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首页> 外文期刊>Nuclear Medicine Communications >A kit formulation for the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma.
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A kit formulation for the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma.

机译：制备188Re-碘油的试剂盒制剂：不可切除肝细胞癌患者的临床前研究和初步治疗评估。

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摘要

A lyophilized kit formulation for the efficient labelling of lipiodol with generator-produced rhenium-188 is described. The preliminary preparation of the lipophilic complex bis-(diethyldithiocarbamato)nitrido rhenium-188 (188ReN-DEDC) was carried out using a two-vial kit containing S-methyl-N-methyl-dithiocarbazate, SnCl2 and sodium oxalate in the first vial, and diethyldithiocarbamate and a carbonate buffer in the second vial. After mixing of the reaction solution with lipiodol, the complex 188ReN-DEDC was quantitatively extracted and retained by this hydrophobic substance, thus allowing the stable incorporation of the beta-emitting radionuclide. The radiochemical purity of the complex 188ReN-DEDC was 97+/-2%. The activity extracted into the lipiodol phase was 96+/-3% of the initial activity, indicating that the complex 188ReN-DEDC was almost quantitatively removed from the aqueous reaction solution. In vitro stability studies in human plasma, at 37 degrees C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of Re-lipiodol in non-tumour-bearing Wistar rats at 6, 24, 48 and 72 h after intraportal venous injection showed one-third of total activity in the liver at 6 h, declining to 2% retention at 72 h. Bowel uptake at 6 and 24 h declined to low levels at 48 and 72 h. Renal activity peaked at 1.7%, diminishing to 0.6% over 48 h. Rat whole body gamma imaging showed gut activity in addition to hepatic uptake at 6 and 24 h, but only liver was evident from 48 to 72 h. Kidneys were not demonstrable at any imaging time point. In nine patients, activity was localized in the tumours immediately following intrahepatic arterial injection. Computed tomography/single-photon emission computed tomography (CT/SPECT) imaging at 1 and 24 h confirmed the retention of 188Re-lipiodol in the hepatoma, with minimal gut uptake and no lung activity over 24 h. These patients were subsequently treated with activities of 2.5-5 GBq of 188Re-lipiodol fractions without adverse effects. Six patients followed for up to 2 years in the pilot study achieved stable disease and there was objective partial response in one patient. Repeated treatments were performed on two to three occasions in three patients without evident toxicity. An additional patient given 6 GBq of 188Re-lipiodol demonstrated myelosuppression, which recovered with granulocyte colony-stimulating factor (GCSF) and platelet support. It is concluded that 188Re-lipiodol, prepared using our novel kit formulation, is stable in vivo and provides safe and effective therapy of unresectable hepatocellular carcinoma when given via the hepatic artery, either alone or in combination with transarterial chemoembolization.
机译：描述了用发生器产生的rh188有效标记脂质碘的冻干试剂盒制剂。使用在第一小瓶中包含S-甲基-N-甲基-二硫代氨基甲酸酯，SnCl2和草酸钠的两瓶试剂盒进行了亲脂性复合物双-（二乙基二硫代氨基甲酸酯）硝鎓rid188（188ReN-DEDC）的初步制备，在第二小瓶中加入二乙基二硫代氨基甲酸酯和碳酸盐缓冲液。将反应溶液与碘油混合后，复合物188ReN-DEDC被定量地提取并被该疏水性物质保留，从而允许稳定地掺入发射β射线的放射性核素。配合物188ReN-DEDC的放射化学纯度为97 +/- 2％。提取到碘油相中的活性为初始活性的96 +/- 3％，表明从反应水溶液中几乎定量地除去了复合物188ReN-DEDC。在37度的人体血浆中进行的体外稳定性研究表明，在三个半衰期内释放的活性不到15％。门静脉内注射后6、24、48和72小时，再碘油在未荷瘤的Wistar大鼠中的生物分布显示，在6小时时肝脏中总活性的三分之一，在72小时时下降至2％。 6和24小时的肠吸收在48和72小时降至低水平。肾活性在1.7％达到峰值，并在48小时内降至0.6％。大鼠全身γ成像显示除了在6和24 h摄取肝外，还有肠道活动，但在48至72 h内只有肝脏可见。肾脏在任何成像时间点均无法显示。在9例患者中，肝内动脉注射后立即在肿瘤中定位了活性。计算机断层扫描/单光子发射计算机断层扫描（CT / SPECT）成像在1和24 h证实了188Re-碘油在肝癌中的保留，在24 h内肠吸收最少，无肺活动。这些患者随后接受了188 Re-碘油组分的2.5-5 GBq的活性治疗，而没有不良反应。在这项初步研究中，有6名患者随访了2年，病情稳定，其中1名患者出现了客观的部分缓解。对三名患者进行了两次至三次重复治疗，无明显毒性。另一名给予6 GBq的188Re-碘油患者显示出骨髓抑制，并通过粒细胞集落刺激因子（GCSF）和血小板支持得以恢复。结论是，使用我们新颖的试剂盒制剂制备的188Re-碘油在体内是稳定的，并且当通过肝动脉单独或与经动脉化学栓塞联合使用时，可为不可切除的肝细胞癌提供安全有效的治疗方法。

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