Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds

doi:10.1073/pnas.0511219103

Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds

*Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037;
^§AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA 92111; and
^∥Department of Surgery, University of California, 200 West Arbor Drive, San Diego, CA 92103-8220

Contributed by Erkki Ruoslahti, December 27, 2005

Abstract

Screening of a phage library for peptides that bind to clotted plasma in the presence of liquid plasma yielded two cyclic decapeptides, CGLIIQKNEC (CLT1) and CNAGESSKNC (CLT2). When injected intravenously into mice bearing various types of tumors, fluorescein-conjugated CLT peptides accumulated in a fibrillar meshwork in the extracellular compartment of the tumors, but were not detectable in other tissues of the tumor-bearing mice. The tumor homing of both peptides was strongly reduced after coinjection with unlabeled CLT2, indicating that the two peptides recognize the same binding site. The CLT peptide fluorescence colocalized with staining for fibrin(ogen) present in the extravascular compartment of tumors, but not in other tissues. The CLT peptides did not home to tumors grown in fibrinogen-null mice or in mice that lack plasma fibronectin. The CLT peptides also accumulated at the sites of injury in arteries, skeletal muscle, and skin. We conclude that the CLT peptides recognize fibrin–fibronectin complexes formed by clotting of plasma proteins that have leaked into the extravascular space in tumors and other lesions. These peptides may be useful in targeting diagnostic and therapeutic materials into tumors and injured tissues.

Footnotes

**To whom correspondence should be addressed. E-mail: ruoslahti{at}burnham.org
↵ ^†Present address: Biogen-Idec, 1 Antibody Way, Oceanside, CA 92056.
↵ ^‡Present address: Department of Pathology, University of Alabama at Birmingham, 1670 University Boulevard, VH660, Birmingham, AL 35294-0019.
↵ ^¶Present address: Burnham Institute for Medical Research at the University of California, Santa Barbara, CA 93106.
Author contributions: J.P., D.M.B., M.Y., R.M.H., and E.R. designed research; J.P., M.K., T.A.H.J., and D.P. performed research; D.M.B. contributed new reagents/analytic tools; J.P. analyzed data; and E.R. wrote the paper.
Conflict of interest statement: No conflicts declared.