靶向血管基底膜的智能纳米凝胶载药体系在血管再狭窄治疗中的应用

Vascular restenosis is one of the most serious side effects after interventional therapy of coronary heart disease, which affects the treatment results and the prognosis of patients. The ideal strategy for prevention of restenosis must include inhibition of vascular smooth muscle cells (VSMCs) proliferation and improvement of endothelial structure and function recovery. However, the current therapy for restenosis are still needed to be improved. .Based on our previous studies, we found that the pH-sensitive nanogels exhibited great potential as novel controlled drug delivery systems. We intent to design and prepare pH-sensitive nanogels as a smart drug delivery system since it can achieve a pH-responsive controlled drug-release pattern. We will prepare pH-responsive cross-linked polymeric nanogels for RAPA loading, and with the magnetite (Fe3O4) nanoparticles surface modification, the nanogels can be also used for hyperthermia to inhibit neointima formation. In addition, the collagen IV, which specifically presented on vascular basement membrane will be used as the biomarker for this targeting nanogel systems. The final products is a kind of targeting smart nanogel with magnetic hyperthermia and target-specific properties. According to the in vitro and in vivo studies of targeting smart nanogel systems, we will demonstrate its active targeting effect on injured vessel, and its efficacy on inhibition of VSMCs proliferation and improvement of endothelial repair by combination the effect of antiproliferative agents and magnetic hyperthermia. Overall, these properties make the targeting smart nanogel a promising tool for small molecular drug targeted delivery and controlled release in the treatment of restenosis. Therefore, this study will not only clarify the basic theory of fabrication of targeting smart nanogel systems, but also provide a new method and technical support for treatment of restenosis in clinical situation.

血管再狭窄是冠心病介入治疗后最严重的副反应之一，直接影响治疗效果和患者预后。理想的血管再狭窄防治准则是抑制平滑肌细胞过度增生，同时不影响内皮结构、功能的恢复。基于该治疗准则和前期关于智能纳米凝胶控释载药体系的研究基础，本申请拟设计和制备pH敏感磁性纳米凝胶体系，用以装载抗增殖的化学小分子药物，在其表面修饰特异性靶向血管基底膜的IV型胶原靶向肽，靶向受损伤的血管壁暴露出的基底膜结构，构建出兼具磁感应热疗功效的主动靶向智能纳米凝胶。通过细胞实验和动物血管再狭窄模型，论证其对受损血管部位的靶向性，并研究药物治疗联合磁感应热疗对异常增生血管平滑肌细胞的抑制能力和血管内皮的修复作用，从而综合评价该载药系统对血管再狭窄的治疗作用。本项目的顺利实施，有助于进一步明确多功能靶向纳米载体构建的基础理论，同时将为完善临床血管再狭窄治疗措施提供新的思路和技术支持。

冠状动脉疾病（CAD）是全球死亡率最高的基本之一，虽然经皮冠状动脉介入治疗（PCI）是目前临床上最重要的治疗手段，但血管再狭窄是PCI治疗后的主要缺点。由于再狭窄过程的复杂性，药物是否能够到达病变部位发挥作用，理想的血管再狭窄防治准则是抑制平滑肌细胞过度增生，同时不影响内皮结构、功能的恢复。靶向给药系统是一种有前途的再狭窄治疗的实验方法。基于该治疗准则和前期关于智能纳米凝胶控释载药体系的研究基础，本项目在前期对响应性纳米材料的设计和制备基础上，以pH敏感磁性纳米凝胶体系，用以装载抗增殖药物雷帕霉素，在其表面修饰特异性靶向血管基底膜 的IV型胶原靶向肽，构建出主动靶向智能纳米凝胶。通过体外和细胞实验，验证了该纳米体系药物释放的响应性及对受损血管的靶向性。进一步经建立大鼠左颈总动脉的球囊损伤模型，评价该体系对血管再狭窄防治效果。主动靶向的纳米凝胶体系能够显著抑制血管新生内膜的增厚，免疫组织化学染色结果进一步证明了雷帕霉素的靶向传输能够显著抑制新生内膜中增殖的平滑肌细胞，并且不会影响再内皮化的过程。除了抗增殖药物的有效递送，在血管再狭窄的病理过程中，抗炎也是一个非常重要的方面。利用载体的纳米催化效应的来减轻局部炎性损伤，在如动脉粥样硬化斑块聚集以及发生狭窄的血管壁类这类疾病的微环境调控过程中，是很有潜力的治疗方式。通过引入具有抗炎作用的纳米载体，诱导分化微环境中的巨噬细胞，改变其极化状态，有望进一步提高治疗效果。因此，下一步的研究工作重点是利于纳米催化体系对粥样硬化斑块的进行抗炎治疗。