Endothelial tissue represents both a key target for therapeutic intervention and a barrier to successful extravascular drug delivery. Alas, most drugs have no natural affinity to any therapeutic sites, including endothelial cells (ECs). Thus, only a minute fraction of injected therapeutics actually binds to the endothelium, despite its immediate accessibility to circulation. The goal of endothelial targeting is to promote the specific and safe delivery of a drug to, into, or across ECs, to localize its effects in the lumen, desired intracellular endothelial compartment, or subendothelial space. Ideally, targeting would direct drug accumulation to a desired vascular domain.

The successful pursuit of this goal depends on several parallel lines of research, including the design of drug carriers and the identification of target endothelial determinants. To date, the majority of studies have focused on cell culture systems and animal models, with few published reports in human subjects. In this chapter, we briefly review research efforts in this field and describe basic principles that are important for endothelial targeting in specific disease states. More details on this topic can be found in recent reviews (1–10) as well as in other chapters in this volume.

The pharmacokinetics of most drugs do not favor their delivery to or/and across endothelium due to their: (a) inactivation in vivo and elimination from blood by the reticuloendothelial system (RES), a problem hampering delivery of labile, large (>50 kD) biotherapeutics including proteins and nucleic acids; (b) renal excretion, a problem especially acute for small (<10 kD) drugs; and (c) lack of affinity to ECs, which is characteristic of both classes of drugs.