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

Abstract

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.

Enhancing organophosphate hydrolase efficacy via protein engineering and immobilization strategies

“…62 OPH can also be encapsulated within a zwitterionic polymeric gel comprising poly(carboxybetaine) (PCB). 63 Unlike PEG, coating with PCB has no adverse effect on catalytic efficiency of OPH against paraoxon. The polymeric gel significantly improves the storage stability with OPH being active for 6 months at 4°C under aqueous conditions.…”

De novo design of functional zwitterionic biomimetic material for immunomodulation

“…For example, zwitterionic hydrogels have been shown to prevent the occurrence of foreign body reactions including capsule formation for at least 3 months in mice (5). Moreover, nanoparticles coated with zwitterionic polymers bear reduced interactions with biological systems and are able to escape the immune recognition, exhibiting "immune stealth" (6)(7)(8)(9). Up to date, a number of zwitterionic polymers including poly(2-methacryloyloxyethyl phosphorylcholine) (MPC), poly(sulfobetaine), poly(carboxy betaine), and poly(trimethylamine N-oxide) have been developed (2,3,10), which are being extensively explored to improve the longevity and performance of medical devices, implants, and drug delivery systems.…”

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

“…OP hydrolases are of great biotechnological and medical interest. Phosphotriesterases (PTE) of various origins, in particular, can be used for detection of OPs [13], decontamination and remediation [8,[14][15][16][17][18] and for therapy of OP poisoning as catalytic bioscavengers [7,[19][20][21][22]. Because OPs are hemi-substrates of ChEs, research of novel human ChE mutants capable of hydrolyzing OPs is of great interest for improving catalytic bioscavenger-based medical countermeasures of OP poisoning [23][24][25] and implementation of pseudocatalytic bioscavenger systems composed of ChE-reactivator [26][27][28].…”