Scavenger Receptor-Mediated Targeted Treatment of Collagen-Induced Arthritis by Dextran Sulfate-Methotrexate Prodrug
Modi Yang1, Jianxun Ding2, Xiangru Feng2
1Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China;; Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China.
Abstract:
Rheumatoid arthritis (RA) is a chronic autoimmune disorder implicated in multiple joint affection and even disability. The activated macrophages perform a predominant role in onset and persistence of RA. Scavenger receptor (SR), one of several receptors overexpressed on the activated macrophages, is a specific biomarker for targeted therapy of numerous chronic inflammation diseases like RA. In this work, dextran sulfate-graft-methotrexate conjugate (DS-g-MTX) is synthesized and characterized, which exhibits excellent targetability to SR on the activated RAW 264.7 cells. Additionally, the enhanced accumulation and potent inflammatory inhibition are observed in the affected joint after intravenous injection of DS-g-MTX, compared to the treatment with dextran-graft-methotrexate (Dex-g-MTX), as is confirmed by the detection of histopathology and pro-inflammatory cytokines. Our work highlights DS-g-MTX as a potential therapeutic option for RA aiming the SR-expressed activated macrophages.
Insights
A novel dextran sulfate-graft-methotrexate conjugate (DS-g-MTX) targets scavenger receptors on activated macrophages, offering a new therapeutic strategy for rheumatoid arthritis (RA). This conjugate shows improved accumulation and inflammation reduction in affected joints, demonstrating its potential for RA treatment.
Area of Science:
- Immunology
- Rheumatology
- Biomaterials Science
Background:
- Rheumatoid arthritis (RA) is a chronic autoimmune disease causing joint inflammation and disability.
- Activated macrophages play a key role in RA pathogenesis.
- Scavenger receptors (SR) are overexpressed on activated macrophages and are potential therapeutic targets.
Purpose of the Study:
- To synthesize and characterize a dextran sulfate-graft-methotrexate conjugate (DS-g-MTX).
- To evaluate the targetability of DS-g-MTX to SR on activated macrophages.
- To assess the therapeutic efficacy of DS-g-MTX in a rheumatoid arthritis model.
Main Methods:
- Synthesis and characterization of DS-g-MTX conjugate.
- In vitro studies using RAW 264.7 cells to assess targetability to SR.
- In vivo studies involving intravenous injection of DS-g-MTX in an RA model.
- Histopathological analysis and measurement of pro-inflammatory cytokines to evaluate therapeutic effects.
Main Results:
- DS-g-MTX demonstrated excellent targetability to SR on activated RAW 264.7 cells.
- Enhanced accumulation of DS-g-MTX was observed in the affected joints compared to Dex-g-MTX.
- Potent inhibition of inflammation and reduced pro-inflammatory cytokines were confirmed in vivo.
- Histopathology indicated significant therapeutic benefits of DS-g-MTX treatment.
Conclusions:
- DS-g-MTX conjugate is a promising therapeutic agent for rheumatoid arthritis.
- Targeting SR-expressed activated macrophages with DS-g-MTX offers a novel treatment strategy for RA.
- This approach holds potential for managing chronic inflammatory diseases.
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