ACS Applied Materials & Interfaces
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2022
·
IF 10.383
Xiaoxi Wang,Xueqin Zhu,Bingyu Li,Xiuyu Wei,Yalan Chen,Yun Zhang,Yan Wang,Wenyan Zhang,Sijia Liu,Zimai Liu,Wenjie Zhai,Pingping Zhu,Yanfeng Gao,Zhenzhen Chen
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and it is associated with a high recurrence rate, metastatic potential, and poor prognosis. Thus, effective therapeutic strategies for TNBC are urgently required. The epidermal growth factor receptor (EGFR) is considered to be a potential therapeutic target for TNBC. However, there are limitations to the use of targeted therapies, such as afatinib (AFT), particularly drug resistance. Here, we investigated a poly(d,l-lactide-glycolide) (PLGA)-based intelligent bionic nanoplatform, termed AFT/2-BP@PLGA@MD, which combined targeted therapy with immunotherapy. In this platform, PLGA was used to encapsulate 2-bromo-palmitate (2-BP), a palmitoylation inhibitor, to enhance the efficacy of AFT against TNBC cells. PLGA was coated with a cancer cell membrane anchored with a cleavable peptide by matrix metalloproteinase-2 to block programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1). 2-BP significantly enhanced the capacity of AFT to inhibit the proliferation and migration of tumor cells in vitro. Moreover, the tumor cell membrane-coated AFT/2-BP@PLGA@MD nanoparticles exhibited enhanced tumor targeting ability in vivo. The AFT/2-BP@PLGA@MD nanoparticles significantly inhibited the growth and metastasis of 4T1 tumor and prolonged the survival of tumor-bearing mice. The nanoparticles also triggered antitumor immune response. Collectively, we report an effective therapeutic strategy for clinically refractory TNBC.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2013
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IF 3.499
Dacheng Fan,Weizhi Sun,Peiju Qiu,Zhiyong Wu,Yantuan Li,Shengbiao Wan,Tao Jiang,Lijuan Zhang
We synthesized a series of novel 3-indolyl cyclopent[ b ]indoles by trifluoroacetic acid mediated cyclodimerizations . The reaction showed high stereoselectivity and moderate to good yields. The influencing factors for stereoselectivity were systematically analyzed and a stepwise reaction mechanism was proposed. The cell viability tests in two colon and two lung cancer cell lines indicated the 1-benzyl-2-phenyl-group in 3-indolyl cyclopent[ b ]indoles was critical for the observed lower IC 50 s in these compounds. Western blot analysis demonstrated that the compound inhibited the expression and phosphorylation of EGFR through altered HSP90 expression. Further cell cycle and cell cycle check point protein analyses showed expected anti-cellular proliferation and cell cycle arresting properties associated with suppressed EGFR expression and phosphorylation. These data revealed a novel molecular mechanism explaining the observed cytotoxicities for these compounds.
研究领域:
有机化学
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药物化学
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癌症生物学
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细胞生物学
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药理学
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
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IF 4.9
Pei-Ling Liu,Jia-Lin Wang,Yi-Ying Dong,Hong Liu,Jin-Ju Lei,Bin Xu,Xin-Ru Liao,Di Han,Zi-Hao He,Si-Xue Cheng
Epidermal growth factor receptor (EGFR) targeted cancer therapy offers high selectivity and reduced toxicity. However, the therapeutic efficacy is compromised by the poor bioavailability of hydrophobic drugs such as gefitinib (GEF), and the acquired resistance. Curcumin (CUR) can sensitize tumor cells toward EGFR inhibitors and reverse drug resistance, but its application is also hindered by low solubility. To address these limitations, we developed a zein-based drug delivery system for the co-delivery of GEF and CUR. The dual-drug loaded zein-based nanoparticles (GEF/CUR@ZNP) decorated by pectin were prepared by self-assembly. GEF/CUR@ZNP exhibited a mean diameter less than 300 nm, featuring a narrow size distribution and an encapsulation efficiency higher than 80 %. The therapeutic efficacy was evaluated in vitro using PC-9 cells. Compared with free drugs, GEF/CUR@ZNP led to significantly enhanced cellular uptake, resulting in improved induction of cancer cell apoptosis and higher efficiency in downregulation of proteins promote cancer progression (e.g., Sp1, Bcl-2, VEGF, Snail, and CD44). To evaluate the efficacy of the drug delivery system in a context more relevant to clinical settings, we evaluated the EGFR inhibition efficacy by using the blood samples containing circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC) patients, and immunofluorescence labeling confirmed that GEF/CUR@ZNP achieved most effective suppression of EGFR expression. These findings demonstrate that zein-based co-delivery of GEF and CUR can overcome multiple barriers to targeted cancer therapy, and offer a clinically relevant strategy for enhancing antitumor efficacy and personalizing cancer treatment.
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2023
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IF 3.4
Xin Zhang,Yuhan Jiang,Na Guo,Yifan Ding,Jingting Feng,Chenyang Miao,Yanni Lv
The SNAP-tag-epidermal growth factor receptor (SNAP-tag-EGFR) cell membrane chromatography (CMC) model is a powerful tool for investigating ligand-receptor interactions and screening active ingredients in traditional Chinese medicine. Most tyrosine kinase inhibitors (TKIs) target epidermal growth factor receptors. However, TKIs associated with significant side effects and drug resistance must be addressed immediately. Therefore, there is an urgent need to develop new TKIs with high efficiency and low toxicity. Because of its low toxicity and side effects, traditional Chinese medicine has been widely employed to treat various diseases, including cancer. Hence, this study aimed to use the SNAP-tag-EGFR/CMC-high-performance liquid chromatography-mass spectrometry (HPLC-MS) two-dimensional system model as the research tool to screen and identify potential EGFR antagonists from the Chinese medicine Silybum marianum (L.) Gaertn . The applicability of the system was verified using the positive control drug osimertinib. Four potential EGFR antagonists were screened from the Chinese medicine Silybum marianum (L.) Gaertn. . They were identified as silydianin, silychristin, silybin, and isosilybin. Additionally, their pharmacological activity was preliminarily verified using a CCK-8 assay. The kinetic parameters of the four active ingredients interacting with EGFR and their binding modes with EGFR were analyzed using nonlinear chromatography (NLC) and molecular docking. This study identified silydianin, silychristin, silybin, and isosilybin from Silybum marianum (L.) Gaertn. and verified their potential antitumor effects on EGFR.
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ANALYTICA CHIMICA ACTA
·
2023
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IF 6.2
Xuegang Li,Pengqi Gong,Xue Zhou,Shankun Wang,Yingxuan Liu,Yanan Zhang,Linh V. Nguyen,Stephen C. Warren-Smith,Yong Zhao
An advanced multi-parameter optical fiber sensing technology for EGFR gene detection based on DNA hybridization technology is demonstrated in this paper. For traditional DNA hybridization detection methods, temperature and pH compensation can not be realized or need multiple sensor probes. However, the multi-parameter detection technology we proposed can simultaneously detect complementary DNA, temperature and pH based on a single optical fiber probe. In this scheme, three optical signals including dual surface plasmon resonance signal (SPR) and Mach-Zehnder interference signal (MZI) are excited by binding the probe DNA sequence and pH-sensitive material with the optical fiber sensor. The paper proposes the first research to achieve simultaneous excitation of dual SPR signal and Mach-Zehnder interference signal in a single fiber and used for three-parameter detection. Three optical signals have different sensitivities to the three variables. From a mathematical point of view, the unique solutions of exon-20 concentration, temperature and pH can be obtained by analyzing the three optical signals. The experimental results show that the exon-20 sensitivity of the sensor can reach 0.07 nm nM −1 , and the limit of detection is 3.27 nM. The designed sensor gives a fast response, high sensitivity, and low detection limit, which is important for the field of DNA hybridization research and for solving the problems of biosensor susceptibility to temperature and pH.
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International Journal of Nanomedicine
·
2023
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IF 8
Buyankhishig Dorjsuren,Birendra Chaurasiya,Zixuan Ye,Yanyan Liu,Wei Li,Chaoyang Wang,Di Shi,Colin E Evans,Thomas J Webster,Yan Shen
Background One major limitation of cancer chemotherapy is a failure to specifically target a tumor, potentially leading to side effects such as systemic cytotoxicity. In this case, we have generated a cancer cell-targeting nanoparticle-liposome drug delivery system that can be activated by near-infrared laser light to enable local photo-thermal therapy and the release of chemotherapeutic agents, which could achieve combined therapeutic efficiency.Methods To exploit the magnetic potential of iron oxide, we prepared and characterized citric acid-coated iron oxide magnetic nanoparticles (CMNPs) and encapsulated them into thermo-sensitive liposomes (TSLs). The chemotherapeutic drug, doxorubicin (DOX), was then loaded into the CMNP-TSLs, which were coated with an antibody against the epidermal growth factor receptor (EGFR), cetuximab (CET), to target EGFR-expressing breast cancer cells in vitro and in vivo studies in mouse model.Results The resulting CET-DOX-CMNP–TSLs were stable with an average diameter of approximately 120 nm. First, the uptake of TSLs into breast cancer cells increased by the addition of the CET coating. Next, the viability of breast cancer cells treated with CET-CMNP-TSLs and CET-DOX-CMNP-TSLs was reduced by the addition of photo-thermal therapy using near-infrared (NIR) laser irradiation. What is more, the viability of breast cancer cells treated with CMNP-TSLs plus NIR was reduced by the addition of DOX to the CMNP-TSLs. Finally, photo-thermal therapy studies on tumor-bearing mice subjected to NIR laser irradiation showed that treatment with CMNP-TSLs or CET-CMNP-TSLs led to an increase in tumor surface temperature to 44.7°C and 48.7°C, respectively, compared with saline-treated mice body temperature ie, 35.2°C. Further, the hemolysis study shows that these nanocarriers are safe for systemic delivery.Conclusion Our studies revealed that a combined therapy of photo-thermal therapy and targeted chemotherapy in thermo-sensitive nano-carriers represents a promising therapeutic strategy against breast cancer.
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Small
·
2019
·Vol. 15
·期 33
·1900309
·
IF 10.856
Chenyue Zhan,Yong Huang,Guifang Lin,Shuailing Huang,Fang Zeng,Shuizhu Wu
Gold nanocages (AuNCs) and gold nanoclusters (AuClusters) are two classes of advantageous nanostructures with special optical properties, and many other attractive properties. Integrating them into one nanosystem may achieve greater and smarter performance. Herein, a hybrid gold nanostructure for fluorescent and optoacoustic tomography imaging, controlled release of drugs, and photothermal therapy (PTT) is demonstrated. For this nanodrug (EA–AB), an epidermal growth factor receptor (EGFR) inhibitor erlotinib (EB) is loaded into AuNCs, which are then capped and functionalized by biocompatible AuCluster@BSA (BSA = bovine serum albumin) conjugates via electrostatic interaction. Upon cell internalization, the lysosomal proteases and low pH cause the release of EB from EA–AB, and also induce fluorescence restoration of the AuCluster for imaging. Irradiation with near-infrared light further promotes the drug release and affords a PTT effect as well. The AuNC-based nanodrug is optoacoustically active, and its biodistribution and metabolic process have been successfully monitored by whole-body and 3D multispectral optoacoustic tomography imaging. Owing to the combined actions of PTT and EGFR pathway blockage, EA–AB exhibits marked tumor inhibition efficacy in vivo.
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Revista Brasileira de Farmacognosia-Brazilian Journal of Pharmacognosy
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2024
·Vol. 34
·期 3
·637-646
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IF 1.4
Guo Liyang,Xue Xuexue,Zhou Yang,Chen Chunli,Sheng Zunlai
Diarrhea continues to be a major public health problem and is thought to be the cause of 525,000 child fatalities annually. Studies have shown that Macleaya cordata (Willd.) R.Br., Papaveraceae, has a good therapeutic effect on diarrhea due to its action on ion channels. However, its antidiarrheal mechanisms and key targets are not supported by scientific research. This study aimed to identify the mechanisms of action and targets of the primary active antidiarrheal compounds of M. cordata . We used network pharmacology and molecular docking to identify the antidiarrheal mechanisms and the key targets of M. cordata and its main chemical constituents. Subsequently, the experiments performed with dihydrosanguinarine (25, 50, and 100 mg/kg), which included the evaluation of the inhibitory potential of the epidermal growth factor receptor in osimertinib-induced diarrhea, real-time quantitative PCR, and western blotting, were performed for further verification of its mechanism of action. The findings revealed that of all the genes, tyrosine-protein kinase Lck, receptor tyrosine-protein kinase Erbb2, and epidermal growth factor receptor had the highest capacity of action, and the NF-kappa B and the calcium signaling pathways may play essential roles in M. cordata against diarrhea. Dihydrosanguinarine is the most active ingredient, and it significantly inhibits the increase in incidence and decreased the fecal water content of osimertinib-induced diarrhea. Western blot and qRT-PCR showed that dihydrosanguinarine works as an antidiarrheal agent by upregulating the expression of the core target epidermal growth factor receptor, affecting the NF-kappa B and the calcium ion signaling pathways, downregulating the expression of calcium-activated chloride channel and NK-kappa B P-65. Graphical
研究领域:
药理学
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分子生物学
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中药研究
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SENSORS AND ACTUATORS B-CHEMICAL
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2022
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IF 9.221
Xuegang Li,Pengqi Gong,Qiming Zhao,Xue Zhou,Yanan Zhang,Yong Zhao
A novel DNA hybridization optical fiber sensor with temperature and pH compensation for detecting a common lung cancer gene of epidermal growth factor receptor (EGFR) gene was demonstrated in this paper. The paper proposes the first research to achieve dual surface plasmon resonance (SPR) in an Fiber Bragg grating (FBG) and implement a three-parameter detection of DNA sequence , temperature and pH using a single fiber. Probe DNA sequences (pDNA) and PAA/CS, a pH-sensitive material, are immobilized on the sensor surface for EGFR gene exon-20 detection and temperature and pH monitoring simultaneously. The effectiveness of this functionalized method has been proved by using an atomic force microscope (AFM) and scanning electron microscope (SEM). The limit of detection (LOD) of EGFR gene was experimentally verified to 13.5 nM. The advantages of fast response, high sensitivity, label free, plug in, low LOD and three-parameter detection demonstrated by this sensor in the experiment are important for the field of DNA hybridization research and solving the problems of biosensor susceptibility to temperature and pH.
研究领域:
生物医学工程
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分子生物学
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光学传感
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Journal of Extracellular Vesicles
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2023
·Vol. 12
·期 9
·12364
·
IF 16
Jie He,Hengyu Li,John Mai,Yuqing Ke,Chunhui Zhai,Jiao Jiao Li,Lai Jiang,Guangxia Shen,Xianting Ding
Extracellular vesicle (EV) surface proteins, expressed by primary tumours, are important biomarkers for early cancer diagnosis. However, the detection of these EV proteins is complicated by their low abundance and interference from non-EV components in clinical samples. Herein, we present a MEmbrane-Specific Separation and two-step Cascade AmpLificatioN (MESS2CAN) strategy for direct detection of EV surface proteins within 4 h. MESS2CAN utilises novel lipid probes (long chains linked by PEG2K with biotin at one end, and DSPE at the other end) and streptavidin-coated magnetic beads, permitting a 49.6% EV recovery rate within 1 h. A dual amplification strategy with a primer exchange reaction (PER) cascaded by the Cas12a system then allows sensitive detection of the target protein at 10 EV particles per microliter. Using 4 cell lines and 90 clinical test samples, we demonstrate MESS2CAN for analysing HER2, EpCAM and EGFR expression on EVs derived from cells and patient plasma. MESS2CAN reports the desired specificity and sensitivity of EGFR (AUC = 0.98) and of HER2 (AUC = 1) for discriminating between HER2-positive breast cancer, triple-negative breast cancer and healthy donors. MESS2CAN is a pioneering method for highly sensitive in vitro EV diagnostics, applicable to clinical samples with trace amounts of EVs.
研究领域:
生物技术
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医学诊断
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癌症研究
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分子生物学
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iScience
·
2021
·
IF 5.458
Xidong Yang,Meiyan Liao,Hanfei Zhang,JinBo Gong,Fan Yang,Mengying Xu,Pier-Luc Tremblay,Tian Zhang
Summary A liquid biopsy is a noninvasive approach for detecting double-stranded circulating tumor DNA (ctDNA) of 90–320 nucleotides in blood plasma from patients with cancer. Most techniques employed for ctDNA detection are time consuming and require expensive DNA purification kits. Electrochemiluminescence resonance energy transfer (ECL-RET) biosensors exhibit high sensitivity, a wide response range, and are promising for straightforward sensing applications. Until now, ECL-RET biosensors have been designed for sensing short single-stranded oligonucleotides of less than 45 nucleotides. In this work, an ECL-RET biosensor comprising graphitic carbon nitride quantum dots was assessed for the amplification-free detection in the blood plasma of DNA molecules coding for the EGFR L858R mutation, which is associated with non-small-cell lung cancer. Following a low-cost pre-treatment, the highly specific ECL-RET biosensor quantified double-stranded EGFR L858R DNA of 159 nucleotides diluted into the blood within a linear range of 0.01 fM to 1 pM, demonstrating its potential for noninvasive biopsies.
研究领域:
医学诊断
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生物传感技术
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癌症研究
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 6.7
Hongyan Lin,Hongwei Han,Minkai Yang,Zhongling Wen,Qingqing Chen,Yudi Ma,Xuan Wang,Changyi Wang,Tongming Yin,Xiaoming Wang,Guihua Lu,Hongyuan Chen,Jinliang Qi,Yonghua Yang
Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis , but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity , we proposed a “two-step approach” that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin ( SK ) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50 = 4.56 μmol/L) and the positive control gefitinib (IC 50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK . Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes , thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5 , a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation.
研究领域:
肿瘤学
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药理学
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癌症生物学
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代谢途径
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