Nitroxide Spin Labels as NMR Contrast Agents: Delivery, Metabolism and Relaxation
Chan, Hsiao Chang
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https://hdl.handle.net/2142/70716
Description
Title
Nitroxide Spin Labels as NMR Contrast Agents: Delivery, Metabolism and Relaxation
Author(s)
Chan, Hsiao Chang
Issue Date
1988
Doctoral Committee Chair(s)
Magin, Richard
Swartz, Harold M.
Department of Study
Physiology and Biophysics
Discipline
Biophysics
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, General
Abstract
In this project, the potential of nitroxides as contrast agents for magnetic resonance imaging (MRI) has been studied. The difficulties involved in using nitroxides as in vivo MRI contrast agents, such as premature metabolic convertion of nitroxides to their nonparamagnetic state, lack of tissue selectivity, and relatively low relaxivity of nitroxides, were, in part, overcome by the use of liposomes as the delivery system.
A positively charged aqueous nitroxide, 2,2,6,6-tetramethyl-piperidine-N-oxyl-4-trimethylammonium (Cat1), which does not cross the cell membrane readily, was encapsulated in liposomes. This protected the nitroxide from reduction by external ascorbate. The metabolic reduction of liposome-delivered Cat1 by cells was studied as a function of oxygen concentration, and the rate was found to be increased under hypoxic conditions. This suggests the use of nitroxides to provide differentiated MRI contrast to diseased areas, which are poorly oxygenated.
Liposomes with different phospholipid compositions were constructed. The physical states, "fluid" or "solid", of these liposomal membranes were found to determine the mechanisms by which the liposomes interact with cells. Other liposome properties, such as membrane permeability and vesicle structure, were also found to have an important influence on nitroxide-induced water relaxation and on in vivo liposome stability and clearance from blood.
To enhance the relaxivity of a nitroxide, it was covalently bound to an albumin molecule using a relatively simple procedure. The effects of protein conformation, water accessibility, and pH on the relaxivity of the albumin-bound nitroxide were examined. Interactions of cells with albumin-nitroxide complex, such as reduction and digestion of the complex, were studied: the effect of these cellular processes on the relaxivity of the nitroxide-albumin complex was pronounced.
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