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Biomaterials. 2018 Sep;178:293-301. doi: 10.1016/j.biomaterials.2018.06.025. Epub 2018 Jun 18.

A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters.

Author information

1
Department of Surgery, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
2
Department of Materials Science and Engineering, and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
3
Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA.
4
Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA. Electronic address: Lianwang.Guo@osumc.edu.
5
Department of Materials Science and Engineering, and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA; Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53715, USA. Electronic address: shaoqingong@wisc.edu.
6
Department of Surgery, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA. Electronic address: KC.Kent@osumc.edu.

Abstract

Drug-eluting stents are the most commonly employed method to control post-angioplasty restenosis. Unfortunately, they exacerbate life-threatening stent thrombosis because of endothelium damage caused by both drug and stenting. To solve this major medical problem, an endothelium-protective and stent-free anti-restenotic method is highly desirable. Here we have generated a biomimetic intravenous delivery system using dendritic polymer-based nanoclusters, which were coated with platelet membranes for targeting to the injured arterial wall where restenosis occurs. These nanoclusters were loaded with an endothelium-protective epigenetic inhibitor (JQ1) or an endothelium-toxic status quo drug (rapamycin), and compared for their ability to mitigate restenosis without hindering the process of re-endothelialization. Fluorescence imaging of Cy5-tagged biomimetic nanoclusters indicated their robust homing to injured, but not uninjured arteries. Two weeks after angioplasty, compared to no-drug control, both rapamycin- and JQ1-loaded biomimetic nanoclusters substantially reduced (by >60%) neointimal hyperplasia, the primary cause of restenosis. However, whereas the rapamycin formulation impaired the endothelial re-coverage of the denuded inner arterial wall, the JQ1 formulation preserved endothelial recovery. In summary, we have created an endothelium-protective anti-restenotic system with biomimetic nanoclusters containing an epigenetic inhibitor. This system warrants further development for a non-thrombogenic and stent-free method for clinical applications.

KEYWORDS:

Biomimetic nanoclusters; Endothelium-protective; JQ1; Rapamycin; Re-endothelialization

PMID:
29958152
PMCID:
PMC6082402
[Available on 2019-09-01]
DOI:
10.1016/j.biomaterials.2018.06.025

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