SENSORS
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2026
·Vol. 26
·期 3
·836
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IF 3.5
Yixin Miao,Tao Zhou,Qinghong Ji,Min Hong
Cancer remains a leading global cause of death, with conventional treatments often limited by toxicity and recurrence. Recent advances in gene therapy and nanodrug delivery offer new avenues for precision oncology. Human telomerase reverse transcriptase (hTERT) and glutathione peroxidase 4 (GPX4) are overexpressed in many cancers and linked to apoptosis and ferroptosis, respectively. Here, we developed a manganese dioxide nanosheet (MnO2-NS) probe co-loaded with antisense oligonucleotides targeting hTERT and GPX4 mRNA to synergistically down-regulate both genes and induce dual cell death pathways. The probe, assembled via adsorption of fluorescently labeled antisense strands, showed controllable release in the presence of glutathione (GSH). Cellular uptake and antisense release were confirmed in multiple cancer cell lines. The MnO2-NS probe significantly suppressed cell proliferation, outperforming single-target or carrier-only controls. Molecular analyses confirmed reduced hTERT and GPX4 expression, along with GSH depletion, ROS accumulation, and elevated lipid peroxidation—collectively promoting enhanced cancer cell death. In summary, this MnO2-NS-based co-delivery system enables synergistic gene silencing and GSH depletion, enhancing antitumor efficacy and providing a promising strategy for multifunctional nanotherapy.
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PubMed
高影响因子
CANCER SCIENCE
·
2012
·Vol. 103
·期 8
·1434-1439
·
IF 3.325
Bing Xiu Ren,Fan Yang,Gao Hong Zhu,Zi Xing Huang,Hua Ai,Rui Xia,Xi Jiao Liu,Man Lu,Bin Song
To develop a molecular probe for MRI detection of human tumor telomerase reverse transcriptase (hTERT) mRNA expression. Uniformly phosphorothioate-modified hTERT antisense oligonucleotide (ASON) homing hTERT mRNA was labeled with gadolinium (Gd) through the bifunctional chelator 1,4,7, 10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) stirred within 45 minutes at 60°C. The Gd labeled probes were characterized in vitro . The cellular uptake rate and biodistribution of 99m Tc-DOTA-ASON was measured instead of that of Gd-DOTA-ASON. A549 lung adenocarcinoma model was established in BALB/c nude mice and Gd-DOTA-ASON was injected intraperitoneally and MR images were acquired using 7.0T Micro-MRI (Bruker Biospec, Ettlingen, Germany) at different time points. Immunohistochemical analysis of telomerase activity of each xenograft was operated two days after in vivo imaging. The binding efficiency of Gd-DOTA-ASON reached as high as 71.7 ± 4.5% ( n = 6). Gd-DOTA-ASON displayed perfect stability in fresh human serum at 37°C for 24 h. Compared with normal lung cells, A549 cells showed an obviously higher uptake of 99m Tc-DOTA-ASON than that of lung cells (10.5 ± 2.7% vs. 4.8 ± 2.6%, P < 0.05). The signal intensity of A549 xenografts can be enhanced by Gd-DOTA-ASON and the signal to noise ratio (SNR) of tumor to muscle reached 2.37 and maintained a relatively high level within 6 h after injection. The activity of hTERT in A549 tumors can be suppressed by Gd-DOTA-ASON in pathological slices. The results of this study show that Gd-DOTA-ASON can be a promising intracellular MR contrast probe for targeting telomerase-positive carcinomas. ( Cancer Sci, doi: 10.1111/j.1349-7006.2012.02316.x, 2012)
研究领域:
医学影像学
·
分子生物学
·
肿瘤学
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PubMed
高影响因子
Nanomaterials
·
2023
·Vol. 13
·期 11
·1779
·
IF 5.3
Shunyu Zhang,Jinxia Li,Liang Yan,Yue You,Feng Zhao,Jixing Cheng,Limin Yang,Yanqi Sun,Qingchao Chang,Ru Liu,Yunhui Li
Telomerase is constitutively overexpressed in the majority of human cancers and telomerase inhibition provides a promising broad-spectrum anticancer therapeutic strategy. BIBR 1532 is a well-known synthetic telomerase inhibitor that blocks the enzymatic activity of hTERT, the catalytic subunit of telomerase. However, water insolubility of BIBR 1532 leads to low cellular uptake and inadequate delivery and thus, limits its anti-tumor effects. Zeolitic imidazolate framework-8 (ZIF-8) is considered as an attractive drug delivery vehicle for improved transport, release and anti-tumor effects of BIBR 1532. Herein, ZIF-8 and BIBR[email protected]were synthesized, respectively, and the physicochemical characterizations confirmed the successful encapsulation of BIBR 1532 in ZIF-8 coupled with an improved stability of BIBR 1532. ZIF-8 could alter the permeability of lysosomal membrane probably by the imidazole ring-dependent protonation. Moreover, ZIF-8 encapsulation facilitated the cellular uptake and release of BIBR 1532 with more accumulation in the nucleus. BIBR 1532 encapsulation with ZIF-8 triggered a more obvious growth inhibition of cancer cells as compared with free BIBR 1532. A more potent inhibition on hTERT mRNA expression, aggravated G0/G1 arrest accompanied with an increased cellular senescence were detected in BIBR[email protected]cancer cells. Our work has provided preliminary information on improving the transport, release and efficacy of water-insoluble small molecule drugs by using ZIF-8 as a delivery vehicle.Keywords:ZIF-8;drug loading;transport;protonation effect;telomerase inhibitor
研究领域:
药学
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癌症研究
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药物递送系统
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分子生物学
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PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
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2018
·Vol. 233
·期 12
·9763-9776
·
IF 3.923
Xing Xie,Yuan Gan,Maoda Pang,Guoqing Shao,Lei Zhang,Beibei Liu,Qi Xu,Haiyan Wang,Yanyan Feng,Yanfei Yu,Rong Chen,Meng Wu,Zhenzhen Zhang,Lizhong Hua,Qiyan Xiong,Maojun Liu,Zhixin Feng
Primary porcine bronchial epithelial cells (PBECs) are an ideal model to study the molecular and pathogenic mechanisms of various porcine respiratory pathogens. However, the short lifespan of primary PBECs greatly limit their application. Here, we isolated and cultured primary PBECs and established immortalized PBECs by transfecting primary PBECs with the pEGFP-hTERT recombinant plasmid containing human telomerase reverse transcriptase (hTERT). Immortalized PBECs (hTERT-PBECs) retained the morphological and functional features of primary PBECs as indicated by cytokeratin 18 expression, telomerase activity assay, proliferation assays, karyotype analysis, and quantitative reverse-transcriptase polymerase chain reaction. Compared to primary PBECs, hTERT-PBECs had higher telomerase activity, extended replicative lifespan, and displayed enhanced proliferative activity. Moreover, this cell line is not transformed in vitro and does not exhibit a malignant phenotype in vivo, suggesting that it can be safely used in further studies. Besides, hTERT-PBECs were susceptible to swine influenza virus of H3N2 subtype and porcine circovirus type 2. In conclusion, the immortalized hTERT-PBECs represent a valuable in vitro model, which can be widely used in the study of porcine respiratory pathogenic infections.
研究领域:
细胞生物学
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病毒学
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分子生物学
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高影响因子
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
·
2015
·Vol. 99
·期 21
·9135-9146
·
IF 3.337
Xie Xing,Pang Maoda,Liang Shan,Yu Lei,Zhao Yanbing,Ma Ke,Kalhoro Dildar Hussain,Lu Chengping,Liu Yongjie
Dogs are susceptible to infectious diseases that occur primarily in the respiratory tract. The airway epithelium acts as a first line of defense and is constantly exposed to microorganisms present in the environment. Respiratory epithelial cells have recently gained wide use as a cell model for studying the pathogenesis of human, murine or swine respiratory pathogen infections. However, studies of the pathogenic mechanisms of canine pathogens have been hindered by the lack of reliable respiratory cell lines. Here, we cultured primary canine bronchiolar epithelial cells (CBECs), whose characteristics were confirmed by their expression of the epithelial cell-specific marker cytokeratin 18, and have provided protocols for their isolation and ex vivo expansion. Further, we established immortalized CBECs containing the human telomerase reverse transcriptase (hTERT) gene via transfection of primary CBECs with the recombinant plasmid pEGFP-hTERT. Immortalized bronchiolar epithelial cells (hTERT-CBECs) retain the morphological and functional features of primary CBECs, as indicated by reverse transcriptase polymerase chain reaction, proliferation assays, karyotype analysis, telomerase activity assay, and Western blotting, which demonstrate that hTERT-CBECs have higher telomerase activity, an extended proliferative lifespan, and a diploid complement of chromosomes, even after Passage 50. Moreover, this cell line is not transformed, as evaluated using soft agar assays and tumorigenicity analysis in nude mice, and can therefore be safely used in future studies. The isolation and establishment of stable hTERT-CBECs is of great importance for use as an in vitro model for mechanistic studies of canine pathogenic infections.
研究领域:
兽医学
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细胞生物学
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分子生物学
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微生物学
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高影响因子
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