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. 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 mino-cycline (MC)-loaded poly(alpha-lipoic acid)-methylprednisolone (P alpha LA-MP) prodrug nanopartides (NPs) for the combined anti-inflammatory treatment of TSCI. Methods: NPs were produced by conjugating MP to P alpha LA and then loading MC. The NP structure was confirmed through H-1 nuclear magnetic resonance (H-1 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 H-1 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-P alpha LA-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-P alpha LA-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-P alpha LA-MP NPs can mitigate secondary inflammation and preserve motor function following experimental TSCI, which suggests their potential for clinical application.

Automated summary

This study describes the design, synthesis, release kinetics, biosafety, and preclinical efficacy of MC-PαLA-MP NPs for the combined anti-inflammatory treatment of TSCI. The NPs showed the ability to mitigate secondary inflammation and preserve motor function following TSCI, suggesting their potential for clinical application.