Targeted Nanotherapy in the Treatment of Inflammatory Arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种慢性炎症性关节病，影响全球约1%的普通人群。该疾病的特征是腹泻关节滑膜衬里的对称炎症，导致软骨和骨破坏，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有一半以上由于继发性疗效丧失和/或危及生命的毒性而最终停止治疗。许多患者最终需要昂贵的关节置换来改善和维持他们的日常活动。这些问题突出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，纳米系统允许将少量但浓缩的治疗药物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应读数，最终转化为改善的结果，同时最大限度地减少系统副作用。我们利用靶向新血管整合素1v23的全氟碳纳米颗粒，将抗血管生成药物富马青霉素输送到关节炎小鼠体内。我们的初步数据表明，靶向1v23的全氟碳纳米颗粒可以阻止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治疗中的应用以及对早期治疗反应的无创评估，我们提出了以下目标：具体目标1：在关节炎小鼠模型中开发系统性靶向纳米药物策略来阻止或逆转炎症。通过胶原诱导关节炎（CIA）模型，我们确定将携带富马青霉素的1v23靶向纳米颗粒全身注射到关节炎小鼠体内，可使关节炎症减少50%。这些初步研究表明，靶向纳米颗粒可能是治疗类风湿性关节炎和其他类型炎性关节炎的一种新方法。然而，关于治疗剂的选择、剂量、给药策略和辅助治疗的使用等许多问题仍未解决。为此，我们将测试不同的纳米颗粒配方、靶向和给药策略如何影响小鼠CIA炎症的进展。具体目标2：发展关节内纳米药物策略，以停止和抑制软骨和骨侵蚀。关节内注射是治疗类风湿性关节炎的一个有吸引力的选择，因为局部给药的总剂量要低得多。然而，尽管疾病修饰药物的全身给药存在局限性，但由于药物从关节中快速清除和短暂的有益效果，关节内注射尚未被积极研究。由于它们的大小，纳米颗粒非常适合关节内使用，因为包裹在表面活性剂外层的药物被限制在关节空间内，允许药物的特异性和局部递送，而不会产生全身效应。我们将在兔炎性关节炎模型中开发靶向增殖性滑膜的纳米颗粒制剂，以逆转滑膜形成并抑制软骨和骨侵蚀，并将其与全身纳米颗粒方法相结合进行评估。同时，我们将开发基于靶向纳米颗粒的MR分子成像技术，以跟踪兔炎性关节炎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.