ACS Applied Materials & Interfaces
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2025
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IF 8.2
Xuechun Wang,Jie Yan,Yilei Zhao,Songyan Li,Zilin Ma,Xiuying Duan,Yuelan Wang,Jianwei Jiao,Changping Gu,Guiqiang Zhang
Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy to selectively degrade target proteins in the treatment of various diseases. However, it has low bioavailability due to strong hydrophobicity, poor membrane permeability, and nonspecific distribution in vivo, which greatly limits its application. In this study, self-delivery PROTAC nanoparticles (designated as CP NPs) integrating gefitinib-based PROTACs and photosensitizers were developed to efficiently degrade mutated epidermal growth factor receptor (EGFR), a crucial kinase for cell growth and survival, while simultaneously triggering photodynamic therapy and immunotherapy. The prepared NPs enhanced the tumor accumulation of PROTACs, which led to the selective degradation of EGFR mutations and a reduction in programmed cell death protein ligand 1 levels, thereby alleviating tumor immunosuppression and immune tolerance. Moreover, under laser irradiation, the coloaded photosensitizers triggered potent photodynamic therapy effects and induced immunogenic cell death, which worked synergistically with PROTACs toward eliciting a robust antitumor immune response. In a mouse model of lung cancer, primary, distant, and lung metastatic tumors were significantly suppressed. This work highlights the potential of nano-PROTACs for degrading target proteins and facilitating combination photodynamic immunotherapy toward expanding PROTAC applications in cancer therapy.
研究领域:
肿瘤学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Heliyon
·
2023
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IF 4
Xiao-Ping Zhao,Xiao-Li Zheng,Min Huang,Ya-Jia Xie,Xiao-Wen Nie,Ali Adnan Nasim,Xiao-Jun Yao,Xing-Xing Fan
Although some important advances have been achieved in clinical and diagnosis in the past few years, the management of non-small cell lung cancer (NSCLC) is ultimately dissatisfactory due to the low overall cure and survival rates. Epidermal growth factor (EGFR) has been recognized as a carcinogenic driver and is a crucial pharmacological target for NSCLC. DMU-212, an analog of resveratrol, has been reported to have significant inhibitory effects on several types of cancer. However, the effect of DMU-212 on lung cancer remains unclear. Therefore, this study aims to determine the effects and underlying mechanism of DMU-212 on EGFR-mutant NSCLC cells. The data found that the cytotoxicity of DMU-212 on three EGFR-mutant NSCLC cell lines was significantly higher than that of normal lung epithelial cell. Further study showed that DMU-212 can regulate the expression of cell cycle-related proteins including p21 and cyclin B1 to induce G2/M phase arrest in both H1975 and PC9 cells. Moreover, treatment with DMU-212 significantly promoted the activation of AMPK and simultaneously down-regulated the expression of EGFR and the phosphorylation of PI3K, Akt and ERK. In conclusion, our study suggested that DMU-212 inhibited the growth of NSCLCs via targeting of AMPK and EGFR.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
高影响因子
AAPS Journal
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2017
·Vol. 19
·期 3
·814-826
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IF 3.423
Li Fengqiao,Mei Hao,Xie Xiaodong,Zhang Huijuan,Liu Jian,Lv Tingting,Nie Huifang,Gao Yu,Jia Lee
Lung cancer is the leading cancer and has the highest death rate. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has had a promising response in lung cancer therapy. Unfortunately, individuals with TKI-resistant EGFR mutations often develop acquired resistance against erlotinib. To overcome this resistance, in the present study, we developed liposomes anchored with anti-EGFR aptamer (Apt)-conjugated chitosan (Apt-Cs) as stable carriers to deliver erlotinib to the target. We loaded erlotinib into Apt-Cs-anchored liposomal complexes (Apt-CL-E) and characterized the physicochemistry of Apt-CL-E. The nanoparticles showed good biostability and a binding specificity for EGFR-mutated cancer cells guided by the Apt. The specific binding facilitated the uptake of Apt-CL-E into EGFR-mutated cancer cells. A cytotoxicity study showed an advantage of Apt-CL-E over their nontargeted liposomal counterparts in delivering erlotinib to EGFR-mutated cancer cells, resulting in cell cycle arrest and apoptosis. These results provide a good platform for future in vivo animal studies with Apt-CL-E.
研究领域:
肿瘤学
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药剂学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2019
·Vol. 9
·期 66
·38298-38308
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IF 3.049
Xiaojun Xu,Shu Xing,Mengjia Xu,Pan Fu,Tingting Gao,Xiaokang Zhang,Yang Zhao,Chao Zhao
Screening epidermal growth factor receptor (EGFR) mutations, especially deletions, is essential for diagnosis of non-small cell lung cancer (NSCLC) and also critical to inform treatment decisions for NSCLC patients. Here, we demonstrated a facile peptide nucleic acid (PNA) microarray-based fluorometric method for sensitive and specific detection of EGFR mutation, using rolling circle amplification (RCA), graphene oxide (GO), and a fluorescently-labeled detection probe (F-DP). First, the EGFR gene sequence was efficiently captured by the label-free PNA probe which was attached on the surface of a 96-well plate. And then, the EGFR mutation sequence was specifically amplified by RCA using the circular DNA, which was formed by the ligation of the padlock probe when hybridizing with the EGFR mutation, as a template. The single-stranded RCA product (RCAP) was then sensitively detected with the F-DP and GO system. This method has a detection limit of 0.3 pM for EGFR mutation and a high discrimination capability to target EGFR mutation against EGFR wildtype. The use of a PNA microarray and a fluorescence quenching platform make this system quite suitable for high-throughput analysis of EGFR mutations in resource-limited settings without the need of costly and cumbersome equipment. Furthermore, this detection system provides a novel way for the diagnosis of other diseases that are caused by gene deletion mutations.
研究领域:
分子生物学
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癌症诊断
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2018
·
IF 6.383
Tingting Lv,Ziying Li,Liang Xu,Yingying Zhang,Haijun Chen,Yu Gao
Although novel molecular targeted drugs have been recognized as an effective therapy for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, their efficacy fails to meet the expectation due to the acquired resistance in tumors. Up-regulation of the anti-apoptotic protein Survivin was shown to contribute to the resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutation–positive NSCLC. However, the unorganized tumor blood vessels impeded drug penetration into tumor tissue. The resulting insufficient intracellular drug/gene delivery in drug-resistant cancer cells remarkably weakened the drug efficacy in NSCLC. In this work, a multi-functional drug delivery system AP/ES was developed by using anti-EGFR aptamer (Apt)-modified polyamidoamine to co-deliver erlotinib and Survivin-shRNA. Chloroquine (CQ) was used in combination with AP/ES to normalize tumor vessels for sufficient drug/gene delivery to overcome drug resistance in NSCLC cells. The obtained AP/ES possessed desired physicochemical properties, good biostability , controlled drug release profiles, and strong selectivity to EGFR-mutated NSCLC mediated by Apt. CQ not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation , which further promoted drug delivery and enhanced drug efficacy in erlotinib-resistant NSCLC cells. Our innovative gene/drug co-delivery system in combination with CQ showed a promising outcome in fighting against erlotinib resistance both in vitro and in vivo . This work indicates that normalization of tumor vessels could help intracellular erlotinib/Survivin-shRNA delivery and the down-regulation of Survivin could act synergistically with erlotinib for reversal of erlotinib resistance in EGFR mutation-positive NSCLC. Statement of Significance NSCLC patients who benefited from EGFR-TKIs inevitably developed acquired resistance. Previous research focused on synthesis of new generation of molecular targeted drugs that could irreversibly inhibit EGFR with a particular gene mutation to overcome drug resistance. However, they failed to inhibit EGFR with other gene mutations. Activation of bypass signaling pathway and the changes of tumor microenvironment are identified as two of the mechanisms of acquired resistance to EGFR-TKIs. We therefore constructed multifunctional gene/drug co-delivery nanocomplexes AP/ES co-formulated with chloroquine that could target the both two mechanisms. We found that chloroquine not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery into tumor tissue and enhanced drug efficacy in erlotinib-resistant NSCLC.
研究领域:
肿瘤学
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药学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports Medicine
·
2024
·
IF 11.7
Chao Zhang,Yu-Xuan Sun,Ding-Cheng Yi,Ben-Yuan Jiang,Li-Xu Yan,Ze-Dao Liu,Li-Shan Peng,Wen-Jie Zhang,Hao Sun,Zhi-Yong Chen,Dan-Hua Wang,Di Peng,Song-An Chen,Si-Qi Li,Ze Zhang,Xiao-Yue Tan,Jie Yang,Zhang-Yi Zhao,Wan-Ting Zhang,Jian Su,Yang-Si Li,Ri-Qiang Liao,Song Dong,Chong-Rui Xu,Qing Zhou,Xue-Ning Yang,Yi-Long Wu,Ze-Min Zhang,Wen-Zhao Zhong
The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon’s two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro . Infiltration and T cell receptor (TCR) clonal expansion of CCR8 + regulatory T (Treg) hi /CXCL13 + exhausted T (Tex) lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.
研究领域:
肿瘤学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
·
2018
·
IF 3.702
Xuanxuan Dai,Junru Zhang,Guilong Guo,Yuepiao Cai,Ri Cui,Changtian Yin,Weidong Liu,Rajamanickam Vinothkumar,Tingting Zhang,Guang Liang,Xiaohua Zhang
Introduction Targeted therapies using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutations, leading to the approval of gefitinib and erlotinib as standard first-line clinical treatment. Inevitably, a considerable proportion of patients develop resistance to EGFR-TKIs due to the acquisition of secondary mutations within EGFR. Therefore, alternative strategies to target NSCLC are desperately needed. Materials and methods In this study, we have evaluated the effect of a reactive oxygen species (ROS)-inducing agent WZ35, a mono-carbonyl analog of curcumin, to target an inherent biological property of cancer cells, increased oxidative stress. To study whether WZ35 can inhibit NSCLC tumorigenesis, we used gefitinib- and erlotinib-resistant cell line H1975. Results In this study, we show that WZ35 treatment dramatically decreases cell viability and induces apoptosis in H1975 cells through the generation of ROS. We also found that the antitumor activity of WZ35 involved ROS-mediated activation of the endoplasmic reticulum stress pathway and mitochondrial dysfunction. Furthermore, WZ35 significantly inhibited H1975 xenograft tumor growth through the inhibition of cell proliferation and induction of apoptosis. Discussion These findings show that WZ35 may be a promising candidate for the treatment of EGFR-TKI-resistant NSCLC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2025
·Vol. 192
·期 9
·1-13
·
IF 5.3
He Linxin,Wei Yuxin,Chen Cizhi,Li Chuanhai,Xu Ying,Chen Mei
A sensitive dual-target electrochemical biosensor was developed integrating circular bipedal DNA walkers with a three-dimensional hollow carbon nanospheres-tetrametallic nanoparticle (3D HCNs-TT NPs) modified platform, enabling concurrent detection of two critical epidermal growth factor receptor (EGFR) exon 19 mutations: E746_A750 deletion (Mut DNA A) and L747_S752delinsS (Mut DNA B). The circular bipedal DNA walkers address the limitations of low amplification efficiency in traditional single-legged DNA walkers and mitigate the sensitivity reduction caused by excessively long walking strands. Additionally, we used the 3D HCNs-TT NPs nanocomposite materials to modify the electrodes, which significantly increased the electron transfer rate and provided more active sites for molecular probe loading, thereby further enhancing the performance of the detection platform. This biosensor demonstrated good performance, with detection limits as low as 3.4 fM (Mut DNA A) and 2 fM (Mut DNA B) (S/N = 3). The designed sensor was applied for detection using clinical samples, including cells with gene mutations and diluted human serum, and these results confirm the sensor’s potential for clinical translation, offering a potential tool for early non-small cell lung cancer (NSCLC) diagnosis and personalized tyrosine kinase inhibitors (TKI) therapy guidance. Graphical abstract
研究领域:
生物传感器
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分子诊断学
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纳米技术
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癌症遗传学
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电化学
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DNA纳米技术
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临床诊断学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）