S1P-(2HP-β-CD)-PLGA纳米复合物洗脱含铜钴基合金支架预防支架内再狭窄的作用与机制研究

Metal stent implantation is the first choice of minimally invasive interventional therapy for the treatment of peripheral arterial occlusive disease. How to reduce the in-stent restenosis (ISR) rate and explore its formation mechanism has been a common problem at home and abroad. In this study, we first proposed to use a new copper bearing cobalt-based alloy, which can induce endothelialization, as a peripheral vascular stent material. And we propose to use S1P-(2HP-β-CD)-PLGA as the coating material, which can not only induce endothelialization, but also inhibit the over-proliferation of smooth muscle cells (SMCs). Based on the above findings, we develop a new drug-eluting copper bearing cobalt-based stent, and implant the stents into the iliofemoral arteries of rabbit arteriosclerosis obliterers (ASO) animal model, we test the release and regulation of functional components of the stent, and then verify its efficacy in preventing ISR. Through molecular biology experiments, we search mechanisms from multiple pathways and multiple targets, verifying that this drug-eluting stent can upregulate growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGF-B), and etc. to activate Akt/ERK-eNOS/Nrf2-ARE signaling pathway. This study will provide theoretical and experimental evidence for the prevention of ISR and improvement of the long-term efficacy of lower limb artery stent implantation.

金属支架置入术已经成为发病率逐年增高的下肢动脉狭窄/闭塞性疾病微创介入治疗的首选方法。但如何有效降低或解决治疗后支架内再狭窄的发生并探索其形成机制一直是国内外面临的共同难题。本项目在前期工作基础上，首次提出将具有促进内皮化功能的含铜钴基合金作为支架主体材料，将同样具有促内皮化功能和抑制平滑肌细胞增殖作用的纳米复合物-S1P-(2HP-β-CD)-PLGA作为支架涂层材料，组合研制一种新型药物洗脱含铜钴基合金支架；通过兔动脉粥样硬化模型在体实验及该支架功能成分的释放与调控，验证并观察其预防支架内再狭窄的作用与功效；与此同时，验证该种药物洗脱支架通过上调VEGF、PDGF等因子的表达，多途径激活eNOS/Nrf2-ARE来促内皮化、抑制平滑肌细胞过度增殖的假说，深入探讨其作用机制。以期为预防支架内再狭窄研究的突破和下肢动脉支架治疗中远期疗效的提高提供可靠的理论与实验依据。

金属支架置入术已经成为发病率逐年增高的下肢动脉狭窄/闭塞性疾病微创介入治疗的首选方法。但如何有效降低或解决治疗后支架内再狭窄的发生并探索其形成机制一直是国内外面临的共同难题。本项目首次提出将具有促进内皮化功能的含铜钴基合金作为支架主体材料，将同样具有促内皮化功能和抑制平滑肌细胞增殖作用的纳米复合物-S1P-(2HP-β-CD)-PLGA作为支架涂层材料，组合研制一种新型药物洗脱含铜钴基合金支架；通过兔动脉粥样硬化模型在体实验及该支架功能成分的释放与调控，验证并观察其预防支架内再狭窄的作用与功效；与此同时，深入探讨其作用机制。.首先，课题组成功制备了涂层形貌光滑，涂层稳定，药物释放合理的S1P-（2HP-β-CD）-PLGA纳米复合物洗脱含铜钴基合金支架。该支架涂层主要成分PLGA在28天内的累积释放量约为90%。将该支架浸泡28天铜离子的溶出量达到5ppb。其次，通过体外实验，验证该种药物洗脱支架具有良好的生物相溶性，并可抑制人主动脉平滑细胞的迁移。再次将其置入至兔髂动脉狭窄动物模型内，观察其抑制支架内再狭窄的作用。最后证实其通过抑制bFGF、PDGF-B、HGF等因子的表达来抑制平滑肌细胞的增殖，并通过激活AKT/Nrf2/ARE信号通路抑制平滑肌细胞过度增殖。.通过上述研究为预防支架内再狭窄研究的突破和下肢动脉支架治疗中远期疗效的提高提供可靠的理论与实验依据。