Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, China.
Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China.
Nano Lett. 2024 Mar 20;24(11):3548-3556. doi: 10.1021/acs.nanolett.4c00856. Epub 2024 Mar 8.
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.
脊髓损伤（SCI）后，连续全身给予微管稳定剂已被证明可促进轴突再生。然而，这种方法受到药物生物利用度差的限制，尤其是考虑到血脊髓屏障的快速恢复。因此，迫切需要长效微管稳定剂制剂来治疗 SCI。在这里，我们通过酸激活的自耗性缩酮连接子将抗氧化剂艾地苯醌与微管稳定剂紫杉醇偶联，形成紫杉醇-艾地苯醌杂二聚体前药，然后将其制成硫酸软骨素蛋白聚糖结合纳米药物，使药物在脊髓内至少保留 2 周，并在单次椎管内给药后显著增强后肢运动功能和轴突再生。进一步的研究发现，艾地苯醌可以抑制小胶质细胞的激活和神经元铁死亡，从而增强紫杉醇的治疗效果。这种基于前药的纳米药物同时实现了神经保护和轴突再生，为 SCI 提供了一种有前途的治疗策略。
