Nanoscavenger provides long-term prophylactic protection against nerve agents in rodents

• Published in: Science translational medicine 2019-01, Vol.11 (473)
• Main Authors: Zhang, Peng, Liu, Erik J, Tsao, Caroline, Kasten, Shane A, Boeri, Michael V, Dao, Thuy L, DeBus, Sandra J, Cadieux, C Linn, Baker, Cetara A, Otto, Tamara C, Cerasoli, Douglas M, Chen, Yantao, Jain, Priyesh, Sun, Fang, Li, Wenchen, Hung, Hsiang-Chieh, Yuan, Zhefan, Ma, Jinrong, Bigley, Andrew N, Raushel, Frank M, Jiang, Shaoyi
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Animal models; Animals; Drug development; Female; Guinea Pigs; Immune response; Immunosuppressive agents; Intoxication; Lethality; Male; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nerve agents; Nerve Agents - toxicity; Neurotoxicity; Organophosphorus compounds; Paraoxon - toxicity; Pharmacokinetics; Protective Agents - administration & dosage; Protective Agents - pharmacokinetics; Protective Agents - pharmacology; Rats, Sprague-Dawley; Sarin; Sarin - toxicity; Survival Analysis; Time Factors; Tissue Distribution
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aau7091

Nerve agents are a class of organophosphorus compounds (OPs) that blocks communication between nerves and organs. Because of their acute neurotoxicity, it is extremely difficult to rescue the victims after exposure. Numerous efforts have been devoted to search for an effective prophylactic nerve agent bioscavenger to prevent the deleterious effects of these compounds. However, low scavenging efficiency, unfavorable pharmacokinetics, and immunological problems have hampered the development of effective drugs. Here, we report the development and testing of a nanoparticle-based nerve agent bioscavenger (nanoscavenger) that showed long-term protection against OP intoxication in rodents. The nanoscavenger, which catalytically breaks down toxic OP compounds, showed a good pharmacokinetic profile and negligible immune response in a rat model of OP intoxication. In vivo administration of the nanoscavenger before or after OP exposure in animal models demonstrated protective and therapeutic efficacy. In a guinea pig model, a single prophylactic administration of the nanoscavenger effectively prevented lethality after multiple sarin exposures over a 1-week period. Our results suggest that the prophylactic administration of the nanoscavenger might be effective in preventing the toxic effects of OP exposure in humans.