Evaluation of 153Sm/177Lu-EDTMP mixture in wild-type rodents as a novel combined palliative treatment of bone pain agent (original) (raw)
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Introduction: Radionuclide therapy (RNT) is an effective method for bone pain palliation in patients suffering from bone metastasis. Due to the long half-life, easy production and relatively low β− energy, 177Lu [T1/2=6.73 days, Eβmax=497 keV, Eγ=113 keV (6.4%), 208 keV (11%)]-based radiopharmaceuticals offer logistical advantage for wider use. This paper reports the results of a multispecies biodistribution and toxicity studies of 177Lu-EDTMP to collect preclinical data for starting human clinical trials. Methods: 177Lu-EDTMP with radiochemical purity greater than 99% was formulated by using a lyophilized kit of EDTMP (35 mg of EDTMP, 5.72 g of CaO and 14.1 mg of NaOH). Biodistribution studies were conducted in mice and rabbits. Small animal imaging was performed using NanoSPECT/CT (Mediso, Ltd., Hungary) and digital autoradiography. Gamma camera imaging was done in rabbits and dogs. Four levels of activity (9.25 through 37 MBq/kg body weight) of 177Lu-EDTMP were injected in four groups of three dogs each to study the toxicological effects. Results: 177Lu-EDTMP accumulated almost exclusively in the skeletal system (peak ca. 41% of the injected activity in bone with terminal elimination half-life of 2130 and 1870 h in mice and rabbits, respectively) with a peak uptake during 1–3 h. Excretion of the radiopharmaceutical was through the urinary system. Imaging studies showed that all species (mouse, rat, rabbit and dog) take up the compound in regions of remodeling bone, while kidney retention is not visible after 1 day postinjection (pi). In dogs, the highest applied activity (37 MBq/kg body weight) led to a moderate decrease in platelet concentration (mean, 160 g/L) at 1 week pi with no toxicity. Conclusion: The protracted effective half-life of 177Lu-EDTMP in bone supports that modifying the EDTMP molecule by introducing 177Lu does not alter its biological behaviour as a specific bone-seeking tracer. Species-specific pharmacokinetic behavior differences were observed. Toxicity studies in dogs did not show any biological adverse effects. The studies demonstrate that 177Lu-EDTMP is a promising radiopharmaceutical that can be further evaluated for establishing as a radiopharmaceutical for human use.
Current Radiopharmaceuticals, 2023
Introduction With its suitable nuclear decay characteristics and large-scale production feasibility with adequate specific activity, 177Lu is regarded as an excellent radionuclide for developing bone pain palliation agent. Ethylenediamine-tetramethylene phosphonic acid (EDTMP) is a preferred carrier molecule for radiolanthanides, such as 177Lu. The present paper describes the synthesis of EDTMP and the development of a ready-to-use kit for the preparation of 177Lu-EDTMP and its quality control in accordance with the quality and safety criteria required for medicinal use.Material and Methods EDTMP was synthesized by a modified Mannich-type reaction, and the structure was characterized using NMR and IR spectroscopy. Optimization of radiolabeling conditions was done with two different salt forms of EDTMP. The labeling yield was checked by paper chromatography with radiation detection. Kit was developed as a lyophilized mixture of EDTMP and sodium bicarbonate in a maximum volume of 5 mL. Labeling efficiency, radionuclidic purity, radiochemical purity, sterility, and pyrogenicity analysis were performed as the quality control of the labeled kit.Results The analytical data for the structure determination and purity of the synthesized ligand were in agreement with authentic commercial samples used in radiopharmacy.177Lu-EDTMP complex was prepared using synthesized EDTMP ligand under optimized labeling conditions with high labelling yield (>99%). The radiolabeling yields of the EDTMP kit at room temperature after 30 min and 48 hours were 99.46% and 99.00%.Conclusion The developed EDTMP kit enables an instant one-step preparation of the radiopharmaceutical of high radiochemical purity (>99%) and has a sufficiently long shelf life. This enables the routine production of the 177Lu-EDTMP in nuclear medicine clinics without requiring experienced staff.
Applied Radiation and Isotopes, 2020
Radiopharmaceuticals with therapeutic applications are designed to deliver high doses of radiation to target organs with minimizing unwanted radiation to healthy tissues. Owing to the potential of targeted radiotherapy to treat a wide range of malignancies, 170 Tm-EDTMP was developed for possible therapeutic applications. This study describes absorbed dose prediction of 170 Tm-EDTMP in human organs after animal injection which is determined via medical internal radiation dose (MIRD) and MCNP-4C code methods. It was estimated that a 1-MBq administration of 170 Tm-EDTMP into the human body would result in an absorbed dose of 37.9 mGy (MIRD method) and 38.02 mGy (MCNP-4C code) in the bone surface after 60 days post injection. Highest and lowest difference between MIRD and MCNP results are for lung and bone surface respectively. Finally, the results show that there is a good agreement between MIRD method and MCNP-4C simulation code for absorbed dose estimation.
177Lu-EDTMP is currently being investigated as a potential agent for providing palliative care to the patients suffering from bone pain due to metastatic skeletal carcinoma. The present article describes the evaluation of 177Lu-EDTMP complex in four different canine patients with different types of primary and metastatic skeletal lesions with respect to its pharmacokinetic properties, dosimetry and therapeutic efficacy. The dogs were treated with a dose of ~44.4 MBq (1.2 mCi) per kg body weight of 177Lu-EDTMP, synthesized in-house with high radiochemical purity (98.8 ± 0.4 %) and excellent in vitro stability. The radiopharmaceutical showed favourable pharmacokinetic properties, such as, preferential accumulation at skeletal lesion sites and fast clearance from blood and other nontarget organs through urinary route. The administered dose of the radiopharmacutical showed excellent therapeutic efficacy in case of a dog suffering from skeletal metastasis originating from primary tumor elsewhere. On the other hand, two of the remaining three patients with primary bone cancer showed stable disease intially with palliative effect. The fourth patient having metal implant induced osteosarcoma with severe limb oedema did not show any response to the treatment.
Asia Oceania journal of nuclear medicine & biology, 2015
Objective(s): Recently, bone-avid radiopharmaceuticals have been shown to have potential benefits for the treatment of widespread bone metastases. Although 177Lutriethylene tetramine hexa methylene phosphonic acid (abbreviated as 177Lu- TTHMP), as an agent for bone pain palliation, has been evaluated in previous studies, there are large discrepancies between the obtained results. In this study, production, quality control, biodistribution, and dose evaluation of 177Lu-TTHMP have been investigated and compared with the previously reported data. Methods: TTHMP was synthesized and characterized, using spectroscopic methods. Radiochemical purity of the 177Lu-TTHMP complex was determined using instant thin-layer chromatography (ITLC) and high performance liquid chromatography (HPLC) methods. The complex was injected to wild-type rats and biodistribution was studied for 7 days. Preliminary dose evaluation was investigated based on biodistribution data in rats. Results: 177Lu was prepared ...
Investigation of 177Lu-labeled HEDP, DPD, and IDP as potential bone pain palliation agents
Journal of Radiation Research and Applied Sciences
Application of bone-seeking radiopharmaceuticals is one of the modalities in the management of metastatic bone pain. The present study aimed to investigate the potential of 177 Lu-labeled phosphate/phosphonate ligands: 1-hydroxyethane 1,1-diphosphonic acid (HEDP), 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), and imidodiphosphate tetrasodium salt (IDP), as bone pain palliation agents. HEDP, DPD, and IDP were radiolabeled with 177 Lu in high radiolabeling yield (98.49%, 93.31%, and 90.69%, respectively), forming in vitro stable radiolabeled complexes in saline and human serum after 96 h. Biodistribution was followed by imaging studies and ex vivo measurement of radioactivity in organs in healthy Wistar rats. Significant bone accumulation and long retention even after 96 h (3.85 ± 0.91%ID/g), as well as relatively low uptake in soft tissue such as liver and spleen (<1%ID/g), were observed for 177 Lu-HEDP. Two other radiolabeled ligands showed lower accumulations in bone (<1% ID/g) and higher accumulations in liver and spleen at examined time points (>1.5% ID/g). Obtained results suggest that difference in the chemical structure of phosphonates/phosphates influences the rate of bone incorporation of 177 Lu-radiolabeled complexes. Desirable biodistribution pattern of 177 Lu-HEDP makes it suitable for its further preclinical investigations as a potential bone pain palliation agent.
170Tm-EDTMP: a potential cost-effective alternative to 89SrCl2 for bone 3 pain palliation
INTRODUCTION:Metastron ((89)SrCl(2)) is a radiopharmaceutical currently used for bone pain palliation in several countries since the long half-life of (89)Sr (50.5 days) favors wider distribution than other radioisotopes approved for this application, which have shorter half-lives. Strontium-89 is not ideal for bone pain palliation due to its high energy beta(-) particle emission [E(beta(max))=1.49 MeV] and is also difficult to produce in large quantities. A (170)Tm [T(1/2)=128.4 days, E(beta(max))=968 keV, E(gamma)=84 keV (3.26%)]-based radiopharmaceutical for bone pain palliation could offer significant advantages over that of (89)Sr. The present study constitutes the first report of the preparation of a (170)Tm-based agent, (170)Tm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and its preliminary biological evaluation in animal models. METHODS: (170)Tm was produced by thermal neutron bombardment on natural Tm(2)O(3) target for a period of 60 days at a flux of 6x10(13) neutrons/cm(2).s. (170)Tm-EDTMP complex was prepared at room temperature. Biodistribution and scintigraphic imaging studies with (170)Tm-EDTMP complex were performed in normal Wistar rats. Preliminary dosimetric estimation was made using the data to adjudge the suitability of (170)Tm-EDTMP for bone pain palliation. RESULTS: (170)Tm was produced with a specific activity of 6.36 GBq/mg and radionuclidic purity of 100%. The (170)Tm-EDTMP was prepared with high radiochemical purity (>99%) and the complex exhibited satisfactory in vitro stability. Biodistribution and imaging studies showed good skeletal accumulation (50-55% of the injected activity) with insignificant uptake in any other vital organ/tissue. Activity was observed to be retained in skeleton until 60 days post-injection demonstrating that (170)Tm-EDTMP exhibits good bone-seeking properties with long retention. It is predicted that a dose of approximately 0.5 microGy/MBq is accrued to red bone marrow and 4.3 Gy/MBq is delivered to the skeleton. CONCLUSION: (170)Tm-EDTMP shows promising biodistribution features, encouraging dosimetric values and warrants further investigation in order to develop it as a bone pain palliative radiopharmaceutical. Despite the relatively long half-life (128.4 days) of (170)Tm, (170)Tm-EDTMP could be explored as a cost-effective alternative to (89)SrCl(2).