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.
摘要：
脊髓损伤（SCI）后，连续全身给药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，特别是考虑到血脊髓屏障的快速恢复。在治疗SCI中迫切需要微管稳定剂的长效制剂。这里,我们将抗氧化剂艾地苯醌与微管稳定紫杉醇结合，通过酸激活，自降缩酮接头，然后将其制成硫酸软骨素蛋白聚糖结合纳米药物，使药物在脊髓内保留至少2周，并在单次脊柱内给药后显着增强后肢运动功能和轴突再生。其他研究发现，艾地苯醌可以抑制小胶质细胞和神经元铁性凋亡的激活，从而放大紫杉醇的治疗效果。这种基于前药的纳米药物同时实现神经保护和轴突再生，为SCI提供有希望的治疗策略。
