Abstract：
Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. To develop a vascular adventitial drug delivery system to treat intimal hyperplasia post vascular injuries, we loaded miR-145-5p-agomir (miR-145) into an injectable and in-situ self-assembling RAD peptide hydrogel. In vitro data showed that the miR-145 could be well incorporated into the RAD peptide hydrogels and released in a slow and controlled manner. The released miR-145 could transfect SMCs successfully, and the transfected SMCs exhibited a reduced migration capacity and higher expressions of SMC contractile biomarkers as compared to the non-transfected SMCs. In vivo data showed that the retention of the miR-145 was greatly elongated by the RAD peptide hydrogels. In addition, the application of the miR-145-loaded RAD peptide hydrogels surrounding injured arteries decreased the proliferative SMCs, promoted the regeneration of endothelium, reduced the macrophage infiltration, inhibited the neointimal formation and prevented adverse ECM remodeling via downregulation of KLF4 expression. The RAD peptide hydrogels loaded with miR-145 can successfully inhibit intimal hyperplasia after vascular injuries and thus hold great potential as an innovative extravascular drug delivery approach to treat vascular diseases. STATEMENT OF SIGNIFICANCE: Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. Our work here demonstrates that the RAD peptide hydrogels loaded with miR-145-5p-agomir (miR-145) can successfully reverse intimal hyperplasia after vascular injuries and thus hold great potential as an innovative vascular adventitial drug delivery approach to treat vascular diseases. Our work proposes a possible paradigm shift from endovascular drug delivery to extravascular drug delivery for vascular disorder treatment.
摘要：
内膜增生是一种常见的病变，可以在各种血管疾病中观察到。药物洗脱支架和药物涂层球囊，可以释放抗增殖剂抑制平滑肌细胞（SMC）增殖，是为了防止内膜增生。然而,这些介入治疗装置仍不能取得满意的临床疗效.与血管内药物递送相反，血管外膜给药是一种新的策略。开发血管外膜给药系统治疗血管损伤后内膜增生，我们将miR-145-5p-agomir(miR-145)加载到可注射和原位自组装RAD肽水凝胶中.体外数据显示，miR-145可以很好地掺入RAD肽水凝胶中，并以缓慢和受控的方式释放。释放的miR-145可以成功转染SMC，与未转染的SMC相比,转染的SMC表现出降低的迁移能力和更高的SMC收缩生物标志物表达。体内数据显示miR-145的保留被RAD肽水凝胶大大延长。此外,负载miR-145的RAD肽水凝胶在损伤动脉周围的应用减少了SMC的增殖,促进内皮的再生，减少了巨噬细胞的浸润,通过下调KLF4的表达来抑制新生内膜形成并防止不良ECM重塑。负载有miR-145的RAD肽水凝胶可以成功地抑制血管损伤后的内膜增生，因此具有作为治疗血管疾病的创新血管外药物递送方法的巨大潜力。意义声明：内膜增生是一种常见的病变，可在多种血管疾病中观察到。药物洗脱支架和药物涂层球囊，可以释放抗增殖剂抑制平滑肌细胞（SMC）增殖，是为了防止内膜增生。然而,这些介入治疗装置仍不能取得满意的临床疗效.与血管内药物递送相反，血管外膜给药是一种新的策略。我们的工作表明，装载miR-145-5p-agomir（miR-145）的RAD肽水凝胶可以成功逆转血管损伤后的内膜增生，因此作为一种创新的血管外膜药物递送方法来治疗血管疾病具有巨大的潜力。我们的工作提出了从血管内药物递送到血管外药物递送以治疗血管疾病的可能范式转变。
