In vitro aerosol delivery and regional airway surface liquid concentration of a liposomal cationic peptide.
A liposome encapsulation was optimized for the entrapment and aerosol delivery of an alpha-helical cationic peptide, CM3, which had shown good antimicrobial and antiendotoxin activity in vitro. The encapsulation procedure and the phospholipids used were selected to maximize both the encapsulation and nebulization efficiencies, without compromising liposomal integrity during nebulization. The best compromise was found with dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (3:1 molar ratio), which allowed for peptide encapsulation levels of 730 microg/mL using 30 mM lipid concentration. The aerosol produced with the selected liposomal formulation was subsequently analyzed for determination of size distribution and nebulizer efficiencies. These quantities were used as input for a mathematical lung deposition model, which predicted local lung depositions of the liposomal peptides for three models of lung geometry and breathing patterns: an adult, an 8-year-old child, and a 4-year-old child. The deposition results were then applied to a novel model of airway surface liquid in the lung to assess the concentration of the deposited peptide. The resulting concentration estimates indicate that the minimum inhibitory levels of CM3 can be reached over most part of the tracheobronchial region in the adult model, and can be exceeded throughout the same region in both pediatric model subjects, using a valved jet nebulizer with a 2.5mL volume fill.
Lange
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Aerosol Research Laboratory of Alberta, Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada, T6G 2G8.
Hancock
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Samuel
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Finlay
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WH
D000328:Adult; D000336:Aerosols; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005544:Forecasting; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008168:Lung / Q000378:metabolism; D008433:Mathematics; D008954:Models, Biological; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry; D020545:Respiratory Mucosa / Q000378:metabolism*; D013499:Surface Properties; D014867:Water / Q000737:chemistry
D000336:Aerosols; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D008081:Liposomes; D010743:Phospholipids; D014867:Water