title: Collaborative Enhancement of Endothelial Targeting of Nanocarriers by Modulating Platelet-Endothelial Cell Adhesion Molecule-1/CD31 Epitope Engagement.
abstract: Nanocarriers (NCs) coated with antibodies (Abs) to extracellular epitopes of the transmembrane glycoprotein PECAM (platelet endothelial cell adhesion molecule-1/CD31) enable targeted drug delivery to vascular endothelial cells. Recent studies revealed that paired Abs directed to adjacent, yet distinct epitopes of PECAM stimulate each other's binding to endothelial cells in vitro and in vivo ("collaborative enhancement"). This phenomenon improves targeting of therapeutic fusion proteins, yet its potential role in targeting multivalent NCs has not been addressed. Herein, we studied the effects of Ab-mediated collaborative enhancement on multivalent NC spheres coated with PECAM Abs (Ab/NC, ∼180 nm diameter). We found that PECAM Abs do mutually enhance endothelial cell binding of Ab/NC coated by paired, but not "self" Ab. In vitro, collaborative enhancement of endothelial binding of Ab/NC by paired Abs is modulated by Ab/NC avidity, epitope selection, and flow. Cell fixation, but not blocking of endocytosis, obliterated collaborative enhancement of Ab/NC binding, indicating that the effect is mediated by molecular reorganization of PECAM molecules in the endothelial plasmalemma. The collaborative enhancement of Ab/NC binding was affirmed in vivo. Intravascular injection of paired Abs enhanced targeting of Ab/NC to pulmonary vasculature in mice by an order of magnitude. This stimulatory effect greatly exceeded enhancement of Ab targeting by paired Abs, indicating that '"collaborative enhancement"' effect is even more pronounced for relatively large multivalent carriers versus free Abs, likely due to more profound consequences of positive alteration of epitope accessibility. This phenomenon provides a potential paradigm for optimizing the endothelial-targeted nanocarrier delivery of therapeutic agents.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Chacko
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.forename: Blaine J
authors.initials: BJ
authors.lastname: Zern
authors.forename: John L
authors.initials: JL
authors.lastname: Mikitsh
authors.forename: Madhura
authors.initials: M
authors.lastname: Nayak
authors.forename: Divya
authors.initials: D
authors.lastname: Menon
authors.affiliation: #Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Johnston
authors.affiliation: #Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.forename: David M
authors.initials: DM
authors.lastname: Eckmann
authors.forename: Peter F
authors.initials: PF
authors.lastname: Davies
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D054118:Nanospheres / Q000737:chemistry* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000939:Epitopes; D019408:Platelet Endothelial Cell Adhesion Molecule-1
keywords: PECAM-1; collaborative enhancement; multivalent interactions; nanocarrier; targeted drug delivery