ROS-responsive chitosan-SS31 prodrug for AKI therapy via rapid distribution in the kidney and long-term retention in the renal tubule
Di Liu, Gaofeng Shu, Feiyang Jin, Jing Qi, Xiaoling Xu, Yan Du, Hui Yu, Jun Wang, Mingchen Sun, Yuchan You, Minxia Zhu, Meixuan Chen, Luwen Zhu, Qiying Shen, Xiaoying Ying, Xue-Fang Lou, Saiping Jiang, Yongzhong Du
Abstract
The development of drugs with rapid distribution in the kidney and long-term retention in the renal tubule is a breakthrough for enhanced treatment of acute kidney injury (AKI). Here, l-serine-modified chitosan (SC) was synthesized as a potential AKI kidney-targeting agent due to the native cationic property of chitosan and specific interaction between kidney injury molecule-1 (Kim-1) and serine. Results indicated that SC was rapidly accumulated and long-term retained in ischemia-reperfusion-induced AKI kidneys, especially in renal tubules, which was possibly due to the specific interactions between SC and Kim-1. SC-TK-SS31 was then prepared by conjugating SS31, a mitochondria-targeted antioxidant, to SC via reactive oxygen species (ROS)-sensitive thioketal linker. Because of the effective renal distribution combined with ROS-responsive drug release behavior, the administration of SC-TK-SS31 led to an enhanced therapeutic effect of SS31 by protecting mitochondria from damage and reducing the oxidative stress, inflammation, and cell apoptosis.