Kim Jaejeong, Kang Changyu, Yoo Jin-Wook, Yoon In-Soo, Jung Yunjin
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea.
Mol Pharm. 2025 May 5;22(5):2431-2445. doi: 10.1021/acs.molpharmaceut.4c01041. Epub 2025 Apr 17.
The selective agonist of β-adrenergic receptor mirabegron (MBG), clinically used to treat overactive bladders, exerts beneficial effects in animal models of colitis. Here, we aimed to enhance the therapeutic activity and safety of MBG as an anticolitic drug by implementing colon-targeted drug delivery using a prodrug approach. MBG was azo-linked with salicylic acid (SA) to yield SA-conjugated MBG (MAS), which was conjugated with aspartic acid (Asp) and glutamic acid (Glu) to yield more hydrophilic derivatives: Asp-conjugated MAS (MAS-Asp) and Glu-conjugated MAS (MAS-Glu). MBG derivatives reduced the distribution coefficient and cell permeability of MBG, which were greater with the amino acid-conjugated MAS than with MAS. MBG derivatives were cleaved to release MBG in the cecal contents. Upon oral gavage, compared with MBG, MBG derivatives delivered greater amounts of MBG to the cecum while limiting the systemic absorption of MBG, and the amino acid-conjugated MAS exhibited a greater performance than MAS. In a rat colitis model, MBG derivatives were more effective than MBG in ameliorating colonic damage and inflammation, and the amino acid-conjugated MAS was more potent than MAS. MAS-Glu was therapeutically superior to sulfasalazine, a current drug to treat inflammatory bowel disease, against rat colitis. Moreover, MBG activated the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2)-hemeoxygenase (HO)-1 pathway in inflamed colonic tissue, and the MAS-Glu-mediated amelioration of colitis was significantly compromised by an HO-1 inhibitor. Taken together, colon-targeted delivery of MBG may enhance the anticolitic activity, reduce the risk of systemic side effects of MBG, and elicit the therapeutic effects, at least partly by activating the Nrf2-HO-1 pathway.
β-肾上腺素能受体选择性激动剂米拉贝隆（MBG）临床上用于治疗膀胱过度活动症，在结肠炎动物模型中具有有益作用。在此，我们旨在通过前药方法实现结肠靶向给药，以增强MBG作为抗结肠炎药物的治疗活性和安全性。MBG与水杨酸（SA）通过偶氮连接生成SA共轭的MBG（MAS），MAS再与天冬氨酸（Asp）和谷氨酸（Glu）共轭，生成亲水性更强的衍生物：Asp共轭的MAS（MAS-Asp）和Glu共轭的MAS（MAS-Glu）。MBG衍生物降低了MBG的分配系数和细胞通透性，氨基酸共轭的MAS比MAS的降低程度更大。MBG衍生物在盲肠内容物中被裂解以释放MBG。经口灌胃后，与MBG相比，MBG衍生物向盲肠输送了更多的MBG，同时限制了MBG的全身吸收，且氨基酸共轭的MAS表现优于MAS。在大鼠结肠炎模型中，MBG衍生物在改善结肠损伤和炎症方面比MBG更有效，氨基酸共轭的MAS比MAS更有效。在对抗大鼠结肠炎方面，MAS-Glu在治疗上优于目前治疗炎症性肠病的药物柳氮磺胺吡啶。此外，MBG激活了炎症结肠组织中的抗炎核因子红细胞2相关因子2（Nrf2）-血红素加氧酶（HO）-1途径，HO-1抑制剂显著削弱了MAS-Glu介导的结肠炎改善作用。综上所述，MBG的结肠靶向递送可能增强抗结肠炎活性，降低MBG全身副作用的风险，并至少部分通过激活Nrf2-HO-1途径发挥治疗作用。
