基于MIF-HEMT生物传感技术的同仁牛黄清心丸关键质量属性测量研究  

The measurement of critical quality attributes of Tongren niuhuang qingxin pills based on MIF-HEMT biosensor technology

作　　者：马朝富 王子健 马丽娟[1,2] 胡小艳[1,2] 魏宇楠 张晓梦 郭新雨 郇星月 赵静 许谨帆[1,2] 李楠[1,2] 王志斌 杜菁 吴志生[1,2] MA Chao-fu;WANG Zi-jian;MA Li-juan;HU Xiao-yan;WEI Yu-nan;ZHANG Xiao-meng;GUO Xin-yu;HUAN Xing-yue;ZHAO Jing;XU Jin-fan;LI Nan;WANG Zhi-bin;DU Jing;WU Zhi-sheng(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 102488,China;Engineering Research Center of Chinese Medicine Production and New Drug Development,Beijing 102488,China;Beijing Tongrentang Technology Development Co.,Ltd.,Beijing 100079,China;Bejing Tongrentang Co.,Ltd.,Beijing 100031,China)

机构地区：[1]北京中医药大学中药学院,北京102488 [2]中药制药与新药开发教育部工程研究中心,北京102488 [3]北京同仁堂科技发展股份有限公司,北京100079 [4]北京同仁堂股份有限公司,北京100031

出　　处：《药学学报》2023年第10期2853-2861,I0003,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金优秀青年科学基金项目(82022073);国家自然科学基金项目(82274110);国家重点研发计划项目(2022YFC3501902);中央高校基本科研业务费北京中医药大学揭榜挂帅项目(2022-JYB-JBZR-018,2022-JYB-JBZR-019)。

摘　　要：中药复方临床疗效关联的关键质量属性(critical quality attributes,CQAs)测量是中药制造亟待攻克的关键难题之一。为此,以同仁牛黄清心丸为载体,提出生物传感结合超高效液相色谱/串联质谱(ultra-performance liquid chromatography/tandem mass spectrometry,UPLC-MS/MS)的集成策略。首先,以干预缺血性脑卒中的潜在关键靶点巨噬细胞移动抑制因子(macrophage migration inhibitory factor,MIF)为视角,采用高电子迁移率晶体管(high electron mobility transistor,HEMT),创建了MIF-HEMT生物传感,开展了同仁牛黄清心丸不同柱分离组分干预脑卒中作用的测量研究,发现其3段组分均具有较强的脑卒中治疗作用,尤其A段,作用强度达8.722×10^(-10)g·mL^(-1)。进一步采用MIF-HEMT生物传感集成UPLC-MS/MS,实现了同仁牛黄清心丸不同组分干预脑卒中的CQAs分离和鉴定研究。测量得到了芍药内酯苷(albiflorin)、芍药苷(paeoniflorin)、升麻素苷(prim-O-glucosylcimifugin)等19个干预MIF发挥脑卒中治疗作用的潜在CQAs。这为同仁牛黄清心丸干预MIF产生脑卒中治疗作用的CQAs研究提供了关键测量技术与方法借鉴,为优质名方高效利用和质量控制测量提供了重要参考。There is still a serious challenge of the measurement of critical quality attributes(CQAs)related to clinical efficacy for Chinese materia medica manufacturing.To overcome this challenge,an integrated strategy of biosensor and ultra-performance liquid chromatography/tandem mass spectrometry(UPLC-MS/MS)was proposed using Tongren niuhuang qingxin pills as a trial.Firstly,an original biosensor was created using a semiconductor chip material high electron mobility transistor(HEMT)as the transducer and the macrophage migration inhibitory factor(MIF)as the identification element.By this MIF-HEMT biosensor,the efficacy on stoke of different components from Tongren niuhuang qingxin pills was measured.It was clear that allthree components of Tongren niuhuang qingxin pills had strong therapeutic effects on stroke,especially the section A,the K,of which reached to 8.722×10^(-10)g·mL^(-1).Furthermore,MIF-HEMT biosensor integrated UPLC-MS/MS was introduced to identify the efficacy CQAs of different components of Tongren niuhuang qingxin pills.As a result,19 potential CQAs,such as albiforin,paeoniflorin,and prim-O-glucosylcimifugin,were measured as the efficacy CQAs of Tongren niuhuang qingxin pills on stroke treatment by MIF.These results provided vital measurement techniques and methodological guidance for the CQAs study of Tongren niuhuang qingxin pills intervention in MIF-induced stroke treatment.This also provided an essential guideline for the efficient utilization and quality control measurement of high-quality classical recipes.

关 键 词：巨噬细胞移动抑制因子 高电子迁移率晶体管 生物传感 同仁牛黄清心丸 关键质量属性 

分 类 号：R284.1[医药卫生—中药学]