基于速释型结构的中枢靶向纳米药物应用于神经毒剂中毒救治的研究

When infected by nerve agents, the acetylcholinesterase (AChE), the most important enzyme in human body, would be restrained quickly and irreversibly by the compounds, leading the invalidation of hydrolysis of acetylcholine. The induced breakage of central nervous cholinergic system is the main reason of poisoning death. The existing antidotes of reactivators could reactivate the AChE effectively. But owing to the restriction of the blood-brain barrier (BBB), the current reactivators could only work on the peripheral nervous system (PNS). So how to transport the reactivators into brain quickly and effectively is key point for antichemical medicine. In this research, the nanotechnology is expected to be an effective approach for therapy nerve agent poison rather than the invalid molecular modification ways. Base on the current works, the protein modified mesoporous silica nanoparticles (MSN) and human serum albumin (HSA) were applied as carrier of nanodrugs for loading and transporting HI-6, the best reactivatoer, to cross the BBB and fast release in brain to cure NA poison. By the study of structures, ingredients, kinds of nanocarriers, pharmaceutical effect, brain targeting and drug-safety profiles, the relationship and rules between nano-structure and biological activity would be illustrated systematically. The primary results shown that the nanodrugs have fulfilled the detoxification requirements of strongly targeted characteristics, fast drug releasing and high drug-loading rate, which increased the reactivation rate, protected the brain tissue and enhanced the survival rate of infected animals. The therapeutic index and treatment effect of the nanodrugs we prepared are maximal than the same type of other antidotes in the present reports. This works provide a base for the research and development of new nerve agents antidotes.

神经毒剂中毒后能不可逆的抑制人体乙酰胆碱酯酶，由此引发中枢胆碱能系统的破坏是造成中毒死亡的主要原因。现有的救治药物重活化剂能有效的重活化中毒酶，但由于血脑屏障的存在，仅对外周神经系统有效。如何将现有药物快速、高效输运至中枢起效是防化医学目前关注的重点。本研究率先提出了基于吸附型纳米结构的速释型中枢靶向纳米药物以及超分子结构药物的构筑方案，采用蛋白修饰的纳米多孔硅球和人体血清白蛋白纳米颗粒作为载体将药物高效、快速输运至脑部治疗中毒酶。通过对纳米药物组成、结构、药效、靶向性等研究，系统的阐释了不同纳米药物结构与其生物学活性之间的联系和规律。初步药效结果显示，所提出的速释型中枢靶向纳米药物能有效的满足中毒救治所需的中枢靶向性强、释药迅速、载药量高等要求，显著地活化了中枢中毒酶，有效对抗毒剂，保护脑组织，提高染毒动物存活率，达到目前同类药物中的最高治疗指数，该研究为新型抗毒药物的研发提供了基础。

神经毒剂是目前人类合成的最强毒性的有机化合物。95年东京地铁沙林事件造成大量人员伤亡证实了化学武器的恐怖袭击的威胁已经严重威胁了人民群众的人生安全。因此当前严峻的反恐形式，使得对神经类毒剂急性中毒救治的研究工作提出了更加迫切要求。神经毒剂中毒后能不可逆的抑制人体乙酰胆碱酯酶，由此引发中枢胆碱能系统的破坏是造成中毒死亡的主要原因。现有的救治药物重活化剂能有效的重活化中毒酶，但由于血脑屏障的存在，仅对外周神经系统有效。本研究率先提出了基于吸附型纳米结构的速释型中枢靶向纳米药物的构筑方案，采用蛋白修饰的纳米多孔硅球和人体血清白蛋白纳米颗粒作为载体将药物高效、快速输运至脑部治疗中毒酶。通过扫描电镜等物化表征结果显示，所合成纳米药物尺寸满足高中枢靶向性使用需求，且装载药物能够快速释放，并经血脑屏障体外模型、斑马鱼、小鼠等动物在体实验显示，所合成纳米药物能够穿透血脑屏障进入中枢。药效结果显示，与对照药物HI6相比，所合成纳米药物均大幅提高了核心关键指标中枢乙酰胆碱酯酶的重活化率。其中，修饰转铁蛋白的纳米多孔硅球装载HI-6的纳米药物，将中枢重活化率提升至22%，远超对照药物HI-6 （4%）达五倍以上，有效对抗毒剂，在1.2倍致毒剂致死浓度下保证了染毒动物百分之分存活，达到目前同类药物中的最高治疗指数。且该类型纳米药物生物安全性好，不对动物在体造成影响。该研究为新型抗毒药物的研发提供了参考，为攻克人类最后一个未解的神经毒剂梭曼提供了指导和基础。研究组将基于现有研究的基础上，继续推进相关研究，设计和合成新型纳米药物，进一步提升中毒救治效率，增加药物的安全性等