Zhang Xiaolin, Zhen Xueyan, Yang Yixuan, Feng Quan, Yuan Wanqing, Xie Xiaoyu
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
Shaanxi Engineering Research Center of Cardiovascular Drugs Screening & Analysis, Xi'an 710061, China.
Acta Pharm Sin B. 2023 Feb;13(2):852-862. doi: 10.1016/j.apsb.2022.05.034. Epub 2022 Jun 6.
Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function. However, random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites, especially when applied to intracellular regions of transmembrane proteins. Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem. Herein, inside-out cell membrane camouflaged magnetic nanoparticles (IOCMMNPs) were accurately constructed bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2. Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic FeO nanoparticles to prepare IOCMMNPs. The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay. Ultimately, two compounds, senkyunolide A and ligustilidel, were successfully captured, and their potential antiproliferative activities were further testified by pharmacological experiments. It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.
细胞膜伪装的纳米颗粒因其独特的生物界面靶向功能而在药物先导物发现领域得到广泛应用。然而，细胞膜包被的随机取向并不能保证药物与特定位点有效且适当地结合，尤其是当应用于跨膜蛋白的细胞内区域时。生物正交反应作为一种在不干扰活生物系统的情况下对细胞膜进行功能化的特异性且可靠的方法已得到迅速发展。在此，通过生物正交反应精确构建了外翻细胞膜伪装的磁性纳米颗粒（IOCMMNPs），以筛选靶向血管内皮生长因子受体-2细胞内酪氨酸激酶结构域的小分子抑制剂。叠氮化物功能化的细胞膜作为与炔基功能化的磁性FeO纳米颗粒特异性共价偶联的平台，用于制备IOCMMNPs。通过免疫金染色和唾液酸定量测定成功验证了细胞膜的外翻取向。最终，成功捕获了两种化合物，即川芎内酯A和藁本内酯，并通过药理学实验进一步证实了它们潜在的抗增殖活性。预计所提出的外翻细胞膜包被策略为工程化细胞膜伪装的纳米颗粒赋予了巨大的通用性，并促进了药物先导物发现平台的发展。
