基于表面等离激元共振技术的生物剂量计研究
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摘要
核技术在军民领域的广泛应用必然会伴随着核辐射事故的发生。核辐射事故发生时人体受照剂量信息的获取是核安全事故有效处理的基础。生物剂量计是利用可测量和分析的生物指标的改变来刻度受照剂量的一类生物标记物与分析方法，它具有物理剂量计无法比拟的忠实性及可重复获得和预测预后的特性。本课题将灵敏度高、免标记和便于事故现场检测的表面等离激元共振（Surface plasma resonance,SPR）生物传感技术与辐射敏感的次黄嘌呤鸟嘌呤磷酸核糖转移酶(Hypoxanthine guanine phosphoriobsyl transferase,HPRT)、DNA和神经酰胺相结合，分别发展基于SPR方法的HPRT、DNA断片及神经酰胺三种生物剂量计体系。
在基于SPR方法的HPRT生物剂量估计体系的研究中，首先采用6-硫代鸟嘌呤为探针，抗HPRT抗体为信号扩增分子的SPR方法灵敏的检测HPRT分子含量，其最低检测限可达2.1ng/ml；然后采用此检测策略检测不同剂量γ射线辐照小鼠的淋巴细胞HPRT，所获得的SPR信号与γ射线辐照剂量之间存在线性关系（其线性关系的数学表达式为y=-11.05x+113.43，相关系数为-0.96），建立基于SPR方法的HPRT生物剂量重建体系，该剂量体系的剂量估算范围为0.05～10Gy；最后采用HPRT剂量效应关系重建辐照小鼠的生物剂量，所获得的重建剂量与双盲剂量接近，重建剂量的精度高。
在基于SPR方法的DNA断片生物剂量估计体系的研究中，首先采用碱性磷酸酶为探针的SPR方法检测辐照诱导的小牛胸腺DNA断裂，建立SPR检测DNA断片的方法；然后采用此检测策略检测不同剂量γ射线辐照淋巴细胞的DNA断片，DNA断片的SPR信号与γ射线辐照剂量之间存在指数关系（y=162.94×(1-exp-0.99x)，相关系数为0.93），建立基于SPR方法的DNA断片生物剂量重建体系，该剂量体系的剂量估算范围为0.02～7Gy；最后采用DAN断裂剂量效应关系估算小鼠的辐照剂量，所获得的重建剂量与双盲剂量接近，剂量估算的精度比较高。
在基于SPR方法的神经酰胺生物剂量估计体系的研究中，首先优化抗神经酰胺单克隆抗体15B4为探针，抗神经酰胺单克隆抗体NHCER-2为信号扩增分子的SPR检测小鼠尿液神经酰胺的方法，建立SPR检测小鼠尿液神经酰胺的方法；然后采用此检测策略检测不同剂量γ射线辐照小鼠尿液的神经酰胺，所获SPR信号与γ射线辐照剂量之间存在线性平方关系（y=-1.26x2+15.60x+17.45，相关系数为0.92），建立基于SPR方法的神经酰胺生物剂量重建体系，该剂量体系的剂量估算范围为1～7Gy；最后采用神经酰胺剂量效应关系估算小鼠的辐照剂量，所获得的重建剂量的精度较低。
本研究发展的基于SPR方法的HPRT和DNA断片生物剂量体系灵敏、简便、快速，其估算范围和估算的精度均优于同类生物剂量计；而在这三种基于SPR方法的新型生物剂量计中，HPRT生物剂量体系的估算范围最宽，估算精度最高，其性能优于其它两种生物剂量体系。
The wide application of nuclear technology in the field of military and civilianinevitably accompanies by the nuclear radiation accidents. The information of absorbeddose is the foundation of triage of human beings in the accidental area as well as thekey of correct diagnosis and treatment for the suspected viticms. Therefore, theacquisition of this information is the basis for effective processing of the nuclearradiation accidents. A biological dosimeter is a detectable variation of a biologicalparameter after ionizing radiation, which is used for quantification of the absorbeddose in an exposed individual.It’ s characteristics is loyal,reusable andprognosis.Biological dose assessment can help develop a treatment strategy for theradiation victim a short time after a radiation catastrophe.The research is to develophypoxanthine guanine phosphoriobsyl transferase (HPRT), DNA breaks and ceramidebiological dosimetries, respectively. These three kinds of biological dosimeters areall based on the surface plasma resonance biosensor technology which is high sensitivity,label-free and easy to detect in the scene of the accident.
In the research of establishment of HPRT biodosimetry, the SPR biosensor with6-thioguaine as a probe and the anti-HPRT antibody as a signal enhancement was firstlyused to detect HPRT. The lowest detection limit achieves at2.1ng/ml. This detectionstrategy was then used to detect HPRT in lymphocytes extracted from mice irradiatedwith gamma doses range from0.01to10Gy. There is a linear relationship between thecorresponding SPR singanl and gamma dose.The dose estimation range based on this linearrelationship is0.05～10Gy. Finally, the linear relationship was used to reconstructthe absorbed dose of mice. The reconstructed doses are similar to the “double-blinded”dose.
In the research of establishment of DNA breaks biodosimetry, the SPR biosensor withalkaline phosphase as the probe was firstly used to determinate DNA breaks of calf thymusinduced by gamma dose. This detection strategy was then used to determinate DNA breaksof lymphocytes irradiated with different gamma doses (0.01～7Gy). There is anexponential relationship between the corresponding SPR singanl and gamma dose.The doseestimation range based on this expinential relationship is0.02～7Gy. Finally, theexponential relationship was used to reconstruct the absorbed dose of mice. The reconstructed doses are similar to the “double-blinded” dose.
In the research of establishment of ceramide biodosimetry, the detection ofceramide in urine of mice using the SPR biosensor with the anti-ceramide monoclonalantibody15B4as the probe and anti-ceramide monoclonal antibody NHCER-2as the signalenhancement was firstly optimized.The optimized method was then used to detect ceramideof urine collected from irradiated mice (0.5～7Gy).There is a linear quandraticrelationship between the corresponding SPR signal and gamma dose. The dose estimationrange based on this linear quandratic relationship is1～7Gy. Finally, the linearquandratic relationship was used to reconstruct the absorbed dose of mice. Thereconstructed doses are lower than the “double-blinded” dose.
In this study, HPRT and DNA breaks biodosimetries based on the SPR technology aresensitive, simply and rapid.Both of dose estimation range and estimation accuracy aresuperior to their traditional dosimeters.Comparison of performance of these three newlydeveloped biodosimeters, the dose estimation range and estimation accuracy of HPRTdosimeter is the best.
在基于SPR方法的HPRT生物剂量估计体系的研究中，首先采用6-硫代鸟嘌呤为探针，抗HPRT抗体为信号扩增分子的SPR方法灵敏的检测HPRT分子含量，其最低检测限可达2.1ng/ml；然后采用此检测策略检测不同剂量γ射线辐照小鼠的淋巴细胞HPRT，所获得的SPR信号与γ射线辐照剂量之间存在线性关系（其线性关系的数学表达式为y=-11.05x+113.43，相关系数为-0.96），建立基于SPR方法的HPRT生物剂量重建体系，该剂量体系的剂量估算范围为0.05～10Gy；最后采用HPRT剂量效应关系重建辐照小鼠的生物剂量，所获得的重建剂量与双盲剂量接近，重建剂量的精度高。
在基于SPR方法的DNA断片生物剂量估计体系的研究中，首先采用碱性磷酸酶为探针的SPR方法检测辐照诱导的小牛胸腺DNA断裂，建立SPR检测DNA断片的方法；然后采用此检测策略检测不同剂量γ射线辐照淋巴细胞的DNA断片，DNA断片的SPR信号与γ射线辐照剂量之间存在指数关系（y=162.94×(1-exp-0.99x)，相关系数为0.93），建立基于SPR方法的DNA断片生物剂量重建体系，该剂量体系的剂量估算范围为0.02～7Gy；最后采用DAN断裂剂量效应关系估算小鼠的辐照剂量，所获得的重建剂量与双盲剂量接近，剂量估算的精度比较高。
在基于SPR方法的神经酰胺生物剂量估计体系的研究中，首先优化抗神经酰胺单克隆抗体15B4为探针，抗神经酰胺单克隆抗体NHCER-2为信号扩增分子的SPR检测小鼠尿液神经酰胺的方法，建立SPR检测小鼠尿液神经酰胺的方法；然后采用此检测策略检测不同剂量γ射线辐照小鼠尿液的神经酰胺，所获SPR信号与γ射线辐照剂量之间存在线性平方关系（y=-1.26x2+15.60x+17.45，相关系数为0.92），建立基于SPR方法的神经酰胺生物剂量重建体系，该剂量体系的剂量估算范围为1～7Gy；最后采用神经酰胺剂量效应关系估算小鼠的辐照剂量，所获得的重建剂量的精度较低。
本研究发展的基于SPR方法的HPRT和DNA断片生物剂量体系灵敏、简便、快速，其估算范围和估算的精度均优于同类生物剂量计；而在这三种基于SPR方法的新型生物剂量计中，HPRT生物剂量体系的估算范围最宽，估算精度最高，其性能优于其它两种生物剂量体系。
The wide application of nuclear technology in the field of military and civilianinevitably accompanies by the nuclear radiation accidents. The information of absorbeddose is the foundation of triage of human beings in the accidental area as well as thekey of correct diagnosis and treatment for the suspected viticms. Therefore, theacquisition of this information is the basis for effective processing of the nuclearradiation accidents. A biological dosimeter is a detectable variation of a biologicalparameter after ionizing radiation, which is used for quantification of the absorbeddose in an exposed individual.It’ s characteristics is loyal,reusable andprognosis.Biological dose assessment can help develop a treatment strategy for theradiation victim a short time after a radiation catastrophe.The research is to develophypoxanthine guanine phosphoriobsyl transferase (HPRT), DNA breaks and ceramidebiological dosimetries, respectively. These three kinds of biological dosimeters areall based on the surface plasma resonance biosensor technology which is high sensitivity,label-free and easy to detect in the scene of the accident.
In the research of establishment of HPRT biodosimetry, the SPR biosensor with6-thioguaine as a probe and the anti-HPRT antibody as a signal enhancement was firstlyused to detect HPRT. The lowest detection limit achieves at2.1ng/ml. This detectionstrategy was then used to detect HPRT in lymphocytes extracted from mice irradiatedwith gamma doses range from0.01to10Gy. There is a linear relationship between thecorresponding SPR singanl and gamma dose.The dose estimation range based on this linearrelationship is0.05～10Gy. Finally, the linear relationship was used to reconstructthe absorbed dose of mice. The reconstructed doses are similar to the “double-blinded”dose.
In the research of establishment of DNA breaks biodosimetry, the SPR biosensor withalkaline phosphase as the probe was firstly used to determinate DNA breaks of calf thymusinduced by gamma dose. This detection strategy was then used to determinate DNA breaksof lymphocytes irradiated with different gamma doses (0.01～7Gy). There is anexponential relationship between the corresponding SPR singanl and gamma dose.The doseestimation range based on this expinential relationship is0.02～7Gy. Finally, theexponential relationship was used to reconstruct the absorbed dose of mice. The reconstructed doses are similar to the “double-blinded” dose.
In the research of establishment of ceramide biodosimetry, the detection ofceramide in urine of mice using the SPR biosensor with the anti-ceramide monoclonalantibody15B4as the probe and anti-ceramide monoclonal antibody NHCER-2as the signalenhancement was firstly optimized.The optimized method was then used to detect ceramideof urine collected from irradiated mice (0.5～7Gy).There is a linear quandraticrelationship between the corresponding SPR signal and gamma dose. The dose estimationrange based on this linear quandratic relationship is1～7Gy. Finally, the linearquandratic relationship was used to reconstruct the absorbed dose of mice. Thereconstructed doses are lower than the “double-blinded” dose.
In this study, HPRT and DNA breaks biodosimetries based on the SPR technology aresensitive, simply and rapid.Both of dose estimation range and estimation accuracy aresuperior to their traditional dosimeters.Comparison of performance of these three newlydeveloped biodosimeters, the dose estimation range and estimation accuracy of HPRTdosimeter is the best.
引文
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