Enhancing Inflammation Resolution in Atherosclerosis via Targeted Nanoparticle-Mediated Delivery of Biologics

通过靶向纳米颗粒介导的生物制剂递送增强动脉粥样硬化的炎症消退

• 批准号: 9199092
• 负责人: OMID C FAROKHZAD
• 金额: $ 74.66万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199092
• 关键词: Affect; Area; Arterial Fatty Streak; Atherosclerosis; Binding; Blood Circulation; Blood coagulation; Caliber; Cause of Death; Cell physiology; Cells; Cessation of life; Charge; Chronic; Cicatrix; Clinic; Clinical; Collagen; Collagen Type IV; Dangerousness; Data; Developed Countries; Developing Countries; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Economic Burden; Encapsulated; Engineering; Fatty acid glycerol esters; Future; Generations; Goals; Half-Life; Heart Diseases; Heart Research; Human; Industrialization; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Inflammatory Response; Interleukin-10; Kinetics; Knowledge; Lesion; Ligands; Link; Mediating; Mediator of activation protein; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Necrosis; Outcome; Oxidative Stress; Paper; Pathologic Processes; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Polymers; Prevention; Process; Property; Resolution; Site; Surface; System; Testing; Therapeutic; Thick; Time; Tissues; Translations; Treatment Efficacy; Vascular Diseases; Weight; Work; atheroprotective; base; bench to bedside; clinical translation; clinically relevant; clinically significant; clinically translatable; combat; controlled release; density; design; high risk; innovation; mortality; nanomedicine; nanoparticle; nanotherapeutic; nanotherapy; novel therapeutics; prevent; protective effect; public health relevance; skills; spatiotemporal; success; targeted delivery; targeted treatment; translation to humans

 DESCRIPTION (provided by applicant): A critical goal in heart research is to elucidate the mechanisms that promote clinically significant atherosclerosis and then use this knowledge to design novel therapies. We believe it is essential to couple new concepts with new drug delivery strategies, and we have thus formed a unique multi‐PI team with complementary expertise in atherosclerosis and nanomedicine. The overarching concept is that plaque progression represents a pathologic process called defective inflammation resolution. The nanomedicine theme is based on the concept that encapsulation of biologics inside biodegradable, targeted polymeric nanoparticles (NPs) protects the cargo until it is delivered to atheromata and then facilitates controlled release of the biologic. We have demonstrated this principle using a peptide mediator of resolution called Ac2‐26. To move closer to human translation, we now propose iterative NP optimization, in‐depth mechanistic studies, and application to another type of biologic. The overarching hypothesis is that clinically translatable polymeric NPs packaged with various types of resolution mediators will, via specific molecular mechanisms related to cellular processes of resolution, prevent advanced plaque progression. In Aim 1, we will iteratively optimize and evaluate collagen IV (Col IV) ‐ targeted NPs for effective delivery of Ac2‐26 to atherosclerotic plaques. Modifications to NP size, charge, loading capacity, and targeting properties will be carried out to increase delivery of bioactive Ac2‐26 to atherosclerotic lesions in a manner that optimizes prevention of plaque progression. In Aim 2, we will elucidate athero‐protective mechanisms of Ac2‐26 NPs focusing on oxidative stress, collagen formation, defective efferocytosis, and inflammation. In Aim 3, we will explore the molecular‐cellular mechanisms of the pro‐resolving protective effects of IL‐10 in advanced atherosclerosis using athero‐ targeted IL‐10 NPs, which will be optimized for controlled release kinetics, optimal bioactivity, and efficacy. At the conclusion of this project, we hope t have elucidated mechanistic links between inflammation resolution and atherosclerosis while simultaneously developing nanomedicines capable of blocking plaque progress in high‐risk humans. RELEVANCE: Atherothrombotic vascular disease is the leading cause of death in the industrialized world, with global spread predicted for the future. Important mechanistic and therapeutic gaps exist in combatting this disease. This proposal will study mechanisms that promote atherosclerosis progression in a manner that is highly translatable to human therapy through the use of nanomedicine.

 描述（由适用提供）：心脏研究的关键目标是阐明促进临床上重要的动脉粥样硬化的机制，然后使用这些知识来设计新型疗法。我们认为，将新概念与新的药物输送策略相结合至关重要，因此我们组成了一个独特的多PPI团队，具有完全专业的动脉粥样硬化和纳米医学。总体概念是，斑块的进展代表纳米医学主题的基础，该概念概念概念是封装了可生物降解的，有针对性的聚合物纳米粒子（NPS）内部的生物制剂保护货物，直到将其递送到Atheromata并促进生物学的受控释放。我们使用称为AC2-26的肽介质证明了这一原理。为了更接近人类翻译，我们现在提出迭代NP优化，深度机械研究以及应用于另一种类型的生物学。总体假设是，通过与分辨率的细胞过程有关的特定分子机制，将临床翻译后的聚合物NP包装，这些NP将防止晚期斑块进展。在AIM 1中，我们将迭代优化和评估胶原蛋白IV（COL IV）的靶向NP，以有效递送AC2-26向动脉粥样硬化斑块。将对NP大小，充电，加载能力和靶向特性进行修改，以通过优化预防斑块进展的方式增加生物活性AC2-26向动脉粥样硬化病变的递送。在AIM 2中，我们将阐明专注于氧化应激，胶原蛋白形成，缺陷效率和炎症的AC2-26 NP的动脉保护机制。在AIM 3中，我们将使用靶向动脉粥样硬化的IL-10 NPS探索IL-10在晚期动脉粥样硬化中的促溶解保护作用的分子细胞机制，该动脉粥样硬化的IL-10 NP将对受控释放动力学，最佳生物活性和有效性进行优化。在该项目的结论中，我们希望阐明炎症解决和动脉粥样硬化之间的机械联系，同时开发能够阻止高风险人类斑块进展的纳米药物。相关性：动脉粥样硬化的血管疾病是工业化世界中死亡的主要原因，将预测未来的全球传播。对抗这种疾病的重要机械和治疗差距存在。该建议将研究以高度转化为人类治疗的方式通过使用纳米医学来促进动脉粥样硬化进展的机制。