Zhao Dianfa, Liu Jie, Zhou Yunshan, Zhang Lijuan, Zhong Yuxu, Yang Yang, Zhao Baoquan, Yang Mengru, Wang Yong'an
State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P. R. China.
ACS Appl Mater Interfaces. 2023 Mar 15;15(10):12631-12642. doi: 10.1021/acsami.2c18929. Epub 2023 Mar 3.
It is very important to establish a sustained-release pralidoxime chloride (2-PAM) drug system with brain targeting function for the treatment of neurotoxicant poisoning. Herein, Vitamin B1 (VB1), also known as thiamine, which can specifically bind to the thiamine transporter on the surface of the blood-brain barrier, was incorporated onto the surface of MIL-101-NH(Fe) nanoparticles with a size of ∼100 nm. Pralidoxime chloride was further loaded within the interior of the above resulted composite by soaking, and a resulting composite drug (denoted as 2-PAM@VB1-MIL-101-NH(Fe)) with a loading capacity of 14.8% (wt) was obtained. The results showed that the drug release rate of the composite drug was increased in PBS solution with the increase of pH (2-7.4) and a maximum drug release rate of 77.5% at pH 4. Experiments on the treatment of poisoning by gavage with the nerve agent sarin in mice combined with atropine revealed that sustained release of 2-PAM from the composite drug was achieved for more than 72 h. Sustained and stable reactivation of poisoned acetylcholinesterase (AChE) was observed with an enzyme reactivation rate of 42.7% in the ocular blood samples at 72 h. By using both zebrafish brain and mouse brain as models, we found that the composite drug could effectively cross the blood-brain barrier and restore the AChE activity in the brain of poisoned mice. The composite drug is expected to be a stable therapeutic drug with brain targeting and prolonged drug release properties for nerve agent intoxication in the middle and late stages of treatment.
建立具有脑靶向功能的氯解磷定（2-PAM）缓释给药系统用于治疗神经毒剂中毒非常重要。在此，维生素B1（VB1），也称为硫胺素，其可特异性结合血脑屏障表面的硫胺素转运体，被负载到尺寸约为100nm的MIL-101-NH(Fe)纳米颗粒表面。通过浸泡将氯解磷定进一步负载到上述所得复合物内部，得到负载量为14.8%（重量）的复合药物（记为2-PAM@VB1-MIL-101-NH(Fe)）。结果表明，在PBS溶液中，随着pH值（2-7.4）的升高，复合药物的药物释放速率增加，在pH 4时最大药物释放速率为77.5%。在小鼠中通过灌胃给予神经毒剂沙林并联合阿托品进行中毒治疗实验表明，复合药物中2-PAM的持续释放时间超过72小时。在72小时时，眼部血样中毒性乙酰胆碱酯酶（AChE）的酶复活率为42.7%，观察到中毒的AChE持续且稳定地复活。以斑马鱼脑和小鼠脑为模型，我们发现复合药物能够有效穿过血脑屏障并恢复中毒小鼠脑中的AChE活性。该复合药物有望成为一种稳定的治疗药物，在神经毒剂中毒的中晚期治疗中具有脑靶向和延长药物释放特性。
