Enzyme-based Intravascular Defense Against Organophosphorus Neurotoxins: Synergism of Dendritic-enzyme Complexes with 2-PAM and Atropine
Novel, enzyme-complexed, nano-delivery systems have been developed to antagonize the lethal effects of organophosphorus (OP) molecules such as diisopropylfluorophosphate and paraoxon. Polymeric nanocapsules can be used to deliver metabolizing enzymes to the circulation, often increasing the enzyme's efficacy by extending their circulatory life and, in some cases, enhancing their specific activity. The bacterial enzymes organophosphorus hydrolase (OPH) and organophosphorus anhydrolase (OPAA) were encapsulated within a nanocapsule, polyoxazoline-based dendritic polymer carrier and employed in combination with the OP antagonists pralidoxime (2-PAM) and atropine. The effective doses for OPH and OPAA, respectively, were 500–550 and 1500–1650 units/kg mice; the size of the entire complex is approximately 200 nm in diameter. These studies compare the efficacy of the two enzymes as prophylactic systems encapsulated within the dendritic polymer. When used in combination with 2-PAM and atropine, the dendritic encapsuled OPAA provided a 25×LD50protection against DFP intoxication, while the similarly constructed OPH complex showed a more dramatic protection (780×LD50) against paraoxon intoxication in Balb/c mice. The studies demonstrate a synergistic enhancement of the antagonist, since the antidotal protection of 2-PAM+atropine against DFP and paraoxon is approximately 8 and 60×LD50, respectively.
DOI of Published Version
Petrikovics, I.; Wales, M. E.; Jaszberenyi, J. C.; Budai, M. I.; Baskin, S. I.; Szilasi, M.; Logue, B. A.; Chapela, Patricia; and Wild, J. R., "Enzyme-based Intravascular Defense Against Organophosphorus Neurotoxins: Synergism of Dendritic-enzyme Complexes with 2-PAM and Atropine" (2007). Chemistry and Biochemistry Faculty Publications. 40.