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Dissertation
The use of cyclodextrins for the study of intracellular cholesterol transport and metabolism
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Dec 1998
DOI:
https://doi.org/10.17918/00003884
Abstract
Cyclodextrins have been used extensively in the pharmaceutical industry as vehicles for drug delivery. Their ability to interact with hydrophobic molecules and form host/guest inclusion complexes have been found to improve aspects of drug delivery such as solubility and dissolution rate, drug absorption and taste. Although, cyclodextrins have been widely used in industry, their use in basic science research has been limited. This dissertation project focuses on the ability of [beta]-cyclodextrins to complex with cholesterol and deliver this cholesterol to cells so that intracellular cholesterol transport and metabolism can be studied. Results from Aim 1 and 2 indicate that M[beta]CDs are preferred to deliver cholesterol to a variety of cells over a short period of time. We also demonstrate that M[beta]CD-delivered cholesterol is metabolically available as shown by an increase in esterified [3H]cholesterol over time. Furthermore, we indicate there are two protocols that can be employed for labeling and loading cells with CD-delivered cholesterol: the continuous labeling protocol and the pulse/chase protocol. Results from Aim 3 and 4 discuss the different applications for the study of cholesterol metabolism using cyclodextrins. Specifically, Aim 3 indicates that cyclodextrins, at low concentrations, have the ability to catalyze the exchange of free cholesterol from cells to serum lipoproteins. For this study, we screened several synthesized [beta]-cyclodextrin derivatives and double-decker cyclophane compounds for their cholesterol-shuttling ability. Aim 4 illustrates several other applications for CD-cholesterol delivery systems, including the use of metabolic inhibitors to explore the mechanism of cholesterol transport from the cell plasma membrane to the intracellular site of esterification. The ability of cyclodextrins to complex with sterols other than cholesterol and to supply these sterols to cells was also investigated. The results from all aims of this thesis project illustrate the usefulness of cyclodextrins as tools to study intracellular cholesterol transport and metabolism.
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Details
- Title
- The use of cyclodextrins for the study of intracellular cholesterol transport and metabolism
- Creators
- Aimee Elizabeth Christian
- Contributors
- George H. Rothblat (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xi, 111 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888801204721