Selective delivery of superoxide dismutase and catalase for restenosis prevention

选择性递送超氧化物歧化酶和过氧化氢酶以预防再狭窄

• 批准号: 10315701
• 负责人: Ana Cartaya
• 金额: $ 3.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315701
• 关键词: 3-Dimensional; Aftercare; Antioxidants; Arterial Injury; Arteries; Atherosclerosis; Biological Availability; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Proliferation; Cell Survival; Cells; Collection; Data; Development; Disease; Drug Delivery Systems; Event; Failure; Fellowship; Gene Transfer; Genes; Goals; Government; Histologic; Homeostasis; Human; Hyperplasia; In Vitro; Inflammation; Injury; Institution; Intervention; Intravenous; Kinetics; Knowledge; Label; Measures; Mediating; Methods; Microscopy; Modeling; Monitor; North Carolina; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Outcome; Oxidation-Reduction; Phagocytes; Pharmacy facility; Phenotype; Positioning Attribute; Pre-Clinical Model; Prevention; Procedures; Process; Production; Publishing; Rattus; Reactive Oxygen Species; Reporting; Research; Research Project Grants; Role; Site; Smooth Muscle Myocytes; Superoxide Dismutase; Surveys; System; Techniques; Testing; Therapeutic; Time; Toxic effect; Training; Travel; Treatment Efficacy; United States; Universities; Vascular Smooth Muscle; Work; adenoviral-mediated; antioxidant enzyme; antioxidant therapy; base; catalase; cell motility; design; effectiveness evaluation; experimental study; fluorescence imaging; healing; in vivo; in vivo Model; injured; innovation; interest; light scattering; macrophage; mid-career faculty; migration; nanoformulation; nanoparticle; nanoparticle delivery; novel; novel strategies; novel therapeutics; particle; preclinical study; preventive intervention; recruit; response; restenosis; stem; success; surgery outcome; targeted delivery; treatment as prevention; uptake; vascular injury; vascular smooth muscle cell proliferation

Cardiovascular disease (CVD) is the leading cause of death in the United States. CVD often stems from the development of atherosclerosis. Severe atherosclerosis requires surgical revascularization procedures to widen the vessel and restore blood flow. However, revascularization procedures often fail due to neointimal hyperplasia (NH). After revascularization there is an increased and localized over production of reactive oxygen species in the vessel wall. This pro-oxidant loss of redox homeostasis leads to an exacerbated proliferation, and migration of vascular smooth muscle cells (VSMC) towards the inner vessel wall, thereby causing NH. NH limits the successful outcomes of vascular interventions. Localized treatment with antioxidants, like the antioxidant enzymes superoxide dismutase and catalase, successfully reduces the rates of NH in a rabbit arterial injury model. In humans, localized treatment is rarely an option given the inaccessibility of full diseased vessels, leaving us with the option of systemic delivery. However, systemic delivery of antioxidants, fail to reach the necessary concentration at the site of interest underscoring the need for an approach that can be delivered systemically and can target the site of interest without the need of an accessible site. Macrophages are excellent candidates for antioxidant delivery to sites of inflammation, such as the site of arterial intervention, where they are naturally recruited to. Moreover, macrophages do deliver NP cargo to sites of inflammation. Therefore, the objective of this application is to determine the effectiveness of selective macrophage-mediated antioxidant enzyme delivery to the site of vascular intervention for prevention of NH. I hypothesize that macrophages will deliver antioxidant enzymes to the site of intervention, restoring redox homeostasis and inhibiting NH. To test this innovative hypothesis, I will obtain macrophages that will be loaded ex vivo with protected antioxidant enzymes in the form of nanoparticles for treatment of rats undergoing arterial surgery. Aim 1 will focus on the antioxidant enzyme nanoformulation and characterization, their interaction with macrophages; and will also interrogate the effects of antioxidant enzymes loaded macrophages on vascular cells in vitro. Aim 2 will interrogate the effect of antioxidant enzymes loaded macrophages on NH in vivo, using a novel unbiased 3D method to assess vascular injury. Successful completion of this project will elucidate whether selective antioxidant enzyme treatment inhibits NH; as well as establish a new approach for selective delivery of therapeutics to damaged sites in the vasculature. I, Ana Cartaya, will conduct the experiments outlined in this proposal in Dr. Edward Bahnson’s lab at the University of North Carolina-Chapel Hill (UNC-CH). Alongside Dr. Bahnson, Dr. Batrakova will serve as my co-sponsor during the course of my training. Dr. Batrakova is an associate professor and professor of Pharmacy at UNC- CH, and a close collaborator. My co-sponsors and I have together designed a training plan that will widen my research prowess and professional development. Upon completion of this proposal I will be positioned to undertake any competitive postdoctoral fellowship position at a research-intensive or governmental institution.

心血管疾病（CVD）是美国主要的死亡原因。 严重的动脉粥样硬化需要手术血运重建手术来扩大。 然而，血运重建手术常常因新生内膜增生而失败。 (NH) 血运重建后，体内活性氧产生增加且局部过量。 氧化还原稳态的促氧化丧失导致增殖和迁移加剧。 血管平滑肌细胞 (VSMC) 向内血管壁移动，从而导致 NH 限制。 使用抗氧化剂（如抗氧化剂）进行局部治疗的成功结果。 超氧化物歧化酶和过氧化氢酶，成功降低了兔动脉损伤中的 NH 率 在人类模型中，由于无法接触到完整的病变血管，局部治疗很少是一种选择。 我们可以选择全身递送，但是全身抗氧化剂的递送未能达到必要的水平。 集中在感兴趣的部位强调需要一种可以系统地提供的方法 并且可以靶向感兴趣的位点而不需要可访问的位点，巨噬细胞是很好的候选者。 用于将抗氧化剂输送到炎症部位，例如动脉介入部位，它们天然存在的地方 此外，巨噬细胞确实将 NP 货物运送到炎症部位。 该应用旨在确定选择性巨噬细胞介导的抗氧化酶递送的有效性 到血管介入部位预防 NH 我发现巨噬细胞会提供抗氧化剂。 酶到达干预部位，恢复氧化还原稳态并抑制 NH 来测试这一创新。 假设，我将获得巨噬细胞，这些巨噬细胞将在体外负载受保护的抗氧化酶，其形式为 用于治疗接受动脉手术的大鼠的纳米颗粒的研究目标 1 将重点关注抗氧化酶。 纳米制剂和表征及其与巨噬细胞的相互作用； 体外血管细胞上负载抗氧化剂酶的目标 2 将探讨抗氧化剂的作用。 体内酶将巨噬细胞负载到 NH 上，使用一种新颖的无偏 3D 方法来评估血管损伤。 该项目的成功完成将阐明选择性抗氧化酶处理是否会抑制NH； 以及建立一种选择性地将治疗药物递送至脉管系统受损部位的新方法， Ana Cartaya，将在大学 Edward Bahnson 博士的实验室进行本提案中概述的实验 北卡罗来纳州教堂山分校 (UNC-CH) 的 Batrakova 博士将与 Bahnson 博士一起担任我的共同发起人。 在我的培训期间，Batrakova 博士是北卡罗来纳大学药学系的副教授和教授。 CH 和我的一位密切合作者共同设计了一个培训计划，该计划将拓宽我的视野。 研究能力和专业发展完成后，我将定位于： 在研究密集型机构或政府机构中担任任何有竞争力的博士后研究员职位。