Doctoral Dissertations

Date of Award

12-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

Michael D. Best

Committee Members

David C. Baker, Bin Zhao, Francisco N. Barrera

Abstract

Liposomes are promising agents for drug delivery. They have the ability to encapsulate therapeutic drugs, resulting in decreased toxicity and prolonged circulation time. However, many obstacles to achieving broad utility in liposomal drug delivery still exist, including the ability to control release of therapeutic drugs and modulate surface reactivity. A primary focus of this dissertation involves the development of synthetic photocleavable lipids for controlled release from membranes.

Phosphatidylcholine (PC) is a natural lipid that comprises the majority of structural membranes. It contributes heavily to the formation of lipid bilayers in cell membranes, and modifications to the bilayer can induce membrane transitions and changes in permeability. As such, a PC analogue has been developed with a photocleavable 2-nitrobenzyl acyl chain. This lipid (NB-PC) was synthesized in nine steps from 4-(aminomethyl)benzoic acid and lyso-phosphatidylcholine (LPC). This system is designed such that ultraviolet light degrades the fatty acid tail, changing the properties of the liposomes they form and releasing entrapped hydrophobic molecules. This occurred in about half an hour, as determined by a fluorescence assay involving the release of the dye Nile red. Phosphatidylethanolamine (PE), cholesterol, and polyethylene glycol (PEG) were incorporated as additives to examine the versatility of release from liposomes with varying membrane properties. It was found that release remained robust regardless of lipid content. Furthermore, another photocleavable lipid was developed containing an extended conjugated system, 2-nitrobiphenethyl, to enhance photocleavage efficiency and enable two-photon release. This lipid, NBP-PC, was synthesized in seven steps, and UV irradiation reached maximal release within five minutes.

This dissertation also describes molecules that have been synthesized or are in progress for other projects. A nitrobenzyl-protected diacylglycerol has been synthesized, which is suitable for in situ binding studies with DAG-binding proteins, such as protein kinase C (PKC). Also synthesized are a biotin–azide linker for anchoring molecules onto streptavidin-coated surfaces and various azobenzene derivatives for studying chiral isomerization.

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