Targeted Nanotherapy in the Treatment of Inflammatory Arthritis

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性炎症性关节病，影响全球约1%的总人口。该病的特征是腹泻性关节滑膜衬里的对称性炎症，导致软骨和骨骼破坏，并导致显著的发病率。尽管类风湿性关节炎的治疗取得了进展，但许多患者对目前的治疗没有反应。最初有反应的患者中，超过一半的人最终因继发性疗效丧失和/或危及生命的毒性而停止治疗。其中许多患者最终将需要昂贵的关节置换来改善和维持他们的日常活动。这些问题凸显了继续开发其他治疗类风湿性关节炎的方法的必要性。与传统药物不同，纳米系统允许有针对性地将少量但集中的治疗剂输送到所需的炎症部位。此外，这些纳米系统允许非侵入性和基于图像的药物效应定量读数，最终转化为改善结果，同时将全身副作用降至最低。使用针对新生血管整合素1v23的全氟碳纳米粒，我们给关节炎小鼠注射了抗血管生成药物伏马西林。我们的初步数据表明，1v23靶向的全氟碳纳米颗粒阻止了类风湿关节炎小鼠模型的炎性关节炎的进展。为了进一步探索纳米颗粒用于炎性关节炎治疗和早期治疗反应的非侵入性评估，我们提出了以下目标：具体目标1：开发系统性靶向纳米药物策略，以阻止或逆转关节炎小鼠模型的炎症。利用胶原诱导性关节炎(CIA)模型，我们已经确定，全身注射1v23靶向携带烟美西林的纳米颗粒到关节炎小鼠体内，关节炎症减少了50%。这些初步研究表明，靶向纳米颗粒可能代表着一种治疗类风湿性关节炎和其他类型炎性关节炎的新方法。然而，关于治疗药物的选择、剂量、给药策略和辅助治疗的使用等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配方、靶向和给药策略将如何影响小鼠CIA炎症的进展。具体目标2：开发关节内纳米药物策略，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，因为局部给药给药的总剂量要低得多。然而，尽管全身给药有局限性，但由于药物从关节迅速清除，以及短期的有益效果，关节内注射没有得到积极的研究。由于其尺寸，纳米颗粒非常适合关节内使用，因为包裹在外表面活性剂层中的药物被限制在关节间隙，允许特定和局部给药，而不会产生全身影响。我们将开发以增殖性滑膜为靶点的纳米颗粒制剂，以逆转炎症性关节炎兔模型的血管疙瘩形成并抑制软骨和骨侵蚀，并结合全身纳米颗粒方法进行评估。同时，我们将开发基于靶向纳米颗粒的磁共振分子成像技术，以跟踪炎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.