Controlled microfluidic synthesis of biological stimuli-responsive polymer nanoparticles for drug delivery applications

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dc.contributor.authorHuang, Yuhang
dc.contributor.supervisorMoffitt, Matthew
dc.date.accessioned2020-08-29T03:23:21Z
dc.date.available2020-08-29T03:23:21Z
dc.date.copyright2020en_US
dc.date.issued2020-08-28
dc.degree.departmentDepartment of Chemistry
dc.degree.levelMaster of Science M.Sc.en_US
dc.description.abstractPolymer nanoparticles (PNPs) that exhibit selective stimuli-responsive degradation and drug release at tumor sites are promising candidates in the development of smart nanomedicines. In this thesis, we demonstrate a microfluidic approach to manufacturing biological stimuli-responsive PNPs with flow-tunable physicochemical and pharmacological properties. The investigated PNPs contain cleavable disulfide linkages in two different locations (core and interface, DualM PNPs) exhibiting responsivity to elevated levels of glutathione (GSH), such as those found within cancerous cells. First, we conduct a mechanistic study on the microfluidic formation of DualM PNPs without encapsulated drug. We show that physicochemical properties, including size, morphology, and internal structure, of DualM PNPs are tunable with manufacturing flow rate. Microfluidic formation of DualM PNPs is explained by the interplay of shear-induced coalescence, shear-induced breakup, and intraparticle chain rearrangements. In addition, we demonstrate that rates of GSH-triggered changes in size and internal structure are linearly correlated with initial PNP sizes and internal structures, respectively. Next, we expand our study to focus on microfluidic control of pharmacological properties of DualM PNPs containing either an anticancer drug (paclitaxel, PAX-PNPs) or a fluorescent drug surrogate (DiI-PNPs). Microfluidic PAX-PNPs and DiI-PNPs show similar sizes and morphologies with their non-drug-loaded counterparts under the same flow conditions. We then show that pharmacological properties of DualM PNPs, including encapsulation efficiency, GSH-triggered release rate, cell uptake, cytotoxicity against MCF-7 (cancerous) and HaCaT (healthy), and relative difference in MCF-7 and HaCaT cytotoxicity, all increase linearly as flow-directed PNP size decreases, providing remarkably simple process-structure-property relationships. In addition, we show that microfluidic manufacturing improves encapsulation homogeneities within PNPs relative to bulk nanoprecipitation. These results highlight the potential of flow-directed shear processing in microfluidics for providing controlled manufacturing routes to biological stimuli-responsive nanomedicines optimized for specific therapeutic applications. Finally, we summarize various design strategies of biological stimuli-responsive PNPs. We show that the location and density of disulfide linkages within PNPs determines stimulus-triggered degradation mechanism and kinetics. In addition, we show various bottom-up approaches to tune PNP responsivities that involves chemical processing, including formulation chemistry and intramolecular forces. Along with the top-down microfluidic approach that we demonstrate experimentally, this chapter provides a more comprehensive understanding of process-structure-property relations opening up vast possibilities for manufacturing smarter nanomedicines.en_US
dc.description.scholarlevelGraduateen_US
dc.identifier.bibliographicCitationHuang, Y., Jazani, A. M., Howell, E. P., Reynolds, L. A., Oh, J. K., & Moffitt, M. G. (2020). Microfluidic shear processing control of biological reduction stimuli-responsive polymer nanoparticles for drug delivery. ACS Biomaterials Science & Engineering, doi:10.1021/acsbiomaterials.0c00896en_US
dc.identifier.bibliographicCitationHuang, Y., Moini Jazani, A., Howell, E. P., Oh, J. K., & Moffitt, M. G. (2019;2020;). Controlled microfluidic synthesis of biological stimuli-responsive polymer nanoparticles. ACS Applied Materials & Interfaces, 12(1), 177-190. doi:10.1021/acsami.9b17101en_US
dc.identifier.urihttp://hdl.handle.net/1828/12053
dc.languageEnglisheng
dc.language.isoenen_US
dc.rightsAvailable to the World Wide Weben_US
dc.subjectstimuli-responsive block copolymersen_US
dc.subjectnanoparticlesen_US
dc.subjectmicrofluidicsen_US
dc.subjectdirected self-assemblyen_US
dc.subjectdrug deliveryen_US
dc.titleControlled microfluidic synthesis of biological stimuli-responsive polymer nanoparticles for drug delivery applicationsen_US
dc.typeThesisen_US

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