A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters.
A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters.
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DOI：
10.1016/j.biomaterials.2018.06.025
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发表时间：
2018-09
期刊：
影响因子：
14
通讯作者：
Kent KC
中科院分区：
文献类型：
--
作者：
Wang B;Chen G;Urabe G;Xie R;Wang Y;Shi X;Guo LW;Gong S;Kent KC
药物洗脱支架是控制血管成形术后再狭窄最常用的方法。不幸的是，由于药物和支架植入引起的内皮损伤，它们加剧了危及生命的支架血栓形成。为了解决这一重大的医学问题，一种内皮保护和无支架的抗再狭窄方法是非常可取的。在这里，我们用树突聚合物纳米簇制造了一种仿生静脉输送系统，该系统被涂有血小板膜，用于靶向发生再狭窄的损伤动脉壁。这些纳米团簇装载了内皮保护表观遗传抑制剂（JQ1）或内皮毒性药物（雷帕霉素），并比较了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标记的仿生纳米团簇的荧光成像表明，它们对受伤动脉有很强的归巢性，但对未受伤动脉没有。血管成形术两周后，与无药物对照相比，雷帕霉素和jq1负载的仿生纳米团簇均显著减少了新生内膜增生（减少了60%），新生内膜增生是再狭窄的主要原因。然而，雷帕霉素制剂损害了内皮细胞对剥离的动脉内壁的重新覆盖，而JQ1制剂则保持了内皮细胞的恢复。总之，我们已经创建了一个内皮保护抗再狭窄系统与仿生纳米团簇含有表观遗传抑制剂。该系统保证进一步发展为临床应用的非血栓性和无支架的方法。
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.
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