CONSERVATIVE AND DISSIPATIVE FORCE MEASUREMENT TO ENGINEER STEALTH DRUG DELIVERY PARTICLES
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Date
2014-09-15
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Johns Hopkins University
Abstract
ABSTRACT
Conservative and dissipative forces between drug delivery particles and mucus play a pivotal role in effective pulmonary drug delivery. Improved understanding of forces between DDPs and mucus is essential to engineering particles that efficiently penetrate the tenacious mucosal barrier. In this dissertation, specific thermodynamic and hydrodynamic interactions between differently coated DDPs and mucus were directly measured, creating a platform for engineering virus-mimicking stealth particles capable of efficient pulmonary drug delivery.
Total Internal Reflection Microscopy combined with Bayesian inference analysis was used to directly measure specific and nonspecific interactions between DDP polymer brush coatings and mucin polymer brushes on the energetic kT-scale. Considering that viruses with coexisting positive and negative charges in their outer coating rapidly penetrate the pulmonary mucosal barrier, particles were physiadsorbed with polymer brushes that mimicked these viral coatings. PEO copolymer physiadsorbed to DDPs formed an uncharged, chemically inert and sterically stabilizing polymer coating. Polyelectrolytes in mono- or multi-layers and bovine serum albumin formed charged drug delivery particle coatings. Novel analytical theory was developed to characterize the conformation of the layers and define the steric interactions between polymer brushes. Methodical analysis of interactions between symmetric and asymmetric brush layers ii facilitated identification of nonspecific and specific interactions and relative interaction strength. Protein layers with small size-scale charge separation were determined to have the greatest potential as mucoso-penetrating drug delivery particles.
TIRM experiments identified physiadsorbed PEO copolymer and BSA as having significant potential as mucoso-penetrating drug delivery particles. Confocal fluorescence microscopy was then used to measure diffusion through mucus of DDPs baring these coatings. Gradient diffusion, long time self diffusion, and diffusion into a mucus suspension were studied for each of these particle coatings in order to differentiate between specific and nonspecific hydrodynamic interactions. A constant pressure microfluidic system injecting solutions into a Y-junction microfluidic device combined with a novel analytical technique facilitated diffusion characterization with unprecedented accuracy and precision. Experimental data was fit to data generated via Comsol computational platform and to theoretical solutions with exceptional correlation. DDPs physiadsorbed with polyethylene glycol diffused rapidly through mucin suspensions. ConA and BSA protein bound to mucins via electrostatic and hydrophobic interactions, respectively. These results provide new insight into hydrodynamic interactions as they affect diffusion of virus-mimicking drug delivery particles through mucus. This dissertation combines thermodynamic and hydrodynamic measurements to develop a detailed understanding of forces dictating mucosal penetration of pulmonary drug delivery particles.
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Keywords
mucus, drug delivery, TIRM, diffusion, polymer brush