Das Tapas, Sarma Haladhar D, Shinto Ajit, Kamaleshwaran Koramadai K, Banerjee Sharmila
1 Radiopharmaceuticals Chemistry Section, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre , Mumbai, India .
Cancer Biother Radiopharm. 2014 Dec;29(10):412-21. doi: 10.1089/cbr.2014.1664.
The objective of the present work was to develop a freeze-dried ethylenediaminetetramethylene phosphonic acid (EDTMP) kit, suitable for the convenient and single-step preparation of (177)Lu-EDTMP, which is currently being evaluated as a promising radiopharmaceutical for providing palliative care to patients suffering from skeletal metastases and to assess the potential of the agent in human patients.
Lyophilized EDTMP kits having identical composition with Quadramet(®) were prepared using EDTMP, NaOH, and anhydrous CaCO3. The (177)Lu-EDTMP patient dose was prepared by incubating the kit materials dissolved in 1 mL of water for injection and (177)LuCl3, produced in-house, at room temperature for 15 minutes. Pharmacokinetic behavior of the agent was studied by carrying out biodistribution and scintigraphic imaging studies in normal Wistar rats. Clinical studies were performed by administering the preparation in patients suffering from disseminated skeletal metastases.
Five batches of freeze-dried EDTMP kits with 50 kit vials in each batch were prepared. Each kit vial comprised a lyophilized mixture of 35 mg EDTMP, 14.1 mg NaOH, and 5.8 mg of CaCO3. The (177)Lu-EDTMP complex was prepared with excellent radiochemical purity (>99%) and high stability (>98% until 9 days postpreparation) using these kits. Radiochemical studies showed that this kit could be used within a pH range of 6-9 and with (177)Lu having specific activity as low as 925 GBq · g(-1) (25 Ci · g(-1)) for the preparation of up to 3.7 GBq (100 mCi) of (177)Lu-EDTMP. Biodistribution studies in animals revealed selective accumulation of the agent in skeleton (∼ 60% of the injected activity) with major renal clearance. Preliminary clinical studies in 10 patients exhibited selective accumulation of the radiotracer in skeletal lesions and provided significant pain relief thereby improving the quality of life of the patients.
Freeze-dried EDTMP kits, suitable for the preparation of patient doses of (177)Lu-EDTMP, have been developed and used in preliminary studies for treating the cancer patients with disseminated skeletal metastases. The kit may also find use for the preparation of other potential bone pain palliation agents, such as (153)Sm-EDTMP.
本研究的目的是开发一种冻干乙二胺四亚甲基膦酸（EDTMP）试剂盒，适用于便捷的一步法制备（177）Lu-EDTMP，目前（177）Lu-EDTMP作为一种有前景的放射性药物正在接受评估，用于为患有骨转移的患者提供姑息治疗，并评估该药物在人类患者中的潜力。
使用EDTMP、NaOH和无水CaCO3制备了与Quadramet®成分相同的冻干EDTMP试剂盒。通过将试剂盒材料溶解于1 mL注射用水中，并与自制的（177）LuCl3在室温下孵育15分钟来制备（177）Lu-EDTMP患者剂量。通过在正常Wistar大鼠中进行生物分布和闪烁成像研究来研究该药物的药代动力学行为。通过向患有弥漫性骨转移的患者给药该制剂进行临床研究。
制备了五批冻干EDTMP试剂盒，每批50个试剂盒小瓶。每个试剂盒小瓶包含35 mg EDTMP、14.1 mg NaOH和5.8 mg CaCO3的冻干混合物。使用这些试剂盒制备的（177）Lu-EDTMP复合物具有优异的放射化学纯度（>99%）和高稳定性（制备后9天内>98%）。放射化学研究表明，该试剂盒可在pH值6 - 9范围内使用，且对于比活度低至925 GBq·g-1（25 Ci·g-1）的（177）Lu，可用于制备高达3.7 GBq（100 mCi）的（177）Lu-EDTMP。动物体内生物分布研究显示该药物在骨骼中选择性蓄积（约占注射活度的60%），主要通过肾脏清除。对10名患者的初步临床研究显示放射性示踪剂在骨病变中选择性蓄积，并显著缓解了疼痛，从而改善了患者的生活质量。
已开发出适用于制备（177）Lu-EDTMP患者剂量的冻干EDTMP试剂盒，并用于治疗患有弥漫性骨转移的癌症患者的初步研究。该试剂盒也可用于制备其他潜在的骨痛缓解药物，如（153）Sm-EDTMP。
