Deng Yiping, Liu Li, Li Yao, Ma Huan, Li Chuang, Yan Kexin, Tian Ji, Li Chunhong
Analysis and Testing Center, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
Department of Anaesthesiology, The affiliated hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
Drug Deliv Transl Res. 2025 Jan 29. doi: 10.1007/s13346-025-01791-2.
Atherosclerosis (AS) is a chronic inflammatory disease characterized by vascular endothelial dysfunction. In the early stage of the disease, endothelial cell injury induces the infiltration of inflammatory macrophages, which secrete large amounts of inflammatory factors, further aggravating endothelial cell dysfunction and exacerbating the disease. Therefore, it is promising for co-targeting endothelial cells and macrophages further regulating the inflammatory microenvironment and endothelial cell function for effective treatment. The current nano-drug delivery system (NDDS) for AS treatment is mainly focused on anti-inflammatory therapy, while ignoring the potential value of suppressing inflammation and simultaneously improving vascular endothelial function. In this study, a pH-responsive dual-targeted NDDS based on plaque microenvironment, BC@CS/cRGD NPs, was prepared by combining baicalin (BC) with chondroitin sulfate (CS) through amidation reaction, and further modified with a targeting group cRGD peptide. In vitro release experiments illustrated a faster release of the nanoparticle at pH 5.0 than at pH 7.4. Meanwhile, in vitro cellular experiments demonstrated its ability to target activated endothelial cells and macrophages. In a mouse model of AS, BC@CS/cRGD NPs accumulated at plaque sites and effectively attenuated the plaque progression. In conclusion, this pH-sensitive BC@CS/cRGD NPs offered a very potential strategy for modulating endothelial dysfunction and inflammatory microenvironment for the treatment of AS.
动脉粥样硬化（AS）是一种以血管内皮功能障碍为特征的慢性炎症性疾病。在疾病早期，内皮细胞损伤会诱导炎性巨噬细胞浸润，这些巨噬细胞分泌大量炎性因子，进一步加重内皮细胞功能障碍并使疾病恶化。因此，共同靶向内皮细胞和巨噬细胞以进一步调节炎症微环境和内皮细胞功能从而实现有效治疗具有广阔前景。目前用于治疗AS的纳米药物递送系统（NDDS）主要集中于抗炎治疗，而忽视了抑制炎症并同时改善血管内皮功能的潜在价值。在本研究中，通过酰胺化反应将黄芩苷（BC）与硫酸软骨素（CS）结合，并进一步用靶向基团cRGD肽修饰，制备了一种基于斑块微环境的pH响应性双靶向NDDS，即BC@CS/cRGD NPs。体外释放实验表明，纳米颗粒在pH 5.0时的释放速度比在pH 7.4时更快。同时，体外细胞实验证明了其靶向活化内皮细胞和巨噬细胞的能力。在AS小鼠模型中，BC@CS/cRGD NPs在斑块部位聚集并有效减缓了斑块进展。总之，这种pH敏感的BC@CS/cRGD NPs为调节内皮功能障碍和炎症微环境以治疗AS提供了一种极具潜力的策略。
