Drug targeting to the endothelial cells (EC) along with proper sub-cellular targeting of specific drugs are important and challenging therapeutic goals. One area of special interest is the pulmonary vasculature, a circulation that is a privileged target after IV administration. Pulmonary thrombosis and oxidative stress are important pathological factors in many cardiovascular and pulmonary diseases, such as acute lung injury (ALl). Normal or pathological EC surface determinants could be used for the targeting. Preliminary data indicates that antibodies to InterCellular Adhesion Molecule-i (anti-ICAM) might be especially useful in vascular targeting since: 1) EC poorly internalize monomeric antibodies thus permitting targeting of certain drugs (e.g., anti-thrombotic agents) to the vascular lumen, 2) modification of anti-ICAM antibodies to produce conjugates that are 100-250 nm in diameter allows the intracellular delivery of drugs (e.g antioxidant enzymes, AOE) to EC, 3) expression of ICAM-1, a constitutive EC antigen, is further enhanced upon inflammation, thus potentially facilitating targeting to activated EC, and 4) blockade of ICAM-i by anti-ICAM conjugates may provide secondary anti-inflammatory benefit. The fundamental hypotheses of this proposal are that: 1) anli-ICAM is a unique carrier permitting both surface and intracellular targeting of drugs to endothelium; 2) cellular targeting may be controlled more precisely by regional administration of anti-ICAM conjugates; 3) sub-cellular targeting of cargo may be controlled by the size of the conjugates; and, 4) inflammation facilitates ICAM targeting, while antibody/conjugate binding to ICAM suppresses inflammation. This study will systematically characterize ICAM immunotargeting to endothelium in cell culture and animal models by pursuing the following Specific Aims: 1) Define mechanisms regulating sub-cellular targeting of anti-ICAM conjugates of diverse size; 2) Characterize ICAM-directed targeting in vivo; 3). Evaluate fibrinolysis by anti-thrombotic drugs targeted via ICAM to EC surface; 4) Evaluate protection by antioxidant enzymes (AOE) targeting to ICAM. Our long-term objective is to develop strategies for safe, specific and effective delivery of drugs to EC and to develop methodologies that may be applicable to other cell types. This study will extend and strengthen the ICAM-directed vascular immunotargeting paradigm that may be used for a prophylaxis and therapies of diverse pulmonary and cardiovascular diseases, in particular, ALl.
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