Targeted Nanotherapy in the Treatment of Inflammatory Arthritis

描述（由申请人提供）：风湿性关节炎（RA）是一种慢性炎症性关节病，影响全球约1%的普通人群。该疾病的特征在于双关节的滑膜衬里的对称性炎症，导致软骨和骨破坏并导致显著的发病率。尽管RA治疗取得了进展，但许多患者对目前的治疗没有反应。超过一半的最初有反应的患者最终因继发性疗效丧失和/或危及生命的毒性而停止治疗。这些患者中的许多人最终将需要昂贵的关节置换术来改善和维持他们的日常活动。这些问题突出了需要继续开发RA的其他疗法。与传统药物不同，纳米系统允许将少量但浓缩的治疗剂靶向递送到所需的炎症部位。此外，这些纳米系统允许非侵入性和定量的基于图像的药物效果读数，最终转化为改善的结果，同时最大限度地减少全身副作用。使用靶向新血管系统上整合素1v 23的全氟化碳纳米颗粒，我们将抗血管生成药物烟曲霉素递送给关节炎小鼠。我们的初步数据表明，1v 23靶向的全氟化碳纳米颗粒阻止了RA小鼠模型中炎症性关节炎的进展。为了进一步探索纳米颗粒在炎症性关节炎的治疗和早期治疗反应的非侵入性评估中的用途，我们提出了以下目标：具体目标1：开发全身靶向纳米药物策略，以停止或逆转关节炎小鼠模型中的炎症。使用胶原蛋白诱导的关节炎（CIA）模型，我们已经确定将携带烟曲霉素的1v 23靶向纳米颗粒全身注射到关节炎小鼠中导致关节炎症减少> 50%。这些初步研究表明，靶向纳米颗粒可能代表了治疗RA和其他类型炎性关节炎的新方法。然而，关于治疗剂的选择、剂量、给药策略和连续治疗的使用的许多问题仍然没有解决。在这个目标中，我们将测试不同的纳米颗粒制剂，靶向和管理策略将如何影响小鼠CIA炎症的进展。具体目标2：开发关节内纳米医学策略，以阻止和抑制软骨和骨侵蚀。关节内注射是治疗类风湿关节炎的一种有吸引力的选择，因为局部给药的总剂量要低得多。然而，尽管全身给药的疾病修饰药物的局限性，关节内注射尚未积极研究，因为药物从关节的快速清除和短暂的有益效果。由于它们的尺寸，纳米颗粒非常适合关节内使用，因为包埋在表面活性剂外层中的药物被限制在关节间隙，允许特异性和局部递送药物而没有全身效应。我们将开发靶向增殖滑膜的纳米颗粒制剂，以逆转血管翳形成并抑制炎症性关节炎兔模型中的软骨和骨侵蚀，并结合全身纳米颗粒方法对这些进行评估。同时，我们将开发基于靶向纳米颗粒的MR分子成像技术，以跟踪炎症性关节炎兔模型的早期治疗反应。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy affecting approximately 1% of the general population worldwide. The disease is characterized by symmetrical inflammation of the synovial lining of diarthrodial joints, leading to cartilage and bone destruction and resulting in significant morbidity. Despite advances in RA treatment, many patients fail to respond to current therapy. Over half of the patients who initially respond eventually cease therapy due to secondary loss of efficacy and/or life-threatening toxicities. Many of these patients will ultimately require costly joint replacement to improve and maintain their daily activities. These problems highlight the need for continued development of additional therapies for RA. Unlike conventional drugs, nanosystems allow targeted delivery of a small but concentrated amount of therapeutic agents specifically to the desired site of inflammation. In addition, these nanosystems allow non-invasive and quantitative image-based readouts of drug effects, which ultimately translate to improved outcomes while minimizing systemic side effects. Using perfluorocarbon nanoparticles that target the integrin 1v23 on neovasculature, we delivered the anti-angiogenic drug fumagillin to arthritic mice. Our preliminary data indicate that 1v23-targeted perfluorocarbon nanoparticles halt the progression of inflammatory arthritis in a mouse model of RA. To further explore the use of nanoparticles for therapy and non-invasive evaluation of early treatment response in inflammatory arthritis, we propose the following aims: Specific Aim 1: Develop systemic targeted nanomedicine strategies to halt or reverse inflammation in a mouse model of arthritis. Using a collagen-induced arthritis (CIA) model, we have determined that systemic injection of 1v23-targeted nanoparticles carrying fumagillin into arthritic mice led to > 50% decrease in joint inflammation. These preliminary studies suggest that targeted nanoparticles may represent a novel way to treat RA and other types of inflammatory arthritis. However, many issues regarding the therapeutic agent selection, the dose, the administration strategy, and the use of adjunctive treatment remain unresolved. In this aim, we will test how different nanoparticle formulations, targeting and administration strategies will impact on the progression of inflammation in murine CIA. Specific Aim 2: Develop intra-articular nanomedicine strategies to halt and inhibit cartilage and bone erosions. Intra-articular injection is an attractive alternative in treating RA because of the much lower total dose of medication given by local delivery. Yet despite the limitations of systemic administration of disease modifying drugs, intra-articular injections have not been actively investigated because of the rapid clearance of drugs from the joint and the short-lived beneficial effect. Due to their size, nanoparticles are well suited for intra-articular use because the drugs entrapped in the outer surfactant layer are restricted to the joint space, allowing specific and local delivery of drugs without systemic effects. We will develop nanoparticle formulations that target proliferative synovium to reverse pannus formation and inhibit cartilage and bone erosions in a rabbit model of inflammatory arthritis and evaluate these in combination with systemic nanoparticle approaches. In conjunction, we will develop MR molecular imaging technologies based on targeted nanoparticles to track early therapeutic responses in a rabbit model of inflammatory arthritis.