School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, 100 Science Road, Zhengzhou, 450001, China.
School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
Eur J Pharmacol. 2022 Sep 5;930:175131. doi: 10.1016/j.ejphar.2022.175131. Epub 2022 Jul 21.
The oxidative stress and activation of the fibrosis pathway are essential pathological mechanisms of acute kidney injury (AKI). In this article, we designed a drug delivery system that could effectively improve oxidative stress and relieve fibrosis by the combination of precise targeting, solubilization, and reducing the toxicity of nano-transport system to strengthen the efficacy of AKI. Folic acid (FA) was used as the targeting molecule, and curcumin (Cur) and resveratrol (Res), which are Chinese medicine monomers with anti-inflammatory and antioxidant effects, were used as model drugs. Here, the targeting nanosystem (Cur/Res@FA-F127/TPGS) co-loaded with Cur and Res was successfully synthesized. Finally, the comprehensive therapeutic effect of the nanosystem was evaluated through the targeted and pharmacodynamic researches on the AKI models induced by cisplatin (CDDP) in vitro and in vivo. The studies in vitro proved that the nanosystem could not only specifically target HK-2 cells and promote the effective accumulation of Cur and Res in the kidney, but also effectively improve oxidative stress by eliminating reactive oxygen species (ROS), stabilizing mitochondrial membrane potential (MMP), and reducing the expression of apoptosis-related proteins. The studies in vivo showed that the nanosystem could effectively play the role of anti-oxidation, anti-inflammatory and alleviate fibrosis to reduce the apoptosis and necrosis of renal tubular cells. The nanosystem could coordinately repair damaged HK-2 cells by improving oxidative stress, inhibiting inflammation and tissue fibrosis, which provided a new idea for the treatment of AKI.
氧化应激和纤维化途径的激活是急性肾损伤（AKI）的重要病理机制。在本文中，我们设计了一种药物传递系统，通过精确靶向、增溶和降低纳米转运系统的毒性相结合，可以有效地改善氧化应激和缓解纤维化，从而增强 AKI 的疗效。叶酸（FA）被用作靶向分子，姜黄素（Cur）和白藜芦醇（Res）被用作具有抗炎和抗氧化作用的中药单体作为模型药物。在这里，成功合成了共载有 Cur 和 Res 的靶向纳米系统（Cur/Res@FA-F127/TPGS）。最后，通过体外和体内顺铂（CDDP）诱导的 AKI 模型对纳米系统进行靶向和药效学研究，评估了纳米系统的综合治疗效果。体外研究证明，纳米系统不仅可以特异性靶向 HK-2 细胞，并促进 Cur 和 Res 在肾脏中的有效积累，还可以通过消除活性氧（ROS）、稳定线粒体膜电位（MMP）和降低凋亡相关蛋白的表达来有效改善氧化应激。体内研究表明，纳米系统可以有效发挥抗氧化、抗炎和减轻纤维化的作用，减少肾小管细胞的凋亡和坏死。纳米系统可以通过改善氧化应激、抑制炎症和组织纤维化来协调修复受损的 HK-2 细胞，为 AKI 的治疗提供了新的思路。
