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A temporo-spatial pharmacometabolomics method to characterize pharmacokinetics and pharmacodynamics in the brain microregions by using ambient mass spectrometry imaging

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3341-3353页

作者： Dan Liu Jianpeng Huang Shanshan Gao Hongtao Jin jiuming he State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Clinical Pharmacy First People’s Hospital of HuaihuaHuaihua 418000China New Drug Safety Evaluation Center Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug Beijing 100050China

The brain is the most advanced organ with various complex structural and functional microregions. It is often challenging to understand what and where the molecular events would occur for a given drug treatment in the brain. herein, a temporo-spatial pharmacometabolomics method was proposed based on ambient mass spectrometry imaging and was applied to evaluate the microregional effect of olanzapine(OLZ) on brain tissue and demonstrate its effectiveness in characterizing the microregional pharmacokinetics and pharmacodynamics of OLZ for improved understanding of the molecular mechanism of drugs acting on the microregions of the brain. It accurately and simultaneously illustrated the levels dynamics and microregional distribution of various substances, including exogenous drugs and its metabolites, as well as endogenous functional metabolites from complicated brain tissue. The targeted imaging analysis of the prototype drug and its metabolites presented the absorption, distribution, metabolism, and excretion characteristics of the drug itself. Moreover, the endogenous functional metabolites were identified along with the associated therapeutic and adverse effects of the drug, which can reflect the pharmacodynamics effect on the microregional brain. Therefore, this method is significant in elucidating and understanding the molecular mechanism of central nervous system drugs at the temporo and spatial metabolic level of system biology.

关键词： Pharmacometabolomics Pharmacokinetics Pharmacodynamics Mass spectrometry imaging Antipsychotic drug

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Promise of spatially resolved omics for tumor research

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药物分析学报:英文版 2023年第8期13卷 851-861页

作者： Yanhe Zhou Xinyi Jiang Xiangyi Wang Jianpeng Huang Tong Li Hongtao Jin jiuming he State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China New Drug Safety Evaluation Center Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug Beijing10050China

Tumors are spatially heterogeneous tissues that comprise numerous cell types with intricate structures.By interacting with the microenvironment,tumor cells undergo dynamic changes in gene expression and metabolism,resulting in spatiotemporal variations in their capacity for proliferation and metastasis.In recent years,the rapid development of histological techniques has enabled efficient and high-throughput biomolecule analysis.By preserving location information while obtaining a large number of gene and molecular data,spatially resolved metabolomics(SRM)and spatially resolved transcriptomics(SRT)approaches can offer new ideas and reliable tools for the in-depth study of tumors.This review provides a comprehensive introduction and summary of the fundamental principles and research methods used for SRM and SRT techniques,as well as a review of their applications in cancer-related fields.

关键词： Tumor Spatially resolved transcriptomics Spatially resolved metabolomics

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Design and characterizing of robust probes for enhanced mass spectrometry imaging and spatially resolved metabolomics

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Chinese Chemical Letters 2023年第5期34卷 397-402页

作者： Jianpeng Huang Shanshan Gao Kai Wang Jin Zhang Xuechao Pang Junwen Shi jiuming he State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China NMPA Key Laboratory of Safety Research and Evaluation of Innovative Drug Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Viktor Technology Co. Ltd.Beijing 101100China

As for the emerging and cut edge spatially resolved metabolomics,mass spectrometry imaging(MSI)is a powerful tool that can map thousands of metabolites from bio-tissue sections without chemical labels.However,the stability,sensitivity and spatial resolution of MSI are always limited by the performance of its ionization probe.herein,two types of probes(fine probe(P-100)and large probe(P-200))were designed and characterized to perform air-flow assisted desorption electrospray ionization(AFA-DESI)MSI analysis for spatially resolved metabolomics.It was determined that the spray introduced by P-100 was homogenous and stable under the spray solvent at a flow rate of 5-10μL/min,while P-200 can endure a high flow rate of up to 10-30μL/min.Moreover,the MSI images were acquired by AFA-DESI-MSI with P-100 from rat brain tissue section and with P-200 from whole-body tissue section of mouse,and these results presented unambiguous tissue structure with the distribution information of numerous metabolites.Furthermore,the spatially resolved metabolomic analysis of tumor tissue was successfully realized to discover the tumor associated biomarkers.As the key parts of AFA-DESI-MSI system,it has been demonstrated that the designed probs have excellent performance for spatially resolved metabolomics,and it will further promote its application in life science,and drug research and development.

关键词： Air-flow assisted desorption electrospray ionization Mass spectrometry imaging Molecular imaging Spatially resolved metabolomics Brain

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Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

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药物分析学报:英文版 2023年第7期13卷 776-787页

作者： Xiangyi Wang Jin Zhang Kailu Zheng Qianqian Du Guocai Wang Jianpeng Huang Yanhe Zhou Yan Li Hongtao Jin jiuming he State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China NMPA Key Laboratory of Safety Research and Evaluation of Innovative Drug Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China New Drug Safety Evaluation Center Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

关键词： Mass spectrometry imaging Spatially resolved metabolomics Small molecule-drug conjugate Tumor metabolism Targeted tumor therapy

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Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1699-1710页

作者： Bo Jin Xuechao Pang Qingce Zang Man Ga Jing Xu Zhigang Luo Ruiping Zhang Jiangong Shi jiuming he Zeper Abliz State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug Beijing 100050China Key Laboratory of Mass Spectrometry Imaging and Metabolomics(Minzu University of China) National Ethnic Affairs CommissionBeijing 100081China Key Laboratory of Ethnomedicine of Ministry of Education School of PharmacyMinzu University of ChinaBeijing 100081China

Deconvolution of potential drug targets of the central nervous system(CNS)is particularly challenging because of the complicated structure and function of the brain.here,a spatiotemporally resolved metabolomics and isotope tracing strategy was proposed and demonstrated to be powerful for deconvoluting and localizing potential targets of CNS drugs by using ambient mass spectrometry imaging.This strategy can map various substances including exogenous drugs,isotopically labeled metabolites,and various types of endogenous metabolites in the brain tissue sections to illustrate their microregional distribution pattern in the brain and locate drug action-related metabolic nodes and pathways.The strategy revealed that the sedative-hypnotic drug candidate YZG-331 was prominently distributed in the pineal gland and entered the thalamus and hypothalamus in relatively small amounts,and can increase glutamate decarboxylase activity to elevateγ-aminobutyric acid(GABA)levels in the hypothalamus,agonize organic cation transporter 3 to release extracellular histamine into peripheral circulation.These findings emphasize the promising capability of spatiotemporally resolved metabolomics and isotope tracing to help elucidate the multiple targets and the mechanisms of action of CNS drugs.

关键词： Ambient mass spectrometry imaging Spatiotemporally resolved metabolomics Isotope tracing Drug targets Central nervous system Drug candidate

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Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in hepG2 spheroids

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Journal of Pharmaceutical Analysis 2023年第5期13卷 483-493页

作者： Limei Li Qingce Zang Xinzhu Li Ying Zhu Shanjing Wen jiuming he Ruiping Zhang Zeper Abliz State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Key Laboratory of Mass Spectrometry Imaging and Metabolomics(Minzu University of China) National Ethnic Affairs CommissionBeijing100081China Center for Imaging and Systems Biology College of Life and Environmental SciencesMinzu University of ChinaBeijing100081China

Three-dimensional(3D)cell spheroid models combined with mass spectrometry imaging(MSI)enables innovative investigation of in vivo-like biological processes under different physiological and pathological conditions.herein,airflow-assisted desorption electrospray ionization-MSI(AFADESI-MSI)was coupled with 3D hepG2 spheroids to assess the metabolism and hepatotoxicity of amiodarone(AMI).High-coverage imaging of>1100 endogenous metabolites in hepatocyte spheroids was achieved using AFADESI-MSI.Following AMI treatment at different times,15 metabolites of AMI involved in Ndesethylation,hydroxylation,deiodination,and desaturation metabolic reactions were identified,and according to their spatiotemporal dynamics features,the metabolic pathways of AMI were proposed.Subsequently,the temporal and spatial changes in metabolic disturbance within spheroids caused by drug exposure were obtained via metabolomic analysis.The main dysregulated metabolic pathways included arachidonic acid and glycerophospholipid metabolism,providing considerable evidence for the mechanism of AMI hepatotoxicity.In addition,a biomarker group of eight fatty acids was selected that provided improved indication of cell viability and could characterize the hepatotoxicity of AMI.The combination of AFADESI-MSI and hepG2 spheroids can simultaneously obtain spatiotemporal information for drugs,drug metabolites,and endogenous metabolites after AMI treatment,providing an effective tool for in vitro drug hepatotoxicity evaluation.

关键词： Mass spectrometry imaging hepG2 spheroids hepatotoxicity Drug metabolism Amiodarone

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Self-assembly of Pyrene-modified Rhomboidal Metalloden- drimers via Directional Metal-ligand Bonding Approach

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Chinese Journal of Chemistry 2013年第5期31卷 663-672页

作者： Menglan he Qing Han jiuming he Quanjie Li Zeper Abliz Hongwei Tan Lin Xu Haibo Yang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai 200062 China Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Department of Chemistry Beijing Normal University Beijing 100875 China

设计并且经由方向性的 metal-ligand 的修改分核的长斜方形的 metallodendrimers R1R6 自己组装结合的途径被描述。由采用包含分核 120 敺搠獩牴扩瑵潩 ? 景 ? 偄华 ? 敷敲搠瑥牥業敮 ? 祢搠湹浡捩氠杩?

关键词：斜方晶系金属配体自组装改性树枝状聚合物半经验分子轨道法芘质谱数据

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Rapid and sensitive liquid chromatography–tandem mass spectrometric method for the quantitative determination of potentially harmful substance 5,5′-oxydimethylenebis (2-furfural) in traditional Chinese medicine injections

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Acta Pharmaceutica Sinica B 2018年第2期8卷 235-241页

作者： Qingce Zang Yang Gao Luojiao Huang jiuming he Sheng Lin Hongtao Jin Ruiping Zhang Zeper Abliz State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Science and Peking Union Medical College New Drug Safety Evaluation Center Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Centre for Bioimaging & Systems Biology Minzu University of China

With the rapid development and wide application of traditional Chinese medicine injection(TCMI), a number of adverse events of some TCMIs have incessantly been reported and have drawn broad attention in recent years. Establishing effective and practical analytical methods for safety evaluation and quality control of TCMI can help to improve the safety of TCMIs in clinical applications. In this study, a sensitive and rapid high-performance liquid chromatography–tandem mass spectrometry(HPLC–MS/MS)method has been developed and validated for the quantitative determination of potentially harmful substance5,5′-oxydimethylenebis(2-furfural, OMBF) in TCMI samples. Chromatographic separation was performed on a C18 reversed-phase column(150 mm × 2.1 mm, 5 μm) by gradient elution, using methanol–water containing 0.1% formic acid as mobile phase at the flow rate of 0.3 m L/min. MS/MS detection was performed on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction-monitoring mode. The method was sensitive with a limit of quantification of 0.3 ng/m L and linear over the range of 0.3–30 ng/m L(r = 0.9998). Intra-and inter-day precision for analyte was o9.52% RSD withrecoveries in the range 88.0–109.67% at three concentration levels. The validated method was successfully applied to quantitatively determine the compound OMBF in TCMIs and glucose injections. Our study indicates that this method is simple, sensitive, practicable and reliable, and could be applied for safety evaluation and quality control of TCMIs and glucose injections.

关键词： 5,5′-Oxydimethylenebis (2-furfural) LC–MS/MS Quantitative analytical method Traditional Chinese medicine injection Quality control

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A rapid and sensitive UPLC–MS/MS method for quantitative determination of arformoterol in rat plasma, lung and trachea tissues

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Chinese Chemical Letters 2018年第8期29卷 1284-1286页

作者： Chenglong Sun jiuming he Hongbo Wu Xiaowei Song Jiangshuo Li Luojiao Huang Xiaoyu Xu Manjiangcuo Wang Ruiping Zhang Zeper Abliz 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 Jialin Pharmaceutical Co. Ltd. Center for Imaging and Systems Biology Minzu University of China

A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry（UPLC–MS/MS） method was developed and fully validated for determination of arformoterol in rat plasma, lung and trachea tissues. The chromatographic separation was performed on an Agilent XDB C8 column with gradient elution by using acetonitrile and 0.1% formic acid water. The method presented high sensitivity（LLOQ of 1.83 pg/mL for plasma and 3.90 pg/mL for lung and trachea tissue homogenates） and great linearity over the range of 1.83–458 pg/mL for plasma, 13.9–1560 pg/mL for lung and trachea tissue homogenates. No carry over effect and matrix effect were observed. The intra-and inter-day precision/accuracy were within ±15% at three quality control concentration levels. This robust method was successfully applied to the pharmacokinetic, lung and trachea tissue distribution study after inhalation administration of arformoterol tartrate inhalation solution（50 m g/kg）. The in vivo information indicate that arformoterol can be rapidly absorbed into blood through respiratory systems, lung and trachea tissue maintain a certain amount of arformoterol in 1 h after dosing.

关键词： Arformoterol Inhalation administration LC–MS/MS Pharmacokinetic Tissue distribution

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A high-performance bio-tissue imaging method using air flow-assisted desorption electrospray ionization coupled with a high-resolution mass spectrometer

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Chinese Chemical Letters 2019年第2期30卷 461-464页

作者： Yiwei Lv Tiegang Li Chengan Guo Chenglong Sun Fei Tang Luojiao Huang Zhigang Luo Xin Li Ruiping Zhang Qingce Zang jiuming he Zeper AbliZ 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 State Key Laboratory of Precision Measurement Technology and Instruments Department of Precision Instrument Tsinghua University Center for Imaging and Systems Biology Minzu University of China

Mass spectrometry imaging (MSI) technology can simultaneously obtain the spatial distribution of thousands of chemical compounds and has unique advantages compared to other techniques that allow mapping the surface of bio-tissue. here, we combined an air flow-assisted desorption electrospray ionization (AFADESI) MSI device with a high-resolution mass spectrometer to optimize the system parameters and achieve more accurate spatial distribution characteristics for compounds of interest while investigating bio-tissue sections. The platform set-up, required instrumentation, sample pretreatment, parameter optimization and bio-tissue characterization are described and discussed.Finally, the parameter conditions that can provide optimal ionic intensity and enhanced resolution were confirmed. The reasonable resolution and sensitivity improvements of AFADESI-MSI have been achieved through tandem a high-resolution mass spectrometer system, therefore, it would be a promising technique for the bio-tissue imaging analysis.

关键词： Mass spectrometry imaging Air flow-assisted desorption electrospray ionization High-resolution mass spectrometry Endogenous metabolites Bio-tissue imaging

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