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Abstract：
The in-stent restenosis (IRS) after the percutaneous coronary intervention contributes to the major treatment failure of stent implantation. MicroRNAs have been revealed as powerful gene medicine to regulate endothelial cells (EC) and smooth muscle cells (SMC) in response to vascular injury, providing a promising therapeutic candidate to inhibit IRS. However, the controllable loading and eluting of hydrophilic bioactive microRNAs pose a challenge to current lipophilic stent coatings. Here, we developed a microRNA eluting cardiovascular stent via the self-healing encapsulation process based on an amphipathic poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) triblock copolymer spongy network. The miR-22 was used as a model microRNA to regulate SMC. The dynamic porous coating realized the uniform and controllable loading of miR-22, reaching the highest dosage of 133 pmol cm-2. We demonstrated that the sustained release of miR-22 dramatically enhanced the contractile phenotype of SMC without interfering with the proliferation of EC, thus leading to the EC dominating growth at an EC/SMC ratio of 5.4. More importantly, the PCEC@miR-22 coated stents showed reduced inflammation, low switching of SMC phenotype, and low secretion of extracellular matrix, which significantly inhibited IRS. This work provides a simple and robust coating platform for the delivery of microRNAs on cardiovascular stent, which may extend to other combination medical devices, and facilitate practical application of bioactive agents in clinics.
摘要：
经皮冠状动脉介入治疗后的支架内再狭窄（IRS）导致支架植入的主要治疗失败。MicroRNAs已被揭示为强大的基因药物来调节内皮细胞（EC）和平滑肌细胞（SMC）以响应血管损伤，提供了一个有希望的治疗候选抑制IRS。然而,亲水性生物活性microRNA的可控加载和洗脱对目前的亲脂性支架涂层构成了挑战。这里,我们通过基于两亲性聚（ε-己内酯）-聚（乙二醇）-聚（ε-己内酯）（PCL-PEG-PCL，PCEC)三嵌段共聚物海绵状网络。miR-22用作调节SMC的模型microRNA。动态多孔涂层实现了miR-22的均匀可控加载,最高用量达到133pmolcm-2。我们证明miR-22的持续释放显著增强了SMC的收缩表型，而不干扰EC的增殖。从而导致EC以5.4的EC/SMC比率主导增长。更重要的是,PCEC@miR-22涂层支架显示炎症减少，SMC表型的低转换，和低分泌的细胞外基质，显著抑制了IRS。这项工作提供了一个简单而强大的涂层平台，用于在心血管支架上递送microRNA，可以扩展到其他组合医疗设备，并促进生物活性剂在临床上的实际应用。
