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

项目摘要 骨关节炎（OA）是美国残疾的主要原因，目前无法治愈。 尽管药物发现和细胞疗法取得了进展，但改善疾病的疗法仍然存在 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。关节损伤的连续性产生慢性促炎性反应， 和分解代谢关节环境，这最终破坏关节的解剖和生理功能。那里 是OA治疗的关键需求，以解决整个过程中多个位置的多种疾病机制 接头。虽然许多药物和因子已被确定为促进软骨修复和阻断 各种OA疾病机制、快速的关节清除和差的组织靶向限制了它们的临床应用。 该提案为治疗OA的综合方法奠定了基础，该方法侧重于提供 正确的药物在关节中正确的时间出现在正确的位置。具体来说，这项建议旨在设计药物载体， 它可以同时向软骨传递软骨保护信号和免疫调节信号， 滑膜巨噬细胞我们假设靶向多种疾病过程的位点特异性药物递送 将改善软骨保护，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， 并穿透软骨组织，使软骨保护药物卡托皂苷元在软骨组织内持续释放， 软骨本身。将评估纳米颗粒的生物分布和软骨保留， 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侧重于 生物相容性颗粒的发展，定位于发炎的滑膜，并提供有效的 免疫调节信号CD 200。CD 200对巨噬细胞的影响 将确定极化、炎性细胞因子产生和PTOA进展。第3章将 研究软骨保护和免疫细胞调节药物释放系统的组合， 与单独的每个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。疗效将是 通过综合评估结构，生化和行为（疼痛和步态）指标确定， 这种疾病总的来说，拟议的工作将促进靶向药物输送的知识和技术 在关节内。此外，这项工作还将揭示关于软骨保护作用的新见解， 巨噬细胞对关节结构和功能的免疫调节。通过提供OA的特定站点本地化 同时靶向关节中多个协同途径的药物，我们希望克服一些 现有治疗模式的局限性，并朝着治愈OA的方向迈进。

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.