Tissue-specific targeting based on markers expressed outside endothelial cells.

Effective management of various diseases could greatly benefit from improved approaches to selective delivery of imaging agents and drugs to the pathological site while sparing other organs. Vascular targeting based on markers expressed on endothelial cells is the basis for the success of a number of clinical applications. However, targeted treatment of endothelial cells has turned out to often be insufficient for sustained beneficial effects, and the ability to direct therapy to other cells in the organ/tissue may often be essential for long-term efficacy. Therefore, molecular markers associated with the tissue compartments other than the endothelium may represent viable targets for therapeutic, as well as diagnostic, agents. Accumulating evidence indicates that, in both normal development and pathology, permeability of the vasculature may allow an intravenously administered agent to reach cells underlying the endothelium and the interstitial extracellular matrix (ECM). In such cases, perivascular, stromal, and parenchymal cells become exposed to the agent, and can interact with it through differentially expressed cell surface receptors. Infiltrating cells of the immune system may also contribute to the tissue targeting capacity. Markers expressed on these nonendothelial targets accessible to systemically circulating agents may be expressed in an organ-specific manner. Some proteins have been identified to mark both endothelial and nonendothelial cells in the same tissue, which may contribute to the capacity of the agents targeting this tissue to accumulate and be retained in it. The clinical relevance of these markers of deep tissue layers in disease-specific contexts remains to be established. In this chapter, the progress in the understanding of targetable tissue markers expressed outside the endothelium is overviewed. The challenges in the identification and characterization of differentially expressed nonendothelial proteins exposed to circulation are discussed.