Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect. Academic Article uri icon

Overview

MeSH

  • Acute Lung Injury
  • Animals
  • Antigens, CD31
  • Cell Adhesion Molecules
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Delivery Systems
  • Endothelium, Vascular
  • Epitopes
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein C
  • Receptors, Cell Surface
  • Thrombomodulin

MeSH Major

  • Endothelial Cells
  • Pharmaceutical Preparations

abstract

  • Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood-tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to partner enzymatically to generate enhanced biologic effect. Based on the recent discovery that paired antibodies directed to adjacent epitopes of platelet endothelial cell adhesion molecule (PECAM)-1 stimulate each other's binding, we fused single-chain fragments (scFv) of paired anti-mouse PECAM-1 antibodies to recombinant murine thrombomodulin (TM) and endothelial protein C receptor (EPCR), endothelial membrane proteins that partner in activation of protein C (PC). scFv/TM and scFv/EPCR bound to mouse endothelial PECAM-1 with high affinity (EC50 1.5 and 3.8 nM, respectively), and codelivery induced a 5-fold increase in PC activation not seen when TM and EPCR are anchored to distinct cell adhesion molecules. In a mouse model of acute lung injury, dual targeting reduces both the expression of lung inflammatory markers and trans-endothelial protein leak by as much as 40%, as compared to either agent alone. These findings provide proof of principle for endothelial dual targeting, an approach with numerous potential biomedical applications. © FASEB.

publication date

  • August 2015

has subject area

  • Acute Lung Injury
  • Animals
  • Antigens, CD31
  • Cell Adhesion Molecules
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Delivery Systems
  • Endothelial Cells
  • Endothelium, Vascular
  • Epitopes
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pharmaceutical Preparations
  • Protein C
  • Receptors, Cell Surface
  • Thrombomodulin

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4511192

Digital Object Identifier (DOI)

  • 10.1096/fj.15-271213

PubMed ID

  • 25953848

Additional Document Info

start page

  • 3483

end page

  • 3492

volume

  • 29

number

  • 8