Targeting of the VEGF-kinase inhibitor PTK787 to angiogenic vasculature using RGD-equipped albumin carrier molecules.

INTRODUCTION. Angiogenesis, new blood vessel formation, plays a crucial role in tumor growth (1). Vascular Endothelial Growth Factor (VEGF) has been identified as a strong inducer of angiogenesis and several potent small molecule inhibitors of VEGF signaling are currently in clinical development. Although initial studies indicated that VEGF is an endothelial cell (EC) specific factor recent findings reveal that VEGF also has direct effects on neural cells (2) and on osteoclastic bone resorption, which may lead to side effects of these inhibitors. We therefore propose specific targeting of the VEGF-kinase inhibitor PTK787 to angiogenic endothelial cells to improve the selectivity of the drug. For this purpose, we have developed drug targeting constructs containing cyclic RGD peptides that bind to αvβ3-integrin on surface of the angiogenic endothelial cells. The affinity of such constructs to the target cell can remarkably be increased by coupling multiple RGD peptides to a protein backbone. This type of multivalent RGD-constructs are internalized by angiogenic EC which make them suitable for intracellular delivery of drugs (3, 4). The current study describes the development of these new RGD-equipped constructs for targeting of PTK787 to angiogenic vasculature. These targeting constructs were characterized in terms of drug load, molecular size, and binding to endothelial cells. The effect of the released drug has been determined in-vitro.