Formulation and evaluation of freeze-dried DOTMP kit for the preparation of clinical-scale ¹⁷⁷Lu-DOTMP and ¹⁵³Sm-DOTMP at the hospital radiopharmacy

Abstract

Objective: The objective of the present work is to develop and evaluate freeze-dried DOTMP kit, which could be utilized for the convenient and single-step preparation of clinical-scale 177 Lu-DOTMP and 153 Sm-DOTMP, both of which have shown potential as alternative agents for metastatic bone pain palliation. Experimental: Freeze-dried DOTMP kits, each comprising a lyophilized mixture of 20 mg DOTMP and 8.75 mg NaOH, were prepared. The kits were used for the preparation of clinical-scale 177 Lu-DOTMP and 153 Sm-DOTMP complexes. The agents were prepared by dissolving the lyophilized powder in 1 mL of normal saline and incubating with 177 LuCl 3 or 153 SmCl 3 , produced in-house, for 15 min at room temperature. Pharmacokinetic behavior and biological distribution of the agents were studied by carrying out biodistribution as well as scintigraphic studies in normal male Wistar rats. Shelf-life of the freeze-dried kits was also ascertained.Results: Clinical-scale 177 Lu-DOTMP and 153 Sm-DOTMP complexes, comprising up to 3.7 GBq (100 mCi) of activity, were prepared with > 99% radiochemical purity using the freeze-dried kits. The complexes exhibited high in vitro stability when stored at room temperature. Biological studies showed selective skeletal accumulation and insignificant uptake of the radiotracers in any of the vital organs/tissue. The non-accumulated activity exhibited primary urinary clearance. The kits had a shelf-life of 2 years when stored at 4 ∘ C temperature.Conclusion: Freeze-dried DOTMP kits, suitable for the preparation of clinical-scale 177 Lu-DOTMP and 153 Sm-DOTMP, have been developed and the radiochemical and biological behaviors of the radiolabeled agents have been studied. The use of the kit at the hospital radiopharmacy is expected to make the preparations easy and convenient. This in turn will enable the widespread dissemination of these promising agents towards their application for regular use.

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

“…Paper chromatography was carried out following the standard procedure reported elsewhere 16 . Biodistribution studies were carried out using normal healthy male Wistar rats, bred and reared in our Institute's animal house facility, following the standard procedure.…”

“…Radiochemical purity of the 177 Lu-DOTMP was determined by paper chromatography using normal saline (0.9% NaCl w/v) as the eluting solvent. Paper chromatography was carried out following the standard procedure reported elsewhere 16 . In brief, a small drop of the reaction mixture was spotted at 1.5 cm from the one end of chromatography paper strip, 12 cm in length and 1 cm in width.…”

“…3,4 Such pathological conditions of bones are treated with several modalities which include analgesic medications, cytotoxic chemotherapy, hormone deprivation therapy, radiation therapy as well as administration of bisphosphonates and bone-seeking radiopharmaceuticals. 1,2,[5][6][7][8][9][10][11][12][13][14][15][16][17] However, bone marrow suppression, arising owing to the emission of high energy beta particles, is one of the major concerns for some of the clinically useful bone pain palliative agents. 5 Use of several radiopharmaceuticals have been advocated for this purpose.…”

“…5-6,9-11,16-17 177 Lu is a theranostic radionuclide, as it decays with the emission of βparticle having a maximum energy of 497 keV along with accompanying gamma radiations of 113 keV (6.4%) and 208 keV (11%). [7][8][9][10][11][12][13][15][16][17] Recent clinical studies reported with 177 Lu-DOTMP, although preliminary in nature, has indicated the potential of the agent as an alternative and useful radiopharmaceutical for bone pain palliation applications. Moreover, the possibility of producing 177 Lu using medium flux research reactors in bulk quantity with sufficiently high specific activity enables 177 Lu-labeled products to emerge as an alternative and attractive choice for meeting the global demands of radiolabeled agents for targeted radiotherapy.…”

“…18 DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10tetramethylene phosphonic acid), a macrocyclic analog of a more commonly used ligand EDTMP (ethylenediaminetetramethylene phosphonic acid), is a comparatively new phosphonic acid, which has been labeled with different radionuclides and the potentials of these radiolabeled phosphonates have been evaluated in animal models. [7][8][9][10][11][12][13][15][16][17] Recent clinical studies reported with 177 Lu-DOTMP, although preliminary in nature, has indicated the potential of the agent as an alternative and useful radiopharmaceutical for bone pain palliation applications. 5,17 The high specificity of the radiolabeled phosphonates towards the bone matrix and their preferential accumulation in the metastatic lesions, are the cause of delivering radiation dose to the metastatic cancerous tissues and it may also be able to kill cells.…”