Targeting of tumor blood vessels: a phage-displayed tumor-homing peptide specifically binds to matrix metalloproteinase-2-processed collagen IV and blocks angiogenesis in vivo.

摘要

Proteolytic degradation of the basement membrane by the matrix metalloproteinase-2 and -9 is an essential step in tumor angiogenesis. On proteolytic degradation, cryptic sites in collagen IV are formed, which serve as a migration signal for endothelial cells and are specific for angiogenic blood vessels. The aim of this study was to generate peptides that bind specifically to proteolytically processed collagen IV and to test whether these peptides accumulate in tumor vasculature and are able to block angiogenesis. To obtain such peptides, we performed a combined in vivo and in vitro phage display screen using a recombinant phage-displayed peptide library. We found a phage displaying the peptide sequence TLTYTWS that specifically binds to collagen IV modified by matrix metalloproteinase-2. We then tested the ability of the phage to bind to the vasculature in xenograft tumors and found indeed a significant accumulation of the phage in tumors but not in control organs. The tumor homing of the TLTYTWS phage is specific, as it can be blocked by coinjection chemically synthesized cognate peptide. Moreover, TLTYTWS peptide inhibits angiogenesis in an in vivo assay in a concentration-dependent manner and significantly reduces endothelial differentiation in vitro. In conclusion, we report about a novel tumor-homing peptide that specifically binds to proteolytically processed collagen IV, accumulates in tumors, and blocks angiogenesis. This peptide may be a new useful tool for diagnostic and therapeutic procedures in oncology.