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image of Lung-Targeting Cepharanthine Polymer Micelles Modified with Mannose: Effectiveness against Acute Lung Injury Evaluated Using in vitro and in vivo Analyses

Abstract

Introduction

The currently available therapies for acute lung injury (ALI), including glucocorticoids, protease inhibitors, and heparin, have limited clinical efficacy and are often associated with significant side effects. Cepharanthine (CEP) has demonstrated effectiveness in treating pulmonary diseases, but its clinical application is restricted by low solubility and poor bioavailability. This study aimed to develop mannosylated cepharanthine-loaded polymeric micelles (MA-CEP-PMs) to improve CEP bioavailability and enhance lung-targeted delivery for the treatment of ALI.

Methods

The pharmacokinetics of MA-CEP-PMs in rats were assessed using Ultra-Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (UPLC-Q-TOF-MS). Lung-targeting ability was evaluated through tissue distribution studies and near-infrared imaging. In a rat model of ALI induced by lipopolysaccharide (LPS), anti-ALI effects were assessed via general physiological indicators, Enzyme-Linked Immunosorbent Assay (ELISA), and Western blot analysis. Hematoxylin-eosin (HE) staining was used to examine hepatotoxicity and nephrotoxicity of MA-CEP-PMs in normal rats. Cytotoxicity of the mannosylated polyethylene glycol–poly(lactic-co-glycolic acid) copolymer (MA-PEG-PLGA) on NR8383 cells was evaluated using the Cell Counting Kit-8 (CCK-8) assay. Cellular uptake experiments were performed to determine the targeting ability of MA-PEG-PLGA in NR8383 cells, and the effects of MA-CEP-PMs on inflammatory cytokines were analyzed using ELISA.

Results

MA-CEP-PMs significantly increased the AUC and exhibited better lung targeting ability compared to the unmodified micelles ( < 0.01). In the ALI model, MA-CEP-PMs improved the thymus and spleen indices, decreased the lung wet-to-dry weight ratio ( < 0.05), alleviated model animal damage, and inhibited inflammatory factor and nuclear factor-κB (NF-κB)–related protein levels ( < 0.05). MA-CEP-PMs exhibited no significant hepatotoxicity or nephrotoxicity. MA-PEG-PLGA exhibited low toxicity against NR8383 cells and greater cell uptake, indicating stronger targeting of the lung. MA-CEP-PMs also exhibited more potent anti-inflammatory effects.

Discussion

This study focused on the short-term therapeutic effects of ALI, whereas the clinical management of lung injury often requires long-term intervention. Future research should therefore assess the long-term efficacy of this delivery system in chronic lung injury, along with determining its safety profile and potential impacts on extra-pulmonary organs. While the involvement of the NF-κB pathway in the anti-inflammatory effects has been confirmed, it remains to be deciphered whether mannose modification synergistically regulates other signaling pathways and what the specific intracellular targets of CEP are, which would require further exploration through detailed molecular biology experiments.

Conclusion

The MA-CEP-PMs significantly improved CEP bioavailability and increased lung targeting. They exhibited good safety and had a significant effect on ALI management.

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2025-11-10
2026-02-25

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Lung-Targeting Cepharanthine Polymer Micelles Modified with Mannose: Effectiveness against Acute Lung Injury Evaluated Using in vitro and in vivo Analyses
Bentham Science Publishers ; https://doi.org/10.2174/0113892002413042251015104239
/content/journals/cdm/10.2174/0113892002413042251015104239
/content/journals/cdm/10.2174/0113892002413042251015104239
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  • Article Type:     Research Article
Keywords: mannose ; targeted drug delivery systems ; bioavailability enhancement ; acute lung injury ; Polymer-based drug delivery ; cepharanthine

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