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

 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显著动脉粥样硬化的机制，然后利用这一知识设计新的治疗方法。我们认为，将新的概念与新的药物传递策略结合起来是至关重要的，因此我们形成了一个独特的多PI团队，在动脉粥样硬化和纳米医学方面具有互补的专业知识。最重要的概念是，斑块进展代表一种称为有缺陷的炎症消退的病理过程。纳米医学的主题是基于这样一个概念，即将生物制品封装在可生物降解的靶向聚合物纳米颗粒(NPs)中可以保护货物，直到它被运送到动脉粥样硬化，然后促进生物的受控释放。我们已经使用一种名为Ac2-26的拆分多肽中介来演示这一原理。为了更接近人类翻译，我们现在提出迭代NP优化，深入机理研究，并应用于另一种类型的生物。最重要的假设是，临床上可翻译的聚合物纳米粒包装了各种类型的拆分介体，将通过与细胞拆分过程相关的特定分子机制，阻止晚期斑块的进展。在目标1中，我们将反复优化和评估IV型胶原(Col IV)靶向NPs，以有效地将Ac2-26输送到动脉粥样硬化斑块。将对NP大小、电荷、负载能力和靶向特性进行修改，以增加生物活性Ac2-26对动脉粥样硬化病变的输送，以最佳地防止斑块恶化。在目标2中，我们将阐明Ac2-26纳米颗粒的动脉粥样硬化保护机制，重点是氧化应激、胶原形成、缺陷泡沫化和炎症。在目标3中，我们将利用动脉粥样硬化靶向的IL-10纳米粒来探索IL-10在晚期动脉粥样硬化中促进溶解保护作用的分子-细胞机制，该纳米粒将优化其控制释放动力学、最佳生物活性和有效性。在该项目结束时，我们希望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类斑块进展的纳米药物。相关性：动脉粥样硬化性血栓性血管疾病是工业化世界的主要死亡原因，预计未来将在全球范围内传播。在抗击这种疾病方面存在重要的机制和治疗差距。这项提案将研究通过使用纳米药物促进动脉粥样硬化进展的机制，这种方式对人类治疗具有很高的可译性。

 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.