Clinically significant restenosis occurs in greater than 30 percent of patients receiving percutaneous transluminal coronary angioplasty, and remains prevalent despite efforts to inhibit neointima formation through pharmacological intervention and the use of surface-modified intracoronary stents. The overall goal of the proposed research is to bioengineer new liposome drug delivery systems that selectively bind, or target, cell surface molecules expressed at sites of chronic vascular injury and developing restenotic lesions. We propose to investigate surface modifications of liposomes that (i) target encapsulated drugs directly to the site of vascular injury, by exploiting differences in cell surface phenotypes characteristic of activated cells present in the lesion; and (ii) inhibit protein adsorption to the liposome, thereby increasing the circulation half-life. The proposed targeting strategies are based on the central hypothesis that procoagulant and inflammatory phenotypes of stimulated vascular cells comprise unique cell surface receptors that will bind biomimetic constructs of endogenous ligands presented on the liposome surface. By utilizing these ligands to localize long-circulating liposomes to the lesion, local drug concentrations can be increased to therapeutic levels. Specifically, we shall focus on the design and development of targeting ligands to three cell surface molecules expressed in thrombosis and restenosis: (1) high affinity RGD peptides that bind integrin GPIIb-IIIa on activated platelets; (2) Factor VII-derived peptides that bind tissue factor on stimulated endothelial cells and smooth muscle cells, and (3) high affinity sialyl Lewis x and sialyl Lewis a - derived oligosaccharides that bind E- and/or P-selectins on EC and platelets. We shall examine how the ligand structures modulate binding affinity, and determine how these ligands affect binding and uptake of liposomes by target cells in vitro, and in a rat model of balloon-induced vascular injury in vivo. The physical properties of glycolipids designed to increase circulation lifetimes will be studied to determine the role of surface hydration and bilayer stability in altering liposomal clearance rates. The ability of long-circulating, targeted liposomes to affect neointima formation will be studied in vivo using rapamycin and enoxaparin as a model encapsulated therapeutic agents. By addressing targeting affinity and specificity, and prolonged circulation lifetime, an effective drug delivery vehicle for the management and prevention of thrombosis and restenosis can be achieved.
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