|Year : 2010 | Volume
| Issue : 3 | Page : 117-120
|Date of Web Publication||25-Nov-2010|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Therapy. Indian J Nucl Med 2010;25:117-20
THER 01 (POSTER)
DO3P-AME-DO3P: Therapeutic agent for bone palliation using Sm3+, Lu3+ and Ho3+ metal ions
Tanwar Jyoti 1 , Pal Sunil, Datta Anupama, Tiwari Anjani Kumar, Thirumal Meganathan 1 , Mishra Chuttani Krishna, Anil Kumar
Division of Cyclotron and Radiopharmaceuticals Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, Delhi-110054, 1 Department of Chemistry, University of Delhi, Delhi-110007, India
Purpose: A bone seeking radiopharmaceutical having application in diagnosis and therapy serves dual role in the diagnostic imaging of bone lesions before therapy thus providing information about the extent of damage and radiation doses to be delivered during therapy. This study investigates the synthesis, bone binding affinity, specificity towards osteoclast cells, of a phosphonate derivative, DO3P-AME-DO3P. Coordination behaviour of the compound with three lanthanide ions of therapeutic value viz. Sm(III), Lu(III), and Ho(III) have been explored. Materials and Methods: Phosphonate derivative, DO3P-AME-DO3P was synthesized and the two cavities present in the macrocycle are utilized for binding with different metal ions of diagnostic and therapeutic value. The binding affinity of 99mTc-DO3P-AME-DO3P towards bone minerals were tested in-vitro by using hydroxy apatite as a bone model. The protonation and stability constants were determined by pH-potentiometry titrations. Results: Phosphonate derivative, DO3P-AME-DO3P was synthesized with 90% yield in high purity. It was labeled with 99mTc and exhibited preferential affinity of the compound towards osteoclast (167.95±3.56% dose/mg protein). The stability constants of DO3P-AME-DO3P with Lu(III), Sm(III), and Ho(III) were 19.7, 21.8, and 20.2. The protonation constant were in the range of 12.8-5.07. Conclusion: Synthesis of the phosphonate derivative, DO3P-AME-DO3P, was straight with high yield. 99mTc-DO3P-AME-DO3P showed significantly high uptake in bone specially in osteoclasts compared to the undifferentiated adherent bone marrow derived cells and osteoblast justifies the apparent efficacy of the complex in diagnosis and therapy. Long residence, high uptake in bone after 24 h and high stability constant with Sm(III), Ho(III) and Lu(III) suggests application of DO3P-AME-DO3P in the therapy of bone metastases.
Keywords: Radioiodine therapy, low dose radioiodine, high dose radioiodine, antithyroid drugs, goitre
THER 02 (ORAL)
Preparation and evaluation of 90Y rituximab for its potential as a radioimmunotherapeutic agent for non Hodgkin's lymphoma
Kameswaran Mythili, Pandey Usha, Samuel G, Sarma HD 1 , Venkatesh M
Radiopharmaceuticals Division, 1 Radiation Biology and Health Safety Division, Bhabha Atomic Research Centre, Mumbai, India
Introduction: Radioimmunotherapy (RIT) is an attractive alternative to chemotherapy or radiotherapy in the treatment of B cell lymphoma. Most B-cell lymphomas express CD20, making it a suitable target antigen for therapeutic radioactive monoclonal antibodies. RIT with anti CD20 monoclonal antibody (MoAb) conjugated to a β- emitting radioisotope will deliver radiation to the tumor cells. Rituximab (anti CD20 MoAb), being a human murine chimeric antibody would obviate induction of HAMA response and would allow repeat administration of antibody for treatment. Materials and Methods: The conjugation of Rituximab with DOTA was carried out at various molar ratios of Ab: DOTA and radiolabeled with 90Y to an extent of 85%. Purification of 90Y-DOTA-Ab was carried out using PD-10 column. The 90Y-DOTA-anti CD20 conjugate was characterized by HPLC on a TSK GEL column. In vitro cell binding and inhibition studies of the 90Y labeled complex was carried out using Burkitt's lymphoma cell lines viz. Raji cells which express CD20 antigen on their surface. Results: The radiochemical purity of the labeled antibody was >98%. HPLC patterns after purification have shown single radiolabeled antibody peak with retention time of ~13m while free 90Y+3 had a retention time of 20 minutes. The radiolabeled antibody conjugate was stable up to ~120 h at room temperature. In vitro cell binding studies showed 25% binding with 106 cells which was inhibited to ~11% with the addition to 10΅g of cold antibody. Biodistribution studies in normal Swiss mice with ~1850 kBq of labeled complex at different time intervals showed hepatobilliary clearance. Conclusion: A favorable uptake by the cells and inhibition by the cold antibody indicates that 90Y-DOTA- anti CD20 antibody (Rituximab) could be a promising molecule in the treatment of Non Hodgkin\'s Lymphoma Acknowledgement: The authors are grateful to Dr PS Dhami and his associates, FRD, BARC for providing 90Y for this study.
Keywords: Radioimmunotherapy, rituximab, non Hodgkin's lymphoma
THER 03 (ORAL)
Anatomical barriers to treatment of malignant liver lesions with yttrium-90 microspheres
Rathore B, Novotny J, Holdeman K, Zahiri, Paknikar S, Hankins J
University of Nebraska Medical Center, Omaha, Nebraska, USA
Selective internal radiation therapy (SIRT) with Yttrium - 90 microspheres is a powerful emerging tool to achieve regional tumor response and disease control in hepatic malignancy of various origins such as metastases from colorectal cancer, pancreatic cancer, breast cancer, melanoma along with primary tumors of the liver like HCC and cholangiocarcinoma. Some of the tumors refractory to other treatment modalities respond to this potent therapeutic modality due to achievement of high doses of radiation locally which is not possible by external beam radiation. There are various prerequisites that are to be fulfilled prior to treatment with Y-90 microspheres, to name a few: patient not being an ideal candidate for surgery or chemotherapy, bilirubin levels below 2mg/dl, albumin level more than 3mg/dl, life expectancy of patient more than 3 months and lung shunt fraction less than 20% on Tc 99m MAA scintigraphy. Abnormal anatomy can be a very challenging barrier to treatment with Y-90 microspheres but there can be other barriers too for treatment with SIRT as discussed below. Retrospective review of medical records and relevant images of patients who underwent hepatic arteriogram with selective visceral catheterization and therapy simulation with Tc-99m macroaggregated albumin (Tc-99m MAA) from January/1 st /2009 to July/31 st /2010. These accounted to be total 17 patients. The patients had undergone a non- contrast CT scan and MRI abdomen prior to Tc-99m MAA scintigraphy for accurate evaluation of the liver and lung borders along with assessment of other relevant anatomy. This helped in drawing accurate ROIs (Regions of interest) over the lung and the liver. Accurate extent and position of liver lesions as depicted on Non-Contrast CT and MRI was very helpful in guiding position of catheter during treatment with microspheres. Along with the planar images during Tc-99m MAA scan patients also underwent axial SPECT- CT images which were reconstructed in coronal and sagittal plane as well. SPECT-CT images accurately localized the abnormal radioactivity demonstrated on planar images thereby leading to adequate treatment plan. 4/17 patients did not receive treatment with Y-90 microspheres following scintigraphy with Tc-99m MAA due to the following reasons: (a) 43 year old male with metastatic colon carcinoma demonstrated abnormal radioactivity in gastric antrum on Tc-99m MAA scan due to abnormal vascular anatomy confirmed on visceral arteriogram. (b) 69 year old male with HCC (Hepatocellular carcinoma) demonstrated abnormal radioactivity in anterior mid abdominal wall which was due to recanalized umbilical vein and confirmed on CT Scan. (c) 67 year old male with metastatic cholangiocarcinoma although was an ideal candidate for SIRT per Tc-99m MAA scintigraphy had other ongoing more pressing medical issues like chest pain, CAD on cardiac cath, uncontrolled atrial fibrillation and altered mental status which prevented him from receiving treatment with Y-90 microspheres. (d) 75 year old male with history of metastatic malignant melanoma although an ideal candidate for treatment with Y-90 microspheres on Tc-99mMAA scan did not receive SIRT. The cause of him being untreated is unknown by review of medical records and relevant images. A further discussion will be done with the clinicians taking care of the patient to evaluate the reason for him being untreated and discussed in the scientific meeting. It is concluded that a careful patient selection, meticulous pre-treatment assessment and coiling of the relevant abnormal vasculature (the coil eventually degrades) makes it possible for the interventional radiologist to treat the liver lesions with microspheres in spite of abnormal vasculature and thereby lead to treatment optimization even in borderline treatment candidates with abnormal vasculature. 1) Careful patient selection, meticulous pre-treatment assessment and coiling of the relevant abnormal vasculature (the coil eventually degrades) makes it possible for the interventional radiologist to treat the liver lesions with microspheres in spite of abnormal vasculature and thereby lead to treatment optimization even in borderline treatment candidates with abnormal vasculature. 2) The interdisciplinary aspect of the patient management for treatment with Y-90 microspheres is the key point of overall patient management and it must be emphasized repeatedly.
Keywords: Radioembolization, liver tumors, Y-90 Therasphere
THER 04 (ORAL)
Is 177 Lu-DOTMP a better alternative to 177 Lu-EDTMP for palliative radiotherapy of skeletal metastasis? A systematic investigation
Chakraboty Sudipta 1 , Das Tapas 1 , Sarma HD 2 , Venkatesh Meera 1 , Banerjee Sharmila 1
1 Radiopharmaceuticals Division, 2 Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai - 400 085, India
Aim: 177 Lu is presently being considered as an excellent radionuclide for developing bone pain palliation agents owing to its suitable nuclear decay characteristics [T 1/2 = 6.73 d, Eb(max) = 497 keV, Eg =113 keV (6.4%) and 208 keV (11%)] and large scale production feasibility with adequate specific activity using moderate flux research reactors. Among the multidentate polyaminophosphonic acids proven to be desirable carrier molecules in designing agents for palliative radiotherapy of bone pain, ethylenediaminetetramethylene phosphonic acid (EDTMP) is one of the most widely used ligands and is presently being used as 153 Sm-EDTMP (Quadramet; ). The macrocyclic analog of EDTMP, viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) could be chosen as yet another efficacious ligand. This is based on the well-documented phenomenon that macrocyclic chelators form complexes with enhanced stability and kinetic inertness with lanthanides compared to their acyclic analogs. The present paper describes a comparison between 177 Lu complexes of two potential polyaminophosphonic acid ligands namely, EDTMP and DOTMP with respect to their radiochemical and in-vivo biological characteristics. Materials and Methods: 177 Lu was produced by irradiation of natural (2.6% 176 Lu) Lu 2 O 3 target in DHRUVA reactor for 21 d at a thermal neutron flux of 6Χ10 13 n/cm 2 .s. 177 Lu-EDTMP and 177 Lu-DOTMP complexes were prepared at room temperature by incubating the ligands with 177 LuCl 3 in NaHCO 3 buffer at pH ~7. Comparative in vitro stability of the complexes were ascertained in saline (pH ~7), 0.1 M HCl solution as well as in human serum. Comparative biological evaluation of 177 Lu-phosphonate complexes were carried out by biodistribution and scintigraphic imaging studies in Wistar rats as well as by imaging studies in New Zealand white rabbits. Results: 177 Lu was produced with a specific activity of ~12 GBq/mg and radionuclidic purity of 99.98%. Both the 177 Lu-phosphonate complexes were obtained in near-quantitative yields (98.5±0.3% for 177 Lu-EDTMP and 99.1±0.2% for 177 Lu-DOTMP) under optimized reaction conditions (ligand:metal ratio of 10:1). 177 Lu-DOTMP complex could be prepared with very high complexation yield (98.2±0.3%) even when a ligand:metal ratio as low as 2:1 was used. Both the phosphonate complexes showed excellent stabilities at room temperature as both retained >97% radiochemical purity in saline upto 30 d post-preparation in saline. However, when the complexes were stored in 0.1 M HCl medium to assess their stabilities in presence of a large excess of H + , it was found that 177 Lu-DOTMP complex underwent decomposition to a lesser extent compared to 177 Lu-EDTMP indicating superior kinetic inertness of 177 Lu-DOTMP over 177 Lu-EDTMP. Biodistribution studies in Wistar rats showed favorable and comparable features such as, rapid and selective skeletal uptake, fast clearance from blood and almost no uptake in any of the major organs/tissue for both the complexes. 177 Lu-EDTMP showed slightly higher skeletal uptake compared to 177 Lu-DOTMP (46.25±3.48 and 40.23±8.45% injected activity in skeleton at 24 h p.i., respectively) and marginally higher retention in liver and kidneys. Scintigraphic studies carried out in normal Wistar rats and New Zealand white rabbits also demonstrated favorable characteristics similar to those observed in biodistribution studies. Conclusion: The present studies indicate that both 177 Lu-EDTMP and 177 Lu-DOTMP have promising features and could be taken up for further detailed investigations. Though both the agents exhibited almost similar characteristics, the comparative efficacy of the agents in providing the palliative care could only be conclusively decided after extensive human clinical studies.
Keywords: Lu177 EDTMP, Lu 177 TOTMP, Comparative analysis
THER 05 (ORAL)
Development and characterization of 99mTc: Antitumor peptide for tumor scintigraphy
Singh T, Kumar N, Mittal G, Nishad DK, Swaroop K, Seenayya G 1 , Bhatnagar A
Institute of Nuclear Medicine and Allied Sciences (DRDO), Brig. S.K. Mazumdar Road, Timarpur, Delhi-54, 1 Issar Pharmaceuticals, Hyderabad, AP, India
INM-ISPep is a novel cell-penetrating anticancer peptide consists of 23 amino acids in a single chain. It is an anti-tumor regression peptide under development as a lead compound for solid tumor treatment. In the present study we have analyzed the antitumor activity and cancer cell-killing mechanism of this peptide. The peptide showed selective cytotoxicity against cancer cell lines (EAT and BMW) by specifically targeting cancer cells through interaction with cell membrane. It traversed cancer cell membranes without damaging them and accumulates primarily in the nuclei. Once INM-ISPep enters inside cells, it induced mitochondria-dependent apoptosis. In vivo analysis revealed that INM-ISPep possesses significant tumor suppression activity as studied in mice with tumor xenograft. Our findings suggest that INM-ISPep is a novel therapeutic agent for the treatment of variety of cancers. In the present study, we have successfully radiolabeled peptide with 99m-pertechnetate using 2 ME method. The labeling efficiency was consistently more than 95% as ascertained by ITLC-SG chromatography with 100% acetone as mobile phase. 99mTc labeled peptide was found to be fairly stable in vitro as well as in vivo and the stability in the serum indicated the 99mTc labeled peptide remain bound to the chelate up to 24 hrs. Blood clearance of peptide in new zealand white rabbits shows biphasic clearance of INM-ISPep with T1/2 fast = 8.0055 min (time scale -0-15 min) while T1/2 slow = 892.32 min = 14.87 hr (time scale 15-24 hr), which indicate high binding of INM-ISPep with serum protein. Biodistribution studies were performed in EAT bearing bulb-c mice at 0.25, 1, 2, 4, and 24 hrs, that showed a significant accumulation at tumor site. Scintigraphic studies further validated the efficacy of the 99mTc labeled peptide as a potential anticancer agent.
Keywords: INM-ISPep, 99mTc-pertechnetate, anticancer, gamma scintigraphy, biodistribution
THER 06 (ORAL)
Thermoresponsive polymer for localized radiotherapy
Karir T, Samuel G, Padmanabhan D, Sarma HD 1 , Hassan PA 2 , Meera V
Board of Radiation and Isotope Technology, BARC Vashi complex, DAE, Navi Mumbai 400705, 1 Radiation Biology Division, BARC, Mumbai 400 085, 3 Chemistry Division, BARC, Mumbai 400 085, India
We describe a thermoresponsive polymeric drug delivery system based on poly (N-isopropylacrylamide) (PNIPAAm) with isotopically labellable end group, L-tyrosinamide (for 125I and 131I) which is designed for local radiotherapy. The polymer thus prepared was found to be readily soluble in isotonic aqueous solution at room temperature (25C) so that it can be used as an injectable and the phase separation was found to be complete at body temperature (37C) where it can form a depot at the injection site and exert the property of radiotherapy. The most important parameter for its potential use as a loco-regional radiopharmaceutical was evident from Differential Scanning Calorimetric (DSC) and Dynamic Light Scattering (DLS) studies which showed the polymer completed its phase transition at body temperature. PNIPAAm-L-tyrosinamide was then radiolabelled with Na125I by Chloramine-T method and purified by gel chromatography to give >90% radiochemical purity and the specific activity as ~3-3.5 MBq/΅g. The solution of PNIPAAm-125I-tyrosinamide (185kBq/50μl/mice) was injected intratumorally in Swiss mice bearing fibrosarcoma tumor. Biodistribution was carried out for 2h, 1d, 3d and 5d post injection. Another set of mice injected with Na125I intratumorally were treated as controls and studied for biodistribution. The labeled polymer was retained at the tumor site (75% of the injected dose/g of the tumor weight, 2 h post injections) decreasing to 16% at 24h post injection. At 3 days post injection, the retention of radioactivity by the tumor was found to be 3.2% of the injected dose/g of the tumor. No organ specific accumulation of the radioactivity other than the tumor site, including that of thyroid, was observed. Majority of the released radioactivity was excreted via urine and faeces. The preliminary study suggests that the prepared thermoresponsive polymer, could have potential for localized radiotherapy when radiolabeled with Na131I which would be our future scope of studies.
Keywords: Thermoresponsive, local radiotherapy, L-tyrosinamide
THER 07 (POSTER)
Radionuclide re-therapy is a practical option in bone pain palliation therapy
Ora M, Jain S, Madhusudhanan P, Barai S, Pradhan PK, Arya A, Tiwari DK, Gambhir S
Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (U.P.), India
After giving first dose of radionuclide pain palliation therapy in 20 patients, re-therapy was considered again in these patients. 2 nd therapy was done in 20 patients followed by 3 rd therapy in 11 of them which was subsequently followed by 4 th therapy in 4 patients (total 35 re-therapy doses). Phosphorus -32 was used in a mean dose 6.15 mCi (4.5-7 mCi) in 15 pts. and Samarium -153, 60 mCi (45-95 mCi) in 20 therapies. Strict follow up data was available in all patients. Mean follow up duration was 13.75 months (6 month - 20 months). Re-therapy was done after an interval of 4.7 months on an average. Pre-treatment pain score and narcotic score were 6.8 and 3.5. Average Hemoglobin, white blood cell and platelet count was 11.2, 8,600 and 1, 89,000 respectively. After administration of radionuclide therapy there was a predictive but fully recovered fall in platelet counts only. It decreased to a mean 1,63,000 at around 4-5 weeks. Post-treatment pain score and narcotic score were 4.1 and 2.5 (P<0.005 as compared with pretreatment level). No serious toxicity was noted in any patient. Radionuclide pain palliation remains a very safe and effective option. Retherapy can be done very easily will equally good effects. No hematological toxicity was seen in any of the patient.
Keywords: Re-therapy, radionuclide therapy, bone pain, palliation.
THER 08 (POSTER)
Experience of bone pain palliation therapy at SGPGIMS, Lucknow (Uttar Pradesh)
Ora M, Madhusudhanan P, Jain S, Arya A, Barai S, Pradhan PK, Gambhir S
Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (U.P.), India
Radionuclide pain palliation therapy was done in 156 patients (1995-2007). Total 176 therapy were done. Mean age at the time of presentation was 56 yrs (13-81) with 114 patients were male. Most common referral diagnosis was Carcinoma prostate (86 patients) followed by Breast (38), lung (6) and other malignancies. Earlier oral Phosphorus -32 was used in a mean dose 3.15 mCi (2.5-4 mCi) in 20 patients, intravenous Phosphorus-32 6.7 mCi (4.5-7 mCi) in 138 pts and Samarium -153 52.8 mCi (45-95 mCi) in 14 patients. Most of the patients were referred at very advanced stage so follow up rate was low 25~30% (40 patients only). Mean follow up duration was 3.75 months. Out of 40 patient significant pain relief was noted in 33 patients while no change was noted in 7 patients. Pre-treatment pain score and narcotic score were 7.6 and 4.5. Average hemoglobin, white blood cell and platelet count was 10.8, 7,800 and 2, 05,000 respectively. After administration of radionuclide therapy there was a predictive fall in platelet count only.It decreased to 143000 at around 4-5 weeks. Post-treatment pain score and narcotic score were 5 and 3.5 (P<0.005 as compared with pretreatment level). No serious toxicity was noted in any patient. Despite of most of the patient being in very advance stage of cancer significant relief was noted in 83% patients. Radionuclide therapy is a safe option even in advanced cancer with minimal toxicity.
Keywords: Bone pain, palliation, radio-nuclide therapy
THER 09 (ORAL)
Efficient protocol for the preparation 153Sm-EDTMP injection: An agent for bone pain palliative treatment
Shanmugam G, Mathur Anupam, Prabhakar G, Sachdev SS, Sivaprasad N
Radiopharmaceuticals Programme, Board of Radiation and Isotope Technology, Mumbai, India
153Sm-EDTMP injection is the preferred radiopharmaceutical for the palliative treatment of bone pain due to the excellent clinical efficacy and minimal myelosuppression in comparison to other bone pain palliative radiopharmaceuticals. However owing to short half life of 153Sm (46 h), shelf life of 153Sm-EDTMP injection is limited. This in turn poses a number of logistic and operational problems namely, availability of radioisotope, radiochemical processing time, quality control testing, packing and transportation and administration to patients within a limited time. BRIT has been manufacturing and supplying this radiopharmaceutical since 1999, however during the last 2-3 years there has been a gradual increase in demand. Presently The amount of radioactivity, of Sm-153, has gone up from 1-2 Ci per batch to 4-5 Ci per and it is increasing. Considering increased radioactivity per batch, for the preparation of 153Sm-EDTMP injection, and production procedure with steam sterilization step, there is increased possibility of radiation exposure, thus serious concern for radiation safety from personnel and environmental point of view. In order to reduce this probability in accordance with ALARA principale, the whole production process has been modified. A new modular production protocol has been developed and adopted, suitable for easy operation in the existing production plant, for handling large batches without compromising on the quality parameters of the final product. This paper gives the details of the modified production process, involving the three operation modules. First module comprises of heating the reaction mixture containing ligand EDTMP and the calculated quantities of 153Sm radioactivity. Second module is for on-line sterilization of the product by membrane filtration (0.22μ). Third module is for aseptic dispensing of unidose activity, in multiple pre-sterilized vials and sealing with sterilized combination seals. Using these semi automated techniques and gadgets and production modules, several therapeutic batches of 153Sm-EDTMP injection have been processed, QC tested (radiochemical purity, radionuclidic purity, sterility test, bacteriological endotoxin test) and more than 100 doses (70 mCi each) have have been supplied for clinical use, to various Nuclear Medicine Centers in India. Regular production of this product (BRIT Code SAM-2) is being undertaken on monthly frequency.
Keywords: Sm-153, EDTMP, ALARA pain paliation, radiopharmaceutical
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