Human usually uses oximes as acetylcholinesterase (AChE)-activated antidotes to treat organophosphorus (OP) compound poisoning. In addition, drugs such as atropine can also be used for its detoxification treatment. However, the natural blood-brain barrier (BBB) severely limits the penetration of these drugs into the central nervous system. As a widely used reactivator, HI-6 is difficult to penetrate the BBB due to its hydrophilicity. Therefore, we hope that a large amount of HI-6 can penetrate the BBB through the drug delivery system. They can quickly release and activate the inhibited AChE in the center. Polybutylcyanoacrylate (PBCA) has good biodegradability and biocompatibility, which ensures the safety of the treatment. Pluronic P85 gets the advantages of inhibiting P-glycoprotein (P-gp) efflux and improving drug solubility. In this study, the HI-6-loaded nanoparticles that conjugated with c(RGDyK) cyclic peptide were successfully synthesized, with encapsulation efficiency 63.69%, drug loading 6.2%, average particle size 166.9 nm, and zeta potential − 22.0 mV. The shape was round and evenly distributed. The BBB model was established by astrocytes and brain capillary endothelial cells, and the transendothelial cell resistance values of the BBB model could reach 183 Ω. The penetration effect of the c(RGDyK)-modified nanoparticles was about 4 times the free HI-6 on the BBB model in vitro. The c(RGDyK)-modified nanoparticles were more effective at targeting the brain than the unmodified nanoparticles in vivo. In addition, reactivation evaluation showed that the modified nanoparticles had a higher reactivation rate for poisoned mice, indicating that the nanoparticles modified with c(RGDyK) cyclic peptide had more central targeting. The successful implementation of this study is expected to improve the treatment level of nerve agents.

Graphical abstract

人类通常使用肟作为乙酰胆碱酯酶（AChE）激活的解毒剂来治疗有机磷（OP）化合物中毒。另外，诸如阿托品的药物也可以用于其排毒治疗。但是，天然血脑屏障（BBB）严重限制了这些药物渗透到中枢神经系统。作为广泛使用的活化剂，HI-6由于其亲水性而难以渗透BBB。因此，我们希望大量的HI-6可以通过药物输送系统穿透血脑屏障。它们可以快速释放并激活中心受抑制的AChE。聚氰基丙烯酸丁酯（PBCA）具有良好的生物降解性和生物相容性，从而确保了治疗的安全性。Pluronic P85具有抑制P-糖蛋白（P-gp）外流和提高药物溶解度的优势。在这个研究中，成功合成了与c（RGDyK）环肽偶联的HI-6负载纳米粒子，其包封效率为63.69％，药物负载率为6.2％，平均粒径为166.9 nm，ζ电位为-22.0 mV。形状是圆形的，分布均匀。由星形胶质细胞和脑毛细血管内皮细胞建立BBB模型，BBB模型的跨内皮细胞电阻值可达到183Ω。c（RGDyK）修饰的纳米粒子在体外对BBB模型的渗透作用约为游离HI-6的4倍。c（RGDyK）修饰的纳米粒子比未修饰的体内纳米粒子更有效地靶向大脑。此外，再活化评估显示，经修饰的纳米粒子对中毒小鼠的再活化率更高，表明用c（RGDyK）环肽修饰的纳米粒子具有更多的中心靶向性。这项研究的成功实施有望改善神经毒剂的治疗水平。

图形概要