Developing Rapid Screening Tools for Predicting Nanomedicine Transport Limitations

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atmire.migration.oldid5191
dc.contributor.advisorRinker, Kristina
dc.contributor.authorSarsons, Christopher
dc.contributor.committeememberGrainger, David
dc.contributor.committeememberKallos, Michael
dc.contributor.committeememberCramb, David
dc.contributor.committeememberTrifkovic, Milana
dc.contributor.committeememberMurari, Kartikeya
dc.date.accessioned2017-01-03T16:12:06Z
dc.date.available2017-01-03T16:12:06Z
dc.date.issued2016
dc.date.submitted2016en
dc.description.abstractNanomedicines 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.en_US
dc.identifier.citationSarsons, C. (2016). Developing Rapid Screening Tools for Predicting Nanomedicine Transport Limitations (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25629en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/25629
dc.identifier.urihttp://hdl.handle.net/11023/3534
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectMicrobiology
dc.subjectBiology--Molecular
dc.subjectPhysiology
dc.subjectMedicine and Surgery
dc.subjectPharmacology
dc.subjectChemistry--Pharmaceutical
dc.subjectEngineering--Biomedical
dc.subjectEngineering--Chemical
dc.subject.classificationNanomedicineen_US
dc.subject.classificationDrug Deliveryen_US
dc.subject.classificationParticle Transporten_US
dc.subject.classificationNanoparticleen_US
dc.subject.classificationExtracellular Matrixen_US
dc.subject.classificationfluid flowen_US
dc.subject.classificationShear Stressen_US
dc.subject.classificationIn Vitroen_US
dc.subject.classificationZebrafish Embryoen_US
dc.subject.classificationQuantum Dotsen_US
dc.subject.classificationAuNPen_US
dc.subject.classificationDrug Carrieren_US
dc.subject.classificationDiffusionen_US
dc.titleDeveloping Rapid Screening Tools for Predicting Nanomedicine Transport Limitations
dc.typedoctoral thesis
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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