title: Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification.
abstract: The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration.
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Lixue
authors.initials: L
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Feijian
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Sui
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Wanhua
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Functional Nano & Soft Materials, Soochow University, Soochow, 215123, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. yonganw@126.com.
authors.forename: Yongan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D065546:Drug Liberation; D051379:Mice; D053758:Nanoparticles; D000067397:Nerve Agents / Q000378:metabolism*; D010091:Oximes / Q000008:administration & dosage*; D011726:Pyridinium Compounds / Q000008:administration & dosage*; D051381:Rats; D012822:Silicon Dioxide; D012999:Soman / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000067397:Nerve Agents; D010091:Oximes; D011726:Pyridinium Compounds; D012822:Silicon Dioxide; D012999:Soman; C022870:asoxime chloride