Document Type

Dissertation

Date of Degree

Fall 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Jennifer Fiegel

Abstract

Barriers to effective pulmonary drug delivery are inherent to the lung physiology and present a challenge when attempting to bypass the natural defenses against inhaled particles. Inhaled particulate aerosols that deposit in the conducting airways of the lungs can become trapped in the respiratory mucus layer where they are then subjected to rapid clearance by the mucociliary escalator. The details of particle behavior after deposition and before this clearance are not well understood, however. Several physical processes may influence particle behavior on the mucus, including a penetration of particles into the mucus layer or a lateral transport of particles across the lung surface. Particles which deposit onto the respiratory mucus are subject to a number of forces which dictate these behaviors in the lung and may influence the retention of particles in the lungs and the efficacy of pulmonary drug delivery. The goal of this thesis was to investigate the behavior of microparticles deposited on a synthetic mucus model designed to mimic the bulk viscoelastic and surface tension properties of conducting airway mucus. Studies were conducted to determine the effects of mucus surface properties and particle physicochemical properties on the submersion and lateral mobility of single particles and the spreadability of particle-laden droplets at the air-liquid interface.

Synthetic mucus gels were developed with viscoelastic properties that mimicked those of non-diseased tracheobronchial mucus. Infasurf, a calf lung surfactant extract, was spread onto the gel surfaces and compressed in a Langmuir trough to attain physiologically relevant surface tensions (~30-34 mN/m) and to analyze surfactant behavior on viscoelastic subphases. Microparticles were aerosolized onto the model mucus surface and imaged by brightfield microscopy at varying surface tensions on gels of varying viscoelastic properties to determine the extent of capillary submersion, in the fluid interface. Lateral transport of microparticles across the surfactant interface was quantified using particle tracking techniques. Finally, the spreading patterns of surfactant-laden droplets containing model drugs or particles were monitored by time-course imaging.

Studies revealed that key physicochemical properties, including particle size and hydrophobicity, influenced particle submersion and mobility on the mimetic surfaces. Submersion, transport, and droplet spreadability were all inhibited with increasing gel viscoelastic properties, suggesting that such inhibition would be expected by healthy or disease tracheobronchial mucus. While low surface tensions promoted microparticle submersion into the subphase, the lateral transport and droplet spreadability were inhibited on gels with pre-existing surfactant films. The extent of droplet spreading could be enhanced by adding surfactant to the droplets. Overall, these studies aid our understanding of particle behavior and their fate at lung-like fluid surfaces, which has implications for both pulmonary drug delivery and pulmonary toxicity. Particulate aerosols which are designed to be smaller and more hydrophilic would experience improved mobility in the lungs and potentially gain the ability to submerge through the thick and highly viscous mucus barriers of diseased lungs. In healthy lungs, improved submersion could lead to greater particle retention, reduced mucociliary clearance, and a more effective delivery of drug to the epithelium. Lastly, by adding surfactant to drug containing liquid aerosol droplets, the deposition and distribution of drug could be improved in the peripheral regions of the obstructed lungs of cystic fibrosis patients. Results from these studies provide new knowledge that can be used to predict the behavior of aerosols deposited in the lungs and can aid the design of aerosols for drug delivery applications.

Public Abstract

Lining the lung surface, the lung fluids protect the lung from direct exposure to foreign materials that are inhaled. This fluid layer also serves as a barrier to pulmonary drug delivery as it must be crossed for a drug to reach its target. Studies that characterize the behavior of inhaled drugs, such as particle or liquid aerosols, can help to identify properties which influence drug delivery to the lungs. In this study, a polymer-based fluid was developed that had similar properties to human lung fluid. This model fluid was then used to determine how particles and droplets move at the surface of the lung-like fluids and how different particle types influence this movement. The ability of various types of particles to penetrate into the model lung fluid was found to be dependent on the properties of the particles and the consistency of the fluid. Thick model lung fluid was shown to slow down and even stop droplets from spreading on the fluid surface. Particles which stay stuck at the lung fluid surface and cannot move around are poor candidates for drug delivery. Additionally, droplets that do not spread are not as useful for treating diseased lungs as droplets which greatly spread. These studies are important as they provided new information that can be used to make drug-containing particles or droplets that can better reach the regions of the lung where they are needed, which would improve the overall ability to deliver drugs to the lungs.

Keywords

publicabstract

Pages

xxvii, 286 pages

Bibliography

Includes bibliographical references (pages 260-286).

Copyright

Copyright 2015 Daniel Michael Schenck

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