Department of Surgery, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Department of Materials Science and Engineering, and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Biomaterials. 2018 Sep;178:293-301. doi: 10.1016/j.biomaterials.2018.06.025. Epub 2018 Jun 18.
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.
药物洗脱支架是控制血管成形术后再狭窄的最常用方法。不幸的是，由于药物和支架对内皮的损伤，它们会加剧危及生命的支架内血栓形成。为了解决这个主要的医学问题，非常需要一种具有保护内皮和无支架的抗再狭窄方法。在这里，我们使用基于树枝状聚合物的纳米簇生成了一种仿生静脉内递药系统，这些纳米簇用血小板膜包裹，以靶向发生再狭窄的受损动脉壁。这些纳米簇装载了一种具有保护内皮作用的表观遗传抑制剂（JQ1）或一种内皮毒性的现状药物（雷帕霉素），并比较它们在不阻碍再内皮化过程的情况下减轻再狭窄的能力。Cy5 标记的仿生纳米簇的荧光成像表明它们能够强烈归巢到受损但未受损的动脉。血管成形术后 2 周，与无药物对照组相比，载雷帕霉素和 JQ1 的仿生纳米簇均显著减少（>60%）新生内膜增生，这是再狭窄的主要原因。然而，雷帕霉素制剂损害了裸露的内动脉壁的内皮再覆盖，而 JQ1 制剂则保留了内皮恢复。总之，我们已经用含有表观遗传抑制剂的仿生纳米簇创建了一种具有保护内皮作用的抗再狭窄系统。该系统为非血栓形成和无支架的临床应用方法提供了进一步的发展。
