| Cardiovascular disease processes such as atherosclerosis, restenosis, and inflammation are typically localized to discrete regions of the vasculature, affording great opportunity for targeted pharmacological treatment and prevention. Liposomal delivery vehicles are potentially advantageous targeted drug carriers for such intravascular applications. In this study, the targeting strategy investigated is based on the hypothesis that procoagulant and inflammatory phenotypes of pathologically stimulated vascular cells comprise unique cell surface receptors that will bind appropriate ligands presented on the liposome surface. In particular, focus is placed on targeting two receptors expressed in restenosis: (i) integrin GPIIb-IIIa on activated platelets, and (ii) tissue factor (TF) on endothelial cells (EC). A linear RGD peptide directed liposomes to surface-bound, human platelets, and to platelets in suspension, without inducing in vitro platelet aggregation. A TF monoclonal antibody directed liposomes to cultured human pulmonary artery EC. The light chain of coagulation factor VII (fVII) bound to TF with a K d of ∼2 muM, but was unable to compete with fVII binding. Smaller peptides derived from the first epidermal growth factor domain of fVII were inactive. These studies suggest that TF may be a useful molecule for liposome targeting. To develop high affinity peptides, however, contributions of other regions of fVII to TF binding must be examined. Because prolonged liposome persistence in the circulation is a prerequisite for efficient targeted delivery, the ability of oligosaccharides to affect in vivo liposome clearance was examined. In vivo vesicle behavior was studied using a variety of surfactants containing oligodextran, oligomaltose, and heparin headgroups. Vesicle structures and clearance rates were dependent on both the nature of the surfactant headgroup and the alkyl tails. These results provided insight into how vesicle perturbations affect liposome clearance in vivo, indicating the impact of molecular geometry on bilayer structure and circulation lifetimes. Together, these studies underscore the importance of simultaneously considering both targeting specificity and vesicle longevity in the design of effective targeted drug delivery systems. |
