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.

Targeted drug-delivery approaches by nanoparticulate carriers in the therapy of inflammatory diseases

“…Accordingly, it will be a matter of time until targeting approaches in different inflammatory situations or in cancer will be harmonized and there is a great potential to learn from pre-existing targeting strategies in cancer S62 Review. Targeted drug-delivery approaches W. Ulbrich and A. Lamprecht (Bar et al 2009;Chang et al 2009;Simone et al 2009). Research on nanocarrier-mediated inflammatory targeting to endothelial cells has just started and the potential of this relatively novel research topic should be evaluated carefully.…”

“…In detail, antibodies or other specific adhesion molecules are bound to the surface of particles and antigens or other specific adhesion molecule counterparts on the surface of cells can be recognized (Steeber et al 2005;Simone et al 2009). The drug should specifically be delivered to the site of action followed by potential intracellular uptake.…”

Liposomes in Diagnosis and Treatment of Cardiovascular Disorders

“…55,56 later, different molecular determinants on the surface of pulmonary endothelial cells were used for targeted delivery of liposomal nanocarriers. 57,58 liposomes can be used not only as an independent drug delivery system but also in combination with polymer-coated stents. stents coated with polymeric material containing dispersed or encapsulated drugs have been developed and used as a noninvasive method to deal with stent-related complications.…”

Targeted siRNA delivery to diseased microvascular endothelial cells—Cellular and molecular concepts

“…At the same time, carrier systems should allow efficient release of the cargo once the carrier arrives in the endocytotic vesicles and/or in the cytoplasm of the cells [discussed in more details by (44)]. Physicochemical characteristics of the carrier such as composition, size and surface charge can handicap pharmacokinetic behavior by engaging in interactions with serum proteins including serum albumin, lipoproteins and immunoglobulins, which leads to clearance by cells of the reticulo-endothelial system (RES) in the spleen and liver (45). To limit these interactions and prolong circulation half-life, the surface charge can be masked by covering the carrier with a hydrophilic polymer such as (poly)ethylene glycol (PEG) (46).…”