螯合IL-1β单克隆抗体的顺磁性纳米粒子在癫痫诊治中的价值

Epilepsy is one of the most common neurological disorders,which most of the drug treatment can alleviate,but there are still about 30% patients refractory to medical treatment,becoming refractory epilepsy,part ofwhich requires surgical treatment ,however the accurate localization of epileptogenic foci is often a difficult problem.Superpamagnetic nanoparticals(MNP) has the charateristic of specific distribution in organism and controlled motion under the external magnetic field ,because of which MNP has been applied to the tumor cell enrichmwnt,the separation,the magnetic targeting drug as well as the diagnosis and treatment of disease and other aspects .In our study ,we applly MNP chelated alpha methy1 trytophan(AMI) to the location of epileptic foci.Some research has found that the damage of reactions between immune cells and blood vessels may be the key cause of epilepsy .Studies have confirmed that IL-1βis involved in epilepsy formation process through a variety of direct or indirect role to neurons,which makes the application of IL-1βmonoclonal antibody treatment to epilepsy possible.In our study,we applly IL-1βmonoclonal antibodies or MNPchelated IL-1βmonoclonal antibodies to the treatment of refractory epilepsy,in order to explore a new therapeutic strategy of the refractory epilepsy.

癫痫是神经科常见疾患之一,多数经药物治疗可缓解,但约30%患者药物治疗无效,成为难治性癫痫,其中部分患者需要外科手术治疗,然而致痫灶的准确定位常常是一个难题．超顺磁性纳米粒子（MNP）由于具有在生物体内的特异性分布以及在外加磁场下可控运动的特点，已被应用于肿瘤细胞的富集、药物的靶向以及疾病的诊断和治疗等诸多方面。我们应用螯合α-甲基色氨酸（AMT）的MNP功能MRI方法进行癫痫灶定位，探讨难治性癫痫癫痫灶新的定位方法。今年来有研究发现，免疫细胞和血管之间的反应遭到损坏可能是引起癫痫的关键原因。已有研究证实IL-1β通过对神经元的多种直接或间接作用参与癫痫形成过程，这使应用IL-1β单克隆抗体治疗癫痫成为可能。我们应用IL-1β单克隆抗体和螯合IL-1β单克隆抗体的MNP功能MRI方法进行难治性癫痫的治疗，以探讨难治性癫痫新的治疗策略。

癫痫是神经内科最常见的疾病之一，大部分癫痫患者经规范化抗癫痫药物治疗后可控制，仍有约20%-30%难以缓解，称为难治性癫痫，颞叶癫痫是最常见的难治性癫痫。颅脑MRI因图像清晰度高、无电离辐射、对人体无放射性损害等优点成为癫痫病灶最常见的影像学定位方法。超顺磁性氧化铁纳米粒子易透过各种生理屏障到达指定部位。α-甲基色氨酸（alpha-methyl-L-tryptophan，AMT）在致痫灶组织中具有高摄取、高聚集的特点。目前研究表明炎症反应与癫痫发作密切相关，其中IL-1β是参与癫痫发作最常见的炎性因子。本课题通过制作氯化锂—匹罗卡品颞叶癫痫模型，探讨功能性磁性纳米粒子在颞叶癫痫模型中的靶向诊治价值。. 结果显示：①癫痫发作急性期，NLRP3炎症小体被激活，推测NLRP3介导的炎症反应可能参与癫痫的发病过程；②IL-1β单克隆抗体能有效通过血脑屏障，直接中和异常升高的IL-1β，同时阻断IL-1β介导的NF-kB转录水平升高，抑制IL-1β炎症反应、神经元缺失，而起到神经保护作用；③AMT-SPIONs可以透过血脑屏障对癫痫病灶靶向定位；④AMT–SPIONs分子探针MRI最佳扫描时间是注射后240min；⑤anti-IL-1βmAb-SPIONs能对癫痫病灶精确定位，并且通过免疫荧光法及western-blot等方法证明了anti-IL-1βmAb-SPIONs对癫痫组织炎症因子有抑制作用，进一步证明了anti-IL-1β mAb-SPIONs对癫痫病灶的靶向治疗价值；⑥Cy5-AMT-SPIONs双模探针能对急性颞叶癫痫模型中的靶向定位；⑦在AMT的主动靶向定位下IL-1βmAb能更好的透过血脑屏障对癫痫病灶进行靶向治疗。. 我们的研究表明，炎症参与癫痫发病机制，功能性磁性纳米粒子在颞叶癫痫模型中有靶向定位和治疗价值。本研究为功能性磁性纳米粒子应用到难治性癫痫病人致痫灶的定位和治疗提供了理论研究基础。