pillai, M R

    2000-10-01

    Several agents, such as 188ReO4-, 188Re-MAG3 and 188Re-DTPA are currently under investigation as radiation sources in liquid-filled balloons for prevention of restenosis following coronary angioplasty. Bearing in mind the risk factor associated with leakage of radioactivity in the event of balloon rupture, the criteria sought in selecting suitable agents for endovascular radiation therapy (EVRT) are rapid clearance and low dose to vital organs. Since 99Tcm labelled ethylene dicysteine (EC) is a well established agent for renal tubular function imaging, the use of 186Re-ethylene dicysteine as a potential agent for prevention of restenosis after angioplasty has been evaluated previously. Therefore, it was of interest to evaluate the applicability of the more potential isotope of rhenium, 188Re, a high energy beta-emitter (Ebetamax = 2.12 MeV) with a suitable T 1/2 = 16.9 h, obtainable carrier-free from the 188W-188Re generator, as an attractive and alternative radionuclide for labelling with L,L-EC. In this paper, the preparation and pharmacological behaviour of the 188Re complex of ethylene dicysteine are reported. The complex can be prepared in high yields (99.5%) under optimized conditions of pH 2-3, at a ligand concentration of 15 mM, 50 microg (0.18 mM) carrier rhenium and using 2 mg x mL(-1) stannous chloride. On storage at 4 degrees C, the RC purity was more than 97% after 48 h when prepared under optimum conditions. Biodistribution studies in Wistar rats showed the desired characteristics of fast blood clearance and low retention of activity in the vital organs (< 2% in intestine, < 1% in stomach, < 0.5% in liver) with a high renal excretion (90.65+/-0.6%) at 3 h post-injection. These results confirm the advantages of using the 188Re-EC complex compared with perrhenate and other rhenium radiopharmaceuticals currently being used in balloons for EVRT. PMID:11130335

  8. Very stable 188Re-S4 chelates for labelling biomolecules. Preparation with highly concentrated perrhenate eluates

    Aim: The preparation and stability of a new 188Re-S4-complex [S4 (1-aza-18-crown-6)(O)C-C(SH)-C(SH)-C(O)NH-(CH2)3-NH-(CH2)3-NHC(O)- = C(SH)- C(SH )-C(O)(1-aza-18-crown-6)] was studied at therapeutic relevant radioactive concentrations. The results were compared with 188Re-MAG3 (MAG3: mercaptoacetyltriglycine) and 188Re-DMSA preparations (DMSA: dimercaptosuccinic acid) performed with the same highly concentrated [188Re]perrhenate solution (12-15 GBq/ml). Methods: The 188Re complexes were prepared by direct reduction of perrhenate (188Re-S4-complex) as well as via the 188Re-EDTA precursor complex (188Re-MAG3, 188Re-DMSA). The preparations were stabilised with 15 mg of ascorbic acid and analysed after 1, 2, and 24 hours by TLC and HPLC. Additionally, in vitro and in vivo stability studies were performed with the purified complexes. Results: After stabilisation with 15 mg of ascorbic acid, all of the complexes were nearly stable under nitrogen for hours, and only 2-8% of perrhenate was observed after 24 h. In contrast, only the 188Re-S4 complex was completely stable in vitro and in all investigated in vivo samples after separation of ligand excess and reducing agent by HPLC. Conclusion: The bridging amine group or free carboxylic groups of the S4-ligand framework make available reactive positions for coupling biomolecules to the chelate. Thus it appears that the new 188Re-S4 complexes offer the possibility of stable and high specific activity labelling of biomolecules for therapeutic application. (orig.)

  9. Comparative studies of antibody anti-CD20 labeled with 188Re

    Nuclear Medicine is an unique and important modality in oncology and the development of new tumor-targeted radiopharmaceuticals for both diagnosis and therapy is an area of interest for researchers. Rituximab (RTX) is a quimeric monoclonal antibody (mAb) (IgG 1) that specifically binds to CD20 antigen with high affinity and has been successfully used for the treatment of Non-Hodgkin Lymphoma (NHL) of cell B. The CD20 antigen is expressed over more than 90% of cell B NHL. Technetium-99m (99mTc) and rhenium-188 (188Re) are an attractive radionuclide pair for clinical use due to their favorable decay properties for diagnosis (99mTc: T1/2 = 6 h, γ radiation = 140 keV) and therapy (188Re: T1/2 = 17 h, maximum β energy = 2.12 MeV) and to their availability in the form of 99Mo/99mTc and 188W/188Re generators. The radionuclides can be conjugated to mAb using similar chemical procedures. The aim of this work was to study the labeling of anti-CD20 mAb (RTX) with 188Re using two techniques: the direct labeling method [188Re(V)] and the labeling method via the carbonyl nucleus [188Re(I)]. Besides the quality control, the radiolabeled mAb was submitted to in vivo, in vitro and ex vivo biological studies. For the direct labeling, RTX was reducing by incubation with 2-mercaptoethanol for generating sulphydryl groups (-SH) and further labeled with 188Re(V), in a study of several parameters in order to reach an optimized formulation. The labeling via the carbonyl nucleus both 99mTc and 188Re were employed through 2 different procedures: (1) labeling of intact RTX with 99mTc(I) and (2) reduced RTX (RTXred) labeled with 99mTc(I)/188Re(I). Also a parameter study was performed to obtain an optimized formulation. The quality control method for evaluating the radiochemical purity showed a good labeling yield (93%) for the direct method. The labeling method via carbonyl group, the results showed that the - SH groups of RTXred are a possible way of labeling. The formulation of 99m

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

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

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

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

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

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

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

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

    2016-03-15

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

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

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

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

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

    2005-03-01

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

  16. Formulation, radiopharmaceutical kinetics and dosimetry of the {sup 188}Re(V)-DMSA complex; Formulacion, radiofarmacocinetica y dosimetria del complejo {sup 188}Re(V)-DMSA

    Garcia S, L.; Ferro F, G. [Departamento de Materiales Radiactivos. Instituto Nacional de Investigaciones Nucleares, C.P. 52045 Salazar, Estado de Mexico (Mexico); Murphy, C.A. de; Pedraza L, M. [Departamento de Medicina Nuclear, Instituto Nacional de la Nutricion, Salvador Zubiran, Mexico D.F. (Mexico); Azorin N, J. [Departamento de Fisica, Universidad Autonoma Metropolitana Iztapalapa, Mexico D.F. (Mexico)

    1999-07-01

    It was developed through experimental design (ANOVA), a formulation to prepare the {sup 188} Re(V)-Dmsa complex. Likewise, there were realized studies of radiopharmaceutical kinetics and internal dosimetry in animals, its normal and with induced tumors, considering an open bi compartmental model using the MIRD methodology. The {sup 188} Re(V)-Dmsa complex was obtained with a radiochemical purity greater than 95% incubating 30 min at 90 Centigrade under the following formulation: [SnCl{sub 2}] = 1.4 mg/ml, [ascorbic acid] = 0.5 mg/ml, p H = 2.0 - 3.0. The stability test of the formulation, shows that after 48 h of its preparation, does not produce radiolytic degradation neither chemical decomposition. The radiopharmaceutical kinetics data show an average residence time 7.2h, velocity constant {alpha} = 0.6508h{sup -1} and {beta} = 0.1046 h{sup -1} with an apparent distribution volume 6.9 l. The main elimination via was renal and it was observed osseous caption with an accumulated activity 522.049 {+-} 62 MBq h (residence time 14.1094 {+-} 1.69h). In according with the dosimetric calculations, by each 37 MBq injected, the equivalent dose at the tumor was 9.67{+-} 0.33 Sv/g, for an effective dose 0.292 {+-} 0.0017 mSv/MBq. The images obtained in the gamma camera of the mice with induced tumors, show that do not have significant accumulation in the metabolic organs. The caption in bone and in tumors induced of the {sup 188} Re(V)-Dmsa complex, show its potential for be used as a palliative agent for pain in patients with osseous metastasis and in the treatment of tumors of soft tissue. (Author)

  17. Labeling of MDP with {sup 188}Re for bone tumour therapy

    Barbezan, Angelica B.; Osso Junior, Joao A., E-mail: jaosso@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2011-07-01

    {sup 188}Re is one of the most attractive radioisotopes for a variety of therapeutic applications in nuclear medicine, due to its physical decay properties, such as {beta}{sup -} emission of 2.12 MeV, {gamma} emission of 155 keV and half life of 16.9 hours. Biphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in several diseases that cause bone fragility and bone metastases. Because of these characteristics, labeled biphosphonates have been studied for bone pathologies, also acting as palliation of bone pain in case of metastasis.The aim of this study was to optimize the labeling of a phosphonate-MDP (Sodium Methylene Diphosphonate) with {sup 188}Re for use in bone pain palliation. {sup 188}Re was obtained by eluting a {sup 188}W-{sup 188}Re generator from POLATOM. The labeling was performed at room temperature using MDP, SnCl{sub 2} as reducing agent and ascorbic acid. The variables studied were: Mass of ligand (3, 6 and 10 mg), reducing agent mass (5, 7, 10 and 11 mg), ascorbic acid mass (1, 3, 5 and 6 mg), pH (1 and 2) and time of reaction (15, 60, 120, 360 and 4320 minutes), that also reflected the stability of the radiopharmaceutical. The radiochemical control, that also measures the labeling efficiency was evaluated by paper chromatography using Whatman 3MM paper and the solvents acetone and 0.9%NaCl. The best formulation was the following: Mass of ligand MDP: 10 mg, mass of SnCl{sub 2}: 5 mg, ascorbic acid mass: 3 mg, time of reaction: 30 minutes, pH: 1. Under optimum conditions, {sup 188}Re MDP radiolabeling yield was 98,07% and the radiopharmaceutical was stable up to 72 h. (author)

  18. Intracoronary radionuclide therapy with liquid 188Re-filled balloons: Radiopharmaceutical and dosimetric studies

    Full text: Percutaneous transluminal coronary angioplasty (PCTA) associated with radioactive liquid-filled balloons has demostrated useful to inhibit the growth of neointimal tissue and as consequence offers a potential method to decrease restenosis rate. Near 40 to 60% of the patients suffered from restenosis, being necessary to reiterate angioplasty. The spectrum of late effects from the variety of sources types, dosimetric aspects and delivery systems has not became clear. An attractive radionucleid for this purpose is 188Re, that is eluated from a 188W/188Re generator. The generator can be used during 6 months, depending on the initial activity. The specific activity can be increased by a concentration system up to a maximum of 20 GBq/mL. The present study had the purpose of optimizing the relation risk/benefit during a procedure of brachytherapy with 188Re associated to angioplasty. The possibility of balloon rupture exists, with the passage of the radioactive solution towards the patient bloodstream. In order to increase the security during the treatment the evaluation of different agents such as 188Re- DTPA, 188Re-Citrate and 188Re-EC vs 188ReO4- (as the standard agent) was performed. Labelling procedures were optimized considering pH, temperature, reaction time and carrier adition. Dosimetric studies using Mirdose 3, after iv injection to Wistar rats of the three radiopharmaceuticals were performed. Biodistrubion at 1 and 3 hs post-administration and dose estimation showed no difference between all the radiopharmaceuticals, presenting low uptake in thyroid and stomach, and faster renal elimination than 188ReO4-, with smaller residence times in all the organs. As the preparation of 188Re-Citrate and 188Re-EC required less strong conditions than 188Re-DTPA, one of these radiopharmaceuticals could be selected to improve the security of the procedure. A second point of this study was the evaluation of a number of safety requirements in order to estimate

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

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

  20. Assessment of 188Re marked anti MHC class Ⅱ antibody by peripheral blood mononuclear cells stimulated by donor alloantigen

    DING Guo-ping; CAO Li-ping; LIU Jie; LIU Da-ren; QUE Ri-sheng; ZHU Lin-hua; ZHOU Yi-ming; MAO Ke-jie; HU Jun-an

    2011-01-01

    Background Previous studies showed that anti MHC-Ⅱ monoclone antibody (MAb) only had partial inhibiting effect of alloreactive mixed lymphocyte reaction (MLR) in vitro and it was unsteady and non-persistent. The aim of this research was to determine whether radioactive isotope 188Re marked MHC-Ⅱ antibody could benefit the allograft acceptance in transplantation as compared to normal MHC-Ⅱ antibody.Methods 188Re was incorporated to 2E9/13F(ab')2 which is against swine MHC class Ⅱ antigen (MAb-188Re). Porcine peripheral blood mononuclear (PBMC) cells were examined for proliferation and cytokine mRNA expression after stimulation with MHC-Ⅱ MAb or MAb-188Re.Results The proliferative response of recipient PBMCs in mixed lymphocyte reaction (MLR) to donor alloantigen showed that the stimulation index of MAb-188Re group was significantly lower than the MHC-Ⅱ MAb group and control (P<0.05). mRNA expression of interleukin 2, interferon Y and tumor necrosis factor α (type 1 cytokines) was lower in MAb-188Re group than the MHC-Ⅱ MAb group, while interleukin 10 (type 2 cytokines) was higher in MAb-188Re group in the first 24 hours.Conclusion MAb-188Re could help the graft acceptance by inhibiting T cell proliferation, lowering the expression of type 1 cytokines and elevating the type 2 cytokines produced by PBMC.

  1. Dosimetric evaluation of nanotargeted 188Re-liposome with the MIRDOSE3 and OLINDA/EXM programs

    The OLINDA/EXM computer code was created as a replacement for the widely used MIRDOSE3 code for radiation dosimetry in nuclear medicine. A dosimetric analysis with these codes was performed to evaluate nanoliposomes as carriers of radionuclides (188Re-liposomes) in colon carcinoma-bearing mice. Pharmacokinetic data for 188Re-N, N-bis (2-mercaptoethyl)-N', N'-diethylethylenediamine (188Re-BMEDA) and 188Re-liposome were obtained for estimation of absorbed doses in normal organs. Radiation dose estimates for normal tissues were calculated using the MIRDOSE3 and OLINDA/EXM programs for a colon carcinoma solid tumor mouse model. Mean absorbed doses derived from 188Re-BMEDA and 188Re-liposome in normal tissues were generally similar as calculated by MIRDOSE3 and OLINDA/EXM programs. One notable exception to this was red marrow, wherein MIRDOSE3 resulted in higher absorbed doses than OLINDA/EXM (1.53- and 1.60-fold for 188Re-BMEDA and 188Re-liposome, respectively). MIRDOSE3 and OLINDA have very similar residence times and organ doses. Bone marrow doses were estimated by designating cortical bone rather than bone marrow as a source organ. The bone marrow doses calculated by MIRDOSE3 are higher than those by OLINDA. If the bone marrow is designated as a source organ, the doses estimated by MIRDOSE3 and OLINDA programs will be very similar. (author)

  2. Labelling of biorelated compounds and monoclonal antibodies with 188-Re,186-Re and 99mTc

    Some bio-related compounds were labelled with 188Re and 186Re 188Re was obtained from 188W/188Re generator which was produced by neutron irradiation of enriched 186WO3 target (99.79%) in JRR-2 and 186Re was supplied by Production Div., Department of Radioisotopes, JAERI, Japan. Rhenium labelling involved reduction of perrhenate with SnCl2.2H20 in HCI. Bio-related compounds citrate and gluconate were then labelled with reduced rhenium. The labelling yield of labelled compounds as determined by thin-layer chromatography were greater than 98% and 94% for 188Re-citrate and gluconate, respectively. Monoclonal antibodies (mouse,lgG2A and lgG;Fab'2, human lgG2A; anti-hepatoma and IgG) were also successfully labelled with 188Re, 186Re, and 99mTc by direct method using citrate and glucoheptonate as transchelating agents

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

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

    2014-03-15

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

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

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

    2015-05-01

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

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

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

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

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

    2011-12-15

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

  7. Experimental study on target treatment of nasopharyngeal carcinoma using 188Re-BAC5 combined with PYM-BAC5

    Objective: Combination of radiation and chemical agents was supposed to have better effect on nasopharyngeal cancer. This study compared the in vitro inhibiting effects of 188Re-monoclonal anti- body (BACs) with or without pingyangmycin conjugated BACs (PYM-BAC5) on nasopharyngeal carcinoma cells (CNE2). Methods: 188Re-BAC5 was prepared using 2-mereaptoethanol (ME), citric acid and tartaric acid as reducing and transchelation agents. Oxidized dextran T-40 (polyaldehyde dextran, PAD ) was used to conjugate PYM to BAC5. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylte-trazolium bromide (MTT) method was applied to assess anti-tumor effects of 188Re-BAC5 and PYM-BAC5 on CNE2 cells. Results: The labeling efficiency of 188Re-BACs was 92%-95% with a radioactive concentration of 5254 kBq/ml. The composition of PYM-BAC5 was m (PYM): m (BAC5)=1: 0.526, or n (PYM): n(BAC5)=1:51. The inhibition effects of each treatment regime were in a dose dependent manner. The 50% inhibition doses (IC50) of 188Re-BAC5, 188Re-mIgG and 188ReO4- were 264, 1062 and 882 kBq/ml, respectively. The IC50 of the PYM-BAC5 and free PYM were 10.07 and 63.60 μg/ml, respectively. Combining 188Re-BAC5 and PYM-BACs reduced the IC50 of 1'88Re-BAC5 and PYM-BACs down to 32.1 kBq/ml and 1.70 μg/ml. Conclusions: It was proved that targeted therapy had better anti-tumor effect. The combination of targeted radiation and chemical agents (188Re-BAC5 + PYM-BAC5) obtained the best therapeutic effect on cultured CNE2 cells. (authors)

  8. Development of a technology for the preparation of 188W-188Re generators

    A big interest has recently arisen concerning the use of Rhenium-188 (188Re) for various medical applications. Tumor therapy with antibodies labeled with 188Re is the main application, but it is being studied its application in carcinomas of medullar thyroid, bone pain palliation and radionuclide synovectomy, among others. Rhenium-188 decays 79% to the ground state of stable 188Os (Eβ1max - 2,11 MeV) and 20% to the first excited state (Eβ2max = 1,97 MeV). The deexcitation of this state gives a 155 keV gamma ray (15r%) which can be detected by imaging. Another great advantage is the viability of carrier-free 188Re from the decay of 188W (t1/2 = 69.4 days) in a generator system. The objective of this work is the development of the technology for the preparation of 188W- 188Re generators. To accomplish this, the steps of the work are: preparation of the targets of W; irradiation of W targets in order to measure the activation and radionuclidic impurities; development of 188W-188Re generators; development of a method for the quality control of 188Re: chemical, radiochemical and radionuclidic purities. The study of alumina-based generators was performed with the irradiation of targets of natural metallic W and W03 and showed that this kind of generator will only be viable with the importation of 188W, due to the low neutron flux of the Reactor IEA-R1 Reactor for the commercial routine production of this radioisotope, but the technology of production and quality control were successful. The gel type chromatographic generators of WZr were produced with natural WO3 targets and showed that, if enriched targets are to be used and with the power upgrade of the IEA-R1 Reactor, they can be produced by the Radiopharmacy Center at IPEN-SP. The quality control methodology were determined and the results were inside the limits given by the Pharmacopoeia. (author)

  9. Improved conditions for labeling EDTMP with 188Re for bone pain palliation

    Introduction: Ethilenediamine tetramethylene phosphonate (EDTMP) is a tetraphosphonate ligand which, when labeled with 188Re, can be used for relief of metastatic bone pain. The preferential localization of phosphonate complexes in bone is attributed to their affinity for calcium, and tetraphosphonates may be equal or superior to diphosphonates in this regard. In the present study, it was aimed to determine optimal conditions for preparation of a kit of EDTMP to be labeled with 188Re. Methods: EDTMP was dissolved in NaOH 1N, and alkalinity was reversed with HCl till pH 2, when SnCl2. 2H20 and also ascorbic acid were introduced in the mixture, followed by Na188ReO4. The preparation was incubated in water bath for 30 minutes and after cooling radiochemical purity was assessed. Optimization of the process consisted in varying the values of EDTMP mass (20, 30, 40 mg) SnCl2.2H20 concentration (0.5, 1.0, 2.0 and 3.0 mg/mL), and reaction time (15 and 30 minutes). Radiochemical purity and stability were ascertained in vitro and also in Swiss mice. Bone/muscle uptake ratio was calculated from %ID/g of these organs. Results: The best 188Re-EDTMP complex was obtained with 40 mg of the ligand and 2 mg/mL of stannous chloride heated during 15 minutes, and the product was radiochemically stable during 24 hours. Kidney and bone uptake were very significant (respectively 4.5 ± 0.5% and 3.1 ± 0.3 %ID/g). Bone/muscle ratio observed four hours post-injection was also very adequate (28.5). Conclusions: A stable and biologically useful complex of 188Re-EDTMP can be prepared with high concentration of EDTMP and considerable uptake by bone. It compares favorably with 153Sm-EDTMP, as 188Re has more advantageous radioisotopic properties than 153Sm, and it can be recommended for further studies in conditions of painful bone metastases

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

    Luna G, M. A.

    2014-07-01

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