title: Pulmonary Delivery of Butyrylcholinesterase as a Model Protein to the Lung.
abstract: Pulmonary delivery has great potential for delivering biologics to the lung if the challenges of maintaining activity, stability, and ideal aerosol characteristics can be overcome. To study the interactions of a biologic in the lung, we chose butyrylcholinesterase (BuChE) as our model enzyme, which has application for use as a bioscavenger protecting against organophosphate exposure or for use with pseudocholinesterase deficient patients. In mice, orotracheal administration of free BuChE resulted in 72 h detection in the lungs and 48 h in the broncheoalveolar lavage fluid (BALF). Free BuChE administered to the lung of all mouse backgrounds (Nude, C57BL/6, and BALB/c) showed evidence of an acute cytokine (IL-6, TNF-α, MIP2, and KC) and cellular immune response that subsided within 48 h, indicating relatively safe administration of this non-native biologic. We then developed a formulation of BuChE using Particle Replication in Non-Wetting Templates (PRINT). Aerosol characterization demonstrated biologically active BuChE 1 μm cylindrical particles with a mass median aerodynamic diameter of 2.77 μm, indicative of promising airway deposition via dry powder inhalers (DPI). Furthermore, particulate BuChE delivered via dry powder insufflation showed residence time of 48 h in the lungs and BALF. The in vivo residence time, immune response, and safety of particulate BuChE delivered via a pulmonary route, along with the cascade impaction distribution of dry powder PRINT BuChE, showed promise in the ability to deliver active enzymes with ideal deposition characteristics. These findings provide evidence for the feasibility of optimizing the use of BuChE in the clinic; PRINT BuChE particles can be readily formulated for use in DPIs, providing a convenient and effective treatment option.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Tojan B
authors.initials: TB
authors.lastname: Rahhal
authors.affiliation: Department of Chemical & Biomolecular Engineering, North Carolina State University , Raleigh, North Carolina 27695, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fromen
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Department of Chemical & Biomolecular Engineering, North Carolina State University , Raleigh, North Carolina 27695, United States.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Kai
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Tammy W
authors.initials: TW
authors.lastname: Shen
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Luft
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.|Department of Chemical & Biomolecular Engineering, North Carolina State University , Raleigh, North Carolina 27695, United States.|Department of Chemistry, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000008:administration & dosage*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D054426:Chemokine CXCL2 / Q000378:metabolism; D058995:Dry Powder Inhalers / Q000379:methods; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010316:Particle Size; D011208:Powders / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000336:Aerosols; D054426:Chemokine CXCL2; D015850:Interleukin-6; D011208:Powders; D014409:Tumor Necrosis Factor-alpha; D002091:Butyrylcholinesterase
keywords: biologics; butyrylcholinesterase; micro/nanoparticle; pulmonary delivery