Masters Theses

Date of Award

8-2023

Degree Type

Thesis

Degree Name

Master of Science

Major

Chemistry

Major Professor

Michael D. Best

Committee Members

Shawn R. Campagna, Fred A. Heberle, Stephen A. Sarles

Abstract

Liposomal nanoscale delivery vehicles have been shown to aid in the delivery of therapeutic cargo due to their ability to encapsulate and improve the pharmacokinetic properties of a range of drug molecules. However, liposome therapeutic potential could be enhanced by exerting greater control over liposome cargo delivery and release. This is being pursued by designing lipids that are able to respond to specific stimuli, particularly those overexpressed in diseased cells. In this thesis, we describe stimuli-responsive liposomes in which the enzyme alkaline phosphatase is used as the stimulus. This trigger was selected since this enzyme is overexpressed in certain cancer cell lines as well as liver and kidney disease. To develop liposomes that respond to alkaline phosphatase, lipids switches were designed to self-immolate upon enzyme hydrolysis for programmed decomposition into small molecules that are incapable of forming a membrane bilayer. This method of self-immolation upon hydrolysis classifies these lipids as passive release, by utilizing the aberrant conditions within diseased cells to trigger release of cargo, in opposition to active release, which leverages external stimuli such as light or heat. A collection of lipids has been synthesized, each of which was envisioned to respond to excess amounts of alkaline phosphatase enzyme, thereby causing self-immolation to form small molecules that will decompose the liposomal bilayer and cause release of encapsulated cargo. The design, synthesis, and preliminary investigation of these immolating liposome designs are described in this thesis.

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