Targeted Nanotherapy in the Treatment of Inflammatory Arthritis

类风湿关节炎(RA)是一种慢性炎症性关节病，影响约1%的 世界各地的一般人口。这种疾病的特征是滑膜衬里的对称性炎症。 腹泻关节，导致软骨和骨骼破坏，并导致严重的发病率。尽管 随着类风湿关节炎治疗的进展，许多患者对目前的治疗方法无效。超过一半的患者 最初的反应最终由于继发性疗效丧失和/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日常生活 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。不像 传统药物，纳米系统允许靶向输送少量但集中的治疗性药物 药剂特别针对所需的发炎部位。此外，这些纳米系统允许非侵入性和 基于图像的药物效果定量读数，最终转化为改善结果，同时 将系统性副作用降至最低。使用以整合素为靶点的全氟碳纳米颗粒 新生血管方面，我们给关节炎小鼠注射了抗血管生成的药物伏马西林。我们的初步数据 提示靶向全氟碳纳米粒可阻止炎性关节炎的进展。 类风湿关节炎小鼠模型。进一步探索纳米粒子在治疗和非侵入性评估中的应用 对于炎症性关节炎的早期治疗反应，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，以阻止或逆转炎症 小鼠关节炎模型。使用胶原诱导的关节炎(CIA)模型，我们已经确定全身性 向关节炎小鼠注射携带烟美西林的靶向纳米粒可使关节减少50% 发炎。这些初步研究表明，靶向纳米颗粒可能代表着一种新的方式 治疗类风湿关节炎和其他类型的炎症性关节炎。然而，关于治疗剂的许多问题 辅助治疗的选择、剂量、给药策略和使用仍未解决。在这 目的，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 小鼠中央情报局炎症的进展。 具体目标2：开发关节内纳米药物策略以阻止和抑制软骨和骨骼 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，因为关节内注射的总量要低得多。 通过本地递送给药的剂量。然而，尽管系统性疾病管理的局限性 改良药物，关节内注射没有被积极研究，因为快速清除 来自联合的药物和短暂的有益作用。由于它们的大小，纳米颗粒非常适合于 关节内使用因为包裹在外表面活性剂层中的药物仅限于关节间隙， 允许特定和局部给药，而不会产生系统性影响。我们将开发纳米颗粒配方 靶向增殖性滑膜逆转血管疙瘩形成并抑制软骨和骨侵蚀 兔炎性关节炎模型的建立及其与全身纳米颗粒的联合评价 接近了。同时，我们将开发基于靶向的磁共振分子成像技术 纳米颗粒用于跟踪炎症性关节炎兔模型的早期治疗反应。

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 ¿v¿3 on neovasculature, we delivered the anti-angiogenic drug fumagillin to arthritic mice. Our preliminary data indicate that ¿v¿3-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 ¿v¿3-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.