Liao Hengfeng, Ye Jun, Gao Yue, Lian Chunfang, Liu Lu, Xu Xiaoyan, Feng Yu, Yang Yanfang, Yang Yuqi, Shen Qiqi, Gao Lili, Liu Zhihua, Liu Yuling
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China.
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China.
Bioeng Transl Med. 2022 Jun 20;8(1):e10357. doi: 10.1002/btm2.10357. eCollection 2023 Jan.
Cytokine storm is a phenomenon whereby the overreaction of the human immune system leads to the release of inflammatory cytokines, which can lead to multiple organ dysfunction syndrome. At present, the existing drugs for the treatment of cytokine storm have limited efficacy and severe adverse effects. Here, we report a lymphatic targeting self-microemulsifying drug delivery system containing baicalein to effectively inhibit cytokine storm. Baicalein self-microemulsion with phospholipid complex as an intermediate carrier (BAPC-SME) prepared in this study could be spontaneously emulsified to form 12-nm oil-in-water nanoemulsion after administration. And then BAPC-SME underwent uptake by enterocyte through endocytosis mediated by lipid valve and clathrin, and had obvious characteristics of mesenteric lymph node targeting distribution. Oral administration of BAPC-SME could significantly inhibit the increase in plasma levels of 14 cytokines: TNF-α, IL-6, IFN-γ, MCP-1, IL-17A, IL-27, IL-1α, GM-CSF, MIG, IFN-β, IL-12, MIP-3α, IL-23, and RANTES in mice experiencing systemic cytokine storm. BAPC-SME could also significantly improve the pathological injury and inflammatory cell infiltration of lung tissue in mice experiencing local cytokine storm. This study does not only provide a new lymphatic targeted drug delivery strategy for the treatment of cytokine storm but also has great practical significance for the clinical development of baicalein self-microemulsion therapies for cytokine storm.
细胞因子风暴是一种人体免疫系统过度反应导致炎性细胞因子释放的现象，这可能会引发多器官功能障碍综合征。目前，现有的治疗细胞因子风暴的药物疗效有限且不良反应严重。在此，我们报道了一种含有黄芩苷的淋巴靶向自微乳化药物递送系统，可有效抑制细胞因子风暴。本研究制备的以磷脂复合物为中间载体的黄芩苷自微乳（BAPC-SME）在给药后可自发乳化形成12纳米的水包油纳米乳。然后，BAPC-SME通过脂质筏和网格蛋白介导的内吞作用被肠上皮细胞摄取，并具有明显的肠系膜淋巴结靶向分布特征。口服BAPC-SME可显著抑制全身性细胞因子风暴小鼠血浆中14种细胞因子水平的升高，这些细胞因子包括：肿瘤坏死因子-α、白细胞介素-6、干扰素-γ、单核细胞趋化蛋白-1、白细胞介素-17A、白细胞介素-27、白细胞介素-1α、粒细胞-巨噬细胞集落刺激因子、巨噬细胞炎性蛋白诱导因子、干扰素-β、白细胞介素-12、巨噬细胞炎性蛋白-3α、白细胞介素-23和调节激活正常T细胞表达和分泌因子。BAPC-SME还可显著改善局部细胞因子风暴小鼠肺组织的病理损伤和炎性细胞浸润。本研究不仅为细胞因子风暴的治疗提供了一种新的淋巴靶向药物递送策略，而且对黄芩苷自微乳治疗细胞因子风暴的临床开发具有重要的实际意义。
