JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Siyu Wang,Lutong Wang,Jingwen Xu,Yihai Wang,Limin Xiang,Xiangjiu He
The berries of black nightshade (Solanum nigrum L.) are consumed as a favorite fruit in some regions and have been reported to possess a range of biological activities. Previous studies have found that the steroidal saponins from the berries of S. nigrum (SN) showed potential antileukemic activity, although the underlying mechanism remains to be revealed. This study investigated the effects and mechanisms of SN in combination with adriamycin to reverse leukemia multidrug resistance in vivo and in vitro. The results indicated that the combination of SN and adriamycin displayed enhanced suppression ability both in vitro and in vivo by the modulation of drug efflux proteins. Further study revealed that SN and adriamycin co-treatment induced cell apoptosis in K562/ADR cells through caspase pathways and autophagy through the PI3K/Akt/mTOR and MAPK signaling pathway. This study provides a new prospect of the berries of black nightshade in multidrug resistance therapy of cancer.
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CHINESE JOURNAL OF POLYMER SCIENCE
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2022
·Vol. 40
·期 10
·1154-1164
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IF 3.815
Wang Cong-Yu,Sun Min,Fan Zhen,Du Jian-Zhong
Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers, and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability. However, pH-dependent aqueous solubility and relatively high dosage of imatinib mesylate greatly reduce the clinical outcomes. To solve this problem, we developed an intestine enzyme-responsive hydrogel to efficiently encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability through oral administration. Methacrylic anhydride-modified carboxymethyl chitosan (MA-CMCS) was synthesized via amidation reaction and then MA-CMCS was crosslinked with photoinitator under UV-irradation to form a three-dimensional hydrophilic polymer network. The intestine enzyme responsiveness was endowed with imatinib-loaded hydrogel through hydrolyzation of glucosidic bond, which could achieve enzyme-triggered long-term drug release of up to 2 days. Furthermore, sodium deoxycholate was embedded into the hydrogel to synchronously open epithelial tight junctions with improved intestinal permeability. In vitro studies revealed similar lethality against colon cancer cell for both imatinib mesylate and imatinib-loaded hydrogels. Moreover, significantly enhanced in vivo tumor inhibition (6-fold higher compared to imatinib mesylate) was achieved after oral administration with imatinib-loaded hydrogels. Overall, this enzyme-responsive hydrogel could achieve long-term synchronous release of kinase inhibitor (imatinib) and tight junction permeation enhancer (sodium deoxycholate) at intestine with enhanced therapeutic efficiency, which could provide an effective approach to improve the bioavailability of hydrophobic anticancer chemodrugs with oral administration.
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JOURNAL OF CONTROLLED RELEASE
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2021
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IF 9.776
Shengmei Wang,Xuanjun Liu,Shengfeng Wang,Linqi Ouyang,Hui Li,Jinsong Ding,Guiming Deng,Wenhu Zhou
Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (As 4 S 4 ) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While As 4 S 4 is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize As 4 S 4 nanocrystal with uniformed size of ~40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop As 4 S 4 /IMA co-delivery system. Mechanistically, IMA inhibits PTK activity, while As 4 S 4 degrades BCR-ABL1, which co-contribute to tumor suppression via complementary pathways for synergistic effect. Moreover, the nanosystem was modified with folic acid (FA) to enable tumor targetability, which has been demonstrated both in vitro and in vivo, resulting in robust tumor growth inhibition and significantly prolonged mice survival without any noticeable adverse effects. This work designed a synergistic nanoplatform for targeted CML therapy, provided a strategy to address the key limitation of As 4 S 4 for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.
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ANALYST
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2021
·Vol. 146
·期 12
·4080-4086
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IF 4.616
Hao Gu,Kang Ma,Weiqian Zhao,Lirong Qiu,Wei Xu
Matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) has been widely applied for the analysis of large biomolecules. The emergence of inorganic material substrates and new organic matrices extends the use of MALDI MS for small molecule analyses. However, there are usually preferred matrices for different types of analytes. Here, an organic compound, 4-hydroxy-3-nitrobenzonitrile, was found to be a general purpose matrix for the analyses of small organic, peptide and protein molecules. In particular, 4-hydroxy-3-nitrobenzonitrile has a strong UV absorption property, and it provides a clean background in the low mass range. Its analytical performances as a UV-laser matrix were demonstrated for different types of analytes, including organic drugs, peptides, proteins, mouse brain tissue and bacteria. Compared with commercial matrices, this new matrix has better performances when analyzing small molecules, such as drugs, peptides and lipids, while it has similar performances when analyzing proteins.
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Advanced Healthcare Materials
·
2019
·Vol. 8
·期 23
·1900965
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IF 6.27
Yao Yang,Zhengwei Huang,Jinyuan Li,Ziran Mo,Ying Huang,Cheng Ma,Wenhao Wang,Xin Pan,Chuanbin Wu
Combination therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR TKIs) with other chemotherapeutic agents is a feasible strategy to overcome resistance that often occurs after 9–13 months of EGFR TKIs administration in nonsmall cell lung cancer (NSCLC). In this study, a pulmonary microspheres system that codelivers afatinib and paclitaxel (PTX) is developed for treatment of EGFR TKIs resistant NSCLC. In this system, afatinib is loaded in stearic acid-based solid lipid nanoparticles, then these nanoparticles and PTX are loaded in poly-lactide- co -glycolide-based porous microspheres. These inhaled microspheres systems are characterized including geometric particle size, drug encapsulation efficiency, morphology by scanning electron microscopy, specific surface area, in vitro drug release, and aerodynamic particle size. Cell experiments indicate that afatinib and PTX have a synergistic effect and the codelivery system shows a superior treatment effect in drug-resistant NSCLC cells. The biocompatibility, pharmacokinetic, and tissue distribution experiments in Sprague–Dawley rats show that afatinib and PTX in the system can maintain 96 h of high lung concentration but low concentration in other tissues, with acceptable safety. These results demonstrate that this system may be a prospective delivery strategy for drug combination treatment in cancers developing resistance, especially drug-resistant lung cancer.
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ANALYTICAL BIOCHEMISTRY
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2023
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IF 2.9
Yao Liu,Zhichao He,Heng Liang,Minzhen Han,Jinxingyi Wang,Qian Liu,Yanping Guan
Rapidly developing UHPLC-MS/MS bioassays with high throughput and quality are challenging yet desired in routine clinics. Methods & results A high-throughput UHPLC-MS/MS bioassay has been built for simultaneously quantifying gefitinib , ruxolitinib , dasatinib , imatinib , ibrutinib , methotrexate , cyclophosphamide and paclitaxel . After the protein precipitation with methanol, samples were separated on an Acquity BEH C 18 column following a gradient elution system with methanol and 2 mM ammonium acetate in water at 40 °C with a run time of 3 min (flow rate 0.4 mL/min). Mass quantification in the positive ion SRM mode was then performed with electrospray ionization . The method of specificity, linearity, accuracy, precision, matrix effects, recovery, stability, dilution integrity and carryover were all validated as per the guideline of the China Food and Drug Administration whose values met the admissible limits. Application of the bioassay to therapeutic drug monitoring revealed important variability in the studied anti-tumour drugs. Conclusion This validated approach was shown to be reliable and effective in clinical management, being a valuable support in therapeutic drug monitoring and subsequent individualized dosing optimization.
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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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ANALYTICAL CHEMISTRY
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2018
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IF 6.042
Xinwei Liu,Xiao Wang,Jiexun Bu,Xiaoyu Zhou,Zheng Ouyang
Miniature mass spectrometers are of an increasing interest for in-situ analyses, and their coupling with the ambient ionization sources is a valid path for direct analysis of complex samples. In this study, a miniature mass spectrometer using discontinuous atmospheric pressure interface was developed with a dual-LIT (linear ion trap) configuration. The comprehensive scan modes were enabled for tandem mass spectrometry analysis, which are critical for high-quality qualitative and quantitative analysis. A real-time pressure control was implemented to facilitate the ion transfer and collision induced dissociation (CID). Beam-type CID could be performed for tandem analysis at a high number of stages. In-trap CID at high q could also be performed with the fragment ions accumulated in a second trap. A precursor ion scan mode for analyzing target analytes has also been demonstrated.
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JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
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2018
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IF 2.869
Xiaoyu Zhou,Xinwei Liu,Spencer Chiang,Wenbo Cao,Ming Li,Zheng Ouyang
Ion trap is an excellent platform to perform tandem mass spectrometry (MS/MS), but has an intrinsic drawback in resolving power. Using ion resonant ejection as an example, the resolution degradation can be largely attributed to the broadening of the resonant frequency band (RFB) between ion motion and driving alternative-current (AC). To solve this problem, stimulated motion suppression (STMS) was developed. The key idea of STMS is the use of two suppression alternative-current (SAC) signals, which both have reversed initial phases to the main AC. The SACs can block the unexpected sideband ion resonances (or ejections), therefore playing a key role in sharpening the RFB. The proof-of-concept has been demonstrated through ion trajectory simulations and validated experimentally. STMS provides a new and versatile means for the improvement of the ion trap resolution, which for a long time has reached the bottleneck through conventional methods, e.g., increasing the radio-frequency (RF) voltage and decreasing the mass scan rate. At the end, it is worth noting that the idea of STMS is very general and principally can be applied in any RF device for the purposes of high-resolution mass analysis and ion isolation.
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EXPERIMENTAL CELL RESEARCH
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2018
·
IF 3.309
Yanting Zhu,Fangwei Li,Wenhua Shi,Cui Zhai,Jian Wang,Xin Yan,Qingting Wang,Qianqian Zhang,Lan Yang,Li Gao,Manxiang Li
Up-regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor β-transduction repeat-containing protein (β-TrCP) have been shown to be associated with cancer cells proliferation . However, it is unclear whether CSN6 and β-TrCP are also involved in PDGF-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up-regulated CSN6 protein expression , this was accompanied with β-TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF-induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF-induced β-TrCP down-regulation, Cdc25A up-regulation and cell proliferation. Furthermore, pre-treatment of cells with MG-132 also abolished PDGF-induced β-TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre-depletion of Cdc25A by siRNA transfection suppressed PDGF-induced PASMCs proliferation. Taken together, our study indicates that up-regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases β-TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF-induced PASMCs proliferation.
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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
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2024
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IF 2.6
Rongrong Fu,Rui Chang,Andong Peng,Changshun Feng,Weifan Zhu,Yi Chen,Xue Tian,Rui Wang,Hui Yan,Dianlong Jia,Jun Li
To solve the problem of resistance of tumor cells to TRAIL and the inevitable side effects of imatinib during treatment, we successfully prepared a kind of multifunctional liposome that encapsulated imatinib in its internal water phase and inserted TRAIL on its membrane in this study, which named ITLPs. The liposomes appeared uniform spherical and the particle size was approximately 150 nm. ITLPs showed high accumulation in TRAIL-resistance cells and HT-29 tumor-bearing mice model. In vitro cytotoxicity assay results showed that the killing activity of HT-29 cells treated with ITLPs increased by 50% and confirmed that this killing activity was mediated by the apoptosis pathway. Through mechanism studies, it was found that ITLPs arrested up to 32.3% of cells in phase M to exert anti-tumor effects. In vivo anti-tumor study showed that ITLPs achieved 61.8% tumor suppression and little toxicity in the HT-29 tumor-bearing mice model. Overall results demonstrated that codelivery of imatinib and TRAIL via liposomes may be a prospective method in the treatment of the TRAIL-resistance tumor.
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ANALYTICAL AND BIOANALYTICAL CHEMISTRY
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2024
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IF 3.8
Feng Jingting,Jiang Yuhan,Liu Sihan,Deng Linge,Lv Yanni,Chen Nanzheng,Han Shengli
Gastrointestinal mesenchymal tumors, as the most common mesenchymal tumors in the gastrointestinal tract, are adjuvantly treated with multi-targeted tyrosine kinase inhibitors, such as imatinib and sunitinib, but there are problems of drug resistance and complex methods of monitoring therapeutic agents. The pathogenesis of this disease is related to mutations in tyrosine kinase (KIT) or platelet-derived growth factor receptor α, an important target for drug therapy. In recent years, the screening of relevant tyrosine kinase inhibitors from traditional Chinese medicine has become a hotspot in antitumor drug research. In the current study, the KIT-SNAP-tag cell membrane chromatography (KIT-SNAP-tag/CMC) column was prepared with satisfying specificity, selectivity, and reproducibility by chemically bonding high KIT expression cell membranes to the silica gel surface using the SNAP-tag technology. The KIT-SNAP-tag/CMC-HPLC-MS two-dimensional coupling system was investigated using the positive drug imatinib, and the results showed that the system was a reliable model for screening potential antitumor compounds from complex systems. This system screened and identified three potential active compounds of evodiamine (EVO), rutaecarpin (RUT), and dehydroevodiamine (DEVO), which possibly target the KIT receptor, from the alcoholic extract of the traditional Chinese medicine Evodia rutaecarpa . Then, the K D values of the interaction of EVO, RUT, and DEVO with KIT receptors measured using nonlinear chromatography were 7.75 (±4.93) × 10 −6 , 1.42 (±0.71) × 10 −6 , and 2.34 (±1.86) × 10 −6 mol/L, respectively. In addition, the methyl thiazolyl tetrazolium assay validated the active effects of EVO and RUT in inhibiting the proliferation of high KIT-expressing cells in the ranges of 0.1–10 µmol/L and 0.1–50 µmol/L, respectively. In conclusion, the KIT-SNAP-tag/CMC could be a reliable model for screening antitumor components from complex systems. Graphical Abstract
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