Targeted polyelectrolyte complex micelles treat vascular complications in vivo
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
118
Journal Issue
50
Pages
e2114842118
Date Issued
2021-12-14
Author(s)
Zhou, Zhengjie
Mellas, Michael
Oh, Myung-Jin
Zhu, Jiayu
Li, Jin
Huang, Ru-Ting
Harrison, Devin L
Shentu, Tzu-Pin
Wu, David
Lueckheide, Michael
Carver, Lauryn
Chung, Eun Ji
Leon, Lorraine
Tirrell, Matthew V
Fang, Yun
Abstract
Vascular disease is a leading cause of morbidity and mortality in the United States and globally. Pathological vascular remodeling, such as atherosclerosis and stenosis, largely develop at arterial sites of curvature, branching, and bifurcation, where disturbed blood flow activates vascular endothelium. Current pharmacological treatments of vascular complications principally target systemic risk factors. Improvements are needed. We previously devised a targeted polyelectrolyte complex micelle to deliver therapeutic nucleotides to inflamed endothelium in vitro by displaying the peptide VHPKQHR targeting vascular cell adhesion molecule 1 (VCAM-1) on the periphery of the micelle. This paper explores whether this targeted nanomedicine strategy effectively treats vascular complications in vivo. Disturbed flow-induced microRNA-92a (miR-92a) has been linked to endothelial dysfunction. We have engineered a transgenic line (miR-92aEC-TG /Apoe-/- ) establishing that selective miR-92a overexpression in adult vascular endothelium causally promotes atherosclerosis in Apoe-/- mice. We tested the therapeutic effectiveness of the VCAM-1-targeting polyelectrolyte complex micelles to deliver miR-92a inhibitors and treat pathological vascular remodeling in vivo. VCAM-1-targeting micelles preferentially delivered miRNA inhibitors to inflamed endothelial cells in vitro and in vivo. The therapeutic effectiveness of anti-miR-92a therapy in treating atherosclerosis and stenosis in Apoe-/- mice is markedly enhanced by the VCAM-1-targeting polyelectrolyte complex micelles. These results demonstrate a proof of concept to devise polyelectrolyte complex micelle-based targeted nanomedicine approaches treating vascular complications in vivo.
Subjects
atherosclerosis; nanomedicine; nanoparticle; stenosis; vascular remodeling
Atherosclerosis; Nanomedicine; Nanoparticle; Stenosis; Vascular remodeling
SDGs
Other Subjects
fluorescent dye; microRNA; Mirn92 microRNA, mouse; polyelectrolyte; vascular cell adhesion molecule 1; animal; apolipoprotein E knockout mouse; atherosclerosis; endothelium cell; gene expression regulation; genetics; human; inflammation; male; metabolism; micelle; mouse; transgenic mouse; upregulation; Animals; Atherosclerosis; Endothelial Cells; Fluorescent Dyes; Gene Expression Regulation; Humans; Inflammation; Male; Mice; Mice, Knockout, ApoE; Mice, Transgenic; Micelles; MicroRNAs; Network Pharmacology; Polyelectrolytes; Up-Regulation; Vascular Cell Adhesion Molecule-1
Publisher
NATL ACAD SCIENCES
Type
journal article