新型叶酸受体靶向荧光探针的设计及结构优化  

Design and structural optimization of novel folate receptor-targeted fluorescent probe

作　　者：张一宁 罗子俊 郭利霄 郭炳豪 刘玉衡 王磊 ZHANG Yi-ning;LUO Zi-jun;GUO Li-xiao;GUO Bing-hao;LIU Yu-heng;WANG Lei(Department of Medicinal Chemistry,School of Pharmacy,Hebei Medical University,Shijiazhuang 050017,China;Department of Medical Chemistry,School of Pharmacy,Hebei Medical University,Shijiazhuang 050017,China)

机构地区：[1]河北医科大学药学院药物化学教研室,河北石家庄050017 [2]河北医科大学药学院医用化学教研室,河北石家庄050017

出　　处：《河北医科大学学报》2024年第10期1129-1138,共10页Journal of Hebei Medical University

基　　金：国家自然科学基金项目(82073681);河北省自然科学基金生物医药联合基金项目(H2022206327,B2022206008);河北省研究生创新项目(CXZZBS2023106)。

摘　　要：目的筛选多种具有高亲和力的小分子叶酸类似物作为靶向配体以及多种不同的连接基团,总结叶酸受体靶向荧光探针的合理分子设计,开发出一种优秀的新型叶酸受体靶向荧光探针。方法通过多种化学合成反应得到目标荧光探针。流式细胞术探究荧光探针对叶酸受体的选择性,荧光显微成像实验评价荧光探针对肿瘤细胞的靶向成像能力。结果得到了目标荧光探针产物8个,其中荧光探针GT-FITC-1能够特异性结合叶酸受体并进入细胞实现荧光成像。引入谷氨酸侧链会降低细胞摄取的相对平均荧光强度,GT-FITC-2相较于GT-FITC-1下降了约17%,GT-FITC-5相较于GT-FITC-4下降了约15%,含有刚性苯环连接基团的荧光探针GT-FITC-7和GT-FITC-8相较于GT-FITC-4均增加了2~3倍,并且GT-FITC-8表现出最大的相对平均荧光强度。结论本研究设计合成的一系列荧光探针均表现出对叶酸受体的高度特异性,发现了对叶酸受体具有优异亲和力的荧光探针GT-FITC-8。Objective To screen a variety of high-affinity small molecule folate analogs as targeting ligands and different linkers,to summarize the rational molecular design of folate receptor-targeted fluorescent probes,and develop a new type of excellent folate receptor-targeted fluorescent probe.Methods The target fluorescent probe was obtained through various chemical synthesis reactions.Flow cytometry was used to investigate the selectivity of fluorescent probes for folate receptors,and fluorescence microscopy was conducted to evaluate the targeted imaging ability of fluorescent probes on tumor cells.Results Eight targeted fluorescent probe products were obtained,among which the fluorescent probe GT-FITC-1 could specifically bind to folate receptor and enter cells to achieve fluorescent imaging.The introduction of glutamic acid side chains reduced the relative average fluorescence intensity of cell uptake.GT-FITC-2 decreased by about 17%compared with GT-FITC-1,and GT-FITC-5 decreased by approximately 15%compared with GT-FITC-4.The fluorescence intensity of the fluorescent probes GT-FITC-7 and GT-FITC-8 containing rigid benzene ring linkers increased by 2-3 times compared with GT-FITC-4,and GT-FITC-8 showed the largest relative average fluorescence intensity.Conclusion A series of fluorescent probes designed and synthesized in this study all show high specificity for folate receptors,and the fluorescent probe GT-FITC-8 with excellent affinity for folate receptors is discovered.

关 键 词：分子探针 荧光素 叶酸受体 

分 类 号：R914.2[医药卫生—药物化学]