Date of Award
Doctor of Philosophy
Michael D. Best
Andy Sarles, Brian K. Long, Constance Bailey
Liposomes are synthetic vesicles made of phospholipids that are effective for wide-ranging applications in drug delivery and studying biological membranes. Understanding and controlling membrane properties such as fluidity and permeability is crucial for designing liposomes for specific biomedical applications. Pathological changes in these properties can also help us gain insights into disease mechanisms and develop effective treatments. In this dissertation, we describe the design, synthesis, and study of several lipid analogs for a range of applications including liposome triggered cargo release and therapeutic treatment related to lipids.
In Chapters 2-3, we developed smart liposome platforms that can respond to changes in metal ion concentrations and thereby drive cargo release which can be harnessed for drug delivery applications. In Chapter 2, we designed and synthesized an artificial lipid switch that can undergo a programmed conformational change upon zinc binding, leading to perturbations in membrane packing that drive release of encapsulated cargo. In Chapter 3, we employed a slightly different strategy and reported triggered content release brought about by copper chelation to an artificial lipid containing a picolinamide headgroup, wherein the copper-headgroup chelation was sufficient to modulate liposome properties. In both Chapters, we evaluated release efficiency upon zinc/copper treatment through fluorescence-based dye leakage assays and assessed morphological changes in liposome assemblies after metabolite (zinc and copper) treatment.
In Chapters 4-6, we used different strategies for chemical biology and medicinal applications related lipid biological activities. In Chapter 4, we designed and synthesized probes for artificial signal transduction that can respond to metal ions and phosphorylated metabolites as primary messengers to mimic cellular signaling processes. In Chapter 5, we took a different route and developed camptothecin and doxorubicin prodrugs that can respond to reactive oxygen species (ROS). These prodrugs have the potential to be used in their free form as well as after incorporation into liposomes to achieve triggered drug delivery reducing off-target effects. In Chapter 6, we designed a bis-pyrene phospholipid probe for fluorometric detection of disease-associated phospholipase enzyme inhibition. Incorporation of the pyrene probe into liposomes can provide insights into dependence of enzyme activity on membrane lipid composition.
Sagar, Ruhani, "Development of Artificial Lipids for Metal Ion-Responsive Liposomes and Related Medicinal Applications. " PhD diss., University of Tennessee, 2023.
Available for download on Wednesday, May 15, 2024