Developing Rapid Screening Tools for Predicting Nanomedicine Transport Limitations
Creators: name: Sarsons, Christopher
Publisher: name: Graduate Studies
Year: 2016
Subjects: subject: Biology--Cell
subject: Microbiology
subject: FOS: Biological sciences
subject: Biology--Molecular
subject: Physiology
subject: Medicine and Surgery
subject: Pharmacology
subject: Chemistry--Pharmaceutical
subject: Engineering--Biomedical
subject: Engineering--Chemical
subject: Nanomedicine
subject: Drug Delivery
subject: Particle Transport
subject: Nanoparticle
subject: Extracellular Matrix
subject: fluid flow
subject: Shear Stress
subject: In Vitro
subject: Zebrafish Embryo
subject: Quantum Dots
subject: AuNP
subject: Drug Carrier
subject: Diffusion

description: Nanomedicines represent the future of medicine. Targeted therapies promise to increase treatment efficacy while simultaneously reducing side effects. However, despite two decades of dedicated research, this paradigm shift has found little clinical traction. Partly to blame is the multitude of off-target sinks and degrading factors that limit delivery efficiency. Rapid, cost effective, in vitro models may be able to screen novel nanomedicines for their susceptibility to these transport limitations. This thesis focuses on studying nanoparticle transport in two specific domains: endothelium interactions and extracellular matrix diffusion, utilizing in vitro platforms. Laser-scanning confocal microscopy and associated image analysis techniques allow fluorescently-labelled, cell-associated nanoparticles to be quantified. However, image analysis procedures lack standardization. Endothelial cells were exposed to fluorescent nanoparticles to investigate whether different image analysis techniques could impact particle quantification. Significant differences were found when fluorescence quantification and image normalization methods were varied, as well as when image projections were analysed. Fluid flow forces impact nanoparticle interactions with the endothelium. The association of quantum dots with human endothelial cells was studied after flow preconditioning in a parallel plate flow chamber at various flow magnitudes. The results were compared with distribution patterns of quantum dots in zebrafish embryo vasculature. It was found that quantum dots preferentially accumulate in lower flow vessels, and associate more with cells that have undergone lower flow preconditioning. A novel platform was developed to study the transport of gold nanoparticles in extracellular matrix. It was found that matrix density and particle diameter impact the matrix diffusion of particles. These results were supported by a tumour-bearing murine model and in silico predictions of particle behaviour. Characterization of these three models lead to a decision matrix to select nanoparticle properties based on patient-specific pathophysiology. The novel platform was further applied to understanding the effect of polyethylene glycol surface functionalization on liposome diffusion in extracellular matrix. It was found that polymer conformation is an important driver of particle-matrix interactions. Together this work provides new insights into nanoparticle transport limitations, showcases the predicative value of in vitro modelling of particle transport and offers new tools towards increasing the clinical translation of nanomedicines.