Endothelial cells control vascular tone, permeability, angiogenesis, and interactions of blood with tissues and thus represent a key therapeutic target in treatment disease conditions including inflammation, thrombosis, oxidant stress, angiogenesis, acute lung injury, tumor growth, immune disorders, diabetes, hypertension, and atherosclerosis. Agents useful for diagnostic, prophylactic, and therapeutic interventions in endothelial cells in these conditions include label compounds (isotopes), antioxidants, fibrinolytics, anticoagulants, anti-inflammatory agents, pro- and anti-angiogenic mediators, NO donors, and other drugs. In theory, proteins performing some of these functions and genes encoding these proteins can be employed as highly potent and specific "natural" therapeutic agents.

Alas, most exogenous proteins, genetic materials, imaging agents, and drugs are rapidly cleared from blood and lack specific affinity to endothelium. Thus, an inadequately low percent of active agents is delivered to the target cells, while a major fraction of injected drugs is a potentially dangerous waste. Multiple injections of high doses to achieve and sustain a therapy cause side effects. Therapeutic proteins and genetic materials have specific shortcomings—a high propensity for immune reactions, inactivation by inhibitors and enzymes (proteases, nucleases), and the necessity of specific subcellular localization. This chapter briefly describes strategies for optimization of endothelial delivery of drugs. It focuses on targeting to endothelial surface determinants, promising specific delivery of protein and genetic therapeutic agents to selected subcellular compartments of endothelial cells localized in resting or altered vasculature.

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