Identifier

etd-06232011-143040

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

Over the last few decades, liposomes have generated a lot of interest as drug delivery vehicles to address the need for providing both increased therapeutic efficacy and decreased systemic exposure, simultaneously. The challenge of increasing drug accumulation at diseased sites, without compromising the integrity and stability of the liposomal carrier during circulation, has been met with two possible solutions: (1) active targeting and (2) active triggering. To achieve selective and site-specific delivery of drugs to tumors, active triggering methods have been developed wherein a responsive element is incorporated into the liposomal bilayer, which causes destabilization of the liposome upon exposure to the proper stimulus. Endogenous stimuli can offer high specificities and sensitivities, if appropriate trigger groups exist so as to take full advantage of diseased site characteristics. The research described herein involved the synthesis of redox-active, quinone-lipid conjugates that were prepared into liposomes for the containment and subsequent triggered release of encapsulated cargo. Development of said system required (1) the synthesis and then characterization of various simple quinones and quinone propionic acids by cyclic voltammetry and X-ray crystallography and (2) the preparation of substituted quinone dioleoylphosphatidylethanolamine lipids into liposomes and evaluation of their triggered release behaviors by fluorescence emission spectrometry. Elucidation of the electrochemical properties of simple quinones and quinone propionic acids revealed a correlation between quinone substitution and reduction potential, meaning that the electronics of the quinone trigger can be adjusted through their chemical structure. X-ray crystallography showed a highly distorted quinone ring proximal to the trimethyl-locked propionic acid side chain. Upon introduction of a chemical reducing agent, the four different substituted quinone-dioleoylphosphatidylethanolamine liposomes each displayed distinctive release behaviors, as indicated by the time-dependent increase in fluorescence signal as encapsulated calcein was released below its self-quenching concentration. The individual release profiles demonstrate the influence of quinone substitution on the triggered response of these redox-active liposomes; thus, realizing the programmed delivery of liposomal contents through active triggering. The information learned from this research project provides a solid foundation for exploring the triggered release of these redox-active liposomes by NAD(P)H:quinone acceptor oxidoreductase type 1, an over-expressed reductase enzyme in numerous cancer cell lines.

Date

2011

Document Availability at the Time of Submission

Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide.

Committee Chair

McCarley, Robin

Included in

Chemistry Commons

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