Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.

Production and regulatory issues for theranostics.

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer.

Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.

Zirconium Coordination Chemistry and Its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics.

In the past decade, there has been a growth in using Zirconium-89 (89Zr) as a radionuclide in nuclear medicine for cancer diagnostic imaging and drug discovery processes. Although one of the most popular chelators for 89Zr, desferrioxamine (DFO) is typically presented as a hexadentate ligand, our work suggests a different scenario. The coordination structure of the Zr4+-DFO complex has primarily been informed by DFT-based calculations, which typically ignore temperature and therefore entropic and dynamic solvent effects. In this work, free energy calculations using molecular dynamics simulations, where the conformational fluctuations of both the ligand and the solvent are explicitly included, are used to compare the binding of Zr4+ cations with two different chelators, DFO and 4HMS, the latter of which is an octadentate ligand that has been recently proposed as a better chelator due to the presence of four hydroxymate groups. We find that thermally induced disorder leads to an open hexadentate chelate structure of the Zr4+-DFO complex, leaving the Zr4+ metal exposed to the solvent. A stable coordination of Zr4+ with 4HMS, however, is formed by involving both hydroxamate groups and water molecules in a more closely packed structure.

Marshalling the Potential of Auger Electron Radiopharmaceutical Therapy.

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research.

Architectured Therapeutic and Diagnostic Nanoplatforms for Combating SARS-CoV-2: Role of Inorganic, Organic, and Radioactive Materials.

Although extensive research is being done to combat SARS-CoV-2, we are yet far away from a robust conclusion or strategy. With an increased amount of vaccine research, nanotechnology has found its way into vaccine technology. Researchers have explored the use of various nanostructures for delivering the vaccines for enhanced efficacy. Apart from acting as delivery platforms, multiple studies have shown the application of inorganic nanoparticles in suppressing the growth as well as transmission of the virus. The present review gives a detailed description of various inorganic nanomaterials which are being explored for combating SARS-CoV-2 along with their role in suppressing the transmission of the virus either through air or by contact with inanimate surfaces. The review further discusses the use of nanoparticles for development of an antiviral coating that may decrease adhesion of SARS-CoV-2. A separate section has been included describing the role of nanostructures in biosensing and diagnosis of SARS-CoV-2. The role of nanotechnology in providing an alternative therapeutic platform along with the role of radionuclides in SARS-CoV-2 has been described briefly. Based on ongoing research and commercialization of this nanoplatform for a viral disease, the nanomaterials show the potential in therapy, biosensing, and diagnosis of SARS-CoV-2.

Studies on batch formulation of a freeze dried kit for the preparation of 99mTc-HYNIC-TATE for imaging neuroendocrine tumors.

AIM: To formulate freeze dried cold kits for preparation of 99mTc-HYNIC-TATE suitable for use at hospital radiopharmacy and establish clinical utility of 99mTc-HYNIC-TATE prepared using kits for detection of neuroendocrine tumors (NETs). METHODS: Standardization of reagent concentrations for formulation of freeze dried kits of HYNIC-TATE was carried out. Consistency in formulation was tested by six batch preparation. Quality control tests were carried out to establish compliance of specifications of purity and safety criteria for both kits and 99mTc-HYNIC-TATE formulated using kits. Clinical utility of 99mTc-HYNIC-TATE prepared using kits was demonstrated in patients with histopathologically confirmed well-differentiated NETs. RESULTS: Pharmaceutical grade HYNIC-TATE kits compliant with all the quality control criteria were formulated and successfully radiolabeled with 99mTc. Radiopharmaceutical was successfully utilized for detection of NETs in patients and comparison with uptake of 99mTc-HYNIC-TOC and 177Lu-DOTA-TATE was made. CONCLUSION: The formulated kits are robust and provide consistently high radiolabeling yields (> 95%) with 99mTc in short time periods requiring no additional purification. Initial clinical trials demonstrate the utility of 99mTc-HYNIC-TATE using formulated kits.

177 Lu-DOTMP induces G2/M cell cycle arrest and apoptosis in MG63 cell line.

Bone pain is the major manifestation of skeletal metastases. Although various treatment modalities are available for bone pain palliation, use of radiolabeled phosphonates is documented to be more effective. Among radionuclides available for this purpose, lutetium-177 is gaining popularity due to its moderate beta energy, theranostic capability, favorable half-life and convenient production logistics. 177 Lu-DOTMP has shown considerable promise as a metastatic bone pain palliating agent in preliminary evaluations and recent clinical studies. Therefore, an attempt was made to elucidate the possible mechanism of in vitro cell death induced by 177 Lu-DOTMP in MG63 cells. 177 Lu-DOTMP binding studies were carried out in mineralized bone of MG63 cells and around 50% binding was observed. Skeletons of Wistar rats showed 1.78 ± 0.5% IA/g at a 3 h time period which was almost constant up to 7 days. MG63 cells were incubated with 3.7 and 37 MBq of 177 Lu-DOTMP for 48 h prior to perform assays. An increase in the magnitude of cell toxicity and apoptotic DNA fragmentation was observed. Enhancement of G2/M phase cell cycle arrest and apoptosis were documented which were dose-dependent. Thus, 177 Lu-DOTMP induced apoptotic cell death in MG63 cells, which might be one of the primary causes of pain relief in osseous metastases.

Clinical experience with indigenous kit-based preparation of 68Ga-DOTATOC using commercial 68Ge/68Ga generator.

Pharmaceutical grade DOTATOC kits compliant with all the quality control criteria were formulated and radiolabeled with 68Ga in high yields. Comparison with module-based 68Ga-DOTATOC established product equivalency. Clinical utility was evaluated in patients with histopathologically confirmed well-differentiated neuroendocrine tumors. Kit-based preparation of 68Ga-DOTATOC could identify sites of primary and metastatic disease. PET/CT images of patients conformed to the established criteria for somatostatin imaging agents and clinical expectations. Results of this study emphasize the potential of kit-based 68Ga-DOTATOC for PET imaging of neuroendocrine tumors.

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

INTRODUCTION: 177Lu-DOTA-TATE is a clinically useful and promising therapeutic radiopharmaceutical for peptide receptor radionuclide therapy of neuroendocrine tumors (NETs) overexpressing somatostatin receptors. Currently, the radiopharmaceutical is prepared in-house at nuclear medicine centers, thereby restricting its use to limited centers only. In this article, the authors describe systematic studies toward bulk scale formulation of "ready-to-use" 177Lu-DOTA-TATE using medium specific activity 177Lu (740-1110 GBq/mg) at a centralized radiopharmacy facility. METHODS: In an optimized protocol, 177Lu-DOTA-TATE synthesis was carried out by direct heating of 177LuCl3 (Sp. act. 740-1110 GBq/mg) with DOTA-TATE peptide (1.5-3.0 equivalents) in ammonium acetate buffer (0.2 M) containing 2,5-dihydroxy benzoic acid (gentisic acid). Thereafter, the crude labeled product was purified using a Sep-Pak® C18 column and diluted with acetate buffer-gentisic acid (1.5% w/v) solution to final radioactive concentration of 740 MBq/mL. This was further sterilized and dispensed as 7.4 GBq patient dose/vial with 2 days postformulation calibration. RESULTS: A peptide/metal ratio of 1.5-3.0 is essential for complexation wherein radiolabeling yields >90% are obtained minimizing free 177Lu waste. For formulation of 7.4 GBq patient dose (2 days postproduction), even specific activity of about 555 GBq/mg was found to be adequate for the radiometal. The ready-to-use 740 MBq/mL 177Lu-DOTA-TATE formulation with gentisic acid (1.5% w/v) is observed to be safe for human use for more than 1 week (radiochemical purity >98%) from the day of production when stored at -70°C. However, the target specificity may get affected beyond 2 days as the total peptide content for 7.4 GBq dose may exceed the critical peptide limit of 300 µg. Patient treatment carried with several batches of present formulation in diseased NET patients exhibited desired distribution at the tumor and its metastatic site. CONCLUSIONS: A ready-to-use formulation of 177Lu-DOTA-TATE was successfully prepared and optimized for regular bulk scale production and supply to distant nuclear medicine centers.

Clinical utility of 99mTc-ubiquicidin (29-41) as an adjunct to bone scan in differentiating infected versus noninfected loosening of prosthesis before revision surgery.

PURPOSE: The aim of this study was to evaluate the utility of Tc-ubiquicidin (Tc-UBI) (29-41) as an adjunct to an methylene diphosphonate (MDP) bone scan in differentiating septic versus aseptic loosening in patients with painful prosthesis posted for revision surgery. PATIENTS AND METHODS: A two-vial cold kit of UBI (29-41) was prepared and utilized for the preparation of patient dose of Tc-UBI (29-41). Twenty two patients with painful hip or knee prosthesis and scheduled for revision surgery were included in the study. Overall, 370-555 MBq of Tc-UBI (29-41) was injected intravenously in all the patients. A blood pool image at 20 min after injection was followed by spot views of the suspected region of infection (target) and a corresponding normal area (nontarget) at 60 min. All patients underwent a routine Tc-MDP three-phase whole-body bone scan, followed by single-photon emission computed tomography/computed tomography of the prosthesis within a week of the Tc-UBI (29-41) study. For Tc-UBI scans, a visual score (0-3) was used to categorize studies as positive or negative, with scores of 0 (minimal or no uptake; less than soft tissue or contralateral extremity) and 1 (mild; equivalent to soft tissue or contralateral extremity) being considered negative and scores of 2 (moderate; uptake greater than soft tissue or contralateral extremity, but less than the liver) or 3 (intense; uptake greater than soft tissue or contralateral extremity and equivalent to the liver) being considered positive. The final correlation was on the basis of bacterial culture as the major criterion and the results of clinical tests, radiography, fluorine-18-fluorodeoxyglucose PET-CT, and three-phase bone scanning as the minor criteria. RESULTS: In all, 22 studies were carried out with Tc-UBI (29-41). Of these, 16 scans were considered positive and six were negative for infection foci. All negative scans were subsequently confirmed to be true negative. Adverse reactions were not observed during image acquisition and within 5 days after the study. The overall sensitivity, specificity, and positive and negative predictive values were 100, 85.7, 93.75, and 100%, respectively. A combination of an MDP bone scan and UBI scans was considered to yield maximum confidence toward reporting for the presence of infection. CONCLUSION: Patient dose of Tc-UBI (29-41) was prepared successfully and a simple quality control method to check radiolabeling yield was used at the hospital radiopharmacy. Tc-UBI (29-41) showed promise in localizing foci of infection, with optimal visualization at 20-60 min, for the evaluation of prosthesis loosening.

Development of Semiautomated Module for Preparation of 131I Labeled Lipiodol for Liver Cancer Therapy.

Intra-arterial injection of 131I Lipiodol is an effective treatment option for primary hepatocellular carcinoma as it delivers high radiation dose to liver tumor tissue with minimal accumulation in adjacent normal tissue. The present article demonstrates design, fabrication, and utilization of a semiautomated radiosynthesis module for preparation of 131I labeled Lipiodol. The radiolabeling method was standardized for preparation of patient dose of 131I labeled Lipiodol radiochemical yield (RCY); radiochemical purity (RCP) and pharmaceutical purity of the product were determined using optimized procedures. Sterile and apyrogenic 131I labeled Lipiodol in >60% RCY could be prepared with >95% RCP. Preclinical evaluation in animals indicated retention of more than 90% of activity at 24 hours postportal vein injection. This is the first report demonstrating potential application of simple user friendly and safe semiautomated system for routine production of 131I labeled Lipiodol, which is adaptable at centralized hospital radiopharmacies. The described prototype module can be modified as per demand for preparation of other therapeutic radiopharmaceuticals.

Radiolabeling and Preliminary Evaluation of Ga-68 Labeled NODAGA-Ubiquicidin Fragments for Prospective Infection Imaging.

PURPOSE: The present work was aimed at the development of prospective positron emission tomography (PET) agents for infection imaging. Towards this aim, ubiquicidin (UBI) fragments conjugated with the macrocyclic NODAGA chelator were radiolabeled with Ga-68 and evaluated. PROCEDURES: Conformations of custom synthesized NODAGA-UBI (29-41) and NODAGA-UBI (31-38) conjugates were compared with UBI (29-41) by circular dichroism (CD) spectroscopy. Optimization of labeling of NODAGA conjugates of UBI peptides with Ga-68 was performed and quality control analysis was carried out by chromatography techniques. In vitro uptake of [68Ga] NODAGA-UBI (29-41) and [68Ga]NODAGA-UBI (31-38) was studied in Staphylococcus aureus cells. In vivo distribution of [68Ga]GaCl3 and [68Ga]NODAGA-UBI complexes was performed in normal Swiss mice. RESULTS: Conformations of NODAGA-UBI (29-41) and NODAGA-UBI (31-38) conjugates were found to be similar to UBI (29-41). NODAGA-UBI conjugates could be consistently labeled with Ga-68 in high radiochemical yields (>95 %) with high radiochemical purity (>95 %). [68Ga]NODAGA-UBI (29-41) and [68Ga]NODAGA-UBI (31-38) complexes showed retention time of 14 and 14.5 min, respectively, by HPLC radiochromatogram. Specific uptake of [68Ga]NODAGA-UBI fragments was observed in S.aureus cells. Greater than 64 % of the injected dose was cleared via the renal route at 1 h post injection, and no significant uptake in vital organs of mice was observed with both the agents. CONCLUSION: This is the first report on Ga-68 labeled NODAGA-UBI fragments for infection imaging and the agents hold tremendous prospect in PET imaging.

Utility of (99m)Tc-Hynic-TOC in 131I Whole-Body Scan Negative Thyroid Cancer Patients with Elevated Serum Thyroglobulin Levels.

Several studies have reported on the expression of somatostatin receptors (SSTRs) in patients with differentiated thyroid cancer (DTC). The aim of this study was to evaluate the imaging abilities of a recently developed Technetium-99m labeled somatostatin analog, (99m)Tc-Hynic-TOC, in terms of precise localization of the disease. The study population consisted of 28 patients (16 men, 12 women; age range: 39-72 years) with histologically confirmed DTC, who presented with recurrent or persistent disease as indicated by elevated serum thyroglobulin (Tg) levels after initial treatment (serum Tg > 10 ng/ml off T4 suppression for 4-6 weeks). All patients were negative on the Iodine-131 posttherapy whole-body scans. Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was performed in all patients. SSTR scintigraphy was true positive in 23 cases (82.1%), true negative in two cases (7.1%) and false negative in three cases (10.7%) which resulted in a sensitivity of 88.46%, specificity of 100% and an accuracy of 89.2%. Sensitivity of (99m)Tc-Hynic-TOC scan was higher (93.7%) for patients with advanced stages, that is stages III and IV. (18)F-FDG showed a sensitivity of 93.7%, a specificity of 50% and an accuracy of 89.3%. (18)F-FDG PET was found to be more sensitive, with lower specificity due to false positive results in 2 patients. Analysis on a lesion basis demonstrated substantial agreement between the two imaging techniques with a Cohen's kappa of 0.66. Scintigraphy with (99m)Tc-Hynic-TOC might be a promising tool for treatment planning; it is easy to perform and showed sufficient accuracy for localization diagnostics in thyroid cancer patients with recurrent or metastatic disease.

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

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

Improved kit formulation for preparation of (99m)Tc-HYNIC-TOC: results of preliminary clinical evaluation in imaging patients with neuroendocrine tumors.

(99m)Tc-HYNIC-TOC is a cost-effective and logistically viable agent for scintigraphy of neuroendocrine tumors overexpressing somatostatin receptors as compared with [(111)In-DTPA-D-Phe(1)] Octreotide (Octreoscan(®)). Several studies have been reported, wherein the efficacy of this agent is demonstrated. In the present article, the authors report the preparation of a single-vial HYNIC-TOC kit suitable for the preparation of 4-5 patient doses (15 mCi/patient) of (99m)Tc-HYNIC-TOC. The kits were tested for sterility and bacterial endotoxins to assure safety of the product. A significant modification in this kit is the inclusion of buffer in the kit itself, unlike in commercially available kits where the buffer solution has to be added during preparation. (99m)Tc-HYNIC-TOC was prepared by adding 20-80 mCi (740-2960 MBq) of freshly eluted Na(99m)TcO4 in 1-3 mL of sterile saline directly into the kit vial and heating the vial in a water bath at 100°C for 20 minutes. The labeling yield and radiochemical purity of (99m)Tc-HYNIC-TOC, prepared using the lyophilized cold kit, were consistently >90%. The kits were evaluated over a period of 9 months and found to be stable when stored at -20°C. Limited clinical studies performed with the (99m)Tc-HYNIC-TOC, formulated using the kit, showed adequate sensitivity and specificity for the detection of gasteroenteropancreatic neuroendocrine tumors.

Camptothecin Enhances Cell Death Induced by (177)Lu-EDTMP in Osteosarcoma Cells.

Lutetium-177 is an assured therapeutic radionuclide with favorable half-life and suitable ß(-) energy. Radiolabeled (177)Lu-EDTMP (Ethylenediamine tetramethylene phosphonic acid) is by and large used for bone pain palliation in cancer patients. In vitro cell studies are carried out in osteosarcoma cells MG-63 to evaluate the combined effect of anticancer drug camptothecin (CPT) and (177)Lu-EDTMP. Two concentrations of (177)Lu-EDTMP (3.7 and 37 MBq) were incubated with MG63 cell line for 48 hours with and without pretreatment of CPT (10 nM) for 1 hour. After completion of incubation, the cells were harvested and cellular toxicity was estimated by LDH, MTT, and trypan blue dye. Apoptotic DNA fragmentation was estimated by ELISA kit. The expression of proteins such as bcl2, PARP, and MAPK (mitogen-activated protein kinase) that were related to apoptotic signaling pathways was assessed by western blotting. The results indicated that cellular toxicity and apoptosis were relatively higher in MG63 cells that were treated with CPT prior to treating with (177)Lu-EDTMP in comparison with the corresponding individual controls.

Radiosynthesis and biological evaluation of 68Ga-labeled colchicine conjugates.

OBJECTIVE: Colchicine, a plant-derived alkaloid, is a known substrate for P-glycoprotein (Pgp), which confers multidrug resistance (MDR) to cancer cells and tumors, through enhanced efflux of chemotherapeutic drugs. Hence, radiolabeled colchicine can be a suitable probe for imaging of activity of Pgp transport in vivo and early diagnosis of MDR. METHODS: In the present study, colchicine was hydrolyzed to desacetylcolchiceine for conjugation with p-SCN-Bn-DOTA and p-SCN-Bn-NOTA. The resulting conjugates, DOTA-desacetylcolchiceine and NOTA-desacetylcolchiceine, were radiolabeled with 68Ga. The radiotracers 68Ga-DOTA-desacetylcolchiceine (68Ga-1) and 68Ga-NOTA-desacetylcolchiceine (68Ga-2) were evaluated in vitro (MCF-7 and T47D breast cancer cell lines) and in vivo (biodistribution studies, Swiss mice bearing fibrosarcoma tumors). RESULTS: The radiotracers prepared in >97% radiochemical yield showed good in vitro binding and significant inhibition with 100-fold cold colchicine (p<0.05). In vivo the tumor uptake reached maximum at 120 minutes postinjection (68Ga-1: 2.35%±0.39% injected dose per gram [ID/g]; 68Ga-2: 1.5%±0.31% ID/g). Of the two radiotracers 68Ga-2 cleared faster from blood (p<0.05) with lower uptake in nontargeted organs as compared with 68Ga-1. CONCLUSIONS: The radiotracer 68Ga-2 has shown improved pharmacokinetic features over 68Ga-1 and the previously reported 99mTc(CO)3-colchicine radiotracer. The preliminary studies with 68Ga-2 indicate its potential for in vivo targeting of tumor. However, the efficacy of the radiotracer for imaging of multidrug-resistant states will be ascertained in future.

Clinical utility of indigenously formulated single-vial lyophilized HYNIC-TOC kit in evaluating Gastro-entero Pancreatic neuro endocrine tumours.

OBJECTIVES: The objective of this study was to evaluate the performance and utility of (99m)Tc HYNIC-TOC planar scintigraphy and SPECT/CT in the diagnosis, staging and management of gastroenteropancreatic neuroendocrine tumors (GPNETs). METHODS: 22 patients (median age, 46 years) with histologically proven gastro- entero- pancreatic NETs underwent (99m)Tc HYNIC-TOC whole body scintigraphy and regional SPECT/CT as indicated. Scanning was performed after injection of 370-550 MBq (10-15 mCi) of (99m)Tc HYNIC-TOC intravenously. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as semi quantitatively (tumor to background and tumor to normal liver ratios on SPECT -CT images). Results of SPECT/CT were compared with the results of conventional imaging. Histopathology results and follow-up somatostatin receptor scintigraphy with (99m)Tc HYNIC TOC or conventional imaging with biochemical markers were considered to be the reference standards. RESULTS: (99m)Tc HYNIC TOC showed sensitivity and specificity of 87.5% and 85.7%, respectively, for primary tumor and 100% and 86% for metastases. It was better than conventional imaging modalities for the detection of both primary tumor (P<0.001) and metastases (P<0.0001). It changed the management strategy in 6 patients (31.8%) and supported management decisions in 8 patients (36.3%). CONCLUSION: (99m)Tc HYNIC TOC SPECT/CT appears to be a highly sensitive and specific modality for the detection and staging of GPNETs. It is better than conventional imaging for the evaluation of GPNETs and can have a significant impact on patient management and planning further therapeutic options.

Cellular toxicity and apoptosis studies in osteocarcinoma cells, a comparison of 177Lu-EDTMP and Lu-EDTMP.

OBJECTIVE: The most promising bone pain palliative agent such as 177Lu-EDTMP emerges as a newer radiopharmaceutical for cancer management. Thus, it was of interest to study the cell uptake of this agent in osteocarcinoma cell line and investigate the underlying mechanism of cellular toxicity. METHODS: The cell binding studies of 177Lu-EDTMP were carried out in osteocarcinoma cells (MG63) after induction of bone mineralization. Cellular toxicity studies were carried out with varying amounts of 177Lu-EDTMP and compared with equivalent amount of cold Lu-EDTMP. Cell viability was assessed by trypan blue, LDH and MTT assay. Different studies such as DNA fragmentation and Western blotting for apoptosis related proteins were carried out to elucidate the mechanism of cell death. RESULTS: Maximum cell binding of 177Lu-EDTMP, observed with mineralized MG63 cells was 19 ± 0.122%. Nearly 12% cell death was observed in MG63 cells treated with 37 MBq of 177Lu-EDTMP as compared to controls. Apoptosis studies were carried out by ELISA to estimate DNA fragmentation and it was found that DNA enrichment factor was 1.8, compared to the corresponding control. Down regulation of anti-apoptotic protein, bcl-2 and cleavage of PARP protein was evident by Western blot results. CONCLUSION: These studies indicate that the 177Lu-EDTMP binds to mineralized bone cells and induces apoptotic cell death in MG63 cells.