Production, quality control and pharmacokinetic studies of 177Lu–zoledronate for bone pain palliation therapy
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Developing new bone pain palliation agents are a mandate in handling end-stage cancer patient’s around the world. 177Lu (1-hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid (177Lu–ZLD) is a possible therapeutic agent which can be used in bone palliation therapy. In this study, 177Lu–ZLD complex was prepared successfully using commercial ZLD ligand and 177LuCl3 at 25 and 60 °C at various ligand:metal ratios for 60–360 min. 177Lu chloride was obtained by thermal neutron irradiation (4 × 1013 n cm−2s−1) of natural Lu2O3 samples. Radiochemical purity of 177Lu–ZLD was checked by ITLC and HPLC. Stability studies of final preparation in the presence of human serum were performed as well as protein binding studies and hydroxyapatite (HA) binding test. The biodistribution of 177Lu–ZLD and 177LuCl3 in mice were determined for 7 days. A comparative accumulation study for 177Lu–ZLD and 177Lu–EDTMP was performed for vital organs up to 7 days. The complex was obtained in high radiochemical purity ITLC (>97 %) and HPLC (>99.9 %) and satisfactory stability in presence of human serum and final formulations were obtained (≈90 % in 48 h). HA binding assay demonstrated >95 % binding from 5 to 20 mg of HA in 24 h at room temperature. The complex protein binding was about 55–58 %. The high bone uptake ratios at all time intervals was obtained (>9 % at day 7), bone:kidney and bone:liver uptake ratios were significantly high for ZLD at 7 day post injection but not superior to 177Lu–EDTMP. Due to longer physical half life of 177Lu compared to 153Sm and comparable ratios for 177Lu–ZLD compared to 177Lu–EDTMP, 177Lu–ZLD can be an interesting new candidate for clinical trials for bone pain palliation therapy.
Keywords177Lu Zoledronic acid Bone pain palliation therapy Biodistribution Pharmacokinetics
We acknowledge the financial support of Iran National Science Foundation (INSF) for conducting this research project. The authors wish to thank Mr. M. Mazidi for performing animal tests as well as Dr. M. Erfani for HPLC experiments.
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