Nanoparticle targeting of ICAM-1 as a potential treatment for Rheumatoid Arthriti

描述(由申请人提供)： 细胞间黏附分子-1(ICAM-1)在类风湿关节炎患者滑膜腔产生的促炎细胞因子作用下，上调血管内皮细胞的表达。与ICAM-1特异性相互作用的纳米颗粒可能优先聚集到炎症部位，潜在地阻断这一信号和/或促进甲氨蝶呤等治疗药物的输送。本应用的目的是确定靶向ICAM-1的甲氨蝶呤纳米粒在抢救患有胶原性关节炎(CIA)的啮齿动物方面的性能。我们的中心假设是，在CIA啮齿动物模型中，与同等剂量的静脉注射甲氨蝶呤或纳米颗粒相比，负载10%甲氨蝶呤的纳米颗粒将显著降低关节炎评分。我们提出了两个具体目标：具体目标#1：确定针对HUVEC上ICAM-1的纳米颗粒制剂。我们的工作假设是，基于强大的初步数据，显示cLABL多肽的纳米颗粒将优先结合过度表达ICAM-1的HUVEC。具体目标#2：在CIA啮齿动物模型中确定cLABL-纳米颗粒疾病缓解。我们的工作假设也基于强大的初步数据，即靶向ICAM-1并输送甲氨蝶呤的cLABL纳米粒与单独使用甲氨蝶呤或cLABL纳米粒相比，将显著干扰CIA的进展。FDA已经批准使用抗肿瘤坏死因子-a的单抗(英夫利昔单抗)与甲氨蝶呤进行联合治疗，结果令人鼓舞。在这里，我们提出了一种潜在的更具选择性的治疗类风湿性关节炎的方法，试图将药物定位于炎症分子标志物(ICAM-1)作为全身免疫抑制的替代方案。

DESCRIPTION (provided by applicant): Intercellular cell-adhesion molecule-1 (ICAM-1) is up-regulated on the vascular endothelium in response to pro-inflammatory cytokines produced in the synovial cavity of patients with Rheumatoid Arthritis. Nanoparticles that interact specifically with ICAM-1 may preferentially pool to sites of inflammation potentially interrupting this signal and/or facilitating the delivery of therapeutics such as methotrexate. The objective of this application is to identify the performance of methotrexate loaded nanoparticles targeted to ICAM-1 for rescuing rodents with collagen-induced arthritis (CIA). Our central hypothesis is that nanoparticles loaded with 10% methotrexate will significantly reduce arthritis scores in the CIA rodent model compared to an equivalent intravenous dose of methotrexate or nanoparticles alone. We propose two Specific Aims: Specific Aim #1: Identify nanoparticle formulations that specifically target ICAM-1 on HUVECs. Our working hypothesis, based upon strong preliminary data, is that nanoparticles displaying the cLABL peptide will preferentially bind HUVECs overexpressing ICAM-1. Specific Aim #2: Identify cLABL-nanoparticle disease mitigation in the CIA rodent model. Our working hypothesis, also based upon strong preliminary data, is that cLABL-nanoparticles targeted to ICAM-1 and delivering methotrexate will significantly disrupt the progression of CIA compared to methotrexate or cLABL-nanoparticles alone. The FDA has approved combination therapy using mAbs against TNF-a (infliximab) with methotrexate and results have been encouraging. Here, we propose a potentially more selective approach for treating RA by attempting to localize drugs to molecular markers of inflammation (ICAM-1) as an alternative to systemic immunosuppression.