Long-Acting Heterodimeric Paclitaxel-Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Nano letters - 24(2024), 11 vom: 20. März, Seite 3548-3556 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Zunkai [VerfasserIn] |
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| Links: |
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| Themen: |
1339-63-5 |
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| Anmerkungen: |
Date Completed 21.03.2024 Date Revised 21.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.nanolett.4c00856 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM36947015X |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Pang, Yilin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhixia |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yaoyao |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jiawei |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Haoning |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jiao |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shen |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Guangzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Shiqing |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Xue |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Shutao |e verfasserin |4 aut | |
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