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. 2024 Aug;113(8):2492-2505. doi: 10.1016/j.xphs.2024.05.011. Epub 2024 May 19.
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）以呼吸困难和低氧血症为临床表现，仍然是呼吸衰竭的重要原因，具有持续高发病率和死亡率。鉴于 M1 巨噬细胞在急性肺损伤（ALI）发病机制中的核心作用，本研究以抗炎药姜黄素为模型药物。l-精氨酸（L-Arg）作为靶向配体，壳聚糖最初用 l-精氨酸修饰。随后，它被用作表面改性剂来制备负载姜黄素的可吸入纳米晶体（Arg-CS-Cur），旨在针对肺部 M1 巨噬细胞进行特异性靶向。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 巨噬细胞摄取的效率更高，这一点通过流式细胞术显示 Arg-CS-Cur 组的荧光强度最高（P<0.01）得到证明。在体内，炎症肺组织中的积累量更大，小动物成像显示，在大鼠 ALI 模型中，DiR-Arg-CS-Cur 组的肺荧光强度高于 DiR-CS-Cur 组（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，Arg-CS-Cur 处理显著抑制了 RAW264.7 细胞中 NO 的释放和 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 的表达水平明显低于模型组（p<0.01）。此外，肺组织损伤明显减轻，组织学评分明显低于 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，它通过选择性地靶向 M1 巨噬细胞，有效地增加了炎症环境中姜黄素的浓度。因此，本研究为开发针对急性炎症性肺疾病（包括 ALI/ARDS）的靶向治疗干预措施提供了新的视角和理论支持。
