Synergistic Effect of Antiangiogenic Nanotherapy Combined with Methotrexate in The Treatment of Experimental Inflammatory Arthritis

Abstract

Aim: This study examines the effect of combining the antiangiogenic effect of α_vβ₃-targeted fumagillin nanoparticles with the conventional antirheumatic drug methotrexate for the treatment of inflammatory arthritis. Method: Arthritis was induced in mice by K/BxN serum transfer, and disease activity was monitored by clinical score and change in ankle thickness. Groups of mice received nanoparticles or methotrexate as single therapy or nanoparticles and methotrexate as combination therapy. Results: We found that animals treated with a pulse dose of fumagillin nanoparticles followed by methotrexate had significantly improved and sustained clinical response compared with those treated with either agent alone. Histological analysis confirmed a significant decrease in inflammatory cell influx, bone erosions, cartilage damage and angiogenesis with the combination therapy. Conclusion: Analysis of plasma cytokine levels suggests that fumagillin nanoparticles enhanced the systemic anti-inflammatory effects of methotrexate. Antiangiogenic nanotherapy may represent a promising approach for the treatment of inflammatory arthritis when combined with a conventional antirheumatic drug.

Keywords::

• antiangiogenics
• combination therapy
• K/BxN arthritis model
• nanotherapeutics
• rheumatoid arthritis

Financial & competing interests disclosure

Samuel A Wickline and Gregory M Lanza are scientific cofounders of Kereos, Inc., and minority shareholders (<5%). Hui-fang Zhou designed and performed the arthritis model in addition to data analysis. Grace Hu designed and performed the MTX analysis. Samuel A Wickline, Gregory M Lanza and Christine TN Pham conceived and participated in the design of the study and helped draft the manuscript. This work was supported by grants from the NIH (AR056468, CA119342, HL073646, NS059302, and HL094470). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

We extend sincere appreciation to Ralph Fuhrhop for nanoparticle synthesis and Ying Hu for technical expertise. We thank Paul Allen and Fei Shih for generous gift of K/BxN serum.

Additional information

Funding

Samuel A Wickline and Gregory M Lanza are scientific cofounders of Kereos, Inc., and minority shareholders (<5%). Hui-fang Zhou designed and performed the arthritis model in addition to data analysis. Grace Hu designed and performed the MTX analysis. Samuel A Wickline, Gregory M Lanza and Christine TN Pham conceived and participated in the design of the study and helped draft the manuscript. This work was supported by grants from the NIH (AR056468, CA119342, HL073646, NS059302, and HL094470). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.