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Size-dependent dextran transport across rat alveolar epithelial cell monolayers
Y Matsukawa1, V H Lee, E D Crandall
1Department of Pharmaceutical Sciences, University of Southern California, Los Angeles 90033, USA.
Journal of Pharmaceutical Sciences
|March 1, 1997
Summary
This study investigated macromolecular drug transport across the alveolar epithelial barrier using fluorescein isothiocyanate-labeled dextrans (FDs). Results indicate that smaller FDs (<5 nm) cross via paracellular pathways, while larger FDs (>6 nm) use other routes like pinocytosis.
Area of Science:
- Pharmacology
- Cell Biology
- Pulmonary Science
Background:
- Pulmonary drug delivery of macromolecules is challenging due to the alveolar epithelial barrier.
- Understanding transport mechanisms is crucial for developing effective macromolecular therapies.
Purpose of the Study:
- To investigate the effect of molecular size on dextran transport across an in vitro alveolar epithelial barrier model.
- To elucidate the pathways utilized by macromolecules for pulmonary absorption.
Main Methods:
- Utilized fluorescein isothiocyanate-labeled dextrans (FDs) of varying molecular weights (4-150 kDa) as model drugs.
- Measured unidirectional fluxes and apparent permeability coefficients (Papp) across rat alveolar epithelial cell monolayers at different temperatures.
- Analyzed dextran integrity and identified potential transport pathways through equivalent pore analysis.
Main Results:
- Dextran permeability (Papp) decreased with increasing molecular weight for smaller dextrans (4-40 kDa), showing an inverse relationship.
- Larger dextrans (70-150 kDa) exhibited similar, low permeability, which was significantly reduced at lower temperatures.
- Dextrans remained largely intact during transport, suggesting translocation without significant metabolism.
Conclusions:
- The alveolar epithelial barrier exhibits size-dependent permeability to macromolecules.
- Smaller macromolecules (<5 nm radius) likely traverse via paracellular pathways.
- Larger macromolecules (>6 nm radius) appear to cross via alternative mechanisms such as pinocytosis.