Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1

JOURNAL OF CONTROLLED RELEASE

卷:210

Article

Han, Jingyan^1,2,6  Shuvaev, Vladimir V.^1,2  Davies, Peter F.^3,4  Eckmann, David M.⁵  Muro, Silvia⁷  Muzykantov, Vladimir R.^1,2 

[1] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA

[2] Univ Penn, Inst Translat Med & Therapeut, Ctr Translat Targeted Therapeut & Nanomed, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Inst Med & Engn, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA

[6] Boston Univ, Dept Med, Vasc Biol Sect, Boston, MA 02421 USA

[7] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA

关键词: Intracellular delivery;    Endothelial cells;    Vascular immunotargeting;    Cell adhesion molecules;    Endocytosis;    Fluid shear stress;   

DOI  :  10.1016/j.jconrel.2015.05.006

来源: Elsevier

【 摘 要 】

Targeting nanocarriers (NC) to endothelial cell adhesion molecules including Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1 or CD31) improves drug delivery and pharmacotherapy of inflammation, oxidative stress, thrombosis and ischemia in animal models. Recent studies unveiled that hydrodynamic conditions modulate endothelial endocytosis of NC targeted to PECAM-1, but the specificity and mechanism of effects of flow remain unknown. Here we studied the effect of flow on endocytosis by human endothelial cells of NC targeted by monoclonal antibodies Ab(62) and Ab(37) to distinct epitopes on the distal extracellular domain of PECAM. Flow in the range of 1-8 dyn/cm2, typical for venous vasculature, stimulated the uptake of spherical Ab/NC (similar to 180 nm diameter) carrying similar to 50 vs 200 Ab(62) and Ab(37) per NC, respectively. Effect of flow was inhibited by disruption of cholesterol-rich plasmalemma domains and deletion of PECAM-1 cytosolic tail. Flow stimulated endocytosis of Ab(62)/NC and Ab(37)/NC via eliciting distinct signaling pathways mediated by RhoA/ROCK and Src Family Kinases, respectively. Therefore, flow stimulates endothelial endocytosis of Ab/NC in a PECAM-1 epitope specific manner. Using ligands of binding to distinct epitopes on the same target molecule may enable fine-tuning of intracellular delivery based on the hemodynamic conditions in the vascular area of interest. (C) 2015 Elsevier B.V. All rights reserved.

【 授权许可】

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