Development of 166Ho-zoledronate as a bone marrow ablative agent

Over the past 30 years, bisphosphonates were established as an effective new drug class for bone pain palliation in patients with different complicated malignancies such as prostate, breast and lung cancer (1). Bisphosphonates have strong affinity for calcium phosphates and for hydroxyapatite and attach preferentially to bone with increased avidity for areas of osteoblastic and osteoclastic activity (2,3). Nowadays, researches have shown that skeletal targeted radiotherapy in patients with multiple myeloma can improve the response rate in phase I and II trials, with promising long-term survival data (4). Several bone-seeking radiopharmaceuticals have been developed for bone marrow ablation in multiple myeloma and other haematological malignancies (5). Samarium-153-ethylene diamine tetramethylene phosphonate (153SmEDTMP) is now considered as an efficient radiopharmaceutical for bone pain palliation (6). Various other radiopharmaceuticals such as rheniumAbstract In this study, production, quality control and biodistribution studies of 166 Hozoledronate have been presented as a possible bone marrow ablative agent. Ho-166 chloride was produced by thermal neutron irradiation of natural 165 Ho(NO3)3 samples. 166 Ho-zoledronate complex was prepared by adding the desired amount of zoledronate solution (0.2 mL, 150 mg/ml in 1 M NaOH) to appropriate amount of the 166 HoCl3 solution. Radiochemical purity of the complex was monitored by instant thin layer chromatography (ITLC). Stability studies of the complex in the final preparation and in the presence of human serum were performed up to 48 h. The biodistribution of 166 Ho-zoledronate and 166 HoCl3 in wild-type mice was checked up to 72 h. 166 Ho-zoledronate complex was prepared in high radiochemical purity (> 99%, ITLC) and specific activity of 4.4 GBq/mmol. The major accumulation of radiolabelled complex was observed in the bone tissue. These findings suggest 166 Ho-zoledronatehas can be a possible candidate for bone marrow ablation in patients with multiple myeloma.