Nature Biotechnology
17, 768 - 774 (1999)
doi:10.1038/11703
Tumor targeting with a selective gelatinase inhibitorErkki Koivunen1, Wadih Arap2, Heli Valtanen1, Aija Rainisalo1, Oula Penate Medina1, Pia Heikkilä3, Carmela Kantor1, Carl G. Gahmberg1, Tuula Salo4, Yrjö T. Konttinen5, Timo Sorsa3, Erkki Ruoslahti2
& Renata Pasqualini21
Department of Biosciences, Division of Biochemistry,
Viikinkaari 5, University of Helsinki, FIN-00014, Finland
. 2
The Burnham Institute, 10901 North Torrey
Pines Rd., La Jolla, CA 92037. 3
Department of Periodontology, University of Helsinki
, FIN-00014, Finland. 4
Department of Diagnostics and Oral Medicine, University
of Oulu, FIN-90401, Finland. 5
Department of Anatomy, University of Helsinki,
FIN-00014, Finland
Correspondence should be addressed to Erkki Koivunen erkki.koivunen@helsinki.fi or Renata Pasqualini pasqualini@burnham-inst.orgphage displaymatrix metalloproteinasetumor targetingangiogenesiscancer therapySeveral 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.
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