基于多维谱-效关系的温莪术抗肿瘤药效物质辨识及质量控制模式研究

The current drug quality control (QC) mode is not sufficient to evaluate the effects of Traditional Chinese Medicine (TCM) due to the lack of substance basis research. This study is about the pharmacodynamic substances and QC mode of Curcuma wenyujin，one of "Zhe Bawei", by the use of serum drug chemistry, cell biology, bio-instrumentation engineering, computer information science based on our previous works. Multi-dimensional chemical and serum containing drugs (including the prototype, drug metabolites, newborn compounds, etc.) fingerprint spectrums of various habitats Curcuma wenyujin volatile oil and alcohol extracts will be established by chromatogram-MS spectrometry techniques. The effect of serum containing drugs to common tumor cells, including physiology, pathology, cell impedance changes, extracellular ion concentrations, and metabolites, will be analyzed by high-throughput, real-time micro- and nano-electronic cell sensor based on micro-electrode array chip technology dynamically. The multi-dimensional spectrum-effect relationship between multi-dimensional chemical, serum containing drug fingerprint spectrums and effects will be integrated by the artificial neural network technique. The antitumor pharmacodynamic substances of Curcuma wenyujin will be purified, and the new QC mode will be established based on the multi-dimensional spectrum-effect relationship. This study will provide foundation for Curcuma wenyujin for the establishment of quality standards as the core of pharmacodynamic substances and enhancement of the QC level. Our work will provide a new method for QC mode research on TCM.

针对中药药效物质不明、现行质控模式难以有效保障药效的难题，本项目拟以浙八味之一温莪术为代表，在前期基础上采用血清药物化学、细胞生物学、生物仪器工程学、计算机信息科学等多学科交叉技术进一步研究其抗肿瘤作用的药效物质基础及质量控制模式。色-质联用法建立不同产地温莪术挥发油和醇提液的多维化学指纹谱及含药血清指纹谱（原型药物、代谢产物、新生化合物等）；基于微电极陈列芯片技术的微纳米电子细胞传感器高通量、实时、动态观察含药血清对常见肿瘤细胞生理病理特性、细胞阻抗变化及细胞外离子浓度、代谢物的作用；人工神经网络拟合多维化学指纹谱、含药血清指纹谱及其多指标药效三者之间的多维谱-效关系。通过本项目研究，将系统阐明温莪术抗肿瘤作用的药效物质基础，构建基于多维谱-效关系的质量控制新模式，为建立以药效物质基础为核心的质量标准、提升温莪术药材的质控水平奠定基础。本项目研究成果将为中药质量控制模式研究提供新思路。

通过本项目研究，建立了温莪术挥发油和醇提物HPLC指纹谱及LC-MS/MS含药血清指纹谱。温莪术醇提物和挥发油的含药血清中均未检出莪术二酮、牻牛儿酮、莪术烯和呋喃二烯原型成分，而检出其代谢产物。建立了基于细胞传感器技术温莪术醇提物和挥发油抗肿瘤药效评价平台。温莪术醇提物和挥发油含药血清均具有较强的抗肿瘤作用。温莪术抗肿瘤的药效物质是以莪术二酮为代表的倍半萜类物质。采用细胞传感器技术用于评价中药药效具有高通量、实时、动态等特点。