RGD-modified endostatin fragments showed an antitumor effect through antiangiogenesis.

EDSM, an endostatin-derived synthetic polypeptide, contains the amino acids 6-48 of endostatin from its N-terminus, which could inhibit human umbilical vein endothelial cell (HUVEC) migration and tumor growth. To increase the targeted delivery of EDSM to tumors and further enhance its antiangiogenic activity, the RGD sequence (Arg-Gly-Asp) was introduced into EDSM and two peptides were obtained: EDSM-X with RGD on the N-terminus of EDSM and EDSM-Y with RGD on the C-terminus. Both modified peptides showed a significant antiangiogenic activity in the HUVEC migration assay, the HUVEC tube formation assay, and the murine aortic ring formation assay in vitro. In agreement with the in-vitro data, EDSM-X and EDSM-Y also showed a significant antitumor activity in vivo. From the cell adhesion assay, it was confirmed that the molecular target of the modified peptides on HUVECs was integrin αvβ3, rather than integrin α5β1. Furthermore, EDSM-Y exhibited more potent antiangiogenic activity and antitumor activity than EDSM-X in vitro and in vivo, and this phenomenon was attributed to the difference in the two modified peptides in their three-dimensional structure modeling and their molecular dockings with integrin αvβ3.