Chemically synthesized matrix metalloproteinase and angiogenesis-inhibiting peptides as anticancer agents.

By connection of Regasepin2, a heptapeptide inhibitor of matrix metalloproteinases (MMPs), to the N- or C-terminus of ES-2, an anti-angiogenic peptide of 11 residues, two designed peptides CPU1 and CPU2 were generated. Unexpectedly, CPU2 inhibited MMP-8 and MMP-9 activity in the nanomolar range, whereas CPU1 displayed a weaker inhibitory profile than Regasepin2 against TACE, MMP-8 and MMP-9. CPU1 showed a higher affinity than CPU2 with integrin α5β1 in a HUVEC adhesion assay.

Quantitative analysis and pharmacokinetics study of integrin antagonist AP25 in rat plasma.

BALB/c mice were immunized by highly immunogenic recombinant proteins containing amino acid sequence of integrin antagonist AP25. Antibody against AP25 was prepared and purified by affinity chromatography. An indirect enzyme-linked immunosorbent assay for qualitative analysis of AP25 in rat plasma samples was successfully established.

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 vivo pharmacokinetics, immunogenicity and mechanism of PEGylated antitumor polypeptide.

HM-3, An RGD (Arg-Gly-Asp)-modified polypeptide derived from endostatin, is a potent angiogenesis inhibitor. Its robust inhibitory effects on endothelial cell migration and tumor growth have been demonstrated by activity assay both in vitro and in vivo. However, HM-3 has relatively short half-life in vivo.