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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.

Prostate-specific membrane antigen (PSMA), a glutamyl preferring carboxypeptidase, is found in prostate and other carcinomas present on both tumor cells and associated microvascular lining cells. We find that the channel structures delineated by PSMA-expressing cells in human and rat prostate tumors are in functional continuity with the vasculature and thus form part of tumor microvasculature. The PSMA-positive cell-outlined channels are CD31 negative and mutually exclusive of CD31-positive cell-lined channels elsewhere in the tumor consistent with tumor cells adapted to a pseudoendothelial phenotype in vasculogenic mimicry. To assess the functional potential of such PSMA-lined microvasculature to selectively direct infarctive tumor therapy, we coupled the soluble extracellular domain of tissue factor to a PSMA catalytic site inhibitor to create a PSMA-directed selective tumor vascular thrombogen (STVT). This protein induced selective local in vivo infarctive necrosis of the rat Mat Lu prostate tumor when administered i.v. The combined administration of this STVT with low-dose doxorubicin produced a profound tumoricidal effect, resulting in complete eradication of some tumors. This is consistent with the therapeutic potential for a PSMA-directed STVT and expands the potential for selective infarctive ablation of tumors.