Development of macromolecular prodrug for rheumatoid arthritis

Fang Yuan, Ling dong Quan, Liao Cui, Steven R. Goldring, Dong Wang

Research output: Contribution to journalReview article

83 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1205-1219
Number of pages15
JournalAdvanced Drug Delivery Reviews
Volume64
Issue number12
DOIs
StatePublished - Sep 1 2012

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Keywords

  • Drug delivery
  • ELVIS
  • Macromolecular prodrug
  • Rheumatoid arthritis
  • Targeting inflammation

ASJC Scopus subject areas

  • Pharmaceutical Science

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