Wu Shiyue, Guo Pengchuan, Zhou Qiren, Yang Xiaowen, Dai Jundong
Department of Chinese Medicinal Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fangshan District, Beijing 102488, China.
Department of Chinese Medicinal Pharmaceutics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fangshan District, Beijing 102488, China.
J Pharm Sci. 2025 Jan;114(1):105-118. doi: 10.1016/j.xphs.2024.12.001. Epub 2024 Dec 7.
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.
急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）临床表现为呼吸窘迫和低氧血症，仍然是呼吸衰竭的重要原因，其发病率和死亡率一直居高不下。鉴于M1巨噬细胞在急性肺损伤（ALI）发病机制中的核心作用，本研究使用抗炎剂姜黄素作为模型药物。L-精氨酸（L-Arg）用作靶向配体，首先用L-精氨酸对壳聚糖进行修饰。随后，将其用作表面改性剂，制备负载姜黄素的可吸入纳米晶体（Arg-CS-Cur），旨在特异性靶向肺M1巨噬细胞。与未修饰的壳聚糖-姜黄素纳米晶体（CS-Cur）相比，Arg-CS-Cur在体外被M1巨噬细胞摄取的能力更高，流式细胞术显示Arg-CS-Cur组荧光强度最高，证明了这一点（P < 0.01）。在体内，炎症肺组织中的蓄积更大，小动物成像表明，在大鼠ALI模型中，与DiR-CS-Cur组相比，DiR-Arg-CS-Cur组肺荧光强度更高（P < 0.05），在12小时达到峰值。此外，Arg-CS-Cur在LPS诱导的RAW264.7细胞和ALI大鼠模型中均显示出增强的治疗效果。具体而言，用Arg-CS-Cur处理可显著抑制RAW264.7细胞中NO的释放以及TNF-α和IL-6的水平（p < 0.01），而在ALI大鼠模型中，肺组织中TNF-α和IL-6的表达水平显著低于模型组（P < 0.01）。此外，肺组织损伤明显减轻，组织学评分显著低于CS-Cur组（P < 0.01）。总之，这些发现强调了L-精氨酸修饰纳米晶体的靶向潜力，其通过选择性靶向M1巨噬细胞有效提高了炎症环境中姜黄素的浓度。因此，本研究为包括ALI/ARDS在内的急性炎症性肺病的靶向治疗干预开发引入了新的观点和理论支持。
