Document Detail


Development of macromolecular prodrug for rheumatoid arthritis.
MedLine Citation:
PMID:  22433784     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Fang Yuan; Ling-dong Quan; Liao Cui; Steven R Goldring; Dong Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2012-03-10
Journal Detail:
Title:  Advanced drug delivery reviews     Volume:  64     ISSN:  1872-8294     ISO Abbreviation:  Adv. Drug Deliv. Rev.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-22     Completed Date:  2013-01-14     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  8710523     Medline TA:  Adv Drug Deliv Rev     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1205-19     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
Affiliation:
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents / administration & dosage,  adverse effects,  therapeutic use
Antirheumatic Agents / administration & dosage,  adverse effects,  therapeutic use*
Arthritis, Rheumatoid / drug therapy*,  physiopathology
Drug Delivery Systems
Drug Design*
Humans
Inflammation / drug therapy,  pathology
Macromolecular Substances / administration & dosage,  adverse effects,  therapeutic use
Prodrugs
Signal Transduction
Grant Support
ID/Acronym/Agency:
R01 AR053325-03/AR/NIAMS NIH HHS; R01 AR053325./AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Antirheumatic Agents; 0/Macromolecular Substances; 0/Prodrugs
Comments/Corrections

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