Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries
Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries
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DOI：
10.5551/jat.8730
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发表时间：
2011-01-01
影响因子：
4.4
通讯作者：
Egashira, Kensuke
中科院分区：
文献类型：
--
作者：
Masuda, Seigo;Nakano, Kaku;Egashira, Kensuke
目的：目前上市的药物洗脱支架（DES）的使用存在安全性问题，包括患者每年0.6%的晚期血栓形成风险增加，包括急性冠状动脉综合征，这被认为是由内皮细胞愈合作用延迟引起的。因此，需要一种新的针对血管平滑肌细胞且对内皮细胞无不良影响的DES系统。血小板衍生生长因子（PDGF）在再狭窄的发病机制中起核心作用；因此，我们假设甲磺酸伊马替尼（PDGF受体酪氨酸激酶抑制剂）包封的生物可吸收聚合物纳米颗粒（NP）洗脱支架可减轻支架内新内膜的形成。方法：采用猪冠状动脉支架模型，观察伊马替尼联合np洗脱支架对新内膜形成和内皮细胞愈合的影响。在培养细胞中也检测了伊马替尼- np的作用。结果：在培养细胞研究中，伊马替尼- np通过抑制靶分子（PDGF受体- β的磷酸化）来减弱血管平滑肌细胞的增殖，但对内皮细胞的增殖没有影响。在猪冠状动脉支架模型中，通过血管造影、组织病理学和血管内超声成像分析，伊马替尼- np洗脱支架显著减轻了支架内新内膜形成和狭窄约50%。伊马替尼- np洗脱支架也能减弱MAP激酶活性，但不影响炎症和再内皮化。结论：这些数据表明，伊马替尼-NP洗脱支架抑制新内膜形成有望成为一种分子靶向NP递送系统，用于预防支架内再狭窄。
Aim: The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation.Methods: Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells.Results: In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-beta), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NP-eluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib-NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization.Conclusion: These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.