Many therapeutic targets can be expressed in restricted but highly specific and accessible locations in the vascular epithelium. Several peptides that are known to home to blood vessels have been used as carriers to navigate the delivery of drugs to the vasculature. Tapping in on this vascular address system would allow the delivery of targeted therapies to specific locations. In Nature Medicine, Arap et al. used phage-display technology to identify peptides that home to specific vascular beds in a patient with a B-cell malignancy. This technology fuses peptides to capsid proteins on the phage surface. Libraries of phage-displayed peptides can then be screened for binding to specific ligands. Determination of the gene sequence of the selected phage identifies the peptide sequence.

Screening humans is important, as mouse-derived probes do not always achieve the desired targeted delivery. In this study, the patient received an intravenous infusion of a highly diverse, random phage-display peptide library. After infusion, tissue biopsies were taken to recover and identify phage from various organs. Analysis of the tripeptide sequences showed that some were preferentially recovered from several sites, whereas others were recovered only from a single site.These motifs are likely to represent sequences that are present in circulating ligands that home to vascular receptors. This information was used to compile panels of human proteins that contain these motifs.

One protein containing a tripeptide motif that was recovered from bone marrow is bone morphogenetic protein 3B. This protein is a growth factor that regulates bone development, and so it might be therapeutically useful to mimic the isolated ligand for that tissue. Motifs were also found in extracellular or transmembrane proteins that might operate selectively in the target tissue, such as sortilin in fat. Validation studies showed that some ligand–receptor pairs are detectable in numerous unrelated subjects. Tissue specificity of a phage-displayed peptide that mimics interleukin-11 was found to be associated with prostate. The phage bound specifically to prostate endothelium but not to control organs, and this specificity was confirmed by protein–protein interactions in vitro.

Vascular receptors that correspond to the selected peptides have been identified in normal and tumour blood vessels, so it is possible to develop therapeutic strategies based on selective expression of vascular receptors. This work has started to survey some of the uncharted territory in the vascular endothelium.