查找使用阿拉丁产品的科研文献

Co-delivery of gefitinib and hematoporphyrin by aptamer-modified fluorinated dendrimer for hypoxia alleviation and enhanced synergistic chemo-photodynamic therapy of NSCLC

Fangyin Zhu,Liang Xu,Xudong Li,Ziying Li,Jun Wang,Haijun Chen,Xiumei Li,Yu Gao

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-based molecular targeted therapy are proved to be effective in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutation, its efficacy is limited by the acquired drug resistance. The combination of EGFR-TKIs with photodynamic therapy (PDT) has been explored to combat NSCLC with promising synergistic results. However, hypoxic tumor microenvironment is associated with the development of EGFR-TKIs resistance and severely limits the efficacy of PDT. Here, we synthesized an aptamer modified fluorinated dendrimer (APF) as a drug carrier and prepared nanocomplexes APFHG by encapsulation of gefitinib (Gef) and hematoporphyrin (Hp). APF has good oxygen-carrying capacity, high drug entrapment efficiency, and could release Gef and Hp in response to intracellular pH. APF can specifically recognize EGFR-positive NSCLC cells and effectively improve the tumor hypoxic microenvironment due to the targeting effect of aptamer and the good oxygen-carrying capacity of the fluorinated dendrimer. Under the laser irradiation, APFHG can significantly increase the production of the intracellular reactive oxygen species and produce a synergistic therapeutic effect in inhibition of cellular growth and induction of cell cycle arrest and apoptosis on both Gef-sensitive and Gef-resistant EGFR-mutant NSCLC cells through PDT/molecular targeted therapy. This work indicates that fluorinated dendrimer could be a potent drug delivery platform to overcome hypoxia-related resistance and the co-delivery of EGFR-TKI and photosensitizer by the fluorinated dendrimer could be a promising therapeutic approach for reversal of EGFR-TKIs resistance in EGFR mutation-positive NSCLC.

Shenqi Fuzheng injection restores the sensitivity to gefitinib in non-small cell lung cancer by inhibiting the IL-22/STAT3/AKT pathway

Jiali Wang,Xianhai He,Zhirong Jia,Aiwen Yan,Kang Xiao,Shuo Liu,Mengjun Hou,Yaling Long,Xuansheng Ding

Context Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Gefitinib is a first-line treatment for NSCLC. However, its effectiveness is hindered by the development of drug resistance. At present, Shenqi Fuzheng injection (SFI) is widely accepted as an adjuvant therapy in NSCLC.Objective This study investigates the molecular mechanism of SFI when combined with gefitinib in regulating cell progression among EGFR-TKI-resistant NSCLC.Materials and methods We established gefitinib-resistant PC9-GR cells by exposing gefitinib escalation from 10 nM with the indicated concentrations of SFI in PC9 cells (1, 4, and 8 mg/mL). Quantitative real-time polymerase chain reaction was performed to assess gene expression. PC9/GR and H1975 cells were treated with 50 ng/mL of interleukin (IL)-22 alone or in combination with 10 mg/mL of SFI. STAT3, p-STAT3, AKT, and p-AKT expression were evaluated using Western blot. The effects on cell proliferation, clonogenicity, and apoptosis in NSCLC cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and flow cytometry assays.Results SFI treatment alleviated the development of gefitinib resistance in NSCLC. PC9/GR and H1975 cells treated with SFI significantly exhibited a reduction in IL-22 protein and mRNA overexpression levels. SFI effectively counteracted the activation of the STAT3/AKT signaling pathway induced by adding exogenous IL-22 to PC9/GR and H1975 cells. Moreover, IL-22 combined with gefitinib markedly increased cell viability while reducing apoptosis. In contrast, combining SFI with gefitinib and the concurrent treatment of SFI with gefitinib and IL-22 demonstrated the opposite effect.Discussion and Conclusion SFI can be a valuable therapeutic option to address gefitinib resistance in NSCLC by suppressing the IL-22/STAT3/AKT pathway.

Chemical Synthesis of Novel DDR1 Inhibitors and Their Activity Against Gefitinib-Resistant Non-Small Cell Lung Cancer

Xu Xuemei,Chen Siyu,Sun Doudou,Wang Xuebao,Xu Zhouyang

Objective: The discoidin domain receptor-1 (DDR1) has been demonstrated as a potential target in gefitinib-resistant non-small cell lung cancer (NSCLC). However, drug development in this area remains limited. Therefore, this study aims to chemically synthesize novel DDR1 inhibitors and explore their activity against gefitinib-resistant NSCLC. Methods: The structures of the synthesized compounds were confirmed by electrospray ionization mass spectrometry (ESI-MS), 1 H, 13 C NMR, and elemental analysis, followed by kinase screening experiments. The inhibitory impact of these compounds on the proliferation of PC-9 cells and gefitinib-resistant cell lines (PC-9GR and HCC827GR) was evaluated using the cell counting kit-8 (CCK-8) assay. Furthermore, the invasion capability of the cells was assessed using the Transwell assay. Additionally, Western blot analysis was employed to explore the targeting effects of these compounds on DDR1. Results and Discussion: Twenty-four 4,6-disubstituted pyrimidine derivatives were synthesized in series A, B, and C. Some compounds in series A and C exhibited promising inhibitory effects against DDR1 and DDR2, with compounds ( A04 ), ( A05 ), and ( C04 ) demonstrating more pronounced activities. Moreover, compounds ( A02 ), ( A03 ), ( A07 ), and ( C04 ) significantly impeded the viability of PC-9 and PC-9GR cells, with ( A07 ) exhibiting the strongest inhibition, with half-maximal inhibitory concentration (IC 50 ) values of 1.12 ± 0.07, 1.03 ± 0.18, and 1.56 ± 0.19 µM against PC-9, PC-9GR, and HCC827GR cells, respectively. Furthermore, 1 µM of ( A03 ) and ( A07 ) significantly inhibited the protein expression of p -DDR1 and DDR1, with compound ( A07 ) being the most significant inhibitor ( p < 0.001). Additionally, the Transwell assay demonstrated that 1 µM of ( A07 ) substantially inhibited the invasion of PC-9 ( p = 0.0003) and PC-9GR cells ( p = 0.0019). Conclusions: The newly synthesized DDR1 inhibitor ( A07 ) effectively inhibits the proliferation and invasion of gefitinib-resistant NSCLC cells, offering a potential new therapeutic option for treating NSCLC.

Facile synthesis of nitrogen-doped carbon dots for ultrasensitive detection of anticancer drug gefitinib based on IFE

Yuxin He,Hanting Wang,Yuting Yan,Xinhui Jiang,Hecun Zou,Zhengwei Zhang

Gefitinib, a highly significant antitumor drug, is now commonly employed in clinical settings as a first-line treatment for patients with advanced or metastatic non-small cell lung cancer, colon cancer, and breast cancer. Herein, a convenient, rapid, and accurate fluorescence method based on nitrogen-doped carbon dots (NCDs) was designed for ultrasensitive detection of gefitinib. The NCDs were easily synthesized through one-pot hydrothermal process using p -phenylenediamine and D-glutamic acid as the precursors. The sensing strategy relied on the fluorescence of NCDs at 345 nm, which was selectively reduced by gefitinib based on the inner filter effect (IFE). With a broad linear range of 0.025–30 μg/mL and a low limit of detection of 5.5 ng/mL, the probe was successfully applied to the detection of gefitinib in human serum samples, demonstrating strong practicality, affordability, and high accuracy. The proposed sensor is simple in design, fast in detection and cost-effective, and exhibits promising application in drug real-time analysis.

A fluorescent light-up aggregation-induced emission probe for screening gefitinib-sensitive non-small cell lung carcinoma

Yi Hu,Leilei Shi,Yue Su,Chuan Zhang,Xin Jin,Xinyuan Zhu

Fluorescent light-up probes with aggregation-induced emission (AIE) characteristics have been focused on recently. In this report, a new fluorescent probe, namely, DEVD-TPE, which consisted of the substrate peptide Asp-Glu-Val-Asp (DEVD) and the AIE reporter group tetraphenylethene (TPE), was developed for detecting caspase-3 in living cells. In a slightly alkaline solution, the DEVD-TPE probe displayed almost no fluorescence owing to the dynamic rotation of the phenyl rings in solution. However, DEVD-TPE exhibited significant fluorescence when it was cleaved by caspase-3, as well as when the reporter group TPE underwent aggregation. The epidermal growth factor receptor (EGFR) inhibitor gefitinib was used for determining the screening efficacy of the probe for different non-small cell lung carcinoma (NSCLC) cell lines, namely, HCC827, A549 and H1650 cells. Cell proliferation and apoptosis assays indicated that the three cell lines had different sensitivities to gefitinib. The results of analysis by living-cell fluorescence imaging and flow cytometry were consistent with those of the cell proliferation and apoptosis assays. This demonstrated that our probe could detect caspase-3 in living cells, which confirmed the apoptosis of NSCLC cells. Furthermore, our probe indicated that gefitinib was more efficient against HCC827 cells than against the other two NSCLC cell lines. This report proves that the fluorescent probe DEVD-TPE is highly sensitive to caspase-3 and has potential prospects in the rapid screening of NSCLC.

Recyclable detection of gefitinib in clinical sample mediated by multifunctional Ag-anchored g-C3N4/MoS2 composite substrate

Tao Xu,Rongyan Wang,Chenjie Gu,Tao Jiang

Surface-enhanced Raman scattering (SERS) technology enables to satisfy the increasing demand of clinical drug monitoring due to the superiority of fingerprint recognition, real-time response, and nondestructive collection. Here, a novel graphitic carbon nitride (g-C 3 N 4 )/ molybdenum disulfide (MoS 2 )/Ag composite substrate with a 3D surface structure was successfully developed for the recyclable detection of gefitinib in serum. Attributed to the uniform and dense “hotspots” on the shrubby active surfaces in conjunction with the potential synergistic chemical enhancement of g-C 3 N 4 /MoS 2 heterosystem, a remarkable SERS sensitivity with an attractive enhancement factor value of 3.3 × 10 7 was demonstrated. Meanwhile, a type-II heterojunction between g-C 3 N 4 and MoS 2 enabled more efficient diffusion of photogenerated e − -h + pairs assisted by the localized surface plasmon resonance of Ag NPs, which contributed to the reliable recyclable detection of gefitinib. The ultra-low limit of detection at 10 −5 mg/mL and high recycling rates of gefitinib beyond 90% in serum were successfully realized. The results demonstrated the as-prepared SERS substrate has tremendous potential to be untilized for in-situ drug diagnostics.

The combination of MnO2@Lipo-coated gefitinib and bevacizumab inhibits the development of non-small cell lung cancer

Jisong Zhang,Li Xu,Huihui Hu,Enguo Chen

Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells

Jinling Cui,Shuang Zhao,Hui Chen,Yuhan Fu,Kai Han,Shutao Yin,Chong Zhao,Lihong Fan,Hongbo Hu

Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC.

Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells

Cao Wei,Liu Ying,Zhang Ran,Zhang Bo,Wang Teng,Zhu Xianbing,Mei Lin,Chen Hongbo,Zhang Hongling,Ming Pinghong,Huang Laiqiang

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia , on Gefitinib-resistant NSCLC cell lines in vitro and in viv o. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFβ signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo . Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.

Co-delivery of gefitinib and curcumin via zein-based nanoparticles to enhance EGFR signaling inhibition and prevent cancer progression

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.

PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism

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.

Chemo-photodynamic therapy by pulmonary delivery of gefitinib nanoparticles and 5-aminolevulinic acid for treatment of primary lung cancer of rats

Tongtong Zhang,Jianwei Bao,Mengmeng Zhang,Yuanyuan Ge,Jianming Wei,Yu Li,Weixia Wang,Miao Li,Yiguang Jin

Lung cancer is a severe disease with high mortality. Chemotherapy is one major treatment for lung cancer. However, systemic chemotherapeutics usually distribute throughout the body without specific lung distribution so that serious side effects are unavoidable. Photodynamic therapy (PDT) is occasionally used for lung cancer treatment but photosensitizers are also systemically administered and the bronchoscopic intervention under anesthesia may hurt lung tissues. Here, we combined inhaled chemotherapeutics and photosensitizers for chemo-photodynamic therapy (CPDT) of primary lung cancer of rats with external laser light irradiation. Gefitinib PLGA nanoparticles (GNPs) were prepared. The anti-cancer effects of GNPs and/or a common photosensitizer 5-aminolevulinic acid (5-ALA) were explored on A549 cells (adenocarcinomic human alveolar basal epithelial cells) and primary lung cancer rats after intratracheal administration. External light irradiation was applied due to its higher safety compared to internal light irradiation that may result in injuries after a laser optic fiber was intubated into the lung. The remarkable synergistic effect of CPDT was confirmed although the single therapies were also effective, where the high anti-lung cancer effects were shown and some typical lung cancer markers, including CD31, VEGF, NF-κB p65 and Bcl-2, significantly decreased. Moreover, the treatments attenuated inflammation with the downregulation of TNF-α. The combination of pulmonary drug delivery and chemo-photodynamic therapy is a promising strategy for treatment of lung cancer.