M1 Macrophage-Targeted Curcumin Nanocrystals with l-Arginine-Modified for Acute Lung Injury by Inhalation

Shiyue Wu; Pengchuan Guo; Qiren Zhou; Xiaowen Yang; Jundong Dai

doi:10.1016/j.xphs.2024.05.011

M1 Macrophage-Targeted Curcumin Nanocrystals with l-Arginine-Modified for Acute Lung Injury by Inhalation

J Pharm Sci. 2024 May 19:S0022-3549(24)00181-3. doi: 10.1016/j.xphs.2024.05.011. Online ahead of print.

Authors

Shiyue Wu¹, Pengchuan Guo¹, Qiren Zhou¹, Xiaowen Yang¹, Jundong Dai²

Affiliations

¹ Department of Chinese Medicinal Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fangshan District, Beijing 102488, China.
² Department of Chinese Medicinal Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fangshan District, Beijing 102488, China. Electronic address: daijd@163.com.

PMID: 38772450
DOI: 10.1016/j.xphs.2024.05.011

Abstract

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) with clinical manifestations of respiratory distress and hypoxemia remains a significant cause of respiratory failure, boasting a persistently high incidence and mortality rate. Given the central role of M1 macrophages in the pathogenesis of acute lung injury (ALI), this study utilized the anti-inflammatory agent curcumin as a model drug. l-arginine (L-Arg) was employed as a targeting ligand, and chitosan was initially modified with l-arginine. Subsequently, it was utilized as a surface modifier to prepare inhalable nano-crystals loaded with curcumin (Arg-CS-Cur), aiming for specific targeting of pulmonary M1 macrophages. Compared with unmodified chitosan-curcumin nanocrystals (CS-Cur), Arg-CS-Cur exhibited higher uptake in vitro by M1 macrophages, as evidenced by flow cytometry showing the highest fluorescence intensity in the Arg-CS-Cur group (P < 0.01). In vivo accumulation was greater in inflamed lung tissues, as indicated by small animal imaging demonstrating higher lung fluorescence intensity in the DiR-Arg-CS-Cur group compared to the DiR-CS-Cur group in the rat ALI model (P < 0.05), peaking at 12 h. Moreover, Arg-CS-Cur demonstrated enhanced therapeutic effects in both LPS-induced RAW264.7 cells and ALI rat models. Specifically, treatment with Arg-CS-Cur significantly suppressed NO release and levels of TNF-α and IL-6 in RAW264.7 cells (p < 0.01), while in ALI rat models, expression levels of TNF-α and IL-6 in lung tissues were significantly lower than those in the model group (P < 0.01). Furthermore, lung tissue damage was significantly reduced, with histological scores significantly lower than those in the CS-Cur group (P < 0.01). In conclusion, these findings underscore the targeting potential of l-arginine-modified nanocrystals, which effectively enhance curcumin concentration in inflammatory environments by selectively targeting M1 macrophages. This study thus introduces novel perspectives and theoretical support for the development of targeted therapeutic interventions for acute inflammatory lung diseases, including ALI/ARDS.

Keywords: Acute lung injury; M1 macrophages; Nanocrystals; Targeted drug delivery system; l-arginine.