Leveraging molecular heterogeneity of the vascular endothelium for targeted drug delivery and imaging

Patterns of luminal vascular protein expression vary according to tissue of origin, and these so-called vascular zip codes play an important role in the maintenance of normal physiological processes in multiorgan species. These zip codes are also often modified in response to pathology and play a critical role in the response to and recovery from disease. These differentially expressed proteins offer opportunities for organ- and disease-specific ligand-targeted molecular delivery, offering clear pharmacologic advantages to traditional systemic drug delivery. However, this approach depends on the availability of frequently elusive targets. Combinatorial screening is a valuable tool for identifying optimal ligands for targeted delivery to the vasculature, especially when adapted for in vivo selection. Here we discuss molecular heterogeneity of the vascular endothelium and the use of phage display as a combinatorial screening method to exploit this heterogeneity for tissue or disease-specific vascular targeting. We also highlight applications of this approach for both drug delivery and molecular imaging.