Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds.
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.
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Jan
J
Pilch
Darren M
DM
Brown
Masanobu
M
Komatsu
Tero A H
TA
Järvinen
Meng
M
Yang
David
D
Peters
Robert M
RM
Hoffman
Erkki
E
Ruoslahti
D000818:Animals; D001777:Blood Coagulation; D045744:Cell Line, Tumor; D005337:Fibrin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000737:chemistry*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000032:analysis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D014947:Wounds and Injuries / Q000378:metabolism*
D005353:Fibronectins; D019151:Peptide Library; D010456:Peptides, Cyclic; C510873:cyclo(cysteinyl-asparginyl-alanyl-glycyl-glutamyl-seryl-seryl-lysyl-asparaginyl-cysteinyl); C510872:cyclo(cysteinyl-glycyl-leucyl-isoleucyl-isoleucyl-glutaminyl-lysyl-asparaginyl-glutamyl-cysteinyl); D005337:Fibrin