Pulmonary delivery of an aerosolized recombinant human butyrylcholinesterase pretreatment protects against aerosolized paraoxon in macaques

Yvonne J. Rosenberg, Beth Laube, Lingjun Mao, Xiaoming Jiang, Segundo Hernandez-Abanto, Keunmyoung D. Lee, Robert Adams

Research output: Contribution to journalArticle

Abstract

Butyrylcholinesterase (BChE) is the leading pretreatment candidate against exposure to organophosphates (OPs), which pose an ever increasing public and military health. Since respiratory failure is the primary cause of death following acute OP poisoning, an inhaled BChE therapeutic could prove highly efficacious in preventing acute toxicity as well as the associated delayed neuropathy. To address this, studies have been performed in mice and macaques using Chinese Hamster Ovary cells (CHO)-derived recombinant (r) BChE delivered by the pulmonary route, to examine whether the deposition of both macaque (Ma) and human (Hu) rBChE administered as aerosols (aer) favored the creation and retention of an efficient protective "pulmonary bioshield" that could scavenge incoming (inhaled) OPs in situ thereby preventing entry into the circulation and inhibition of plasma BChE and AChE on red blood cells (RBC-AChE) and in cholinergic synapses. In contrast to parenteral delivery of rBChE, which currently requires posttranslational modification for good plasma stability, an unmodified aer-rBChE pretreatment given 1-40 h prior to >1 LD50 of aer-paraoxon (Px) was able to prevent inhibition of circulating cholinesterase in a dose-dependent manner. These studies are the first to show protection by rBChE against a pesticide such as paraoxon when delivered directly into the lung and bode well for the use of a non-invasive and consumer friendly method of rHuBChE delivery as a human treatment to counteract OP toxicity.

Original languageEnglish (US)
Pages (from-to)167-171
Number of pages5
JournalChemico-Biological Interactions
Volume203
Issue number1
DOIs
StatePublished - Mar 25 2013

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Keywords

  • Aerosol delivery
  • Butyrylcholinesterase
  • Monkey model
  • Paraoxon
  • Protection

ASJC Scopus subject areas

  • Toxicology

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