Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 03722, South Korea.
School of Mechanical Engineering, Yonsei University, Seoul 03722, South Korea; Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Biomed Pharmacother. 2023 Dec;168:115702. doi: 10.1016/j.biopha.2023.115702. Epub 2023 Oct 12.
Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced neointima (NI) and vascular fibrosis through mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through the inactivation of Yes-associated protein (YAP). The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, VSMC proliferation, and ECM degradation remodeling through the inhibition of transforming growth factor (TGF)-beta/NF-κB pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced IH in response to endothelial damage. Therefore, this study suggests a promising strategy for treating coronary artery disease through localized drug delivery of customized drug combinations.
内膜增生 (IH) 是旁路手术后血管再狭窄的主要原因，它是旁路移植过程中内皮损伤后，从急性阶段到慢性阶段进展的一系列过程。需要一种反映 IH 病理生理学并最小化全身副作用的策略性局部药物递送系统。在这项研究中，西罗莫司（mTOR 抑制剂）和他汀类药物（HMG-COA 抑制剂）的顺序释放作为基于丝素蛋白的微针装置在体内得以实现。急性阶段释放的西罗莫司通过抑制 mTOR 减少新生内膜 (NI) 和血管纤维化。此外，从急性到慢性阶段持续释放的瑞舒伐他汀通过使 Yes 相关蛋白 (YAP) 失活来降低血管僵硬和细胞凋亡。西罗莫司和瑞舒伐他汀的顺序释放通过抑制转化生长因子 (TGF)-β/NF-κB 通路证实了对血管炎症、VSMC 增殖和 ECM 降解重塑的协同治疗作用。这些结果表明，通过定制药物组合的局部药物递送，对预防再狭窄和内皮损伤引起的 IH 有足够的血管弹性具有治疗效果。因此，本研究为通过局部药物输送治疗冠状动脉疾病提供了一种有前途的策略。
