Long-Acting Heterodimeric Paclitaxel–Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury

• Published in: Nano letters 2024-03, Vol.24 (11), p.3548-3556
• Main Authors: Xu, Zunkai, Liu, Xinjie, Pang, Yilin, Chen, Zhixia, Jiang, Yaoyao, Liu, Tao, Zhang, Jiawei, Xiong, Haoning, Gao, Xiang, Liu, Jiao, Liu, Shen, Ning, Guangzhi, Feng, Shiqing, Yao, Xue, Guo, Shutao
• Format: Article
• Language: English
• ISSN: 1530-6984; 1530-6992
• DOI: 10.1021/acs.nanolett.4c00856

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.