New ways in RGD-peptide mediated drug targeting to angiogenic endothelium: On the nature of drugs, linkers, and carriers.

Endothelial cells (ECs) line the vessels of the entire circulatory system, in arteries, veins and capillaries in each and every organ. In contrast to a previous assumption that the endothelium is only a physical barrier, research in the last four decades has shown that it presents a complex organ-system. This organ is not only involved in many physiological but also pathophysiological processes like e.g., in chronic inflammation or malignant disease. In chronic inflammatory disorders, ECs express a number of cell adhesion molecules leading to an abundant leukocyte infiltration in the inflamed tissue. In cancer tissue ECs are stimulated to constantly build new blood vessels, a process called angiogenesis, to nurture tumor growth. Both inflamed endothelium and angiogenic ECs differ from dormant endothelium by e.g. expression of several receptors and growth factors. The acceptance of the endothelium as a key player in inflammation and cancer was followed by the development of therapeutics that affect extracellular matrix (ECM) degradation, cell migration and proliferation, and vessel stabilization (e.g., kinase inhibitors, tubulin binding agents, matrix metalloproteinase inhibitors). These therapeutics, however, show neither homing to endothelial cells in general nor to activated or angiogenic endothelial cells in particular. Thus, they are widely distributed to most tissues in the body. In the present thesis I aimed at improving the tissue distribution of anti-inflammatory, anti-angiogenic or antivascular therapeutics by redirecting such compounds to activated and angiogenic endothelial cells. A drug targeting approach can increase the drug concentration within the target cell while it reduces the concentration in the rest of the body, which eventually may lead to an improved therapeutic effect and a reduction in side effects. I exploited the fact that activated and angiogenic EC have a high expression of αvβ3-integrin in common and dormant EC hardly express αv-integrins on the cell surface. Adding the excellent accessibility of the endothelium for systemically administered macromolecular therapeutics, αvβ3-integrin is an optimal target receptor for an intracellular drug targeting approach. Cyclic peptides with a arginine-glycine-aspartic acid sequence (RGD) have been shown to bind with high affinity to this integrin.