Nanoparticle targeting within the joint for site-specific delivery of osteoarthritis therapeutics

纳米颗粒靶向关节内，用于骨关节炎治疗药物的位点特异性递送

• 批准号: 10400636
• 负责人: Blanka Sharma
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400636
• 关键词: Address; Anatomy; Anti-Inflammatory Agents; Behavioral; Binding; Biochemical; Biochemical Markers; Biodistribution; Biological Availability; Bone remodeling; CD 200; Cartilage; Cartilage injury; Catabolism; Cell Therapy; Cells; Chemosensitization; Chondrocytes; Chronic; Complex; Data; Degenerative polyarthritis; Development; Disease; Disease Pathway; Disease Progression; Drug Carriers; Drug Delivery Systems; Drug Design; Drug Targeting; Engineering; Environment; Evaluation; Extracellular Matrix; Foundations; Gait; Glycolates; Goals; Histology; Human; Image; Immune; In Vitro; Individual; Inflammation; Inflammatory; Joint by Site; Joints; Knee Osteoarthritis; Knowledge; Location; Modeling; Modification; Pain; Paint; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Play; Process; Production; Rattus; Rodent Model; Role; Signal Transduction; Site; Structure; Synovial Fluid; Synovial Membrane; Synovitis; System; Technology; Therapeutic; Time; Tissues; Treatment Efficacy; United States; Work; adhesive polymer; articular cartilage; base; biomaterial compatibility; cartilage degradation; cartilage repair; clinical application; compare effectiveness; cytokine; design; disability; drug discovery; effective therapy; immunoregulation; improved; in vivo; inflammatory marker; insight; joint inflammation; joint injury; macrophage; nanoparticle; novel strategies; particle; preservation; prevent; recruit; stem cells; targeted delivery; therapeutic effectiveness; treatment strategy

PROJECT SUMMARY Osteoarthritis (OA) is a leading cause of disability in the United States and is presently without a cure. Despite advances in drug discovery and cell based therapies, disease-modifying therapies have remained elusive. OA is a complex disease involving maladaptive remodeling throughout the joint, including cartilage erosion, synovitis, and bone remodeling. The continuum of joint damage creates a chronic pro-inflammatory and catabolic joint environment, which ultimately destroys the joint's anatomy and physiologic function. There is a critical need for an OA therapy to address multiple disease mechanisms in multiple locations throughout the joint. While numerous drugs and factors have been identified for promoting cartilage repair and blocking various OA disease mechanisms, rapid joint clearance and poor tissue targeting limit their clinical application. This proposal lays the foundation for a comprehensive approach to treating OA that focuses on delivering the right drug in the right place at the right time in the joint. Specifically, this proposal aims to design drug carriers that can simultaneously delivery chondroprotective signals to the cartilage and immunomodulatory signals to synovial macrophages. We hypothesize that site-specific drug delivery that targets multiple disease processes will improve cartilage protection and prevent/reduce chronic joint inflammation, synergistically slowing/stopping OA progression. Specific Aim 1 focuses on the development of nanoparticle-based drug carriers that bind to and penetrate cartilage tissue, enabling sustained release of the chondroprotective drug, kartogenin, within the cartilage itself. Nanoparticle biodistribution and cartilage retention will be evaluated, as will the chondroprotective effects of site-specific kartogenin delivery in rodent models of OA. Specific Aim 2 focuses on the development of biocompatible particles that localize to the inflamed synovium and deliver a potent immunomodulatory signal, CD200, to macrophages. The influence of CD200 delivery on macrophage polarization, inflammatory cytokine production, and PTOA progression will be determined. Specific Aim 3 will study the combination the cartilage protecting and immune cell modulating drug delivery systems, and evaluate therapeutic effectiveness compared to each individual system alone. These studies will be performed in rodent model of OA that simulate many of the features observed in human patients. Therapeutic efficacy will be determined by comprehensive evaluation of structural, biochemical, and behavioral (pain and gait) metrics of the disease. Overall, the proposed work will advance knowledge and technologies for targeted drug delivery within the joint. Moreover, this work will also reveal new insights on the role of chondroprotection and macrophage immunomodulation on joint structure and function. By providing site-specific localization of OA drugs that simultaneously target multiple, synergistic pathways in the joint, we hope to overcome some of the limitations with existing treatment paradigms and move closer towards a cure for OA.

项目概要 骨关节炎 (OA) 是美国导致残疾的主要原因，目前尚无治愈方法。 尽管药物发现和细胞疗法取得了进展，但疾病缓解疗法仍然存在 难以捉摸。 OA 是一种复杂的疾病，涉及整个关节（包括软骨）的适应不良重塑 侵蚀、滑膜炎和骨重塑。关节损伤的连续性会产生慢性促炎症 和分解代谢关节环境，最终破坏关节的解剖结构和生理功能。那里 OA 治疗迫切需要解决多个部位的多种疾病机制 联合。虽然已经确定了许多药物和因子可以促进软骨修复和阻塞 各种 OA 疾病机制、快速的关节清除和较差的组织靶向性限制了其临床应用。 该提案为治疗 OA 的综合方法奠定了基础，该方法的重点是提供 在正确的时间将正确的药物用在关节的正确位置。具体来说，该提案旨在设计药物载体 可以同时向软骨传递软骨保护信号和向软骨传递免疫调节信号 滑膜巨噬细胞。我们假设针对多种疾病过程的位点特异性药物递送 将改善软骨保护并预防/减少慢性关节炎症，协同减缓/停止 OA 进展。具体目标 1 侧重于开发基于纳米颗粒的药物载体，该载体可结合 并穿透软骨组织，使软骨保护药物卡托根元在软骨内持续释放 软骨本身。将评估纳米颗粒的生物分布和软骨保留，以及 位点特异性 Kartogenin 递送在 OA 啮齿动物模型中的软骨保护作用。具体目标 2 重点关注 开发生物相容性颗粒，定位于发炎的滑膜并提供有效的 巨噬细胞的免疫调节信号 CD200。 CD200递送对巨噬细胞的影响 极化、炎症细胞因子的产生和 PTOA 进展将被确定。具体目标 3 将 研究软骨保护和免疫细胞调节药物递送系统的组合，并评估 与单独的每个单独系统相比的治疗效果。这些研究将在啮齿动物中进行 OA 模型模拟了在人类患者中观察到的许多特征。治疗效果将是 通过对结构、生化和行为（疼痛和步态）指标的综合评估来确定 这种疾病。总体而言，拟议的工作将推进靶向药物输送的知识和技术 关节内。此外，这项工作还将揭示关于软骨保护和作用的新见解。 巨噬细胞免疫调节对关节结构和功能的影响。通过提供 OA 的特定站点本地化 同时针对关节中多种协同途径的药物，我们希望克服一些问题 现有治疗模式的局限性，并朝着治愈 OA 迈进了一步。