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Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury

PURPOSE: Traumatic spinal cord injury (TSCI) induces a powerful inflammatory response that can significantly exacerbate the extent and severity of neural damage (termed as “secondary injury”). Thus, the suppression of inflammation is crucial for reducing neurological dysfunction following TSCI. Howe...

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Autores principales: Lin, Feng, Liu, Yixuan, Luo, Wenqi, Liu, Shuhan, Wang, Yiming, Gu, Rui, Liu, Wanguo, Xiao, Chunsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752067/
https://www.ncbi.nlm.nih.gov/pubmed/35027828
http://dx.doi.org/10.2147/IJN.S344491
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author Lin, Feng
Liu, Yixuan
Luo, Wenqi
Liu, Shuhan
Wang, Yiming
Gu, Rui
Liu, Wanguo
Xiao, Chunsheng
author_facet Lin, Feng
Liu, Yixuan
Luo, Wenqi
Liu, Shuhan
Wang, Yiming
Gu, Rui
Liu, Wanguo
Xiao, Chunsheng
author_sort Lin, Feng
collection PubMed
description PURPOSE: Traumatic spinal cord injury (TSCI) induces a powerful inflammatory response that can significantly exacerbate the extent and severity of neural damage (termed as “secondary injury”). Thus, the suppression of inflammation is crucial for reducing neurological dysfunction following TSCI. However, the conventional anti-inflammatory drugs show limited efficacy because of poor penetration and release kinetics at the injury site. This study describes the design, synthesis, release kinetics, biosafety, and preclinical efficacy of minocycline (MC)-loaded poly(α-lipoic acid)–methylprednisolone (PαLA-MP) prodrug nanoparticles (NPs) for the combined anti-inflammatory treatment of TSCI. METHODS: NPs were produced by conjugating MP to PαLA and then loading MC. The NP structure was confirmed through (1)H nuclear magnetic resonance ((1)H NMR), Fourier transform infrared spectroscopy, ultraviolet–visible absorption spectroscopy, gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. Drug-loading content and efficacy were measured using high-performance liquid chromatography (HPLC) or (1)H NMR and release kinetics through HPLC. Biosafety was examined using the MTT assay, cell penetration efficiency using confocal microscopy, and flow cytometry using Cyanine5 (Cy5)-labeled MC-PαLA-MP NPs, effects on injury-induced pro-inflammatory cytokine release using enzyme-linked immunosorbent assays and immunofluorescence, and treatment efficacy by measuring motor recovery in a rat model of TSCI. RESULTS: The MC-PαLA-MP NPs exhibited high biocompatibility and released 81% MC and 54% MP within 24 h under TSCI-like conditions, effectively reducing 40% of pro-inflammatory cytokine release both in cultures and injured rat spinal cord tissues. Systemic injection increased the Basso, Beattie, Bresnahan score of TSCI rats from 2.33 ± 0.52 to 8.83 ± 1.83 in 8 weeks, providing effective neuroprotection and enhanced exercise recovery in the TSCI rats. CONCLUSION: The MC-PαLA-MP NPs can mitigate secondary inflammation and preserve motor function following experimental TSCI, which suggests their potential for clinical application.
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spelling pubmed-87520672022-01-12 Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury Lin, Feng Liu, Yixuan Luo, Wenqi Liu, Shuhan Wang, Yiming Gu, Rui Liu, Wanguo Xiao, Chunsheng Int J Nanomedicine Original Research PURPOSE: Traumatic spinal cord injury (TSCI) induces a powerful inflammatory response that can significantly exacerbate the extent and severity of neural damage (termed as “secondary injury”). Thus, the suppression of inflammation is crucial for reducing neurological dysfunction following TSCI. However, the conventional anti-inflammatory drugs show limited efficacy because of poor penetration and release kinetics at the injury site. This study describes the design, synthesis, release kinetics, biosafety, and preclinical efficacy of minocycline (MC)-loaded poly(α-lipoic acid)–methylprednisolone (PαLA-MP) prodrug nanoparticles (NPs) for the combined anti-inflammatory treatment of TSCI. METHODS: NPs were produced by conjugating MP to PαLA and then loading MC. The NP structure was confirmed through (1)H nuclear magnetic resonance ((1)H NMR), Fourier transform infrared spectroscopy, ultraviolet–visible absorption spectroscopy, gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. Drug-loading content and efficacy were measured using high-performance liquid chromatography (HPLC) or (1)H NMR and release kinetics through HPLC. Biosafety was examined using the MTT assay, cell penetration efficiency using confocal microscopy, and flow cytometry using Cyanine5 (Cy5)-labeled MC-PαLA-MP NPs, effects on injury-induced pro-inflammatory cytokine release using enzyme-linked immunosorbent assays and immunofluorescence, and treatment efficacy by measuring motor recovery in a rat model of TSCI. RESULTS: The MC-PαLA-MP NPs exhibited high biocompatibility and released 81% MC and 54% MP within 24 h under TSCI-like conditions, effectively reducing 40% of pro-inflammatory cytokine release both in cultures and injured rat spinal cord tissues. Systemic injection increased the Basso, Beattie, Bresnahan score of TSCI rats from 2.33 ± 0.52 to 8.83 ± 1.83 in 8 weeks, providing effective neuroprotection and enhanced exercise recovery in the TSCI rats. CONCLUSION: The MC-PαLA-MP NPs can mitigate secondary inflammation and preserve motor function following experimental TSCI, which suggests their potential for clinical application. Dove 2022-01-07 /pmc/articles/PMC8752067/ /pubmed/35027828 http://dx.doi.org/10.2147/IJN.S344491 Text en © 2022 Lin et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Lin, Feng
Liu, Yixuan
Luo, Wenqi
Liu, Shuhan
Wang, Yiming
Gu, Rui
Liu, Wanguo
Xiao, Chunsheng
Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury
title Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury
title_full Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury
title_fullStr Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury
title_full_unstemmed Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury
title_short Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury
title_sort minocycline-loaded poly(α-lipoic acid)–methylprednisolone prodrug nanoparticles for the combined anti-inflammatory treatment of spinal cord injury
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752067/
https://www.ncbi.nlm.nih.gov/pubmed/35027828
http://dx.doi.org/10.2147/IJN.S344491
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