Targeted endothelial nanomedicine for common acute pathological conditions

Abstract

Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre-clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal studies provide the basis for the challenging translation endothelial nanomedicine into the clinical domain.

P-selectin is a nanotherapeutic delivery target in the tumor microenvironment

“…Apart from the tumors, the organs exhibiting nanoparticle accumulation were the lungs and the liver, with virtually no uptake in the spleen. Although nanoparticles often accumulate in the liver and spleen, often before hepatobiliary clearance, it was previously found that the use of endothelial targets can modulate nanoparticle biodistribution to the lungs, likely due to the large endothelial component in this organ (51). …”

Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo

“…ECs form not only the largest cellular surface area in the human body, but also a readily accessible membrane decorated with surface molecules evolved to interact with circulating blood components. 36 Like other seemingly straightforward drug delivery applications (eg, anti-neoplastic ADCs), 39,40 however, execution has proven more challenging than initially expected. Some EC surface targets, like the receptors for transferrin and insulin, are poorly suited for surface anchoring, as their biologic functions necessitate rapid internalization in response to binding.…”

“…These issues are of particular interest given substantial preclinical data suggesting the utility of anchoring biotherapeutics to endothelial surfaces. 11,14,18,19,36,46,47 Preliminary studies have mostly used monovalent scFv fusion proteins, favored based on their minimal rate of internalization and uniform molecular conformation. Examples of cargo successfully delivered via scFv fusion protein include single-chain urokinase-type plasminogen activator (scuPA), the first recombinant protein to be fused to anti-PECAM scFv.…”

“…27,35 In contrast, both ICAM-1 and PECAM-1 are known to rapidly internalize multi-avid species (eg, antibody decorated nanocarriers), which induce clustering and distinct endocytic pathways. 34,36 Given this complexity, we felt it was important to test endocytosis of the specific antibodies used in our radiotracing experiments (clone YN1 for αICAM and clone 390 for αPECAM, respectively) and to compare their rate of internalization with that of monovalent scFv derivatives. 37 Supplemental Figure S3A,B show the results of quantitative radio-internalization assays, which were in line with previous data, indicating fairly limited endocytosis of all surface bound affinity ligands (<20% internalized within 1 hour).…”

Endothelium at a Glance

“…Yet, keeping in mind the huge heterogeneity of endothelial cell phenotype, one must not forget that therapy affecting endothelium should be targeted to specific vascular beds. In the last time, endothelium-targeted nanomedicine has evolved as a promising new model to deliver drugs directly into the endothelial cells [24]. Last but not least, exercise has long been appreciated as one of the most efficient measures to improve endothelial (dys)function in various ways: increasing nitric oxide (NO) bioavailability; induction of reactive oxygen species (ROS) scavenging enzymes [25]; affecting the sympathetic nervous system; and increasing the number of endothelial progenitor cells (EPCs) to list just a few.…”