School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou 450001, China.
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.
Toxicol Appl Pharmacol. 2022 Sep 1;450:116155. doi: 10.1016/j.taap.2022.116155. Epub 2022 Jul 5.
To treat acute kidney injury with high efficiency and low toxicity, a novel nanoplatform was developed to remove excess reactive oxygen species (ROS). Lutein (LU) and celastrol (Cel) were loaded into low molecular weight chitosan (CS) to prepare Cel@LU-CA-CS nanomicelles. Renal tubular epithelial (HK-2) cell uptake experiments showed that the drugs could be internalized in renal tubular via the megalin receptor. In this study, the amide bond formed by the reaction of citraconic anhydride (CA) with an amino group of CS could be destroyed under acidic conditions. Therefore, the drugs were released in HK-2 cells due to the acidic environment of the lysosome. In vitro studies showed that the nanomicelles could reduce toxicity in non-target organs and enhance therapeutic efficacy in acute kidney injury (AKI). In addition, Cel@LU-CA-CS micelles had alleviated kidney oxidative stress disorder and stabilized the mitochondrial membrane potential quickly. Next, in vivo studies proved that Cel@LU-CA-CS micelles could inhibit the activation of the NF-κB p65 and p38 MAPK inflammatory signaling pathways. Therefore, the micelles further reduced the overexpression of related inflammatory factors. In conclusion, Cel@LU-CA-CS nanomicelles could treat AKI with high efficiency and low toxicity, and inhibit renal fibrosis.
为了高效低毒地治疗急性肾损伤，开发了一种新型纳米平台来清除过多的活性氧（ROS）。叶黄素（LU）和雷公藤红素（Cel）被装载到低分子量壳聚糖（CS）中，制备 Cel@LU-CA-CS 纳米胶束。肾小管上皮细胞（HK-2）摄取实验表明，药物可以通过巨球蛋白受体被内吞到肾小管中。在本研究中，柠檬酸酐（CA）与 CS 的氨基反应形成的酰胺键可以在酸性条件下被破坏。因此，由于溶酶体的酸性环境，药物在 HK-2 细胞中被释放。体外研究表明，纳米胶束可以降低非靶器官的毒性并增强急性肾损伤（AKI）的治疗效果。此外，Cel@LU-CA-CS 胶束迅速缓解了肾脏氧化应激紊乱并稳定了线粒体膜电位。接下来，体内研究证明 Cel@LU-CA-CS 胶束可以抑制 NF-κB p65 和 p38 MAPK 炎症信号通路的激活。因此，胶束进一步减少了相关炎症因子的过度表达。总之，Cel@LU-CA-CS 纳米胶束可以高效低毒地治疗 AKI，并抑制肾纤维化。
