Inhaled antibiotics are frequently used for treating infections associated with cystic fibrosis (CF) and are under development for other uses including hospital-acquired pneumonias. However, the long-term efficacy of inhaled anti-infectives depends largely on the uniformity of pulmonary drug deposition, which is variable in diseased lungs. In surfactant replacement therapy (SRT), premature infants who lack adequate levels of surfactant receive a bolus of exogenous surfactant through an endotracheal tube. The success of this therapy is due to the pulmonary dispersion of surfactant from convective flows generated by surface tension gradients along the airway surface. Based on this same mechanism, aerosolized surfactant drug carriers have been proposed as a potential means of augmenting drug distribution in diseased lungs. However, little experimental evidence exists to support this. The goal of this study was to assess the potential for aerosolized surfactant drug carriers to improve the dispersion of medications in the lungs following aerosol deposition. This study included the design of an aerosol delivery system that produced an aerosol of respirable size that was delivered onto two realistic in vitro models of the airway surface. The first model incorporated porcine gastric mucin (PGM) and the second utilized human bronchial epithelial (HBE) cell cultures, including CF and non-CF cells. Differences in the dispersion of various surfactants (cationic, anionic, and non-ionic) vs. saline (control) were quantified using fluorescence microscopy and different sized fluorescent tags acting as drug analogs. The tags spanned a size range from the molecular level to a 1.0 micron polystyrene sphere. On the PGM model, surfactants enhanced dispersion by 2-20 fold vs. saline with fairly uniform dispersion for all sized tags. When sufficiently hydrated, the HBE cell cultures, both CF and non-CF, also demonstrated significant surfactant spreading compared to saline, with similar areas and patterns for all sized tags. This study demonstrates the potential for aerosolized surfactant carriers to improve the uniformity of pulmonary drug distribution following deposition. Further studies are required to demonstrate their efficacy in these in vitro models and for in vivo drug applications.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07132006-142658 |
| Date | 13 June 2007 |
| Creators | Marcinkowski, Amy Lise |
| Contributors | Robert Tilton, Stephen Garoff, William Federspiel, Bruce Pitt, Joseph Pilewski, Timothy Corcoran |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-07132006-142658/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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