Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Adv Drug Deliv Rev. 2012 Sep;64(12):1205-19. doi: 10.1016/j.addr.2012.03.006. Epub 2012 Mar 10.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases.
类风湿关节炎（RA）是一种慢性自身免疫性疾病，被认为是全球主要的公共卫生问题之一。针对肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和调节免疫系统的共刺激途径的治疗方法的发展彻底改变了 RA 患者的治疗方法。尽管取得了这些进展，但许多患者仍继续出现症状和功能障碍。为了解决这个问题，最近开发的治疗方法旨在针对参与免疫调节的细胞内信号通路。尽管这种方法令人鼓舞，但由于这些信号通路在多种细胞类型和组织中的广泛分布，与靶向器官副作用和全身毒性相关的主要挑战仍然存在。这些局限性导致人们越来越关注开发将抗风湿药物进行大分子化的策略，从而将它们靶向到发炎的关节。这种方法增强了治疗剂对滑膜炎症的疗效，同时显著降低了非靶向器官的不良反应。在本文中，我们全面概述了用于治疗 RA 的大分子前药的合理设计和优化。前药的优越和持续疗效可能部分归因于它们通过渗漏血管外渗和随后在关节炎关节中的炎症细胞介导的隔离（ELVIS）。这种生物过程提供了一种合理的机制，通过该机制，大分子前药优先靶向关节炎关节，并说明了将这种治疗策略应用于治疗其他炎症性疾病的潜在益处。
