Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

In this dissertation, molecular interactions and changes imposed by nano-scale structures on phospholipid vesicles were investigated. 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) large unilamellar vesicles (LUVs) were used as the model system. Understanding changes of the bilayer structure, interfacial properties, lipid dynamics, and self-assembly, allows bridging relationships between biological cell membrane structure and dynamics to cellular functionalities. For example, membrane curvature changes are linked to membrane protein functions, although the exact mechanisms of control are not yet understood. Moreover, the knowledge gained from vesicle models allows exploring novel strategies for drug delivery applications. To achieve this, DOPC LUVs were synthesized and characterized by a combination of Dynamic Light Scattering (DLS), cryo-Transmission Electron Microscopy (cryo-TEM), Small-Angle X-Ray, and Neutron Scattering (SAXS, SANS). In combination with the lipid dynamics investigated by Neutron Spin-Echo spectroscopy (NSE) and Nuclear Magnetic Resonance (NMR) relaxometry, several new insights related to vesicle self-assembly and control of structure and dynamics were revealed. Lipid dynamics investigated by NSE showed the first experimental evidence for confined lipid dynamics at short Fourier time (<3 >ns) with a mean squared displacement t 0.26. DOPC vesicles in the presence of a hyperosmotic NaCl gradient showed transformation to multilamellar structures and size changes. Size variation showed abrupt changes at certain concentrations as a result of new bilayer formation. Membrane rigidity explored by NSE showed increasing rigidity with increasing external NaCl. Small drug molecules interacting with DOPC vesicles showed different effects on the lipid bilayer structure when introduced in solution-phase and directly inserted into the lipid layer at the beginning of vesicle synthesis. Acetaminophen showed the softening of lipid bilayer by NSE similar to previous studies using Ibuprofen and Aspirin. Interactions between DOPC LUVs and N-alkyl-PEO polymers presented a new way to transform LUVs from unilamellar to multilamellar vesicles. These multilamellar vesicles had a decreased membrane rigidity which is useful for transdermal drug delivery. Lastly, Non-ionic Amphiphilic Alternating Polymers (NAAPs) showing promising solution properties were characterized. They showed LCST behavior close to physiological temperature with high tunability. In the presence of NAAPs, DOPC vesicles showed no significant size changes. However, susceptibility to electron beam/radiation damage appeared to be enhanced.

Committee Chair

Schneider, Gerald

Available for download on Friday, October 27, 2023

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