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

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.

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.

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.

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.