Date of Award


Document Type

Dissertation - Restricted

Degree Name

Doctor of Philosophy (PhD)



First Advisor

Steven L. Regen

Second Advisor

Michael A. McKinney

Third Advisor

William A. Donaldson

Fourth Advisor

Mark G. Steinmetz

Fifth Advisor

William Szabo


Two polymerizable lipoic acid-derived lipids, 1,2-bis (12-(lipoyloxy)-dodecanoyl) -sn-glycero-3-phosphocholine (1), and 1-palmitoyl-2- (12-(lipoyloxy)dodecanoyl) -sn-glycero-3-phosphocholine (2) were synthesized and characterized. The liposomes formed from these lipids were proven to be unilamellar with mean diameters of 0.1 um by 31P NMR, TEM, and dynamic light scattering. Polymerization of these lipids was achieved under very mild conditions using dithiothreitol as an initiator. Spectrophotometry and quantitative thin-layer chromatography were used to estimate that the extent of polymerization was $>$93% for 1 and 89% for 2. The permeability characteristics of liposomes of 1, a cross-linkable lipid, 2, a non-cross-linkable lipid, and mixtures of 1 and 2 were determined by efflux methods using (14C) sucrose. Membranes derived from monomeric 1 were more permeable toward sucrose than those derived from monomeric 2. Increasing the mole percentage of 2 in mixed nonpolymerized liposomes decreased the permeability. Upon polymerization there was a significant decrease in the permeability of 1, while 2 exhibited a significant increase in release rates of sucrose. Increasing the mole percentage of 1 in mixed polymerized liposomes decreased the permeability. These observations are interpreted in terms of the relative packing efficiency of 1 and 2. Defects in the bilayer caused by polymer boundaries is the rationalize used to explain the permeability behavior of the polymerized lipids. Polymerized cross-linked liposomes exhibit resistance towards disruption by SDS and Triton X-100. Non-cross-linked liposomes were readily lysed. Polymerized liposomes of 1 exhibited a shelf-life over 1 year. Phospholipase A2 exhibited no activity towards polymerized liposomes of 1. Phospholipase C had minimal (ca. 5%) activity while phospholipase D exhibited a high degree of activity, hydrolyzing over 50% of the polymerized lipids. The polymerization was readily reversed via thiol reduction with dithiothreitol and octanethiol. Glutathione did not reduce the polymer. In Appendix I, liposomes of 1 and 2 are further characterized by FTIR, DSC, and digital-enhanced video light microscopy. In Appendix II, three other polymerizable lipoic acid-derived lipids, 1,2-bis(16-(lipoyloxy)-hexadecanoyl) -sn-glycero-3-phosphocholine, and 1-(12-(lipoyloxy)dodecanoyl) -2-palmitoyl-sn-glycero-3-phosphocholine and 1,2-bis(lipoyl) -sn-glycero-3-phosphocholine were synthesized and characterized. In Appendix III, the biodegradation of polymerized liposomes of 1,2-bis(12-(methacryloyloxy)-dodecanoyl) -sn-glycero-3-phosphocholine by the phospholipases A2, C, D was examined.


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