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Pharmaceutical Research

, 36:64 | Cite as

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

  • Gang Zhao
  • Xin Wei
  • Jianbo Wu
  • Derrick D. Eichele
  • Subodh M. Lele
  • Libin Yang
  • Fan Zhang
  • Dong WangEmail author
Research Paper
  • 66 Downloads

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.

Key Words

ELVIS inflammation targeting prodrug tofacitinib Ulcerative colitis (UC) 

Notes

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.

References

  1. 1.
    Høivik ML, Moum B, Solberg IC, Henriksen M, Cvancarova M, Bernklev T, et al. Work disability in inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN study. Gut. 2013;62(3):368–75.PubMedGoogle Scholar
  2. 2.
    Molodecky, N.A., et al., Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology, 2012. 142(1): p. 46–54. e42.Google Scholar
  3. 3.
    Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769–78.PubMedGoogle Scholar
  4. 4.
    Loftus EV Jr. Update on the incidence and prevalence of inflammatory bowel disease in the United States. Gastroenterol Hepatol. 2016;12(11):704–7.Google Scholar
  5. 5.
    Cohen R, et al. Systematic review: the costs of ulcerative colitis in Western countries. Aliment Pharmacol Ther. 2010;31(7):693–707.PubMedGoogle Scholar
  6. 6.
    Danese S. New therapies for inflammatory bowel disease: from the bench to the bedside. Gut. 2012;61(6):918–32.PubMedGoogle Scholar
  7. 7.
    De Vries, L., et al., The Future of Janus Kinase Inhibitors in Inflammatory Bowel Disease. Journal of Crohn's and Colitis, 2017: p. jjx003.Google Scholar
  8. 8.
    Friedman, S., Tofacitinib for Ulcerative Colitis—A Promising Step Forward. 2017, Mass Medical Soc.Google Scholar
  9. 9.
    Tanaka Y. Recent progress and perspective in JAK inhibitors for rheumatoid arthritis: from bench to bedside. The Journal of Biochemistry. 2015;158(3):173–9.PubMedGoogle Scholar
  10. 10.
    Wei X, Wu J, Zhao G, Galdamez J, Lele SM, Wang X, et al. Development of a Janus kinase inhibitor prodrug for the treatment of rheumatoid arthritis. Mol Pharm. 2018;15(8):3456–67.PubMedGoogle Scholar
  11. 11.
    Liu X-M, Quan LD, Tian J, Alnouti Y, Fu K, Thiele GM, et al. Synthesis and evaluation of a well-defined HPMA copolymer–dexamethasone conjugate for effective treatment of rheumatoid arthritis. Pharm Res. 2008;25(12):2910–9.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Chassaing, B., et al., Dextran sulfate sodium (DSS)-induced colitis in mice. Current protocols in immunology, 2014: p. 15.25. 1–15.25. 14.Google Scholar
  13. 13.
    De Vries, L., et al. The Efficacy of Tofacitinib and a Selective Janus Kinase 1 Inhibitor in Dextran Sulphate Sodium Colitis Models. in JOURNAL OF CROHNS & COLITIS. 2016. OXFORD UNIV PRESS GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND.Google Scholar
  14. 14.
    Cooper, H.S., et al., Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Laboratory investigation; a journal of technical methods and pathology, 1993. 69(2): p. 238–249.Google Scholar
  15. 15.
    Rumi G, et al. Dual role of endogenous nitric oxide in development of dextran sodium sulfate-induced colitis in rats. Journal of Physiology and Pharmacology: an Official Journal of the Polish Physiological Society. 2004;55(4):823–36.Google Scholar
  16. 16.
    Becker C, Fantini MC, Wirtz S, Nikolaev A, Kiesslich R, Lehr HA, et al. In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy. Gut. 2005;54(7):950–4.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Moolenbeek C, Ruitenberg E. The ‘Swiss roll’: a simple technique for histological studies of the rodent intestine. Lab Anim. 1981;15(1):57–60.PubMedGoogle Scholar
  18. 18.
    Kim, C., et al., L-cysteine supplementation attenuates local inflammation and restores gut homeostasis in a porcine model of colitis. Biochimica et Biophysica Acta (BBA)-General Subjects, 2009. 1790(10): p. 1161–1169.Google Scholar
  19. 19.
    Rieder F, Fiocchi C. Intestinal fibrosis in inflammatory bowel disease—current knowledge and future perspectives. J Crohn's Colitis. 2008;2(4):279–90.Google Scholar
  20. 20.
    Pierezan F, Mansell J, Ambrus A, Hoffmann AR. Immunohistochemical expression of ionized calcium binding adapter molecule 1 in cutaneous histiocytic proliferative, neoplastic and inflammatory disorders of dogs and cats. J Comp Pathol. 2014;151(4):347–51.PubMedGoogle Scholar
  21. 21.
    Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113(10):1490–7.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129(2):550–64.PubMedGoogle Scholar
  23. 23.
    Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–24.PubMedGoogle Scholar
  24. 24.
    Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, et al. OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators., Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–36.PubMedGoogle Scholar
  25. 25.
    Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474(7351):298–306.PubMedGoogle Scholar
  26. 26.
    Yuan F, Quan LD, Cui L, Goldring SR, Wang D. Development of macromolecular prodrug for rheumatoid arthritis. Adv Drug Deliv Rev. 2012;64(12):1205–19.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang D, Miller SC, Liu XM, Anderson B, Wang XS, Goldring SR. Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis. Arthritis research & therapy. 2007;9(1):R2.Google Scholar
  28. 28.
    Wei X, Li F, Zhao G, Chhonker YS, Averill C, Galdamez J, et al. Pharmacokinetic and biodistribution studies of HPMA copolymer conjugates in an aseptic implant loosening mouse model. Mol Pharm. 2017;14(5):1418–28.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Yuan F, Nelson RK, Tabor DE, Zhang Y, Akhter MP, Gould KA, et al. Dexamethasone prodrug treatment prevents nephritis in lupus-prone (NZB× NZW) F1 mice without causing systemic side effects. Arthritis Rheum. 2012;64(12):4029–39.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Ren K, Yuan H, Zhang Y, Wei X, Wang D. Macromolecular glucocorticoid prodrug improves the treatment of dextran sulfate sodium-induced mice ulcerative colitis. Clin Immunol. 2015;160(1):71–81.PubMedGoogle Scholar
  31. 31.
    Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity. 2013;39(5):806–18.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612–6.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Gäbele E, Dostert K, Hofmann C, Wiest R, Schölmerich J, Hellerbrand C, et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol. 2011;55(6):1391–9.PubMedGoogle Scholar
  34. 34.
    Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990;98(3):694–702.PubMedGoogle Scholar
  35. 35.
    Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96(2):795–803.PubMedGoogle Scholar
  36. 36.
    Boirivant M, Fuss IJ, Chu A, Strober W. Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med. 1998;188(10):1929–39.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Low, D., D.D. Nguyen, and E. Mizoguchi, Animal models of ulcerative colitis and their application in drug research. Drug design, development and therapy, 2013. 7: p. 1341.Google Scholar
  38. 38.
    Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 2007;131(1):33–45.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Yang J, Zhang R, Radford DC, Kopeček J. FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy. J Control Release. 2015;218:36–44.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Gang Zhao
    • 1
  • Xin Wei
    • 1
  • Jianbo Wu
    • 1
  • Derrick D. Eichele
    • 2
  • Subodh M. Lele
    • 3
  • Libin Yang
    • 1
  • Fan Zhang
    • 4
  • Dong Wang
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Internal Medicine, Division of Gastroenterology-Hepatology,University of Nebraska Medical CenterOmahaUSA
  3. 3.Department of Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA
  4. 4.Department of Pharmacy Practice, College of PharmacyUniversity of Nebraska Medical CenterOmahaUSA

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