The site-specific treatment of inflammatory diseases by targeting liposomes to vascular adhesion receptors that normally mediate the recruitment and extravasation of leukocytes to inflamed tissues is of growing interest. Endothelial cells play an active role in various diseases such as inflammation or cancer metastasis. They undergo phenotypic modulations to an activated state which is especially marked by expression of several cell surface adhesion molecules. These adhesion receptors are attractive targets for cell selective pharmacological intervention employing drug targeting strategies since they are easily accessible due to the direct contact with the blood. Among these adhesion receptors, E-Selectin seems to be the most attractive candidate for targeting since its expression is strictly time and spatial in relationship to the inflammation. Recently, we could demonstrate that immunoliposomes bearing anti-E-Selectin antibodies specifically accumulate at activated endothelial cells (HUVEC) in vitro. In order to derive therapeutical strategies from liposomal targeting, we analyzed route and degree of cellular uptake of the targeted liposomes. Binding and internalization were correlated with several liposomal parameters such as type of antibody, coupling strategy or sterical stabilization. Following the intracellular trafficking of liposomes, we modified the liposomal lipid composition in order to avoid lysosomal degradation. Therefore, we established pH-sensitive, sterically stabilized immunoliposomes that deliver their content into the cytoplasm due to liposome destabilization in the late endosomes followed by liposome-endosome fusion. In order to apply these carriers for liposomal gene therapy, we prepared different types of plasmide-containing vehicles and analyzed their structural and biological characteristics. The end of this work focuses on the development of pH-sensitive sterically pH-sensitive E-Selectin-directed Immunoliposomes that exhibit optimized transfection properties in vitro. |