Nalinbenjapun Sirinporn, Sripetthong Sasikarn, Basit Abdul, Chaimongkolnukul Khuanjit, Sajomsang Warayuth, Ovatlarnporn Chitchamai
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand; Drug Delivery System Research Excellent Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand; Drug Delivery System Research Excellent Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand; Department of Medicinal Chemistry, College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China.
Int J Biol Macromol. 2025 Jul;318(Pt 3):144734. doi: 10.1016/j.ijbiomac.2025.144734. Epub 2025 May 27.
Site-specific colon drug delivery is crucial in the treatment of colon-localized diseases. In this study, prodrugs of 5-aminosalicylic acid (5-ASA), the drug of choice in ulcerative colitis (UC), were synthesized by conjugating with chitosan having molecular weights (MW) of 30, 80 and 300 kDa to achieve targeted delivery to the colon. FT-IR and UV-Vis analyses confirmed the successful synthesis and varying loading capacities of 5-ASA, with a maximum loading capacity of 11.32 ± 2.0 %. The obtained conjugates (7-9) exhibited gradual drug release characteristics, with up to 30 % of the drug content released after 24 h, in the simulated colonic fluid containing rat gastrointestinal (GI) tract homogenates, demonstrating their colon-specific and slow-release properties. The conjugates were non-toxic to normal human colon epithelial cells at concentrations up to 5-10 μg/mL, suggesting a favorable safety profile. Additionally, conjugate (7) was tested for its efficacy in a mouse model of ulcerative colitis. Necropsy results showed no significant structural changes or lesions in animals treated with conjugate (7). Histopathological analysis revealed mild, multifocal lymphoplasmacytic infiltrates and scattered eosinophils in the lamina propria, indicating a low level of inflammation. Overall, the findings suggest that 5-ASA-azobenzyl-chitosan conjugates hold promise as a potential therapeutic option for ulcerative colitis and other colon localized disorders, with minimal side effects due to reduced systemic exposure.
局部结肠给药在结肠局部疾病的治疗中至关重要。在本研究中，通过与分子量分别为30 kDa、80 kDa和300 kDa的壳聚糖偶联，合成了溃疡性结肠炎（UC）的首选药物5-氨基水杨酸（5-ASA）的前药，以实现对结肠的靶向给药。傅里叶变换红外光谱（FT-IR）和紫外可见光谱（UV-Vis）分析证实了5-ASA的成功合成及其不同的负载能力，最大负载能力为11.32±2.0%。所得到的偶联物（7-9）表现出药物逐渐释放的特性，在含有大鼠胃肠道（GI）匀浆的模拟结肠液中，24小时后药物释放量高达30%，证明了它们的结肠特异性和缓释特性。在浓度高达5-10μg/mL时，偶联物对正常人结肠上皮细胞无毒，表明其具有良好的安全性。此外，对偶联物（7）在溃疡性结肠炎小鼠模型中的疗效进行了测试。尸检结果显示，用偶联物（7）治疗的动物没有明显的结构变化或病变。组织病理学分析显示，固有层有轻度、多灶性淋巴细胞浆细胞浸润和散在的嗜酸性粒细胞，表明炎症水平较低。总体而言，研究结果表明，5-ASA-偶氮苄基-壳聚糖偶联物有望成为溃疡性结肠炎和其他结肠局部疾病的潜在治疗选择，由于全身暴露减少，副作用最小。
