Long-Acting Heterodimeric Paclitaxel–Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury
Zunkai Xu, Xinjie Liu, Yilin Pang, Zhixia Chen, Yaoyao Jiang, Tao Liu, Jiawei Zhang, Haoning Xiong, Xiang Gao, Jiao Liu, Shen Liu, Guangzhi Ning, Shiqing Feng, Xue Yao, Shutao Guo
Abstract
After spinal cord injury (SCI), successive systemic administration of microtubule-stabilizing agents has been shown to promote axon regeneration. However, this approach is limited by poor drug bioavailability, especially given the rapid restoration of the blood-spinal cord barrier. There is a pressing need for long-acting formulations of microtubule-stabilizing agents in treating SCI. Here, we conjugated the antioxidant idebenone with microtubule-stabilizing paclitaxel to create a heterodimeric paclitaxel-idebenone prodrug via an acid-activatable, self-immolative ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding nanomedicine, enabling drug retention within the spinal cord for at least 2 weeks and notable enhancement in hindlimb motor function and axon regeneration after a single intraspinal administration. Additional investigations uncovered that idebenone can suppress the activation of microglia and neuronal ferroptosis, thereby amplifying the therapeutic effect of paclitaxel. This prodrug-based nanomedicine simultaneously accomplishes neuroprotection and axon regeneration, offering a promising therapeutic strategy for SCI.