Doctoral Dissertations

Date of Award

5-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

Michael D. Best

Committee Members

Brian K. Long, Constance B Bailey, Todd B Reynolds

Abstract

Liposomes are spherical vesicles composed of a lipid bilayer membrane that assembles around an internal aqueous core. This duality gives liposomes the ability to encapsulate both hydrophobic cargo within the lipid bilayer and hydrophilic cargo in the aqueous core, making them versatile molecular carriers for drug delivery. Liposome platforms have many advantages and are promising drug delivery carriers, and research is ongoing to improve their designs for continued clinical applications. Many liposome types have been developed, but further work is needed to improve surface modification, site-specific targeting, and triggered cargo release in order to further the therapeutic applications of these platforms. In this dissertation, we mainly present the development of surface-modified and stimuli-responsive liposomal platforms via rationally designed synthetic lipids.

In Chapter 2, we present a liposome platform incorporating a headgroup modified cyclic disulfide lipid (CDL) for the dual purpose of enhancing cell entry and functionalizing the liposome membrane through thiol-disulfide exchange. In Chapter 3, we develop a headgroup modified liposome platform incorporating bis-boronic acid lipids (BBALs) to increase valency in order to achieve selective saccharide sensing and enhance cell surface recognition based on carbohydrate binding interactions. In Chapter 4, we utilize a slightly different strategy in which we chemically modified the headgroups of the non-bilayer lipid DOPE to achieve responsive lipids that show alteration in self-assembly properties upon thiol and cysteine addition. In Chapter 5, we present advances towards an ROS-responsive synthetic system for use in artificial ROS signal transduction. Following the synthesis of the synthetic lipids in all these projects, we evaluated their respective activities using the appropriate techniques including fluorescence-based assays to measure surface binding, conjugation, or cargo release. Changes to liposome nanoparticle morphology were additionally probed using dynamic light scattering (DLS) and electron microscopy (EM) techniques. Finally, enhancements in cell delivery were analyzed through fluorescence-based microscopy experiments.

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