College of Pharmacy , Pusan National University , Busan , Republic of Korea.
Mol Pharm. 2019 Sep 3;16(9):4007-4016. doi: 10.1021/acs.molpharmaceut.9b00664. Epub 2019 Aug 16.
We investigated if the therapeutic switching of sofalcone (SFC), a gastroprotective agent, to an anticolitic agent is feasible using colon-targeted drug delivery. SFC can activate the anti-inflammatory nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-hemeoxygenase-1 (HO-1) pathway in human colon epithelial cells and murine macrophages. For the efficient treatment of colitis, SFC was coupled with acidic amino acids to yield SFC-aspartic acid (SFC-AA) and SFC-glutamic acid, and their colon targetability and therapeutic effects were assessed as an anticolitic agent in a 2,4-dinitrobenezenesulfonic acid-induced rat colitis model. The SFC derivatives were decoupled up to 72% in the cecal contents but remained stable in the small intestinal contents. Oral gavage of SFC-AA (oral SFC-AA, equivalent to 1.67 mg/kg of SFC) delivered SFC (maximal cecal concentration: 57.36 μM) to the cecum, while no SFC was detected with oral gavage of SFC (oral SFC, 1.67 mg/kg). Moreover, oral SFC-AA (equivalent to 10 mg/kg of SFC) did not afford detectable concentration of SFC in the blood but detected up to 4.64 μM with oral SFC (10 mg/kg), indicating efficient colonic delivery and limited systemic absorption of SFC upon oral SFC-AA. Oral SFC-AA ameliorated colonic damage and inflammation in rat colitis with elevating colonic levels of HO-1 and nuclear Nrf2 protein, and the anticolitic effects of SFC-AA were significantly undermined by an HO-1 inhibitor. At an equivalent dose of SFC, oral SFC-AA but not oral SFC increased colonic HO-1 and nuclear Nrf2 levels, and oral SFC-AA was more effective than oral SFC in treating rat colitis. Moreover, oral SFC-AA was as effective against colitis as oral sulfasalazine being used for the treatment of inflammatory bowel disease. In conclusion, colon-targeted delivery of SFC facilitated the therapeutic switching of the drug to an anticolitic drug via Nrf2 activation.
我们研究了使用结肠靶向药物递送将胃保护剂 Sofalone（SFC）转换为抗结肠炎药物是否可行。SFC 可以激活人结肠上皮细胞和鼠巨噬细胞中的抗炎核因子（红系衍生 2）样 2（Nrf2）-血红素加氧酶 1（HO-1）通路。为了有效治疗结肠炎，SFC 与酸性氨基酸偶联，得到 SFC-天冬氨酸（SFC-AA）和 SFC-谷氨酸，并在 2,4-二硝基苯磺酸诱导的大鼠结肠炎模型中作为抗结肠炎药物评估其结肠靶向性和治疗效果。SFC 衍生物在盲肠内容物中解偶联高达 72%，但在小肠内容物中保持稳定。口服 SFC-AA（口服 SFC-AA，相当于 SFC 1.67mg/kg）将 SFC（盲肠最大浓度：57.36μM）递送至盲肠，而口服 SFC 则未检测到 SFC（口服 SFC，1.67mg/kg）。此外，口服 SFC-AA（相当于 SFC 10mg/kg）在血液中未检测到可检测浓度的 SFC，但口服 SFC（10mg/kg）检测到高达 4.64μM，表明口服 SFC-AA 后 SFC 具有有效的结肠递送和有限的全身吸收。口服 SFC-AA 可改善大鼠结肠炎的结肠损伤和炎症，同时提高结肠 HO-1 和核 Nrf2 蛋白水平，HO-1 抑制剂显著削弱 SFC-AA 的抗结肠炎作用。在 SFC 等效剂量下，口服 SFC-AA 而非口服 SFC 增加结肠 HO-1 和核 Nrf2 水平，口服 SFC-AA 在治疗大鼠结肠炎方面比口服 SFC 更有效。此外，口服 SFC-AA 对抗结肠炎的疗效与用于治疗炎症性肠病的口服柳氮磺胺吡啶相当。总之，结肠靶向递送 SFC 通过激活 Nrf2 促进了药物向抗结肠炎药物的治疗转换。
