Prodrug-inspired adenosine triphosphate–activatable celastrol-Fe(III) chelate for cancer therapy
Hanrong Li, Yifan Li, Lingpu Zhang, Nan Wang, Lu Dong, Dongsheng Tang, Yitong Lv, Jinbo Zhang, Heben Yan, He Gong, Ming Zhang, Kaili Nie, Yi Hou, Yingjie Yu, Haihua Xiao, Chaoyong Liu
Abstract
, exhibits broad anticancer activities. However, its poor stability, narrow therapeutic window and numerous adverse effects limit its applications in vivo. In this study, an adenosine triphosphate (ATP) activatable CEL-Fe(III) chelate was designed, synthesized, and then encapsulated with a reactive oxygen species (ROS)-responsive polymer to obtain CEL-Fe nanoparticles (CEL-Fe NPs). In normal tissues, CEL-Fe NPs maintain structural stability and exhibit reduced systemic toxicity, while at the tumor site, an ATP-ROS-rich tumor microenvironment, drug release is triggered by ROS, and antitumor potency is restored by competitive binding of ATP. This intelligent CEL delivery system improves the biosafety and bioavailability of CEL for cancer therapy. Such a CEL-metal chelate strategy not only mitigates the challenges associated with CEL but also opens avenues for the generation of CEL derivatives, thereby expanding the therapeutic potential of CEL in clinical settings.