A Macromolecular Janus Kinase (JAK) Inhibitor Prodrug Effectively Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.
A Macromolecular Janus Kinase (JAK) Inhibitor Prodrug Effectively Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.
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大分子 Janus 激酶 (JAK) 抑制剂前药可有效改善硫酸葡聚糖钠诱导的小鼠溃疡性结肠炎。
DOI：
10.1007/s11095-019-2587-6
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发表时间：
2019
影响因子：
3.7
通讯作者：
Wang,Dong
中科院分区：
文献类型：
--
作者：
Zhao,Gang;Wei,Xin;Wu,Jianbo;Eichele,DerrickD;Lele,SubodhM;Yang,Libin;Zhang,Fan;Wang,Dong
托法替尼（tofacitinib, Tofa）已被批准用于治疗中度至重度活动性溃疡性结肠炎（UC）。为了提高其治疗效果和限制剂量依赖性毒性，我们开发了一种大分子Tofa前药（P-Tofa）。如果前药设计能改善Tofa治疗的效力和持续时间，它将扩大其治疗窗口，潜在地提高UC的安全性和更好的临床管理。方法通过可切割氨基甲酸酯连接剂将Tofa与N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物偶联合成sp -Tofa。用Tofa（每日灌胃，从第8天开始）、P-Tofa（第8天单次静脉给药，剂量相当于Tofa治疗）和生理盐水处理dss诱导的UC小鼠模型。以健康小鼠为阳性对照。采用疾病活动性指数（DAI）、内镜评分和终点组织学评估治疗效果。利用光学成像、免疫组织化学和流式细胞术了解P-Tofa的作用机制。结果dai结果表明，单剂量P-Tofa治疗比等量日Tofa治疗更有效。内镜评估和组织学分析证实，P-Tofa和Tofa均能保护结肠，P-Tofa治疗组结肠完整性更好，组织损伤更少。光学成像、流式细胞术和免疫组织化学结果显示，P-Tofa被动靶向炎症结肠，并通过细胞隔离保留。结论单次静脉给药P-Tofa比每日等量灌胃Tofa更能改善dss性结肠炎。这种观察到的优越的治疗效果可能归因于P-Tofa对发炎结肠的被动靶向和保留。
BackgroundTofacitinib (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.MethodsP-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.ResultsDAI 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.ConclusionsSingle 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.