Journal of Mass Spectrometry and Advances in the Clinical Lab
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2023
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IF 2.2
Fangjun Chen,Wenda Chen,Zhenxin Wang,Yingfei Peng,Beili Wang,Baishen Pan,Wei Guo
Introduction Tyrosine kinase inhibitors (TKIs) are widely used in tumor treatment. The detection of these medicines by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can avoid the interference of structurally similar compounds. Objectives This study aimed to develop and validate a new LC-MS/MS assay for the quantification of eight tyrosine kinase inhibitors in human plasma and to preliminarily evaluate the clinical utility of the therapeutic drug monitoring method. Methods Plasma samples were prepared by simple protein precipitation and separated using an ultra-high-performance reversed phase column. Detection was achieved using a triple quadrupole mass spectrometer in the positive ionization mode. The assay was validated against standard guidelines. We reviewed and analyzed the results of 268 plasma samples obtained from patients administered imatinib and other TKIs collected from January 2020 to November 2021 at Zhongshan Hospital. The analytes were separated and quantified within 3.5 min. Results The newly developed method demonstrated linearity for the detected drug concentration in the range of 20 to 2000 ng/ml for gefitinib (r 2 = 0.991) and crizotinib (r 2 = 0.992), 50 to 5000 ng/ml for nilotinib (r 2 = 0.991) and imatinib (r 2 = 0.995), 1500–150,000 ng/ml for vemurafenib (r 2 = 0.998), 1000–100,000 ng/ml for pazopanib (r 2 = 0.993), 0.5–100 ng/ml for axitinib (r 2 = 0.992) and 5–500 ng/ml for sunitinib (r 2 = 0.991) and N-desethyl sunitinib (r 2 = 0.998). The lower limit of quantification (LLOQ) was 20 ng/ml for gefitinib and crizotinib, 50 ng/ml for nilotinib and imatinib, 1500 ng/ml for vemurafenib, 1000 ng/ml for pazopanib, 0.5, and 5 ng/ml for sunitinib and N-desethyl sunitinib, respectively. Specificity, precision, accuracy, and stability were tested, and met the requirements of the guidelines. At the same dose, there was no significant difference in plasma drug concentration between the original imatinib medicine and the generic medicine after patent expiration. Conclusion We developed a sensitive and reliable method for the quantification of eight TKIs.
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TALANTA
·
2020
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IF 5.339
Yue-Yue Chang,Hai-Long Wu,Huan Fang,Tong Wang,Yang-Zi Ouyang,Xiao-Dong Sun,Gao-Yan Tong,Yu-Jie Ding,Ru-Qin Yu
Three intelligent chemometric multi-way calibration methods including alternating trilinear decomposition (ATLD), alternating trilinear decomposition assisted multivariate curve resolution (ATLD-MCR) and multivariate curve resolution-alternating least squares (MCR-ALS) combined with high performance liquid chromatography-diode array detection (HPLC-DAD) were used to quantify ten molecular targeted anti-tumor drugs in three complex biological matrices (plasma, urine and cell culture media matrices). All analytes can be successfully eluted in 6.5 min. In this experiment, various degrees of time shifts occurred in different samples. While slight time shifts exist in the chromatographic analysis , satisfactory results can be obtained by the three proposed methods. When the time shift was large (5.6 s), the average spiked recoveries obtained by ATLD analysis were in the range of 58.9%–116.5%, which was less than satisfactory. However, the average recoveries obtained by MCR-ALS and ATLD-MCR analysis were 89.8%–114.8% and 84.5%–106.1% respectively, and more satisfactory results were obtained. For further research, ATLD-MCR and MCR-ALS methods were compared, and the results were evaluated by statistical tests. Accuracies of concentrations obtained by them were considered to be no significant difference. In addition, compared with other methods currently published, the proposed chemometric methods combined with the HPLC-DAD can rapidly, simultaneously and accurately determine varieties of molecular targeted anti-tumor drugs in different complex biological matrices even in the presence of severe peak overlaps, severe time shifts, slight baseline drifts and different unknown background interferences.
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JOURNAL OF SEPARATION SCIENCE
·
2021
·Vol. 44
·期 21
·3914-3923
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IF 3.645
Zhao-Yang Wang,Hai-Long Wu,Yue-Yue Chang,Tong Wang,Wei Chen,Gao-Yan Tong,Ru-Qin Yu
An intelligent chemometric second-order calibration method called alternating trilinear decomposition- assisted multivariate curve resolution combined with high-performance liquid chromatography–diode array detection was used for the simultaneous quantification of nine tyrosine kinase inhibitors in three complex biological systems. The method allows simultaneous quantification of the components in different biological matrices without the need for cumbersome pre-treatment steps, complex elution conditions, and complete peak separation. Even with the varying time shift, severe peak overlap, and various unknown interferences, the proposed method can extract pure chromatographic and spectroscopic information for each analyte, while providing accurate qualitative and quantitative results of nine common tyrosine kinase inhibitors in three different biological matrices. All the drugs were eluted in 7 min. The results showed that the nine drugs in each matrix showed good linearity ( r > 0.984) in the calibration range with a root mean square error of calibration less than 0.9 μg/mL. The average spiked recoveries of the target analytes were all in the range of 83.4–110.0%, with standard deviations less than 9.0%. Finally, the classical method was used to validate the proposed method. In comparison to the traditional method, the proposed strategy is accuracy, simultaneous, and interference-free.
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ANALYTICAL AND BIOANALYTICAL CHEMISTRY
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2021
·Vol. 413
·期 28
·6951-6962
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IF 4.157
Wang Huai-Song,Xia Xingya,Wang Yingming,Lyu Weiping,Sang Mangmang,Gu Congcong,Liu Wenyuan,Zheng Feng
Epithelial-mesenchymal transition (EMT) is implicated in the pathological processes of cancer metastasis and drug resistance. Anti-cancer drugs may also potentially lead to EMT, resulting in their reduced therapeutic effect. Therefore, the combination of these anti-cancer drugs with anti-EMT agents has been promoted in clinic. Screening anti-EMT drugs and evaluation of EMT process are highly dependent on EMT biomarkers on cell membrane. At present, the detection of EMT biomarker is mainly by Western blot method, which is time-consuming and complicated. In this work, for effectively screening anti-EMT drugs by evaluation of the EMT process, a type of aptamer probe based on aggregation-induced emission (AIE) was designed. The aptamer SYL3C was employed to target the EMT biomarker EpCAM on cell membrane. Two fluorophores, FAM and tetraphenylethene (TPE, an AIE dye), were modified at the two ends of SYL3C, respectively. This aptamer probe (TPE-SYL3C-FAM) can monitor the EpCAM expression, which can be recovered by anti-EMT drugs. By observation of the change in TPE emission intensity, the anti-EMT effect of drugs can be evaluated. The FAM emission was used as internal reference to reduce environmental interferences. This probe can be potentially used to screen anti-EMT agents as anti-cancer adjuvant drugs with high throughput. Graphical abstract
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TOXICOLOGY MECHANISMS AND METHODS
·
2025
·
IF 2.7
Min Li,Zhouli Yue,Menglin Wang,Yan Wang,Peng Xiao,Wei Yuan,Jiduo Shen,Yucheng Li
Crizotinib, a first-generation tyrosine kinase inhibitor, demonstrates excellent clinical efficacy in treating non-small cell lung cancer (NSCLC). However, its clinical application is often limited by severe hepatotoxicity, the underlying mechanisms of which remain poorly understood. This study aimed to investigate the molecular mechanisms of crizotinib-induced hepatotoxicity in mice using transcriptomic analysis. Male ICR mice were orally administered crizotinib at doses of 100, 200, and 300 mg/kg for 7 consecutive days. Hepatotoxicity was assessed by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, along with histopathological evaluation via hematoxylin and eosin (H&E) staining. Transcriptomic and bioinformatics analyses of liver tissues were conducted to identify potential toxicological pathways. Oxidative stress markers were quantified using biochemical assay kits. Hepatic macrophage activation was examined by F4/80 immunostaining, and protein expression levels were analyzed by western blotting. Crizotinib administration resulted in dose-dependent liver injury, as indicated by elevated serum ALT and AST levels, body weight loss, and histological abnormalities. Transcriptomic profiling revealed significant enrichment of oxidative stress-related pathways, with protein–protein interaction (PPI) analysis identifying Jun as a key hub gene. Crizotinib significantly increased hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) levels, while reducing reduced glutathione (GSH) levels and the GSH/GSSG ratio. Additionally, crizotinib significantly upregulated Bax and downregulated Bcl-2 expression, promoted macrophage infiltration, and increased the expression of JNK and NLRP3 proteins. These findings suggest that crizotinib-induced hepatotoxicity may be mediated by ROS-induced activation of the JNK/NLRP3 signaling pathway, which subsequently promotes hepatic inflammation and apoptosis.
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Advanced Science
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2025
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IF 14.1
Xiaomin Su,Yang Wang,Xifeng Qin,Yaqiong Xiao,Boshu Ouyang,Lina Hu,Lin Kang,Ruizhe Xu,Ce Xu,Zanya Sun,Chenyu Sun,Huishu Guo,Zhiqing Pang,Shun Shen
The high heterogeneity of basal-like breast cancer (BLBC) and the absence of effective therapeutic targets pose ongoing treatment challenges. Pyroptosis, a type of cell death characterized by cell swelling and membrane perforation, offers a promising therapeutic weathervane for BLBC, particularly when induced by physical therapies. In this study, a high-intensity focused ultrasound (HIFU)-driven targeted pyroptosis strategy is developed for BLBC therapy. Through integration of HIFU-driven gene regulation analysis and bioinformatics analysis of pyroptosis-related genes from the TCGA dataset, 20 potential pyroptosis inducers are identified to work synergistically with HIFU. Mitoxantrone, a promising inducer, is encapsulated in platelet membrane-hybridized liposomes to enhance targeted delivery and therapeutic efficacy. Importantly, the combination of HIFU and Plp enhanced tumor delivery of liposomes by 2.46 fold and dramatically inhibited tumor growth, with 50% of female BALB/c mice remaining tumor-free compared to liposome-only treatment. Mechanistically, HIFU significantly downregulated the expression of histone deacetylases 4 and 9, while promoting cathepsin-L (CTSL) gene transcription. Simultaneously, Plp and HIFU synergistically suppressed BCL-2 via CTSL, increasing ROS production. This activated Caspase8 and the NLRP3 inflammasome, leading to GSDMC cleavage and initiating pyroptosis. Collectively, this study provides an innovative pyroptosis therapy strategy combining physical treatment and chemotherapy for BLBC and other refractory diseases.
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