Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China.
Department of Physiology, Medical School of Zhengzhou University, Henan, China.
Drug Deliv Transl Res. 2022 Dec;12(12):2950-2959. doi: 10.1007/s13346-022-01158-x. Epub 2022 Apr 4.
Neointimal hyperplasia is a persistent complication after vascular interventions, and it is also the leading cause of vascular graft restenosis and failure after arterial interventions, so novel treatment methods are needed to treat this complication. We hypothesized that adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle (hydrogel-PLGA-rapamycin) could inhibit neointimal hyperplasia in a rat aortic wire injury model. The HA/SA hydrogel was fabricated by the interaction of hyaluronic acid (HA), sodium alginate (SA), and CaCO; and loaded with PLGA rapamycin nanoparticle or rhodamine uniformly. A SD rat aortic wire injury induced neointimal hyperplasia model was developed, the control group only received wire injury, the adventitial application group received 10 μL hydrogel-PLGA-rapamycin after wire injury, and the adventitial injection group received 10 μL hydrogel-PLGA-rapamycin injected into the aortic adventitia after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with rhodamine can be successfully injected into the aortic adventitia and was encapsuled by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection but was almost degraded at day 21. There was a significantly thinner neointima in the adventitial application group and adventitial injection group compared to the control group (p = 0.0009). There were also significantly fewer CD68 (macrophages) cells (p = 0.0012), CD3 (lymphocytes) cells (p = 0.0011), p-mTOR cells (p = 0.0019), PCNA cells (p = 0.0028) in the adventitial application and adventitial injection groups compared to the control group. The endothelial cells expressed arterial identity markers (Ephrin-B2 and dll-4) in all these three groups. Adventitial injection of hydrogel-PLGA-rapamycin can effectively inhibit neointimal hyperplasia after rat aortic wire injury. This may be a promising drug delivery method and therapeutic choice to inhibit neointimal hyperplasia after vascular interventions.
血管介入后，新生内膜增生是一种持续存在的并发症，也是动脉介入后血管移植物再狭窄和失败的主要原因，因此需要新的治疗方法来治疗这种并发症。我们假设，在大鼠主动脉丝损伤模型中，向血管外膜注射载有 PLGA 雷帕霉素纳米粒的 HA/SA 水凝胶（水凝胶-PLGA-雷帕霉素）可以抑制新生内膜增生。HA/SA 水凝胶是通过透明质酸（HA）、海藻酸钠（SA）和 CaCO 的相互作用制备的，并均匀负载 PLGA 雷帕霉素纳米粒或罗丹明。建立了 SD 大鼠主动脉丝损伤诱导的新生内膜增生模型，对照组仅接受丝损伤，血管外膜应用组在丝损伤后接受 10 μL 水凝胶-PLGA-雷帕霉素，血管外膜注射组在丝损伤后向主动脉外膜内注射 10 μL 水凝胶-PLGA-雷帕霉素。第 21 天采集组织，通过组织学和免疫组织化学染色进行分析。负载罗丹明的水凝胶可以成功地注入主动脉外膜并被外膜包裹。在血管外膜注射后可以在外膜下看到水凝胶，但在第 21 天几乎降解。与对照组相比，血管外膜应用组和血管外膜注射组的新生内膜明显更薄（p=0.0009）。血管外膜应用组和血管外膜注射组的 CD68（巨噬细胞）细胞（p=0.0012）、CD3（淋巴细胞）细胞（p=0.0011）、p-mTOR 细胞（p=0.0019）、PCNA 细胞（p=0.0028）也明显减少。三组中内皮细胞均表达动脉特征标志物（Ephrin-B2 和 dll-4）。在大鼠主动脉丝损伤后，向血管外膜注射水凝胶-PLGA-雷帕霉素可以有效抑制新生内膜增生。这可能是一种有前途的药物输送方法和治疗选择，可抑制血管介入后的新生内膜增生。
