Targeted drug delivery for the treatment of cardiovascular disease and its clinical complications

心血管疾病是世界范围内主要的死亡原因。造成这种情况的两个主要原因是动脉粥样硬化 这会使主要动脉变窄，并形成血栓，导致闭塞的血液凝块。尽管健康状况不佳 包袱，实验疗法的翻译已经停滞不前。治疗方法面临的一个共同挑战 动脉粥样硬化和血栓形成是它们在疾病部位的不良定位，如动脉粥样硬化斑块和 血栓。因此，临床上迫切需要开发新的靶向策略来提高治疗效果。 在这些地点积累。我假设，细胞介导的纳米颗粒包裹疗法将 改善部位特异性治疗蓄积，以治疗动脉粥样硬化和血栓形成。为了测试这一点，我将使用 新一代纳米粒子合成技术(闪速纳米沉淀和反向纳米沉淀)耦合 通过细胞介导性递送将治疗定向递送到动脉粥样硬化斑块和血栓。法国国民警卫队和 IFNP是一种新的聚合物纳米颗粒合成技术，它独特地解决了与 制造业的可扩展性。为了将这些纳米颗粒定向到血管损伤的部位，我将使用细胞介导法 送货。在这种方法中，纳米颗粒既可以在体外被装载到细胞中，也可以在细胞上修饰配体来开发 与体内相关细胞上特异表达的内化受体的相互作用。动脉粥样硬化和 静脉血栓形成是以免疫细胞浸润为特征的两种疾病环境；因此，它们是 独一无二地适用于细胞介导型纳米胶囊疗法的应用。关于…… 动脉粥样硬化，循环激活的单核细胞渗入炎症的动脉壁并分化为 巨噬细胞，这对动脉粥样硬化的形成是至关重要的。值得注意的是，这些细胞过度表达一种 叶酸内化受体：叶酸受体-β。在这里，我将开发治疗携带 与叶酸偶联的纳米颗粒，其目标是通过激活的 单核/巨噬细胞因此利用这些免疫细胞作为药物定位的递送载体 动脉粥样硬化斑块。由于氧化应激是动脉粥样硬化进展的关键驱动因素，我将重点放在 提供抗氧化剂干预。一种使用外源性中性粒细胞的同样创新的策略可以用来 治疗血栓形成。我们治疗血栓形成的一个关键挑战是治疗的时间依赖性减少。 随着血栓的老化，溶解血栓(溶栓)的酶越来越难以穿透。 此外，高剂量的溶栓酶可能会导致危险的出血。我建议解决这个问题 利用中性粒细胞作为聚合物溶栓蛋白的细胞载体的渗透问题 纳米粒子。中性粒细胞主动渗入血栓，并可在体外快速加载聚合物 纳米粒子。使用中性粒细胞作为递送载体将解决凝块穿透的问题，并可以 绕过流血问题。总体而言，我的项目旨在开发新的细胞介导的治疗递送 旨在防止动脉粥样硬化斑块恶化和治疗血栓形成的平台。

Cardiovascular disease is the leading cause of death world-wide. Two main reasons for this are atherosclerosis, which narrows major arteries, and thrombosis, which results in occlusive blood clots. Despite the ongoing health burden, the translation of experimental therapies has stalled. A common challenge for therapies addressing atherosclerosis and thrombosis is their poor localization in sites of disease such as atherosclerotic plaque and thrombi. Thus, there is a pressing clinical need to develop novel targeting strategies to improve therapeutic accumulation in these sites. I hypothesize that cell-mediated delivery of nanoparticle-encapsulated therapies will improve site-specific therapeutic accumulation to treat atherosclerosis and thrombosis. To test this, I will employ next-generation nanoparticle synthesis technologies (Flash NanoPrecipitation (FNP) and inverse FNP) coupled with cell-mediated delivery for the directed delivery of therapies to atherosclerotic plaque and thrombi. FNP and iFNP are new polymeric nanoparticle synthesis technologies that uniquely address challenges related to scalability for manufacturing. To direct these nanoparticles to sites of vascular injury, I will employ cell-mediated delivery. In this method, nanoparticles can be either loaded into cells ex vivo or decorated with ligands to exploit interactions with internalization receptors specifically expressed on pertinent cells in vivo. Atherosclerosis and venous thrombosis are two disease settings characterized by immunological cell infiltration; as such, they are uniquely suited for the application of cell-mediated delivery of nano-encapsulated therapies. With respect to atherosclerosis, circulating activated monocytes infiltrate into the inflamed arterial wall and differentiate into macrophages, which are centrally important to atherogenesis. Notably, these cells over-express an internalization receptor for folic acid: folate receptor-beta. Herein, I will develop therapeutic-carrying nanoparticles conjugated to folic acid, with the goal of being specifically internalized by activated monocytes/macrophages thereby employing these immune cells as delivery vehicles for the localization of drug to atherosclerotic plaque. As oxidative stress is a key driver of atherosclerotic progression, I will focus on delivering antioxidant interventions. An equally innovative strategy using exogenous neutrophils can be used to treat thrombosis. A key challenge in our treatment of thrombosis is a time-dependent decrease in treatment efficacy, as aging thrombi become increasingly difficult for clot-dissolving (thrombolytic) enzymes to penetrate. Moreover, high doses of thrombolytic enzymes can lead to dangerous bleeding. I propose to address this penetration issue by utilizing neutrophils as cell carriers of thrombolytic proteins encapsulated in polymeric nanoparticles. Neutrophils actively infiltrate thrombi, and can be rapidly loaded ex vivo with polymeric nanoparticles. Employing neutrophils as a delivery vehicle would address the issue of clot penetration and could circumvent the problem of bleeding. Overall, my project aims to develop novel cell-mediated therapeutic delivery platforms with the goal of preventing atherosclerotic plaque progression and treatment of thrombosis.