Cardiovascular diseases infect more than 64 million Americans, among which more than 10 million have myocardial infarction and stroke. Thrombosis is a major risk factor associated with these diseases. Restenosis represents another major clinical limitation and concerns after vascular surgical intervention. The overall goal of the proposed research is to bioengineer new liposomal drug delivery systems that selectively bind, or target, activated platelets at sites at risk for thrombotic occlusions, and/or developing restenotic lesions. We propose to investigate surface modifications of liposomes that target encapsulated drugs directly to the sites of vascular injury, by exploiting differences in cell surface phenotypes characteristic of activated platelets present in the lesion. Specifically, we shall focus on the design and development of high affinity Arg-Gly-Asp (RGD)-containing liposomes to platelet GPIIb-llla expressed in thrombosis and restenosis. We propose to: 1) Prepare and characterize RGD-containing liposomes that encapsulate fibrinolytic/anti-clotting/antiproliferative drugs; 2) Determine the in vitro binding of RGD-containing liposomes to activated platelets; 3) Evaluate the in vitro release of therapeutic agents from drug encapsulated liposomes targeted to activated platelets; and 4) Preliminary in vivo evaluation of liposome behavior in a restenosis model. Preliminary in vivo targeting of liposome will be evaluated in a rat acute injury model. From these studies, we shall demonstrate the feasibility of the RGD-containing liposomal drug delivery system for effective targeting to the activated platelets. We anticipate that this project will lead to highly effective liposomal drug delivery system that specifically target to the vascular sites at risk of thrombotic occlusion or developing restenotic lesions for the management and prevention of thrombosis and restenosis. If successful, the proposed research would lead to significant health care savings. Over 400,000 percutaneous coronary interventions (PCI) are performed each year, of those >200,000 are not stented. A significant number of these require repeat Revascularization surgery (as well as some of the stented ones). Repeat revascularizations in one patient population (MCOs) can cost up to $32,000 per patient. In most cases the use of post procedure anti-clotting medications is also required (with long periods associated with some stenting) that increases the costs of PCI. The targeted liposomal system proposed could reduce the costs in both treatment areas with a 5% reduction in revascularizations alone leading to >$60 million annual medical cost savings.
Thesaurus Terms: cardiovascular disorder chemotherapy, cell adhesion molecule, drug delivery system, liposome, method development, peptide, platelet activation, restenosis, thrombosis cell membrane, evaluation /testing, pharmacokinetics, protein binding, transcytosis clinical research, enzyme linked immunosorbent assay, flow cytometry, fluorescence microscopy, high performance liquid chromatography, human subject, laboratory rat, scanning electron microscopy, transfection
