Doctor of Philosophy (PhD)
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.
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Carrier, Nicole Hollabaugh, "Redox-active Liposome Delivery Agents With Highly Controllable Stimuli-responsive Behavior" (2011). LSU Doctoral Dissertations. 1147.