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A Macromolecular Janus Kinase (JAK) Inhibitor Prodrug Effectively Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice

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Abstract

Background

Tofacitinib (Tofa) has been approved for moderately to severely active ulcerative colitis (UC). To improve its therapeutic efficacy and limit dose-dependent toxicity, we developed a macromolecular prodrug of Tofa (P-Tofa). If the prodrug design improves the potency and duration of Tofa therapy, it would widen its therapeutic window, potentially leading to improved safety and better clinical management of UC.

Methods

P-Tofa was synthesized by conjugating Tofa to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a cleavable carbamate linker. DSS-induced UC mouse model were treated with Tofa (daily oral gavage, from day 8), P-Tofa (single intravenous administration on day 8, dose equivalent to Tofa treatment) and saline. Healthy mice were used as a positive control. The therapeutic efficacy was evaluated using disease activity index (DAI), endoscopic score and end-point histology. The optical imaging, immunohistochemistry and flow cytometry were used to understand P-Tofa’s working mechanism.

Results

DAI results suggested that a single dose P-Tofa treatment was more efficacious than dose equivalent daily Tofa treatment. Endoscopic evaluation and histology analyses confirmed that while both P-Tofa and Tofa protected the colon, P-Tofa treated group was observed with better colon integrity with less tissue damage. Optical imaging, flow cytometry and immunohistochemistry results showed that P-Tofa passively targeted the inflamed colon and being retained via cellular sequestration.

Conclusions

Single intravenous administration of P-Tofa was more effective than dose equivalent daily oral Tofa gavage in ameliorating DSS-induced colitis. This observed superior therapeutic efficacy may be attributed to P-Tofa’s passive targeting to and retention by the inflamed colon.

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported in part by the National Institute of Allergy and Infectious Diseases (R01 AI119090) of the National Institute of Health of the United States of America, and China Scholarship Council (XW, GZ, FZ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. Gang Zhao and Xin Wei contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, PDD 3020, Omaha, NE, 68198-6125, USA

    Gang Zhao, Xin Wei, Jianbo Wu, Libin Yang & Dong Wang

  2. Department of Internal Medicine, Division of Gastroenterology-Hepatology,, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Derrick D. Eichele

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Subodh M. Lele

  4. Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Fan Zhang

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  1. Gang Zhao
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  2. Xin Wei
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Correspondence to Dong Wang.

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Zhao, G., Wei, X., Wu, J. et al. A Macromolecular Janus Kinase (JAK) Inhibitor Prodrug Effectively Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice. Pharm Res 36, 64 (2019). https://doi.org/10.1007/s11095-019-2587-6

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