Moreover, targeted catalase significantly decreased injury-induced pro-inflammatory activation of microglia [168]. The last two decades have demonstrated significant progress in the formulation of delivery systems carrying antioxidant enzymes and their applications to pathologies with a critical role of oxidative stress such as organ transplantation, ischemia-reperfusion, or inflammation. efficacy in preclinical models, suggesting the Tomeglovir potential for translation into clinical practice. As with all therapeutics, demonstration of both efficacy and safety are required for successful clinical implementation, which must be considered not only for the individual components (drug, targeting agent, etc.), but also for the sum of the parts (e.g. the drug delivery system), as unexpected toxicities may arise with complex delivery systems. While the use of endothelial targeting has not been translated into the clinic to date, the preclinical results summarized here suggest that there is hope for successful implementation of these agents in the years to come. == Introduction == The endothelial cells that form a thin monolayer lining the inner surface of blood vessels exert many vitally important regulatory functions. The endothelium controls vascular permeability via dynamic intercellular gaps [1], intracellular fenestrae, and vacuolar pathways initiated in endocytic vesicles [2,3]. It also regulates: i) blood fluidity, ii) vascular tone, signaling, and angiogenesis; and iii) blood cell trafficking [46]. Endothelial damage, pathological activation, and other abnormalities are implicated in the pathogenesis of ischemia, thrombosis, inflammation, tumor growth, hypertension, stroke, atherosclerosis, and other maladies (Table 1). In these conditions, endothelial cells represent important therapeutic targets [710]. == Table 1. == Examples of pathological conditions involving endothelial dysfunction Alas, drugs have no natural affinity Tomeglovir to endothelial cells. To overcome this downside, ligands that bind to the endothelium can be used as affinity “vectors” delivering their cargoes to the target cells. Use of optimally devised ligands, configuration of drug delivery systems, and routes of administration allows for concentrating of pharmacological interventions in desirable areas of vasculature, types and phenotypes of endothelia. Furthermore, targeting allows preferential delivery of therapeutic and imaging agents to selected sub-cellular destinations, i.e., to, into, or across endothelium [1116]. Since the 1980s, several groups have been pursuing this strategy (AKA vascular immunotargeting”) [1723,16,24,25]. Here we briefly review this actively evolving field, with focus on endothelial targeting of drugs alleviating inflammation, thrombosis, and oxidative stress. == Endothelial Targeting: specific features == The concept of vascular targeting is based on a fairly straightforward idea: drugs and their carriers can be conjugated chemically or via recombinant techniques with the ligands of the endothelial surface markers (Figure 1). These ligands include monoclonal antibodies and their fragments, natural ligands, and peptides [10] [36]. Endothelial proteins tested for targeting include constitutive angiotensin-converting enzyme (ACE) [37,22,24], caveolar proteins such as aminopeptidase P2 [38], growth factors, integrins, and transferrin receptors, among others [39]. This approach for the specific delivery of drugs to the endothelial epitope of choice has been extensively studied by several labs [22,40,16,23,21,13,4144]. == Figure 1. == Endothelial determinants for targeted drug delivery. (A) Pan-endothelial molecules clustered in apical plasmalemma, (B) located Tomeglovir in the caveolae; (C) Cell adhesion molecules (CAMs); (D) Molecules expressed during angiogenesis or tumor-related; (E) Molecules concentrated in cellular junctions. In particular, cell adhesion molecules, or CAMs, involved in the migration of leukocytes in sites of inflammation represent good targets for favorable vascular localization of agents alleviating pathologies such as oxidative HKE5 stress, inflammation, and thrombosis [45]. CAMs include P- and E-selectins, as well as Ig-family members pan-endothelial Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1) [46], Intercellular Adhesion Molecule-1 (ICAM-1) [47], and Vascular Cell Adhesion Molecule 1 (VCAM-1) [48]. PECAM-1 is stably and constitutively expressed at high density on the luminal surface of all endothelial cells, whereas ICAM-1 is constitutively exposed on endothelium in the vasculature and is further up-regulated by pro-inflammatory agents, abnormal blood flow, and oxidative stress [49,50]. Molecules exposed exclusively on activated endothelium (e.g., E- and P-selectins and VCAM-1) represent attractive targets for delivery of drugs and imaging probes to.