Targeted delivery of therapeutics to endothelium

Abstract

The endothelium is a target for therapeutic and diagnostic interventions in a plethora of human disease conditions including ischemia, inflammation, edema, oxidative stress, thrombosis and hemorrhage, and metabolic and oncological diseases. Unfortunately, drugs have no affinity to the endothelium, thereby limiting the localization, timing, specificity, safety, and effectiveness of therapeutic interventions. Molecular determinants on the surface of resting and pathologically altered endothelial cells, including cell adhesion molecules, peptidases, and receptors involved in endocytosis, can be used for drug delivery to the endothelial surface and into intracellular compartments. Drug delivery platforms such as protein conjugates, recombinant fusion constructs, targeted liposomes, and stealth polymer carriers have been designed to target drugs and imaging agents to these determinants. We review endothelial target determinants and drug delivery systems, describe parameters that control the binding of drug carriers to the endothelium, and provide examples of the endothelial targeting of therapeutic enzymes designed for the treatment of acute vascular disorders including ischemia, oxidative stress, inflammation, and thrombosis.

Fig. 1

Determinants of drug carrier binding to vascular endothelium (black Ys, solid line, high affinity antibodies, green Ys, dashed line, low affinity antibodies, arrows endothelial antigens). a Effect of antibody affinity on carrier binding. b Effect of surface density coating of carriers with antibodies and of antigen (Ag) density (the number of antigens per unit area of endothelium). c Effect of shear stress on binding. The upper curve is relevant to firm adhesion targeting, such as CAM targeted carriers, whereas the bottom curve (bell-shaped) illustrates catch-slip binding and the shear threshold effect, typical of lower affinity selectin targeting. Binding is schematically depicted here as the number of carriers bound to the endothelium

Fig. 2

Selectively permeable antioxidant polymer nanocarriers (large gray sphere polymer nanocarrier with internal aqueous cavities containing catalase, green circles catalase). The red cylinders represent generic proteases that cannot penetrate the polymer material. However, the small molecule H₂O₂ easily permeates through the polymer matrix and can thus be dissociated into inert water and oxygen by the encapsulated catalase

Fig. 3

“On demand” fibrinolysis by vascular targeting of thrombin-activated anti-PECAM scFv/uPA (scFv/uPA-T). scFv-uPA/T circulates in a pro-drug form, viz., single-chain uPA (scuPA), binds to PECAM-1, and remains anchored on the endothelial luminal surface for at least several hours. Upon environmental stress or tissue injury, thrombin is generated to cleave fibrinogen (Fg) and form fibrin clots. While this causes in situ thrombosis, the generated thrombin also converts the endothelium-bound scFv/uPA-T to enzymatically active tcuPA, inducing local conversion of plasminogen (Pg) into plasmin (Pn). The active plasmin subsequently facilitates fibrinolysis, which restores the blood flow and mitigates tissue ischemia and injury