Roopmani Purandhi, Satheesh Santhosh, Raj David C, Krishnan Uma Maheswari
Department of Cardiology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Pondicherry-605006, India.
ACS Biomater Sci Eng. 2019 Jun 10;5(6):2899-2915. doi: 10.1021/acsbiomaterials.9b00303. Epub 2019 May 8.
The pleiotropic effects of the atorvastatin-fenofibrate combination can be effectively harnessed for site-specific therapy to minimize stent-related complications. The present study aims to utilize the pleiotropic effects of these two drugs entrapped in a uniform and defect-free coating of poly(l-lactide--caprolactone) (PLCL) on a stainless steel stent to overcome stent-associated limitations. The stent coating parameters were optimized using ultrasonic spray coating technique to achieve a thin, smooth, and defect-free dual drug-loaded polymer coating on the stent. The dual drug-loaded polymer coated stent was characterized for surface morphology, thickness and coating integrity. drug release kinetics of the fabricated stent reveals a sustained release of both drugs for more than 60 days. Significant reduction of thrombus formation and adhesion of lipopolysaccharide-stimulated macrophages on the dual drug containing polymer-coated stent indicates that the drug combination possesses antithrombotic and anti-inflammatory effects. The combination did not adversely influence endothelialization but significantly retarded smooth muscle cell proliferation indicating its potential to overcome restenosis. No bacterial biofilm formation was observed on the stent due to the antibacterial activity of atorvastatin. A rat subcutaneous model was used to evaluate the biocompatibility of the coated stent and compared with the commercial stent. MicroCT, scanning electron microscopy, and morphometric analyses revealed that the coated stents exhibited excellent histocompatibility with no inflammatory response as evidenced from the cytokine levels measured 28 days postimplantation. Our data demonstrates for the first time that the combination of atorvastatin and fenofibrate can be successfully employed in cardiovascular stents to overcome the current limitations of conventional drug-eluting stents.
阿托伐他汀与非诺贝特联合用药的多效性可有效用于特定部位治疗，以将支架相关并发症降至最低。本研究旨在利用这两种药物包裹在不锈钢支架上均匀且无缺陷的聚（L-丙交酯-己内酯）（PLCL）涂层中的多效性，克服与支架相关的局限性。使用超声喷涂技术优化支架涂层参数，以在支架上获得薄、光滑且无缺陷的双药负载聚合物涂层。对双药负载聚合物涂层支架的表面形态、厚度和涂层完整性进行了表征。所制备支架的药物释放动力学显示两种药物持续释放超过60天。在含双药的聚合物涂层支架上，血栓形成以及脂多糖刺激的巨噬细胞黏附显著减少，表明该药物组合具有抗血栓和抗炎作用。该组合对内皮化没有不利影响，但显著抑制平滑肌细胞增殖，表明其具有克服再狭窄的潜力。由于阿托伐他汀的抗菌活性，在支架上未观察到细菌生物膜形成。使用大鼠皮下模型评估涂层支架的生物相容性，并与商用支架进行比较。微型计算机断层扫描、扫描电子显微镜和形态计量分析显示，涂层支架表现出优异的组织相容性，植入后28天测量的细胞因子水平证明没有炎症反应。我们的数据首次证明，阿托伐他汀和非诺贝特的组合可成功应用于心血管支架，以克服传统药物洗脱支架目前的局限性。
