|Year : 2011 | Volume
| Issue : 2 | Page : 216-225
Abstracts of Poster Presentations (NET/ PRRT/ Molecular Imaging/ Radiopharmacy)
|Date of Web Publication||12-Nov-2011|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Abstracts of Poster Presentations (NET/ PRRT/ Molecular Imaging/ Radiopharmacy). World J Nucl Med 2011;10:216-25
Normal Uptake Value of C-11 Acetate in Some Organs
Trinh Thi Minh Chau, V. T. Ngo, K. N. Vo
PET/CT and Cyclotron, Cho Ray Hospital, Ho Chi Minh City, Vietnam
Introduction: PET/CT with C-11 Acetate has been put into clinical practice in our center. C-11 Acetate is used for the evaluation of the fatty acid metabolic activity of the tumors. We have performed initial cases of PET/CT with C-11 Acetate for diagnosis and follow-up of HCC and urological cancers. We want the assessment of C-11 Acetate uptake in the normal-appearing tissue of some organs in the body.
Materials and Methods: All male patients were fasted for at least 6 hours before C-11 Acetate PET/CT whole-body scanning (Biograph true D w/true V 64 slice, Siemens) at Cho Ray hospital, Viet Nam. C-11 Acetate was intravenously injected at 10 MBq/kg body weight (0.27 mCi/kg). Whole-body scanning was performed at 15 minutes after C-11 Acetate injection from skull base to upper thigh. The uptake of C-11 Acetate in the normal-appearing tissue of some organs was semi-quantified by maximum and mean standardized uptake value (maxSUV and meanSUV) calculated by radioactivity in ROI (Bq/ml) x body weight (kg)/injected radioactivity (Bq).
Results: Nine male patients were included in the study. The mean age was 59±13.9 years (46 to 79). There were 7 patients with HCC, 1 with combined bladder and prostate cancers and 1 with resected renal cancer with bladder seeding. The maxSUV and meanSUV of the normal-appearing tissue of liver were 4.8±1.0 and 3.7±0.7, spleen were 5.6±0.9 and 4.7±0.8, pancreas were 11.4±3.0 and 8.9±2.9, prostate were 4.1±1.4 and 3.2±0.6, renal cortices were 3.8±0.7 and 3.3±0.6, parotid gland were 4.7±1.7 and 3.6±0.9 and bone marrow were 1.8±0.8 and 1.8±0.8, respectively.
Conclusion: PET/CT showed the normal highest uptake of C-11 Acetate in pancreas and the C-11 Acetate uptake in order of descending level were spleen, liver, parotid gland, renal cortice, prostate and bone marrow. These value would be used as the reference value necessary for certification of normal uptake of C-11 Acetate in the human body and for clinical interpretation of PET/CT with C-11 Acetate.
Development of Nanoradiopharmaceuticals
S. O. Ralph, A. Marta de Souza, A. L Sergio, B. Thiago, B. Augusto, F. Beatriz, P. F. Jenifer, F. C. Bianca
Department of Radiopharmaceuticals, Laboratory of Nanoradiopharmaceuticals, Rua Prof Rodolpho Paulo Rocco 252, Rio de Janeiro, 21941906, Brazil
The use of nanotechnology has been increasing everyday. New advances in pharmaceuticals compounds and polymers developed a new field called nanopharmaceuticals. In this new scenario the development of nanoradiopharmaceuticals are of high importance. In this study we made a overview in the recent advances in this field as also possible applications for the development of nanoradiopharmaceuticals.
Nanoradiopharmaceuticals: Development of Labelling Process
S. O. Ralph, S. A. Marta, L. Sergio Augusto, B. Thiago, B. Augusto, F. Beatriz
Department of Radiopharmaceuticals, Nuclear Engineering Institute, Rua Helio de Almeida 75, Rio de Janeiro, Brazil
Nanomedicine is the future of modern medicine. Hence, there is a global effort being made in the development of nanopharmaceuticals. Among all the nanopharmaceuticals developed so far, radiopharmaceuticals are the fewest in number of published studies. The development of nanoradiopharmaceuticals is complex but not impossible. In this work we discuss the possibility and the results of developing 3 nanoradiopharmaceuticals based on 3 different types of nanopharmaceuticals as alternative drug delivery systems.
Synthesis, Radio Labeling and Biological Evaluation of [67Ga]- 5,10,15,20-tetRakis (Pentafluorophenyl) Porphyrin Complexe as an Imaging Agent
M. Aboodzadeh, Y. Fazaeli, A. R. Jalilian, M. Amini, A. Rahiminejad, F. Bolourinovin, S. Moradkhani, A. Majd Abadi
Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Karaj, Iran
Introduction: Porphyrins appeal large attention because of their impersonation in the human body, ability to accumulate in many kinds of cancer cells, as well as magnetic and optical properties. Radiolabelled porphyrins have been developed for the therapeutic purposes such as, 109Pd-protoporphyrins, 109Pd-porphyrins, and 188Re-porphyrin. In continuation of our previous work, we report, synthesis, radiolabelling, partition coefficient, quality control and biodistribution studies (using: SPECT and scarification) of 67Ga-F20P in wild-type rats.
Materials and Methods: [67Ga]labeled 5,10,15,20-tetrakis(pentafluorophenyl) porphyrin ([67Ga]-F20P) was prepared using freshly prepared [67Ga]GaCl3 and 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin (F20PH2) for 50 min at 25°C (radiochemical purity: >97% ITLC, >98% HPLC, specific activity: 13-14 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P=0.58). The biodistribution of the labeled compound in vital organs of wild-type and tumor bearing rats was studied using scarification studies and SPECT imaging up to 24 h. A detailed comparative pharmacokinetic study performed for 67Ga cation and [67Ga]-F20P.
Results: Total labeling and formulation of [67Ga]- F20P took about 30-60 min (RCP >97% ITLC, >98% HPLC, specific activity: 13-14 GBq/mmol). The complex was stable in final formulation and human serum at least for 24 h. At the pH.7, the logP was 0.58. The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and SPECT imaging up to 24 h. The complex is mostly washed out from the circulation through liver and kidneys and can be an interesting tumor imaging/targeting agent due to high tumor uptake and rapid excretion through the urinary tract.
Conclusion: It is suggested that 67Ga-F20P could be a possible SPECT tracer, however considering the fast wash-out, the short half life gallium-68 can be a suitable candidate for tumor imaging applications and future 68Ga-PET studies and less imposed radiation doses to patients.
Synthesis, Radiolabelling and Biological Evaluation of [111In]-Maltolate Complex as an Imaging Agent
Y. Fazaeli, A. Jalilian, M. A. Mostafa, M. A. Mohammad, M. Abbas, R. Ali, B. Fateme, A. Mohammadreza, A. Gholamreza
Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Karaj, Iran
Introduction: Maltol (3-hydroxy-2-methyl-4-pyrone), is a naturally occurring non-toxic compound and common food additive. There are numerous metal-maltol complexes used in biomedical application. In this work we report, synthesis, radiolabeling, partition coefficient, quality control and biodistribution studies (using SPECT and scarification) of 111In -maltolate in wild type rats . The time/activity diagrams for the labeled compound in vital organs have been plotted.
Materials and Methods: [111In] labeled 3-hydroxy-2-methyl-4H-pyran-4-onate ([111In]- maltolate) was prepared using freshly prepared [111In] In Cl3 and 3-hydroxy-2-methyl-4H-pyran-4-onate in a sodium salt form for 25 min at 45°C (radiochemical purity: >98% ITLC, >98% HPLC, specific activity: 15-17 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P=0.278). The biodistribution of the labeled compound in vital organs of wild type rats studied using scarification studies and SPECT imaging up to 24 h.
Results: Total labeling and formulation of [111In]-maltolate took about 30 min (RCP >98% ITLC, >98% HPLC, specific activity: 15-17 GBq/mmol). The complex was stable in final formulation and human serum at least for 24 h. At the pH.7, the logP was 0.278. The biodistribution of the labeled compound in vital organs of wild type rats was studied using scarification studies and SPECT imaging up to 24 h.The complex is mostly washed out from the circulation through kidneys and can be an interesting tumor imaging agent due to the fact that the compound has a potential therapeutic agent for cancer, infectious disease, and inflammatory disease.
Conclusion: Indium maltolate has significant solubility in both water and lipids and hence the complex is mostly washed out from the circulation through kidneys and liver and can be an interesting agent for tumor treatments for liver cancer and gastrointestinal cancers. It is suggested that [111In]-maltolate could be a possible SPECT tracer, however considering the fast wash-out, [111In]-maltolate can be a suitable candidate for tumor imaging applications and future 110mIn-SPECT studies may lead to less use and therefore less imposed radiation doses to patients.
Production, Quality Control and Imaging of 64Cu- Atsm0 in Healthy Rabbits for Clinical Applications
Y. Fazaeli, A. Jalilian, G-M Mohammad, K. Mohsen, M. Abbas, R. Ali, B. Fateme, Y. Kamran, G. Aslani
Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Karaj, Iran
Introduction: [64Cu] diacetyl-bis (N4-methylthiosemicarbazone) ([64Cu] ATSM) is a well-established hypoxia-imaging tracer with reproducible production and significant specificity. In this work, the high yield production and quality control as well as imaging studies in healthy rabbits is reported.
Materials and Methods: Copper-64 produced via the 68Zn (p,an) 64Cu nuclear reaction (30 MeV protons at 180 μA) was used for the preparation of [64Cu]diacetyl-bis(N4-methylthiosemicarbazone)([64Cu]ATSM). Followed by quality control and administration to healthy rats as well as healthy rabbits for biodistribution and imaging studies respectively
Results: 64Cu2+ (500 mCi, separation yield> 95%, radionuclide purity>96%) was used for [64Cu]ATSM production (radiochemical purity>99%, specific activity of 300 Ci/mmol) followed by administration to healthy rabbits and coincidence imaging demonstrating uptake in liver, kidney and bowel as shown by other reports in various rodents and human.
Conclusion: Copper-64 in the form of 64Cu2+ (500 mCi, separation yield> 95%, radionuclide purity>96%) was used for [64Cu] ATSM production (radiochemical purity>99%, specific activity of 300 Ci/mmol) in 10 min. No other labeled by-products were observed upon RTLC/HPLC analysis of the final preparations after solid phase extraction (SPE) purification. The radiolabelled complex was stable in aqueous solutions for at least 12 hours and no significant amount of other radioactive species were detected by RTLC 12 hours after labeling. The biodistribution of the tracer in normal rats up to 210 min demonstrated similar biodistribution to the other reports for [64Cu] ATSM. Intravenous administration of the tracer to healthy rabbits and coincidence imaging demonstrated uptake in liver, kidney and bowel as shown by other reports in various rodents and human. [64Cu]ATSM, is PET radiotracer with a long half-life, and the high yield, large-scale production and stability of this radiopharmaceutical make it an accessible diagnostic agent for clinical trial initiation in the country.
Synthesis, Radiolabeling and Biological Evaluation of [67Ga]-maltolate Complex as an Imaging Agent
Y. Fazaeli, A. Jalilian, M. A. Mostafa, G. Mohammad, M. Abbas, R. Ali, B. Fateme, M. Sadighe, A. Gholamreza
Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Karaj, Iran
Introduction: The interesting physical properties and availability of gallium-67 make it an interesting nuclide for radiopharmaceutical research .Recently Studies of gallium maltolate as a potential treatment for liver cancer and gastrointestinal cancers has been done.Gallium maltolate is stable in aqueous solutions between about pH 5 and 8,and it has significant solubility in both water and lipids. In this work we report, synthesis, radiolabelling, partition coefficient, quality control and biodistribution studies (using SPECT and scarification) of 67Ga-maltolate in Swiss mice. The time/activity diagrams for the labeled compound in vital organs have been plotted compared to gallium cation.
Materials and Methods: [67Ga] labeled 3-hydroxy-2-methyl-4H-pyran-4-onate ([67Ga]- maltolate) was prepared using freshly prepared [67Ga]GaCl3 and 3-hydroxy-2-methyl-4H-pyran-4-onate in a sodium salt form for 25 min at 40°C (radiochemical purity: >96% ITLC, >98% HPLC, specific activity: 13-17 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P=0.40). The biodistribution of the labeled compound in vital organs of Swiss mice studied using scarification studies and SPECT imaging up to 24 h. A detailed comparative pharmacokinetic study performed for 67Ga cation and [67Ga]-maltolate.
Results: Total labeling and formulation of [67Ga]-maltolate took about 30 min . The complex was stable in final formulation and human serum at least for 24 h. At the pH.7, the logP was 0.4. The biodistribution of the labeled compound in vital organs of Swiss mice was studied using scarification studies and SPECT imaging up to 24 h.
Conclusion: It is suggested that [67Ga]-maltolate could be a possible SPECT tracer, however considering the fast wash-out and the short half life gallium-68, [67Ga]-maltolate can be a suitable candidate for tumor imaging applications and future 68Ga-PET studies and less use and therefore less imposed radiation doses to patients.
Preparation and Evaluation of [67Ga]-Tetra Phenyl Porphyrin Complexes as Imaging Agents
Y. Fazaeli, A. Jalilian, M. A. Mostafa, R. Ali, M. Abbas, A. Khosro, B. Fateme, M. Sadighe, A. Gholamreza
Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Karaj, Iran
[67Ga]labeled tetraphenyl porphyrin ([67Ga]-TPP) was prepared using freshly prepared [67Ga]GaCl3 and tetraphenyl porphyrin (TPPH2) for 30-60 min at 25°C (radiochemical purity: >97% ITLC, >98% HPLC, specific activity: 13-14 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P. 1.89). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and SPECT imaging up to 24 h. A detailed comparative pharmacokinetic study performed for 67Ga cation and [67Ga]-TPP. The complex is mostly washed out from the circulation through kidneys and can be an interesting tumor imaging/targeting agent due to low liver uptake and rapid excretion through the urinary tract. The biological evaluation of the tracer must be evaluated in tumor-bearing animal models.
Radiosynthesis and Biological Evaluation of [111In]-5,10,15,20-tetrakis (Pentafluorophenyl) Porphyrin ComPlex as a Possible Imaging Agent
M. Aboudzadeh Rovais, F. Yousuf, A. Jalilian, M. A. Mostafa, S. Kamaleddin, M. Mohammad, R. Ali, M. Abbas
Agricultural, Medical and Industrial Research School, Nuclear Science and Technology Research Institute, Karaj, Iran
Due to the interesting pharmacological properties of radiolabelled porphyrin derivatives such as low toxicity, tumor avidity and rapid washout, [111In] labeled 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin ([111In]- TFPP) was developed in this work. [111In]- TFPP was prepared using freshly prepared [111In] InCl3 and 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin (H2TFPP) for 60 min at 100°C (radiochemical purity: >99% ITLC, >99% HPLC, specific activity: 13-14 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 48 h. The partition coefficient was calculated for the compound (log P=0.69). The biodistribution of the labeled compound in vital organs of wild-type rats and fibrosarcoma-bearing mice was studied using scarification studies and SPECT up to 24 h. A detailed comparative pharmacokinetic study performed for 111In cation and [111In]-TFPP performed up to 24h. The complex is mostly washed out from the circulation through kidneys and liver. The tumor: blood and tumor: muscle ratios 24 hr- post injection were 1.44 and 66 respectively.
Emergency Handling in a Medical Cyclotron Facility
R. Kumar, R. Sonkawade, M. Jacob, A. Pandit, D. Singh
PET Scan Centre and Medical Cyclotron facility, Army Hospital Research and Referral Centre, New Delhi, India
Medical cyclotron is a particle accelerator used in producing short-lived radioisotopes such as 18F, 11C, 15O, 13N, 18F -2 gas etc. Positron emission tomography (PET) is a nuclear imaging modality that has rapidly gained favor. 18F-FDG is the most widely used radiopharmaceutical with a half-life of 109.8min.Having more than 3000 run experience in this field we faced lots of emergency situations in the medical cyclotron facility. Radioactive gas leak, Target foil and vacuum window rupture are considered as the major emergency situations during medical cyclotron operations because there is a potential of over exposure to the working personnel. Emergency situation may arise from initialization of cyclotron to end product i.e. radiopharmaceuticals production. Radiation protection survey of a self-shielded medical cyclotron installation was carried out during normal and emergency conditions. It is found that the induced activity in the target foil increases with its successive usages. On the basis of harm, we have divided it into three categories i.e. Harm of a) working personnel, b) Equipment and c) environment. Recommendations have also been made to reduce personal exposure while handling the radioactive gas leak and target foil rupture conditions.
Development and Evaluation of a New Protocol for Synthesis of 6-(18F) Fluoro-L-DOPA
R. Kumar, C. Bal, G. P. Bandopadhyaya, A. Malhotra
Nuclear Medicine and PET Scan Centre, All India Institute of Medical Sciences, New Delhi, India
Objective: The objective of this study was to develop and evaluate a new synthesis protocol for 6-fluoro-L-3, 4-dihydroxyphenylalanine (6-fluoro-L-DOPA) by using 11 MeV RDS 111 self shielded cyclotron and ray test synchrom module.
Materials and Methods: 18(F) FDOPA is produced in place where cyclotron is available locally. There are several methods of synthesis of 18(F) FDOPA. The most common method is fluoro-demetallation by using electrophilic fluorinating agent. [18F] FDOPA was synthesized in high yield with a radio- fluorodestannylation procedure followed by an acidic hydrolysis by Hcl. The solution obtained from HPLC purification into product vessels in which Ascorbic acid is added for stability. Then it was passed through a 0.22mm membrane filter into sterile vials as a final product. Its chemical purity and radiochemical purity were determined by HPLC method.
Results and Discussion: The first synthesis was done in May 2009.An average of 40-50-mCi [18F] FDOPA was obtained since last two and half years. The total synthesis time was 45 minutes after trapping of 18F2 gas in to reaction vessels. We did many modifications to develop a new protocol. We started using Chloroform D, instead of Freon. The amount of precursor prescribed by the company is 60 mg and we have successively decreased it up to 30 mg. We have also started reusing O-18 gas after some modification in Cryotrap. We have replaced the Helium gas by Nitrogen gas in the synthesis module. The overall chemical yield was about 27-33%, and the quality product was above 95%. We did QC test was and it has passed for all the batches. We have scanned more than 200 patients and all are having very good images.
Conclusion: An automated new synthesis protocol has been developed for synthesis of [18F] FDOPA production by using the Ray test module. In this method we have reduced the cost of up to fifty percent.
The Value of 18F-FDG PET/CT in Detection of Primary Hepatic Carcinoma and in Monitoring Recurrence Combined with AFP
S. Wu, J. Liu, G. Huang
Institute of Clinical Nuclear Medicine, Shanghai Jiaotong University, Shanghai, China
Objective: To compare the value of 18F-FDG PET/CT in detection of primary hepatic carcinoma (PLC) and in monitoring recurrence by combining with alpha-fetoprotein (AFP).
Materials and Methods: 18F-FDG PET/CT images of 63 patients (72 studies)who had been confirmed PLC by histology or clinic were retrospectively analyzed.According to serum AFP, we divided them into two groups, positive and negative group. By the results of histology and follow-up, than the diagnostic values were calculated respectively.
Results: Sensitivity and positive predictive value of PET/CT is 73.24% and 98.11%,vs AFP 73.24% and 100.00% respectively, in detection and monitoring recurrence of PLC. In AFP positive group, sensitivity and positive predictive value for PET were higher than they were in AFP negative group, (80.77%?100.00% vs 52.63%?90.91%, respectively). In addition, 98 metastasis were discovered in 59 cases of total 63 patients.
Conclusion: 18F-FDG PET/CT is a outstanding aid to AFP in detection PLC and in monitoring recurrence of HCC, especially in cases with abnormal serum AFP levels.? PET/CT is a more powerful method in detection the metastasis of PLC than PET or CT respectively. And in tumor staging and predict prognosis, PET/CT appear to be a very useful method.
Simple, Reliable and Cost Effective Radiochemical Purity Test Technique for N-13 Ammonia
D. K. Singh, R. Kumar, A. V. Pandit, M. J. Jacob
Department of Nuclear Medicine, Army Hospital Research and Referral Centre, New Delhi, India
Introduction: A well established method for Nitrogen-13 Cyclotron based production is an O-16 (p, ά) N-13.In which O-16 irradiation reaction is carried out with proton and simultaneously emission of alpha particle and production of Nitrogen-13. Nitrogen -13, ammonia is produced by reduction of nitrogen-13 labeled nitrates and nitrites. Target material for N-13 Ammonia production is sterile water (for injection) mixed with 5 millimolar 200% proof ethyl alcohol.
Materials, Methods, Results: N-13 radioisotope is a very short half-lives carrying radioisotopes having only 9.98 minutes half-life. HPLC based method for radiochemical purity is very time consuming and tedious as well as also required very experienced Radiochemist. Average time required is for HPLC based radiochemical purity is around 50 minutes. We have developed a new technique (with the support of PETNET USA) and incorporated a cartridges based Radiochemical purity (quality control) test for N-13 Ammonia. In this method we are using the Cation exchange cartridge (Water Corporation) and conditioned it with sodium chloride, 0.9% (Saline). Once the N-13 ammonia is produced, a known amount of activity is passed through cartridge and output of cartridges is collected in a waste vial. After that we measured the activity trapped in a cartridge and waste vial. Once we finished the measurement of activity (Dose calibrator based), simply we have calculated the percentage of activity trapped in cartridges out of total activity injected in cartridges. And finally percentage of activity trapped in cartridge is Radiochemical purity and percentage of activity present in waste vial is radiochemical impurity (because Cation cartridge is trapped positive charged carrying N-13 Ammonium Ion) of N-13 Ammonia and we can very easily express the result in a percentage and in that way we are estimating the Radiochemical Purity of N-13 Ammonia very easily.
Conclusion: Cartridges based radiochemical purity method is very simple, cost effective, less time consuming, and also very reliable. We can finish the radiochemical purity test by using cartridges method is within 5 Minutes (in comparison of HPLC based that is very time consuming and costly).
99mTc-doxorubicin Labeling and its Pre-clinical Evaluation as a Potential Scintigraphic Probe for Tumor Imaging
B. Singh, P. Kumar, S. Sharma, B. Mittal
Department of Nuclear Medicine, PGIMER, Chandigarh, India
Background: The currently available radiopharmaceuticals are not specific for tumor imaging.
Purpose: The present study was conducted to radiolabel doxorubicin with 99mTc as a scintigraphic marker of high DNA turnover/intercalation in malignant cells.
Materials and Methods: Doxorubicin was labeled with 99mTc by using direct labeling method. The developed radiotracer was subjected to quality control parameters. The blood kinetics, biodistribution and scintigraphy of tumor bearing mice were studied after intravenous injection of about 7.4 MBq of 99mTc-doxorubicin. The isotime (5-min) anterior images were acquired at different time intervals of 1.5h, 3h and 4h in 256 × 256 matrix.
Results: The labeling efficiency of 99mTc-doxorubicin was estimated to be more than 95%. The protein binding efficiency was greater than 88% and in-vitro stability was up to 24 h. The data of blood kinetics revealed that approximately 0.97% of the radioactivity remained in blood at 24 h. The biodistribution data supports the clearance of the radioligand by dual (renal and hepatic) pathways. A semi-quantitative data analysis of the anterior images indicated that a focal concentration of the radiotracer was seen in the tumor at 1.5-h which either remained consistent or rose in 3-h and 4-h images respectively.
Conclusion: This scintigraphic approach, therefore, could be a powerful tool for cancer detection at early stage. The technique however, needs further validation through animal experimentation and clinical studies.
Engineering Salmonella More Details Typhimurium to Become a Dual Purpose-probe for Therapeutic and in vivo Monitoring Applied in Cancer or Myocardial
V. H. Nguyen, J. Chung, U. Le, Y. Hong, H. E. Choy, H. S. Bom, J. J. Min
Department of Nuclear Medicine, CNU Medical School, Hwasun, South Korea
Along with traditional cancer therapies as chemotherapy and radiotherapy, some of the modern strategies using adenovirus, retrovirus, minicells or bacteria are currently studied intensively with some of its advantages compared with the traditional ones as economic, effective and specific. Among these modern systems, bacterial strategy with over 150 years history using various bacteria strains including anaerobes as well as aerobes is considered as the most promising candidate with completely sequenced genome information, genomic stability, ease of genetically engineering as well as low-cost production. In our study, popup-defected attenuated Salmonella typhimurium, a facultative anaerobe, has been explored to visualize as well as treat solid tumors. To combine bacterial capability of cancer killing with visualization power, we engineered S. typhimurium to express a cytotoxic protein, cytolysis A (ClyA) for tumor cell killing, as well as to express bacterial luciferase (lux) operon for optically in vivo monitoring. In addition, the specific expression of therapeutic gene was secured by using inducible promoter PBAD controlling the cytotoxic protein, ClyA. The results showed the mice treated with transformed Salmonella in the presence of inducer, tumor growth was completed inhibited. On the other hand, interestingly, this ppGpp defective S. typhimurium also shows the potential to accumulate in infarcted site of the myocardial infarction (MI) models while the other bacteria including E. coli or various kinds of mutated Salmonella strains are not. The bacteria labeling with lux gene could be easily detected in the infarction site using cooled-CCD camera after intravenous injection. No sign of serious local or systemic inflammatory reactions was noted following intravenous administration of attenuated Salmonella. These results provided proof of principle that attenuated S. typhimurium has the specific affinity for tumor and could be engineered to become a dual purpose-probe to specifically express and secrete a therapeutic protein in the tumor tissue or MI site as well as to generate light signal for in vivo monitoring using molecular imaging modalities.
Preliminary Results of Various Pegylated i-RGD Peptides for Animal PET-imaging
A. Ahonen 1 , T. Lipponen 1 , L. Nikula, G. Schumacher 2 , T. Nikula 3 , A Roivainen 3
ITG Isotope Technologies Garching GmbH, Garching Germany, 1 HUSLAB, Helsinki, Finland, 2 ITM Isotope Technologies Munich AG, Garching, Germany, 3 PET Center Turku, Department of Clinic, Physiol. and Nuclear Medicine Division of Nuclear Medicine, Helsinki, Finland
Introduction: Many integrin family members are needed to the initiation, progression and metastasis of solid tumors. Therefore the integrins have been proposed as the molecular targets for the treatment of cancer, thrombosis and other diseases in last years. Several radiolabelled RGD-peptide derivatives are proposed for tumor imaging. Especially, integrin alpha v beta 3 is studied extensively for its role in the tumor growth and angiogenesis. Ga-68 labeled arginine-glycine-aspartate (RGD) peptides allow PET quantization of integrin alpha v beta 3 expression in vivo. Recently, new RGD peptide i-RGD has been developed. 1 After binding alpha v, beta 3 -integrin part of the peptide is cleaved and it gets high affinity to neuropilin-1 receptor and is then internalized. Five modified DOTA- i-RGD derivatives have been synthesized (Iris Pharmaceuticals) and labeled with lutetium-177 and gallium-68.
Materials and Methods: Five different S-S cyclised i-RGD peptides (CRGDKGPDC) were synthesized, where DOTA group was added to C-1 amino acid either directly or over PEG-group (200 or 5000 D). On two peptides PEG-groups were added C-9 amino acid [Table 1]. Peptides were labeled with gallium-68, which was obtained directly from the 68Ge/68Ga-generator. Labeling kinetic, radiolysis and stability were studied. One rat with cardiac insufficiency model was imaged using animal PET device. Two mice with melanoma and one mouse with prostata xenografts were imaged using HRRT PET/CT device. Ga-68 pegylated iRGD compound was injected into animals and fool-lowed distribution of tracer up to 30-90 min. One mouse with melanoma was co-injected cold iRGD.
Results: After injection of Ga-68 iRGD compounds no focal activity uptake into mouse xeno-grafts were obtained. Radiotracers were rapidly excreted via kidneys into bladder. Also rat with cardiac insufficiency model did not reveal any focal uptake in the cardiac region. Kinetics was very fast and pegylation didn't slow down kinetics as predicted.
Conclusions: Pegylated iRGD compounds used in this work are not suitable for tumour or cardiac in-sufficiency model.
- Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, et al. Cancer Cell 2009;8:510-20.
Medical Cyclotron: Accidental Scenarios and Analysis
T. C. Nguyen, T. K. M. Dang, V. N. Dinh
Cho Ray Hospital, HCMC, South Vietnam
In December 2008, the first medical cyclotron and PET/CT imaging scanner was commissioned in HCMC, South Vietnam. Among the other modern facilities that existed such as CT scanner, MRI, DSA, SPECT and SPECT/CT, so on. Now, with PET-CT imaging scanner, our hospital has more useful tools in disease diagnosis and treatment to enhance health care for patients. The medical Cyclotron is a self-shielded cyclotron, capable of producing four kinds of PET radionuclide 18F-, 18F2, 13N-NH 3 and 11C-CO 2 . It uses negative ion technology to accelerate the proton beam to 11 MeV, with the compact design and capability of running in single beam or dual beam mode (depending on the number of activity required of the facility). Since the day of initial operation, there weren't many troubles for the cyclotron. Most of the time the cyclotron was working properly, just a few minor problems had occurred such as the ion gauge filament broken, water leakage, lost connection, etc. However, for three years working with the cyclotron, I have collected some experience and have designed some accidental scenarios. It is completely possible to happen in practice if we don't pay proper attention to the following. The accidental scenarios are:
Scenarios 1: Over current on Target in manual control mode
Scenarios 2: Making beam without material in the Target
Scenarios 3: Impurity Enriched Water
Conclusion: With modern technology integrated into manufacturing cyclotron design and its control software. Built-in, user-friendly graphic interface and automated workflow prevent harmful problems whilst operating cyclotron. However, the accidents would still happen if the cyclotron operation engineer didn't properly pay attention or neglect of protocol. From the analysis of the several foreseen accidental scenarios as described we hope the real accidents won't ever have to occur at your institute.
To Establish A Synthesis Protocol of 68Gallium-DOTANOC Using 0.05 MHCl as Eluant of 68Ge/68Ga Generator for PET Imaging of Neuroendocrine Tumors
S. Lata, P. Kundu, C. S. Bal, A. Malhotra
Department of Nuclear Medicine and PET, All India Institute of Medical Sciences, New Delhi, India
Introduction: The somatostatin analogue NOC has high affinity for somatostatin receptor subtypes (sstr) 2, 3, and 5. These sstr 2,3,5 have been shown to be over expressed in neuroendocrine tumors (NETs). DOTA-NOC is a conjugate of (1,4,7,10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid)-1-Nal3-Octreotide (DOTA NOC). 68Gallium (half life - 68 minutes) is a 68Germanium /68Gallium generator (half-life - 271days) produced and an excellent positron emitter with 89% positron branching accompanied by low photon emission (1.077 KeV, 3.22%).
Aim: To standardize the synthesis protocol of radiolabel ling DOTANOC with radiogallium (68Ga) eluted from 68Ge/68Ga generator (iTG) using 0.05M hydrochloric acid.
Materials and Methods: 68Ge/68Ga generator (30mCi-50mCi) iTG, isotope Technologies Germany, PC- controlled synthesis device Modular - Lab, Eckert and Ziegler Eurotope, Berlin, Germany, TLC Scanner, Silica Gel TLC plates, Strata-X-C, Phenomenex, tC-18 cartridge, DOTANOC from ABX, extra pure acetone, ethanol and hydrochloric acid, metal free water etc. All the chemicals were of extra pure quality and minimum metal content. Generator was eluted with 6-7 ml of 0.05M HCl and eluant was loaded onto a cation exchanger (Strata-X-C, Phenomenex) cartridge to preconcentrate and to remove the impurities from the eluate i.e. 68Ga. A solution containing 97.7%acetone/0.05MHCl was passed through the cartridge to elute the concentrated and purified 68Ga directly into the reaction vial containing 30-50μg of DOTANOC. Synthesis was carried out for 8 minutes at 90-95°C followed by purification of labeled peptide on tC-18 reverse phase column. Preparation was passed through 0.22μm filter, which has low protein binding property, and diluted with 8 ml normal saline. All the synthesis steps were controlled automatically. Procedure was over within 17-18 minutes. Quality control parameters like clarity, pH, radiochemical purity, endotoxin test were performed before releasing the product for clinical application.
Results: 68Ga-DOTANOC preparation was a clear, transparent with pH-6.5-7.0. Labelled NOC remained at origin (Rf - 0.0) on TLC plates. Radiochemical Purity was found to be >99% and 60-65% yield. Endotoxin test was negative.
Conclusion: 68Ga-DOTANOC can be synthesized using 0.05M HCl as an eluant of 68Ge/68Ga generator (iTG) for PET imaging of neuroendocrine tumors. Moreover, it is more specific as it binds directly to the receptors expressed in tumors.
Producing Radiopharmaceuticals FDG F-18 and Acetate C-11 Using Cyclotron 11 MeV in Cho Ray Hospital
T. K. M. Dang, V. N. Dinh, T. C. Nguyen
PET-CT and Cyclotron, Cho Ray Hospital, HCMC Vietnam
Cyclotron RDS (Radioisotope Delivery System) Eclipse HP was installed in Cho Ray Hospital in March 2009. Cyclotron-based system is designed to produce positron-emitting radionuclides. With single or optional dual beam capability, the cyclotron can be used in conjunction with optional chemistry modules to produce the radioactively labeled compound needed in a positron-imaging center. This cyclotron uses proton with energy of 11 MeV to produce the radionuclide Fluoride F-18 and Carbon C-11. This paper shows a short overview of the cyclotron RDS Eclipse and brief summary of the running Cyclotron to produce F-18 and C-11 in three years. In addition, the radiation safety aspect is also mentioned here to avoid the radiation contamination for operators.
Radionuclide Imaging for Neuroendocrine Tumors: Experience of Singapore General Hospital, the Largest Acute Tertiary Hospital in Singapore
S. P. Thang, W. Xie, A. K. Padhy
Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore
Neuroendocrine tumor is defined as a heterogeneous group of neoplasm characterized by their endocrine metabolism and histological pattern, originating mainly from the gastroentero-pancreatic tract. It is a rare tumor affecting less than 5 in 100 000 person per year in Singapore. In the early years of neuroendocrine tumor imaging, Singapore General Hospital (SGH) had performed 59 Indium-111 Octreotide scan from 1997 to 2009. This service had now ceased and since 17 March 2009, SGH has started 68Ga-DOTATATE PET/CT scan and more recently (since 18 October 2010), 68Ga-DOTANOC PET/CT scan for the imaging of neuroendocrine tumors. SGH has performed 110 68Ga-DOTATATE PET/CT scans for 87 patients and 11 68Ga-DOTANOC PET/CT scans for 11 patients up to April 2011. The main indications for scanning are for diagnosis, for staging of the disease and to assess treatment response. The main site of involvement among the patients scanned with 68Ga-DOTATATE PET/CT is the pancreas, followed by the lungs and bowels. For those who underwent 68Ga-DOTANOC PET/CT imaging, the most common site of involvement is again the pancreas, followed by duodenum and stomach. As a result of the increasing use of radionuclide imaging for neuroendocrine tumors, SGH has obtained funding to build a clinical service of peptide receptor radionuclide therapy to treat patients with somatostatin receptor positive tumors in this region.
Cyclotron Production of 99mTc in Canada
A. Zyuzin, E. J. van Lier, K. Gagnon 1 , D. Abrams 1 , J. Wilson 1 , S. McQuarrie 1 , R. Lecomte 2 , J. E. van Lier 2 , B. Guérin 2
Advanced Cyclotron Systems Inc., Vancouver, BC, 1 University of Alberta, Edmonton, AB, 2 Université de Sherbrooke, Sherbrooke, QC, Canada
Objective: In an effort to find a reliable and sustainable solution to the recent ongoing world-wide shortages of 99mTc produced from nuclear reactors Canadian government has committed $35 million over two years to invest in research, development and demonstration (RD&D) of non-reactor-based technologies for the production of 99mTc (Non-reactor-based Isotope Supply Program, NISP). A collaborative multi-institutional initiative - including Advanced Cyclotron Systems (ACSI), University of Alberta and University of Sherbrooke - has been established to evaluate the commercial viability of routine, large scale cyclotron production of 99mTc via the 100Mo(p, 2n) 99mTc reaction using high power, 24 MeV cyclotrons. Over 30 mln dollars, including 11 mln. from NISP program, were allocated from different federal and provincial sources, to establish two pilot cyclotron facilities, at the Centre Hospitalier Universitaire de Sherbrooke (CHUS) and Edmonton Radiopharmaceutical Center, which will demonstrate the technological, regulatory and commercial foundation for high-level cyclotron-based 99mTc production technology that, between 2012 and 2014, would become a viable alternative source of 99mTc. Two more production sites, Thunder Bay Regional Research Institute and University of Saskatchewan, will joint cyclotron network for 99mTc production in 2012-2013 over. With cyclotron and facility construction underway researcher from different labs are currently focusing on development of high power cyclotron targetry, separation techniques and addressing regulatory requirements for Health Canada approval of cyclotron produced 99mTc for clinical use.
Results: All experiments to date employed the variable energy TR-19 cyclotron (ACSI). Targets were prepared by melting, pressing or sintering of metallic natural molybdenum and 100Mo powder into a target substrate. Efficient separation of 99mTc from irradiated 100Mo has been developed. Cyclotron produced 99mTc was formulated in several commonly used imaging agents using standard labelling kits. The measured excitation functions for the 100Mo(p,2n)99mTc reaction and thick target yields were in agreement with recently reported data. ICP-MS analysis of decayed cyclotron-produced pertechnetate (6-h bombardment, 16.4 MeV) gave 19% 99mTc/totalTc EOB, corresponding to the specific activity of a 36-h old generator. Multi-Curie amounts of 99mTc were produced using pressed and sintered Mo-100 targets. 99mTc was efficiently recovered from irradiated targets using aqueous biphasic extraction chromatographic (ABEC) materials and formulated in various 99mTc radiopharmaceuticals. Comparison of cyclotron vs. generator produced 99mTc-radiopharmaceuticals in healthy rats gave identical scintigraphic images. ACSI has successfully factory tested new generation of high current, >500 μA, 24 MeV cyclotron, TR-24. Four TR-24 cyclotrons will be delivered to customers by the end of 2011. First TR-24 in Russia will be installed in Moscow Federal BioMedical Center of FMBA.
Conclusion: Initial results of our quality control tests and in vivo experiments support the concept that cyclotron-produced 99mTc is suitable for preparation of 99mTc radiopharmaceuticals. Extrapolating production yield to 24 MeV suggests that up to 2.75 TBq of 99mTc can be produced in two 6-hour bombardments with 500 μA proton beam. This amount would suffice to prepare up to 800 patient doses of 99mTc-radiopharmaceuticals, fulfilling the daily 99mTc requirements for a large metropolitan area.
Diagnosis of Pulmonary Neuroendocrine Tumors with 99mTc-Tectrotide (99mTc-HYNIC -TOC) SPECT/CT and 18F-FDG PET-CT in the Selection of the First Line of Treatment and Determining Staging and Restaging
N. Szalus, Z. Podgajny, G. Kaminski, M. Dziuk
Department of Nuclear Medicine, Endocrinology and Radioisotope Therapy, Military Institute of Medicine, Warsaw, Poland
Introduction: Neuroendocrine lung carcinomas (NLC) accounting for 20 - 25% of all lung cancers. There are four main types of neuroendocrine lung tumors: Small-cell lung cancer (SCLC). SCLC represents one of the most rapidly growing types of cancer and accounting for 15-20% of all NLC. Large-cell neuroendocrine carcinoma a rare form of cancer, similar to SCLC in prognosis and treatment, except that the cancer cells are unusually large. The other is a typical and atypical Carcinoid. NLC constitute a major diagnostic and therapeutic problem. Proper diagnosis mainly radionuclide enables accurate assessment of the nature of lesions and thus the optimal treatment for the patient.
Aim: Assessment of usefulness of the combined study using somatostatin analog - 99mTc-Tectreotide (99mTc-HYNIC-TOC) SPECT / CT and 18F-FDG PET-CT in the selection of the first line of treatment (like - "cold", "hot" somatostatin analogs or/and chemotherapy) as well as identify staging and restaging of diseases.
Materials and Methods: Seven patients with NET of the lungs histopathological confirmed were included to the study: 2 pts with large-cell neuroendocrine carcinoma, 1 pts with SCLC, 2 pts with typical Carcinoid and 2 patients with atypical Carcinoid. 99mTc-HYNIC-TOC SPECT/CT and 18F-FDG PET-CT studies were performed in all patients. Interval time between these two studies was 2 - 4 weeks. The conventional scintigraphy was acquired on the hybrid gamma camera SPECT/CT in 2-4 h after intravenous injection of 99mTc-HYNIC-TOC. The injected activity was 550-740 MBq (15-20mCi). The following views were gathered: planar AP, PA and SPECT/CT of the chest and abdomen. PET-CT scans were acquired 45 - 60 min post injection of 120 - 200 MBq (3,5 - 5,5 mCi) of 18F-FDG PET-CT (routinely with 16-row CT). Data acquisition was performed by means of a dedicated PET scanner with15-cm axial field of view (FOV) and 55-cm transaxial FOV. Patients were imaged in 2-dimensional mode using septa. The duration of acquisition was 3 - 4 min per bed position (axial FOV) in emission mode.
Results: In 3 cases (patient with typical Carcinoid and 2 patients with atypical Carcinoid) were seen high uptake of 99mTc-Tectreotide and 18F-FDG - patients were treated by Sandostatin LAR, 177Lu-DOTA-TATE and chemotherapy. In 1 patient with typical Carcinoid high uptake of 99mTc-Tectreotide was seen without 18F-FDG - patients were treated by Sandostatin LAR and 177Lu-DOTA-TATE without chemotherapy. In 3 cases (2 patients with large-cell neuroendocrine carcinomas, 1 patient with small cell carcinoma) moderate uptake of 18F-FDG were seen without uptake of 99mTc-Tectreotide - these patients were treated only by chemotherapy.
Conclusions: The combined study using 99mTc-Tectreotide SPECT/CT and 18F-FDG PET-CT allows early selection of appropriate treatment, as well as the accurate assessment of restaging and staging of lung neuroendocrine tumors.
Peptide Receptor Radionuclide Therapy: Colombian Experience - A Collection of Data from Four Centers in Colombia [Fundacion Santa Fe de Bogota (Bogota), Fundacion Cardioinfantil (Bogota), National Cancer Institute (INC) and Fundacion Valle de Lili (Cali)]
Consultant - Nuclear Medicine and PET, Fundacion Santa Fe de Bogota, Bogota, Colombia
Inclusion Criteria: 99mTc-Octreoscan, which confirms that the primary tumor and metastases express somatostatin receptor positive, Life expectancy greater than 12 months; Hb: ≥ 8, Leukocytes: ≥ 2000, Platelets ≥ 75,000, Creatinine ≤ 1.7; creatinine clearance ≥ 50 ml / min., Bilirubin <3; AST, ALT, FA.DHL; Karnovsky > 50%177Lu-DOTATATE: Protocol: SSN hydration prior and post-therapy, Antiemetic (ondansetron 8 mg IV). l-Lysine + Argenine (1000 cc) starting 30 min before to apply DOTATE 177Lu and continued until 4 hours later. DOTATATE 177Lu. IV for 60 minutes. Images post therapy
Materials and Methods: 29 patients were included. 19 patients received 3-4 doses (150-200mCi)
10 patients received 1-2 doses. 22 patients had minor complications: Headache (1) 3.8%, Nausea (6) 23%; Thrombocytopenia (3) 11.5%; pain (1) 3.8%; Hair Loss (5) 19%; Diarrhea (a) 3.8%; Abdominal pain (6) 23%; Decreased renal function (3) 11.5%
Follow up: Monitoring of patients was between 2 and 28 months (mean 10 months). Till date, the patient status are: Stable 14 (48%), Dead 5 (18%), Reduction of lesions 5 (17%), Progression 4 (13%), Operable 1 (3%).
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