Tumor targeting with a selective gelatinase inhibitor.
Several lines of evidence suggest that tumor growth, angiogenesis, and metastasis are dependent on matrix metalloproteinase (MMP) activity. However, the lack of inhibitors specific for the type IV collagenase/gelatinase family of MMPs has thus far prevented the selective targeting of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) for therapeutic intervention in cancer. Here, we describe the isolation of specific gelatinase inhibitors from phage display peptide libraries. We show that cyclic peptides containing the sequence HWGF are potent and selective inhibitors of MMP-2 and MMP-9 but not of several other MMP family members. Our prototype synthetic peptide, CTTHWGFTLC, inhibits the migration of human endothelial cells and tumor cells. Moreover, it prevents tumor growth and invasion in animal models and improves survival of mice bearing human tumors. Finally, we show that CTTHWGFTLC-displaying phage specifically target angiogenic blood vessels in vivo. Selective gelatinase inhibitors may prove useful in tumor targeting and anticancer therapies.
Koivunen
E
E
Department of Biosciences, Division of Biochemistry, Viikinkaari 5, University of Helsinki, FIN-00014, Finland.
Arap
W
W
Valtanen
H
H
Rainisalo
A
A
Medina
O P
OP
Heikkilä
P
P
Kantor
C
C
Gahmberg
C G
CG
Salo
T
T
Konttinen
Y T
YT
Sorsa
T
T
Ruoslahti
E
E
Pasqualini
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D017931:DNA Primers; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019151:Peptide Library; D010456:Peptides, Cyclic; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9