Title:Aerosolized Liposomal Formulation Prevents Enhanced Drug Transfer from Fibrotic Lungs to the Systemic Circulation
Volume: 18
Issue: 7
Author(s): Kohei Togami*, Kaede Kurasho, Yukimune Kanehira, Hitoshi Tada and Sumio Chono
Affiliation:
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo, Hokkaido 006-8585,Japan
Keywords:
Polyethylene glycolylated liposomes, bleomycin-induced pulmonary fibrosis, idiopathic pulmonary fibrosis, pulmonary
drug delivery system, alveolar epithelial cells, NCI-H441, in vivo imaging.
Abstract:
Background: Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive respiratory
disease characterized by the destruction of the alveolar structure. In pulmonary fibrosis, aerosolized
drugs are easily transferred to the systemic circulation via leakage through the injured alveolar
epithelium. Therefore, pulmonary drug delivery systems for sustained distribution in fibrotic lungs
are needed.
Objective: We evaluated the intrapulmonary pharmacokinetics of aerosolized liposomes as pulmonary
drug delivery systems in mice with bleomycin-induced pulmonary fibrosis.
Methods: The aerosolized liposomal formulations and solutions of model compounds, including indocyanine
green and 6-carboxyfluorescein (6-CF), were intrapulmonary administered to mice with
bleomycin-induced pulmonary fibrosis. In vivo imaging for indocyanine green and 6-CF measurements
in lung tissues and plasma were performed. Additionally, in vitro permeation experiments using
NCI-H441 cell monolayers as a model of alveolar epithelial cells were performed.
Results: The fluorescence signals of indocyanine green following the administration of liposomal
formulations were observed longer in the lungs than those in solution-treated mice. Compared with
the solution, the 6-CF concentrations in lung tissues after the administration of liposomal formulations
were determined higher, whereas those in the plasma were lower. 6-CF permeability was significantly
increased by transforming growth factor-β1 in NCI-H441 cell monolayers treated with
the solution but unchanged in the presence of the liposomal formulation.
Conclusion: The aerosolized liposomal formulation can prevent enhanced drug transfer from fibrotic
lungs into the systemic circulation via the injured alveolar epithelium. This system may be useful
for the sustained distribution of anti-fibrotic agents in fibrotic lungs and the optimization of IPF
therapy.