Yang Yi, Zoulikha Makhloufi, Xiao Qingqing, Huang Feifei, Jiang Qi, Li Xiaotong, Wu Zhenfeng, He Wei
Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China.
School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, China.
Acta Pharm Sin B. 2023 Nov;13(11):4607-4620. doi: 10.1016/j.apsb.2023.05.024. Epub 2023 May 26.
Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction. Herein, we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin (IND) and antioxidant superoxide dismutase (SOD) by assembling the biopharmaceutical SOD onto the "vector" of rod-like pure IND crystals, followed by coating with anti-ICAM-1 antibody (Ab) for targeting endothelial cells. The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39% IND and 2.3% SOD. Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide (LPS)-induced inflammatory murine model. Particularly, the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect. , the preparation shows the synergistic anti-inflammatory and antioxidant effects in LPS-activated endothelial cells. , the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers, such as TNF-, IL-6, COX-2, and reactive oxygen species (ROS), in the lungs. In conclusion, the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation. The study offers a promising approach to combat pulmonary endothelium-associated diseases.
肺部炎症是多种疾病的重要诱因，与肺内皮功能障碍密切相关。在此，我们通过将生物制药用超氧化物歧化酶（SOD）组装到棒状纯吲哚美辛（IND）晶体的“载体”上，随后用抗ICAM - 1抗体（Ab）包被以靶向内皮细胞，构建了一种肺部内皮靶向共递送系统，用于递送抗炎药物吲哚美辛（IND）和抗氧化剂超氧化物歧化酶（SOD）。该共递送系统长度为237纳米，药物载量极高，吲哚美辛为39%，超氧化物歧化酶为2.3%。药代动力学和生物分布研究表明，在脂多糖（LPS）诱导的炎症小鼠模型中静脉注射后，该系统具有延长的血液循环时间和强烈的肺部蓄积。特别是，由于其棒状形状和抗体包被作用，该系统具有强大的靶向肺内皮的能力。此外，该制剂在LPS激活的内皮细胞中显示出协同的抗炎和抗氧化作用。再者，该制剂通过显著下调肺部炎症/氧化应激标志物，如肿瘤坏死因子 - 、白细胞介素 - 6、环氧化酶 - 2和活性氧（ROS），表现出卓越的药效学功效。总之，基于棒状纯晶体的共递送系统能够很好地靶向肺内皮并有效减轻肺部炎症。该研究为对抗肺内皮相关疾病提供了一种有前景的方法。
