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Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect
Author(s) -
Greineder Colin F.,
Brenza Jacob B.,
Carnemolla Ronald,
Zaitsev Sergei,
Hood Elizabeth D.,
Pan Daniel C.,
Ding BiSen,
Esmon Charles T.,
Chacko Ann Marie,
Muzykantov Vladimir R.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-271213
Subject(s) - thrombomodulin , microbiology and biotechnology , endothelial stem cell , endothelial protein c receptor , chemistry , epitope , antibody , recombinant dna , protein c , endothelium , cancer research , immunology , biology , biochemistry , thrombin , platelet , in vitro , gene , endocrinology
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 (EC 50 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.—Greineder, C. F., Brenza, J. B., Carnemolla, R., Zaitsev, S., Hood, E.D., Pan, D.C., Ding, B.‐S., Esmon, C. T., Chacko, A. M., Muzykantov, V. R. Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect. FASEB J. 29, 3483‐3492 (2015). www.fasebj.org