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

靶向给药治疗心血管疾病及其临床并发症

• 批准号: 10371510
• 负责人: Sophie Maiocchi
• 金额: $ 10.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371510
• 关键词: Accounting; Address; Aging; Antioxidants; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological; Blood coagulation; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Clinical; Coagulation Process; Coupled; Dangerousness; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Targeting; Encapsulated; Enzymes; Exhibits; FDA approved; Folic Acid; Formulation; Generations; Goals; Health; Hemorrhage; Immune; Immunologics; In Vitro; Infiltration; Inflammatory; Intervention; Investigational Therapies; Lead; Learning; Lesion; Ligands; Mediating; Mentorship; Methods; Modeling; Nano delivery; Nanotechnology; Oxidative Stress; Penetration; Pharmaceutical Preparations; Pharmacology; Phase; Polymers; Procedures; Process; Production; Progressive Disease; Proteins; RNA; Recruitment Activity; Research; Site; Techniques; Technology; Testing; Therapeutic; Thrombosis; Thrombus; Time; Translations; Treatment Efficacy; Venous Thrombosis; atherogenesis; base; cardiovascular disorder therapy; clinical translation; delivery vehicle; folate-binding protein; improved; in vivo; innovation; macrophage; monocyte; mouse model; nanoencapsulated; nanoparticle; nanoparticle delivery; neutrophil; new technology; next generation; novel; overexpression; prevent; receptor internalization; targeted delivery; vascular injury

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.

心血管疾病是全球死亡的主要原因。造成这种情况的两个主要原因是动脉粥样硬化， 这会狭窄的主要动脉和血栓形成，从而导致闭塞性血凝块。尽管健康状况持续 负担，实验疗法的翻译停滞了。解决治疗的共同挑战 动脉粥样硬化和血栓形成是他们在疾病部位（例如动脉粥样硬化斑块和 血栓。因此，有迫切需要开发新的靶向策略来改善治疗性的临床需求 在这些站点中积累。我假设细胞介导的纳米颗粒封装疗法的递送将 改善现场特异性的治疗积累，以治疗动脉粥样硬化和血栓形成。为了测试这一点，我将雇用 下一代纳米颗粒合成技术（闪光纳米沉淀（FNP）和逆FNP）耦合 通过细胞介导的递送，将治疗疗法转移到动脉粥样硬化斑块和血栓上。 FNP和 IFNP是新的聚合物纳米颗粒合成技术，它独特地应对与 制造的可扩展性。要将这些纳米颗粒引导到血管损伤部位，我将采用细胞介导的 送货。在这种方法中，纳米颗粒可以被装入细胞，或用配体装饰以利用 与体内相关细胞上特异性表达的内在化受体的相互作用。动脉粥样硬化和 静脉血栓形成是两个以免疫细胞浸润为特征的疾病环境。因此，他们是 独特的适合应用细胞介导的纳米封装疗法的递送。关于 动脉粥样硬化，循环激活的单核细胞浸润到发炎的动脉壁，并分化为 巨噬细胞对动脉粥样硬化非常重要。值得注意的是，这些细胞过表达 叶酸的内在化受体：叶酸受体β。在这里，我将开发治疗性携带 纳米颗粒与叶酸结合，目的是被激活 单核细胞/巨噬细胞，因此使用这些免疫细胞作为药物定位的输送车辆 到动脉粥样硬化斑块。由于氧化应激是动脉粥样硬化进展的关键驱动力，我将重点放在 提供抗氧化剂干预措施。使用外源性嗜中性粒细胞的同样创新的策略可用于 治疗血栓形成。我们治疗血栓形成的关键挑战是治疗的时间依赖 功效，随着衰老血栓的衰老变得越来越困难，凝块溶解（溶栓）酶无法穿透。 此外，高剂量的溶栓酶会导致危险的出血。我建议解决这个问题 通过利用嗜中性粒细胞作为封装在聚合物中的溶栓蛋白的细胞载体来穿透问题 纳米颗粒。嗜中性粒细胞主动浸润血栓，可以在体内快速加载聚合物 纳米颗粒。使用中性粒细胞作为送货工具将解决凝块穿透的问题，可以 避免出血问题。总体而言，我的项目旨在开发新颖的细胞介导的治疗性交付 平台的目的是防止动脉粥样硬化斑块的进展和血栓形成治疗。