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（由申请人提供）：心脏研究的一个关键目标是阐明促进临床上显着的动脉粥样硬化的机制，然后利用这些知识设计新的疗法。我们相信将新概念与新的药物输送策略结合起来至关重要，因此我们组建了一个独特的多PI团队，在动脉粥样硬化和纳米医学方面拥有互补的专业知识。总体概念是斑块进展代表一种称为炎症消退缺陷的病理过程。纳米医学主题基于这样的概念：将生物制剂封装在可生物降解的靶向聚合物纳米颗粒 (NP) 内，可以保护货物，直到其被输送到动脉粥样硬化区，然后促进生物制剂的受控释放。我们已经使用称为 Ac2-26 的肽介导物证明了这一原理。为了更接近人类翻译，我们现在提出迭代 NP 优化、深入的机制研究以及在另一种类型的生物制品中的应用。总体假设是，与各种类型的消退介质包装在一起的临床可翻译聚合纳米颗粒将通过与细胞消退过程相关的特定分子机制，阻止晚期斑块进展。 在目标 1 中，我们将迭代优化和评估 IV 型胶原 (Col IV) 靶向纳米粒子，以将 Ac2-26 有效递送至动脉粥样硬化斑块。 对 NP 大小、电荷、负载能力和靶向特性进行修改，以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。 在目标 2 中，我们将阐明 Ac2-26 NP 的动脉粥样硬化保护机制，重点关注氧化应激、胶原蛋白形成、胞吞作用缺陷和炎症。在目标 3 中，我们将利用动脉粥样硬化靶向 IL-10 纳米颗粒探索 IL-10 对晚期动脉粥样硬化的促缓解保护作用的分子细胞机制，该纳米颗粒将针对控释动力学、最佳生物活性和功效进行优化。 在这个项目结束时，我们希望能够阐明炎症消退和动脉粥样硬化之间的机制联系，同时开发能够阻止高危人群斑块进展的纳米药物。 相关性：动脉粥样硬化血栓性血管疾病是工业化世界的首要死因，预计未来将在全球蔓延。在对抗这种疾病方面存在重要的机制和治疗差距。 该提案将研究通过使用纳米医学以高度可转化为人类治疗的方式促进动脉粥样硬化进展的机制。