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

项目总结 骨关节炎(OA)在美国是导致残疾的主要原因，目前还没有治愈的方法。 尽管药物发现和基于细胞的疗法取得了进展，但改变疾病的疗法仍然存在。 难以捉摸。骨关节炎是一种复杂的疾病，涉及整个关节，包括软骨在内的适应性不良的重塑。 侵蚀、滑膜炎和骨骼重塑。关节损害的连续体造成慢性促炎 和分解的关节环境，最终破坏关节的解剖和生理功能。那里 迫切需要一种OA疗法，以解决整个过程中多个地点的多种疾病机制 那家大麻店。虽然已经确定了许多促进软骨修复和阻断的药物和因素 不同的骨性关节炎发病机制、关节清除速度快、组织靶向性差限制了其临床应用。 这一建议为治疗OA的综合方法奠定了基础，该方法的重点是交付 正确的药物在正确的时间出现在正确的位置。具体地说，这项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特定部位的药物输送 将改善软骨保护，预防/减少慢性关节炎症，协同减缓/阻止 办公自动化进展。具体目标1集中在基于纳米颗粒的药物载体的开发 并穿透软骨组织，使软骨保护药物Kartogenin在关节内持续释放 软骨本身。将评估纳米颗粒的生物分布和软骨保留情况，以及 部位特异性促红细胞生成素在骨关节炎啮齿动物模型中的软骨保护作用。《特定目标2》侧重于 生物相容颗粒的发展，定位于发炎的滑膜，并提供有效的 免疫调节信号，CD200，巨噬细胞。CD200传递对巨噬细胞的影响 极化、炎性细胞因子的产生和PTOA的进展将被确定。具体目标3将 软骨保护和免疫细胞调节给药系统的联合应用研究与评价 比较每个单独系统单独的治疗效果。这些研究将在啮齿动物身上进行。 模拟在人类患者身上观察到的许多特征的骨性关节炎模型。治疗效果将是 由结构、生化和行为(疼痛和步态)指标的综合评估确定 这种疾病。总体而言，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，这项工作还将揭示对软骨保护和 巨噬细胞对关节结构和功能的免疫调节作用。通过提供特定于站点的办公自动化本地化 同时靶向多个、协同作用的联合途径的药物，我们希望克服一些 与现有治疗模式的局限性，并朝着治愈骨性关节炎更近一步。

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.