Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Drug Deliv. 2022 Dec;29(1):3270-3280. doi: 10.1080/10717544.2022.2142700.
Liver fibrosis is a global life-threatening disorder with no approved treatment. It leads to serious hepatic complications when progressive, such as cirrhosis and carcinoma. Luteolin (LUT) is a plant flavonoid possessing a promising therapeutic potential in various liver diseases particularly, liver fibrosis. It was reported to have potent anti-inflammatory and antioxidant properties. It also suppresses the proliferation of activated hepatic stellate cells (HSC) and induces their apoptosis. However, its poor aqueous solubility and exposure to metabolism hinder its clinical use. Mesenchymal stem cells (MSCs)-derived exosomes, nano-sized extracellular vesicles, have recently emerged as natural biocompatible drug delivery vehicles permitting efficient drug delivery. Accordingly, the present study aimed for the first time to investigate the potential of bone marrow MSCs-derived exosomes to improve LUTs antifibrotic effectiveness. LUT-loaded exosomes (LUT-Ex) were successfully developed, optimized and subjected to both and characterization. The elaborated LUT-Ex presented good colloidal properties (size; 150 nm, PDI; 0.3 and ζ-potential; -28 mV), typical vesicular shape, reasonable drug entrapment efficiency (40%) with sustained drug release over 72 h. Additionally, the cellular uptake study of coumarin-6-loaded exosomes in HEP-G2 revealed a significant enhancement in their uptake by 78.4% versus free coumarin-6 solution ( ≤ 0.001). Following a single intraperitoneal injection, LUT-Ex revealed a superior antifibrotic activity compared with either LUT-suspension or blank exosomes as evidenced by the results of biochemical and histopathological evaluation. In conclusion, the elaborated LUT-Ex could be addressed as a promising nanocarrier for effective treatment of liver fibrosis.
肝纤维化是一种全球性的危及生命的疾病，目前尚无批准的治疗方法。当病情进展时，它会导致严重的肝并发症，如肝硬化和肝癌。木樨草素（LUT）是一种植物类黄酮，在各种肝病中具有有前途的治疗潜力，特别是肝纤维化。它具有很强的抗炎和抗氧化特性。它还能抑制活化的肝星状细胞（HSC）的增殖并诱导其凋亡。然而，其较差的水溶性和易受代谢影响限制了其临床应用。间充质干细胞（MSCs）衍生的外泌体，纳米级细胞外囊泡，最近作为天然的生物相容性药物递送载体而出现，能够实现有效的药物递送。因此，本研究首次旨在研究骨髓间充质干细胞衍生的外泌体提高 LUT 抗纤维化效果的潜力。成功开发、优化了负载 LUT 的外泌体（LUT-Ex），并对其进行了 和 表征。精心设计的 LUT-Ex 具有良好的胶体特性（粒径为 150nm，PDI 为 0.3，ζ-电位为-28mV）、典型的囊泡形态、合理的药物包封效率（40%），并能在 72 小时内持续释放药物。此外，在 HEP-G2 细胞中摄取香豆素-6 负载的外泌体的细胞摄取研究表明，与游离香豆素-6 溶液相比，其摄取量显著增加了 78.4%（ ≤ 0.001）。单次腹腔注射后，与 LUT 混悬液或空白外泌体相比，LUT-Ex 显示出更好的抗纤维化活性，这可从生化和组织病理学评估结果得到证明。总之，精心设计的 LUT-Ex 可以作为一种有前途的纳米载体，用于有效治疗肝纤维化。
