A novel vascular endothelial growth factor heparin-binding domain substructure binds to glycosaminoglycans in vivo and localizes to tumor microvascular endothelium.
Vascular endothelial growth factor has an exon 7-encoded heparin-binding domain. To explore the expression of complementary ligands on endothelial surfaces in vivo and to assess potential for localization within the vascular tree, we introduced a truncated version of this domain (HBDt) into a modified M13 phage. Despite the small size and trace-level expression, this HBDt endowed the phage with affinity for heparin to which it bound in vitro. It also preferentially and selectively localized the phage in vivo to vascular endothelial surfaces, especially of tumors. Competition assays demonstrated that accumulation and localization of this phage was attributable to expression of the HBDt on the phage surface and sequence comparison suggests its novelty. We propose to use this novel HBDt structure to explore the expression of the ligand glycosaminoglycans within the vascular tree. This structure may facilitate directed delivery of therapeutic molecules.
El-Sheikh
Amr
A
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. ammor@scripps.edu
Liu
Cheng
C
Huang
Haining
H
Edgington
Thomas S
TS
D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017104:Bacteriophage M13 / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D016466:CHO Cells; D003110:Colonic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D006025:Glycosaminoglycans; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D006493:Heparin