Objectives

5-Fluorouracil (5-FU), a chemotherapeutic drug, has severe deteriorating effects on the intestine, leading to mucositis. Glycyrrhizic acid is a compound derived from a common herbal plant Glycyrrhiza glabra, with mucoprotective, antioxidant and anti-inflammatory actions, however, associated with poor pharmacokinetics. Owing to the remarkable therapeutic action of glycyrrhizic acid-loaded polymeric nanocarriers in inflammatory bowel disease, we explored their activity against 5-FU-induced intestinal mucositis in mice. Polymeric nanocarriers have proven to be efficient drug delivery vehicles for the long-term treatment of inflammatory diseases, but have not yet been explored for 5-FU-induced mucositis. Therefore, this study aimed to produce glycyrrhizic acid-loaded polylactic-co-glycolic acid (GA-PLGA) nanoparticles to evaluate their protective and therapeutic effects in a 5-FU-induced mucositis model.

Methods

GA-PLGA nanoparticles were prepared using a modified double emulsion method, physicochemically characterized, and tested for in vitro drug release. Thereafter, mucositis was induced by 5-FU (50 mg/kg; IP) administration to the mice for the first 3 days (day 0, 1, 2), and mice were treated orally with GA-PLGA nanoparticles for 7 days (day 0–6).

Results

GA-PLGA nanoparticles significantly reduced mucositis severity measured by body weight, diarrhea score, distress, and anorexia. Further, 5-FU induced intestinal histopathological damage, altered villi-crypt length, reduced goblet cell count, elevated pro-inflammatory mediators, and suppressed antioxidant enzymes, all of which were reversed by GA-PLGA nanoparticles.

Conclusion

Morphological, behavioral, histological, and biochemical results suggested that GA-PLGA nanoparticles were efficient, biocompatible, targeted, and sustained release drug delivery nano-vehicle for enhanced mucoprotective, anti-inflammatory, and antioxidant effects in 5-FU-induced intestinal mucositis.

Graphic abstract

中文翻译：

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通过抑制炎症介质和氧化应激评估载有甘草酸的聚合物纳米颗粒在 5-氟尿嘧啶诱导的肠道粘膜炎小鼠模型中的粘膜保护作用

目标

5-氟尿嘧啶 (5-FU) 是一种化学治疗药物，对肠道有严重的恶化作用，导致粘膜炎。Glycyrrhizic acid 是一种源自常见草本植物 Glycyrrhiza glabra 的化合物，具有黏膜保护、抗氧化和抗炎作用，但药代动力学较差。由于载有甘草酸的聚合物纳米载体在炎症性肠病中的显着治疗作用，我们探索了它们对 5-FU 诱导的小鼠肠道粘膜炎的活性。聚合物纳米载体已被证明是长期治疗炎症性疾病的有效药物递送载体，但尚未针对 5-FU 诱导的粘膜炎进行探索。所以，

方法

GA-PLGA 纳米粒子采用改良的双乳液法制备，对其进行物理化学表征，并进行体外药物释放测试。此后，在前 3 天（第 0、1、2 天）向小鼠施用 5-FU（50 mg/kg；IP）诱导粘膜炎，并用 GA-PLGA 纳米颗粒口服治疗小鼠 7 天（第0-6）。

结果

GA-PLGA 纳米颗粒显着降低了通过体重、腹泻评分、痛苦和厌食来衡量的粘膜炎严重程度。此外，5-FU 诱导肠道组织病理学损伤、改变绒毛隐窝长度、减少杯状细胞计数、升高促炎介质和抑制抗氧化酶，所有这些都被 GA-PLGA 纳米颗粒逆转。

结论

形态学、行为学、组织学和生化结果表明，GA-PLGA 纳米颗粒是高效、生物相容、靶向和缓释的纳米药物载体，可增强 5-FU 诱导的肠道粘膜炎的粘膜保护、抗炎和抗氧化作用。

图形摘要