Formulation and evaluation of freeze-dried DOTMP kit for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP at the hospital radiopharmacy (original) (raw)
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Journal of labelled compounds & radiopharmaceuticals, 2017
Use of bone seeking radiopharmaceuticals is an established modality in the palliative care of pain due to skeletal metastases. (177) Lu-DOTMP is a promising radiopharmaceutical for this application owing to the ideally suited decay properties of (177) Lu and excellent thermodynamic stability and kinetic rigidity of the macrocyclic complex. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of clinical doses of (177) Lu-DOTMP at hospital radiopharmacy. After extensive radiochemical studies, an optimized strategy for formulation of clinical doses of (177) Lu-DOTMP was developed which involves simple mixing of ~3.7 GBq of (177) Lu activity as (177) LuCl3 solution to an aqueous solution containing 5 mg of DOTMP and 8 mg of NaHCO3. The proposed protocol yielded (177) Lu-DOTMP with >98% radiochemical purity and the resultant formulation showed excellent in vitro stability and desired pharmacokinetic properties in animal model. Preliminary ...
Production and quality control177Lu (NCA)-DOTMP as a potential agent for bone pain palliation
Journal of Applied Clinical Medical Physics
Skeletal uptake of radiolabeled-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10tetramethylene phosphoric acid (e.g., 177 Lu-DOTMP) complex, is used for bone pain palliation. The moderate energy of β-emitting 177 Lu (T ½ = 6.7 d, E βmax = 497 keV) has been considered as a potential radionuclide for development of the bone-seeking radiopharmaceutical. Since the specific activity of the radiolabeled carrier molecules should be high, the "no-carrier-added radionuclides" have significant roles in nuclear medicine. Many researchers illustrated no-carrier-added 177 Lu production; among these separation techniques such as ion exchange chromatography, reversed phase ion-pair, and electrochemical method, extraction chromatography has been considered more capable than other methods. In order to optimize the conditions, some effective factors on separation of Lu/Yb were investigated by EXC. The NCA 177 Lu, produced by this method, was mixed with 300 μl of DOTMP solution (20 mg in 1 mL of 0.5 M NaHCO 3 , pH = 8) and incubated under stirring at room temperature for 45 min. Radiochemical purity of the 177 Lu-DOTMP complex was determined using radio-thin-layer chromatography (RTLC) method. The complex was injected to wild-type rats and biodistribution was then studied for seven days. The NCA 177 Lu was produced with specific activity of 48 Ci/mg and with a radinuclidic purity of 99.99% through irradiation of enriched 176 Yb target (1 mg) in a thermal neutron flux of 4 × 10 13 n.cm-2 .s-1 for 14 days. 177 Lu-DOTMP was obtained with high radiochemical purities (> 98%) under optimized reaction conditions. The radiolabeled complex exhibited excellent stability at room temperature. Biodistribution of the radiolabeled complex studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation within the other nontargeted organs.
177Lu-DOTMP: A viable agent for palliative radiotherapy of painful bone metastasis
Radiochimica Acta, 2008
The suitable nuclear decay characteristics [T 1/2=6.73 d, E β (max)=497 keV, E γ=113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production with adequate specific activity and radionuclidic purity using a moderate flux reactor are important attributes towards 177Lu to be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study describes the preparation of 177Lu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) and its preliminary biological evaluation in animal models with an aim to proposing it as a viable radiopharmaceutical for bone pain palliation. The choice DOTMP as the polyaminophosphonic acid carrier ligand is based on the enhanced thermodynamic stability and kinetic inertness of the metal-ligand complexes with macrocyclic chelators. 177Lu was produced with a specific activity of ∼12 GBq/mg (∼324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural...
Preparation and biological evaluation of 153Sm-DOTMP as a potential agent for bone pain palliation
Nuclear Medicine Communications, 2004
Wistar rats demonstrated selective skeletal uptake (4.52% ± 0.49% of injected activity per gram in tibia at 30 min post-injection) with rapid blood clearance and minimal uptake in any of the major organs. No leaching of skeletal activity was observed up to 48 h post-injection. Scintigraphic studies carried out in rabbits also showed significant skeletal accumulation and almost no retention of activity in other vital organs/tissues. Nucl Med Commun 25:1169-1176 c 2004 Lippincott Williams & Wilkins.
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 ...
Nuclear Medicine and Biology, 2012
Sm-DOTMP has previously been investigated by Simón, et al.[5-7], Chakraborty, Banerjee, et al.[8,9], and Chiotellis, et al[10]. Their preclinical results demonstrated skeletal uptake fractions of 0.69, 0.60 and 0.39 respectively with good long term retention. While these earlier data suggest that 153 Sm-DOTMP has promise as a bone-seeking radiopharmaceutical, it has not yet been investigated in human clinical trials either for bone pain palliation, treatment of bone lesions or bone marrow ablation with curative intent.
Journal of Radioanalytical and Nuclear Chemistry, 2014
In this work, the cocktail complex 153 Sm/ 177 Lu-EDTMP was prepared in high radiochemical purity (more than 99 %) using in house synthesized EDTMP ligand for obtaining a possible synergistic wide range palliative agent. The mixture was administered to wild-type rats and biodistribution data collected after 2 h to 7 days showed at least 70 % accumulation of the radioactivity in the bone tissues. Scintigraphic images were taken from wild-type rats injected with 153 Sm/ 177 Lu-EDTMP after 24 h and the biodistribution was shown to be consistent with post-mortem data. A comparative accumulation study was performed for vital organs up to 7 days. 153 Sm/ 177 Lu-EDTMP seemed a promising agent for bone pain palliation therapy in skeletal metastases in humans as a novel combined radiopharmaceutical.
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.