Doctoral Dissertations

Orcid ID

Date of Award


Degree Type


Degree Name

Doctor of Philosophy



Major Professor

Michael D. Best

Committee Members

Johnathan N. Brantley, Christopher A. Baker, Stephen A. Sarles


Liposomes are spherical nano-assemblies that are proven to be effective drug delivery vehicles. Due to their unique bilayer structures, they are able to encapsulate both hydrophilic and hydrophobic drugs in their aqueous inner core and membrane bilayers, respectively. While liposomal delivery platforms exbibit numerous advantages, the therapeutic efficacy of these platforms would be enhanced by developing triggered release strategies such that one can tune the timing and location of the cargo release in a controlled manner. In this dissertation, we mainly present the development of stimuli-responsive liposomes targeting different disease-associated metabolites utilizing rationally designed synthetic lipid switches.

In Chapter 2, we developed stimuli-responsive liposomes based on molecular recognition principles, employing synthetic lipid switches that can undergo programmed conformational changes upon binding to calcium. While simple ions validated that molecular recognition principles can be harnessed for smart liposome design, in Chapters 3-4, we expanded this field by targeting more complicated phosphorylated small molecule metabolites, such as adenosine triphosphate (ATP) and inositol 1,4,5-trisphosphate (IP3), which are known to be associated with diseases. Utilizing a slightly different strategy, in Chapters 5-6, we present the design of synthetic lipids that can respond to enzymes (esterases, phosphatases, and galactosidases) and reactive oxygen species (ROS). In all of these works, after obtaining the designed synthetic lipid switches, we evaluated release efficacy upon stimulus treatment using fluorescence-based dye release assays. Morphology changes to the lipid nanoparticles were probed with dynamic light scattering (DLS) and electron microscopy (EM) techniques.

Other than triggering release, enhancing the targeting of liposomes to diseased rather than healthy cells can also improve diseased-cell specificity and drug release/potency. In Chapter 7, we introduce a boronate-caged guanidine lipid that can show site-specific targeting properties upon treatment with ROS, which is known to be upregulated in certain diseased cells.

Outside liposome projects, we also attempted to develop high-throughput assays for detection of phospholipase inhibition. In Chapter 8, we designed fluorescent probes containing two pyrene moieties based on the lipids cardiolipin and phosphatidylethanolamine. Taking advantage of the pyrene excimer properties, these lipids are expected to exhibit fluorescent changes upon catalytic hydrolysis by disease-associated phospholipase enzymes.

Appendix-Charaterization of synthetic compounds.pdf (16349 kB)
NMR characterizations for all synthetic compounds

Files over 3MB may be slow to open. For best results, right-click and select "save as..."