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: 10514528
• 负责人: Ana Cartaya
• 金额: $ 3.62万
• 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/10514528
• 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; delivery vehicle; 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）是美国的主要死亡原因。心血管疾病往往源于 动脉粥样硬化的发展。严重的动脉粥样硬化需要外科血管重建手术来扩大 血管和恢复血液流动。然而，血管重建手术经常由于新生内膜增生而失败 （NH）.在血管重建后，存在增加的和局部的活性氧簇的过度产生， 血管壁。这种氧化还原稳态的促氧化剂损失导致细胞增殖和迁移加剧 血管平滑肌细胞（VSMC）向血管内壁移动，从而引起NH。限制了 血管介入治疗的成功结果。使用抗氧化剂（例如抗氧化剂）进行局部治疗 酶超氧化物歧化酶和过氧化氢酶，成功地降低了兔动脉损伤的NH率 模型在人类中，由于无法进入全部患病血管，因此局部治疗很少是一种选择， 我们可以选择系统性分娩。然而，全身提供的抗氧化剂，未能达到必要的 在感兴趣的部位的浓度强调了对可以全身递送的方法的需要 并且可以瞄准感兴趣的部位而不需要可接近的部位。宏程序是很好的候选程序 用于将抗氧化剂递送到炎症部位，例如动脉介入部位，在那里它们天然地 招募到。此外，巨噬细胞确实将NP货物递送至炎症部位。因此， 本申请旨在确定选择性巨噬细胞介导的抗氧化酶递送的有效性 用于预防NH的血管介入部位。我假设巨噬细胞会将抗氧化剂 酶的干预网站，恢复氧化还原稳态和抑制NH。为了测试这一创新 假设，我将获得巨噬细胞，其将在体外负载受保护的抗氧化酶， 纳米粒子用于治疗接受动脉手术的大鼠。目标1将集中在抗氧化酶 纳米制剂和表征，它们与巨噬细胞的相互作用;还将询问 抗氧化酶负载的巨噬细胞在体外血管细胞上的作用。目的2探讨抗氧化剂的作用 酶加载的巨噬细胞在体内NH，使用一种新的公正的3D方法来评估血管损伤。 成功完成此项目将阐明选择性抗氧化酶处理是否抑制NH; 以及建立一种新的方法用于选择性地将治疗剂递送到脉管系统中的受损部位。我，我， 安娜·卡塔亚将在该大学爱德华·班森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（UNC-CH）。巴特拉科娃博士将与班森博士一起担任我的共同赞助人 在我的训练过程中。Batrakova博士是一名副教授和药学教授， CH，一个亲密的合作者。我和我的合作赞助商一起设计了一个培训计划， 研究实力和专业发展。在完成这项建议后，我将能够 在研究密集型或政府机构从事任何竞争性博士后奖学金职位。