PEG-纳米石墨烯-DTPA对放射性钚元素促排效果的研究

Plutonium is one of the most common actinides which caused radioactive internal pollution in nuclear accidents. Upto now, Ca-DTPA and Zn-DTPA are the only approved agents for plutonium decorporation in clinic, which are fail to cross cellular membrane, and difficultly remove the plutonium deposited in the main retention sites, such as liver and skeleton. Our preliminary study discovered that PEG-NGS, which had no cyto_toxicity, majorly accumulated in liver, skeleton and spleed, passed into and out of the cells freely, and was easy to be excreted from the animal body. Therefore, PEG-NGS-DTPA by a combination of PEG-NGS and DTPA was designed and synthesed to improve the decorporation efficency of plutonium. The purpose of the current study is to demonstrate the efficient chelation of PEG-NGS-DTPA to plutonium in vitro and to demonstrate the plutonium decorporation efficency and the best delivery pathway, time and dosage of PEG-NGS-DTPA in animal models. These promising studies will provide the necessary foundation for potent application of PEG-NGS-DTPA as a new chelation agent for the more effective decorporation of the radioactive actinides, in the medical emergency therapy of patient with plutonium pollution.

钚是核事故后造成放射性内污染最常见的锕系元素之一。目前唯一应用于临床的钚促排药为DTPA钙盐和锌盐，但其缺点在于不能透过细胞膜，难以清除积聚在骨和肝脏的钚。我们前期的动物实验发现无毒副作用的PEG-纳米石墨烯主要聚集在肝、脾和骨，能自由出入细胞，且易于排出体外。因此我们以PEG-纳米石墨烯为载体与DTPA连接合成了新促排剂PEG-纳米石墨烯-DTPA，以提高DTPA对钚促排的效果。本项目拟通过体外实验以明确PEG-纳米石墨烯-DTPA与钚的螯合能力；在此基础上，以大鼠为模型，研究PEG-纳米石墨烯-DTPA促排钚的效果及其最佳给药途径，最佳时间和最佳剂量。本项目的完成将为PEG-纳米石墨烯-DTPA作为一更有效的新型促排药物在放射性钚等锕系元素内污染事故的医学应急处理和治疗中的应用提供必要的实验基础和依据。

利用125I 标记PEG-纳米石墨烯-DTPA，得到的药代动力学参数为t1/2Alpha为0.72±0.12 h，t1/2Beta为7.79±0.98h，AUC0-t为20.01±3.56 %ID/g*h；体内分布实验和活体成像结果表明PEG-纳米石墨烯-DTPA主要聚集在肝脾（网状内皮系统）。体外实验PEG-纳米石墨烯-DTPA与Th（NO3）4的螯合率大约为57.11%±2.56%。染钍后即刻给药PEG-纳米石墨烯-DTPA组尿和粪中钍排出量明显高于DTPA-ZnNa3组；并且PEG-纳米石墨烯-DTPA组钍在肝和骨的滞留量低于DTPA-ZnNa3组。延迟给药明显降低PEG-纳米石墨烯-DTPA组和DTPA-ZnNa3对钍的促排作用，但明显高于对照组，但延迟给药PEG-纳米石墨烯-DTPA与传统促排药DTPA-ZnNa3组对钍的促排效果没有明显差异；PEG-纳米石墨烯-DTPA组和DTPA-ZnNa3组肝脏和骨中钍的滞留量明显低于对照组。染毒后延迟给药对钍的促排作用明显低于即刻给药。血生化指标ALT、AST 和ALP水平在注射钍后明显升高，但给予PEG-纳米石墨烯-DTPA后其水平恢复，并且比DTPA-ZnNa3组明显。病理HE染色结果显示对照组、DTPA-ZnNa3组和PEG-纳米石墨烯-DTPA组大鼠的肝脏、脾脏和肾脏的细胞形态学及结构均未见明显异常，骨髓涂片各组未见明显异常。静脉注射给药、肌肉注射给药促排效果明显优于口服给药（本实验是灌胃）。说明PEG-纳米石墨烯-DTPA组对钍的促排效果优于传统促排药DTPA-ZnNa3。为PEG-纳米石墨烯-DTPA作为一更有效的新型促排药物在放射性钍等锕系元素内污染事故的医学应急处理和治疗中的应用提供必要的实验基础和依据。