Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis

Jianbo Wu, Xin Wei, Gang Zhao, Josselyn Galdamez, Subodh M Lele, Xiaoyan Wang, Yanzhi Liu, Dhruvkumar M. Soni, P. Edward Purdue, Ted R Mikuls, Steven R. Goldring, Dong Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

While highly efficacious in treating rheumatoid arthritis (RA), the approved Janus kinase (JAK) inhibitor, Tofacitinib (Tofa, CP-690 550), has dose-dependent toxicities that limit its clinical application. In this study, we have examined whether a prodrug design that targets arthritic joints would enhance Tofa's therapeutic efficacy, which may provide an opportunity for future development of safer Tofa dosing regimens. A prodrug of Tofa (P-Tofa) was synthesized by conjugating the drug to the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via an acid cleavable carbamate linker. The therapeutic efficacy of a single dose of P-Tofa was compared to the dose-equivalent daily oral administration of Tofa in an adjuvant-induced arthritis (AA) rat model. Saline treated AA rats and age-matched healthy rats were used as controls. Observational analyses support the superior and sustained efficacy of a single dose P-Tofa treatment compared to the dose-equivalent daily Tofa administration in ameliorating joint inflammation. Micro-CT and histological analyses demonstrated that the P-Tofa treatment provided a structural preservation of the joints better than that of the dose-equivalent Tofa. Optical imaging, immunohistochemistry, and fluorescence-activated cell sorting analyses attribute P-Tofa's superior therapeutic efficacy to its passive targeting to arthritic joints and inflammatory cell-mediated sequestration. In vitro cell culture studies reveal that the P-Tofa treatment produced sustained the inhibition of JAK/STAT6 signaling in IL-4-treated murine bone marrow macrophages, consistent with a gradual subcellular release of Tofa. Collectively, a HPMA-based nanoscale prodrug of P-Tofa has the potential to enhance the therapeutic efficacy and widen the therapeutic window of Tofa therapy in RA.

Original languageEnglish (US)
Pages (from-to)3456-3467
Number of pages12
JournalMolecular Pharmaceutics
Volume15
Issue number8
DOIs
StatePublished - Aug 6 2018

Fingerprint

Janus Kinases
Prodrugs
Rheumatoid Arthritis
Joints
Experimental Arthritis
Therapeutics
Arthritis
Carbamates
Optical Imaging
Interleukin-4
Oral Administration
Flow Cytometry
Cell Culture Techniques
Bone Marrow
Immunohistochemistry
Macrophages
Inflammation

Keywords

  • ELVIS mechanism
  • Janus kinase inhibitor
  • Tofacitinib
  • inflammation targeting
  • prodrug
  • rheumatoid arthritis

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis. / Wu, Jianbo; Wei, Xin; Zhao, Gang; Galdamez, Josselyn; Lele, Subodh M; Wang, Xiaoyan; Liu, Yanzhi; Soni, Dhruvkumar M.; Purdue, P. Edward; Mikuls, Ted R; Goldring, Steven R.; Wang, Dong.

In: Molecular Pharmaceutics, Vol. 15, No. 8, 06.08.2018, p. 3456-3467.

Research output: Contribution to journalArticle

Wu, J, Wei, X, Zhao, G, Galdamez, J, Lele, SM, Wang, X, Liu, Y, Soni, DM, Purdue, PE, Mikuls, TR, Goldring, SR & Wang, D 2018, 'Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis', Molecular Pharmaceutics, vol. 15, no. 8, pp. 3456-3467. https://doi.org/10.1021/acs.molpharmaceut.8b00433
Wu, Jianbo ; Wei, Xin ; Zhao, Gang ; Galdamez, Josselyn ; Lele, Subodh M ; Wang, Xiaoyan ; Liu, Yanzhi ; Soni, Dhruvkumar M. ; Purdue, P. Edward ; Mikuls, Ted R ; Goldring, Steven R. ; Wang, Dong. / Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis. In: Molecular Pharmaceutics. 2018 ; Vol. 15, No. 8. pp. 3456-3467.
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AU - Soni, Dhruvkumar M.

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