Design of Cyclodextrin Derivatives as Artificial Lipid Carriers that are not Receptor-directed

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Atherosclerosis involves deposits of excessive cholesterol and its esters mainly in the vascular system. On the cellular level, this excessive deposition is result of receptor-regulated uptake of oxidized forms of low-density lipoproteins. It may be possible to correct this situation by introducing into the circulation an alternate lipid carrier that woudd not be receptor directed and that would distribute lipids wore evenly. The objective of this study, therefore, is to investigate the potential use of sulfated cyclodextrins as artificial carriers for atherogenic lipids in a non-receptor mediated manner. The results obtained were as hollows.1. Sulfoalkylated cyclodextrins enhanced the aqueous solubility of cholesterol and its esters though inclusion complexation, while sulfated cyclodextrins, which have the electric charges located near the cavity, were less effective.2. Electrophoretic and gel permeation chromatographic studies revealed that the sulfated cyclodextrins showed a selective reactivity toward chyromicron and very-low-density lipoprotein fractions, leading to their aggregation to macroparticles.3. The intravenous administration of the sulfated cyclodextrins was well tolerated in rats without conspicuous changes in blood chemistry values. Furthermore, the in-vitro hemolytic activity and local tissue irritancy of the sulfated cyclodextrins were much less than those of the parent and their hydrophilic derivatives.4. Repeated intravenous administration of the sulfated cyclodextrins to hereditary hyperlipidemic rabbits led to a gradual increase in total cholesterol in circulation and eventually to a relief of atherosclerotic lesions in the thoracic aorta.The intravenous administration of the sulfated cyclodextrins may be used in catalysis of distribution of lipids in organisms and in invasive procedures such as angioplasty, when lipids debris may be released into the blood stream.