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Abstract
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×LD50 protection 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.
| Acronyms | ||
| OPH | = | Organophosphorus Hydrolase |
| OPAA | = | organophosphorus acid anhydrolase |
| Demeton-S | = | O,O-diethyl S-2-ethylthioethyl phosphorothioate |
| DFP | = | diisopropylfluorophosphate |
| Paraoxon | = | diethyl p-nitrophenyl phosphate |
| Sarin (GB) | = | isopropyl methylphosphonofluoridate |
| Soman (GD) | = | pinacolyl methylfluorophosphonate |
| Tabun (GA) | = | O-ethyl dimethylamidophosphorylcyanidate |
| VX | = | O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate |
| Acronyms | ||
| OPH | = | Organophosphorus Hydrolase |
| OPAA | = | organophosphorus acid anhydrolase |
| Demeton-S | = | O,O-diethyl S-2-ethylthioethyl phosphorothioate |
| DFP | = | diisopropylfluorophosphate |
| Paraoxon | = | diethyl p-nitrophenyl phosphate |
| Sarin (GB) | = | isopropyl methylphosphonofluoridate |
| Soman (GD) | = | pinacolyl methylfluorophosphonate |
| Tabun (GA) | = | O-ethyl dimethylamidophosphorylcyanidate |
| VX | = | O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate |
Acknowledgements
The authors are thankful to Dr Ray Yinn (ANP Technologies, Inc. 824 Interchange Boulevard, Newark, DE 19711).for providing the polyoxazoline-based dentritic polymers for these studies. These studies were supported by research funds from Texas A&M University, NATO (NATO Linkage Grant #: 977579) and U.S. Army Medical Research Institute of Chemical Defense (Dr Gary A. Rockwood) under the auspices of the U.S. Army Research Office Scientific Services Program administered by Battelle (Delivery Order 0504 Contract No. DAAD19-02-D-0001-0878), the US Army Medical Research Materiel Command (Cooperative Agreement #DAMD 17-00-2-0010), and from National Institute of Health (Grant #: 5UO1 NSO58035-02).
Notes
1. Prophylaxis describes a preventative measure taken to reduce harmful effects of, as used in this study, OP exposure. It is used broadly to include both strict prophylaxis, where no subsequent therapy is utilized, and the ‘pre-treatment’ condition, where additional therapy after exposure may occur. Likewise, ‘treatment’ is used broadly to include both pre-and post-exposure treatments.