Targeted polyelectrolyte complex micelles treat vascular complications in vivo.

Autor:	Zhou Z; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637.; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Yeh CF; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637.; Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei 100, Taiwan., Mellas M; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637., Oh MJ; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Zhu J; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Li J; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Huang RT; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Harrison DL; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637.; Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637., Shentu TP; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Wu D; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Lueckheide M; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637., Carver L; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637.; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637., Chung EJ; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637., Leon L; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637., Yang KC; Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei 100, Taiwan., Tirrell MV; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637; mtirrell@uchicago.edu yfang1@medicine.bsd.uchicago.edu.; Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637.; Materials Science Division, Argonne National Laboratory, Lemont, IL 60439., Fang Y; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637; mtirrell@uchicago.edu yfang1@medicine.bsd.uchicago.edu.; Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Dec 14; Vol. 118 (50).
DOI:	10.1073/pnas.2114842118
Abstrakt:	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-92a EC-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. Competing Interests: The authors declare no competing interest. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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