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Co-delivery of indomethacin and uricase as a new strategy for inflammatory diseases associated with high uric acid

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Abstract

Uric acid is the final metabolite in humans. High level of uric acid chronically induces urate deposition, aggravates kidney damage, and concomitantly causes an increase in inflammatory factors. Alleviating acute inflammation and decreasing uric acid levels are the key points in the treatment of inflammatory diseases associated with high uric acid. However, a drug delivery system that combines anti-inflammatory and uric acid reduction functions at the same time remains a challenge to be settled. Here, we designed a nanocrystal-based co-delivery platform, IND Nplex, characterized by loading of indomethacin (IND) and uricase. Compared with free IND or uricase, IND Nplex possessed a better anti-inflammatory effect by restraining the release of inflammation-related factors in vitro. In addition, pharmacokinetic and biodistribution studies revealed that IND Nplex significantly prolonged the retention time in vivo and was more concentrated in the kidney. In acute gouty arthritis model rats, IND Nplex markedly relieved ankle joint swelling and mitigated synovial inflammation. In acute kidney injury model rats, IND Nplex indicated better biocompatibility and significant amelioration of renal fibrosis. Moreover, IND Nplex showed the effect of anti-inflammatory and improved renal function via determination of inflammatory factors and biochemical markers in the serum and kidney. In conclusion, these results indicate that IND Nplex exerts anti-inflammatory activity and uric acid–lowering effect and could become a promising candidate for the treatment of uric acid–related diseases.

Graphical Abstract

In this study, a stable neutral co-delivery platform (IND Nplex) was fabricated by using a co-delivery strategy, allowing for a combination of the anti-inflammation drug IND and the metabolic enzyme uricase. IND Nplex showed a good therapeutic effect on rats with acute gouty arthritis or acute kidney injury due to the dual effects of anti-inflammatory and uric acid lowering. This platform provided a novel strategy for high uric acid–related illnesses.

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Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge the Public platform of the Pharmaceutical Animal Experimental Center for the use of living imaging system, and also thank Liuyi Zhong for her help with taking images.

Funding

This study was supported by the Jiangsu Funding Program for Excellent Postdoctoral Talent (2022ZB313).

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Author notes

  1. Jie Liu and Chenshi Lin contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, China

    Jie Liu, Man Wu, Taiwang Yang, Chenlu Xie, Yue Kong, Wenliang Wu & Jiaping Wang

  2. School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Jie Liu, Chenshi Lin, Xiaonan Ma & Chao Teng

  3. Center for Translational Imaging, Northeastern University, 360 Huntington Ave., Boston, MA, 02115, USA

    Yingjie Wang

  4. Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

    Shenyu Chen

  5. Public Experimental Platform, China Pharmaceutical University, Nanjing, 210009, China

    Xiaonan Ma

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  1. Jie Liu
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Contributions

Chao Teng conceived and designed the research work. Jie Liu and Chenshi Lin performed the experiments and analyzed the results. Man Wu, Yingjie Wang, Shenyu Chen, Taiwang Yang, Chenlu Xie, Yue Kong, Wenliang Wu, and Jiaping Wang assisted in the conduct of the experiment and the writing of the article. Xiaonan Ma and Chao Teng co-wrote the paper. All of the authors discussed the results and commented on the manuscript. All of the authors have read and approved the final manuscript.

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Correspondence to Xiaonan Ma or Chao Teng.

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All the experimental protocols were approved by the Institutional Animal Care and Use Committee of China Pharmaceutical University (approval number 2019–06-005).

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Liu, J., Lin, C., Wu, M. et al. Co-delivery of indomethacin and uricase as a new strategy for inflammatory diseases associated with high uric acid. Drug Deliv. and Transl. Res. 14, 1820–1838 (2024). https://doi.org/10.1007/s13346-023-01487-5

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  • DOI: https://doi.org/10.1007/s13346-023-01487-5

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