Acta Biomaterialia
·
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
·
药学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yonggan Xue,Jimei Chi,Bobin Ning,Lijun Cheng,Wenchen Wang,Qingyu Meng,Liang Huang,Mu Ke,Sen Li,Meng Su,Baoqing Jia
Due to non-specific signs in the early stage of colorectal cancers, most patients result in a low early diagnosis rate. Survivin protein is upregulated in many malignant tumors, making it an ideal diagnostic and therapeutic target for colorectal cancers. However, the survivin protein is located in the cell nucleus, which needs the probe to penetrate the complex nuclear membrane structure for targeting and recognizing. Here, we have developed a sub-100 nm perovskite-based fluorescent probe modified with the survivin antibody, which can freely target survivin protein through the nuclear membrane. Polyvinyl pyrrolidone (PVP) coated perovskite crystals are obtained by the supersaturated crystallization, which keep the probe with great fluorescence intensity and resistance of water and oxygen. We have established colorectal cancer cell lines and colorectal cancer tissues to test the feasibility and efficacy of the probe. After investigating the fluorescence intensity values of 20 probing samples, the average fluorescence intensity of colorectal cancer sections is 8.7 times higher than that of paracancerous tissues. Our work demonstrates that the survivin can be an ideal fluorescence target for rapid diagnosis of colorectal cancer, which also provides a research foundation for fluorescence-guided surgery and nano-therapy for targeting the survivin protein.
研究领域:
肿瘤学
·
分子生物学
·
医学影像学
✓ 已验证
DOI
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2019
·
IF 3.131
Chuanmin Zhang,Shubiao Zhang,Defu Zhi,Yinan Zhao,Shaohui Cui,Jingnan Cui
This work designed a new delivery system (L-PTX-PSur), which could efficiently co-deliver paclitaxel (PTX) and survivin siRNA (Sur) to overcome the dose-limiting toxicity by effectively accumulating PTX in tumor and obtain enhanced therapy by synergistic effect. In this co-delivery system, protamine was selected to condense siRNA into a compacted ‘core’, and a carbamate-linked cationic lipid was used to develop PTX-loaded liposome to entrap the core. L-PTX-PSur with protamine could facilitate Sur entry into NCI-H460 cells and exhibited high encapsulation efficiency of PTX. In vitro studies on the NCI-H460 lung cancer cells revealed that L-PTX-PSur offered significant advantages over the control groups, and it had the highest cellular uptake, the lowest cell viability and the strongest apoptosis. Western blot result showed that survivin protein expression could be noticeably suppressed by L-PTX-PSur in NCI-H460 cells. And the down-regulation of survivin protein could lower the apoptotic threshold of cancer cells and render PTX more effective with low doses. Collectively, L-PTX-PSur with a low dose of PTX could induce a synergistic inhibitory effect on cancer cells growth by the collaboration of PTX and Sur. This work provides a promising strategy for the treatment of lung cancer.
研究领域:
肿瘤学
·
药学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2013
·
IF 7.604
Feifei Yang,Wei Huang,Yunfei Li,Shan Liu,Mingji Jin,Yuli Wang,Lihua Jia,Zhonggao Gao
Recently, survivin has been attracting great attention because it plays an important role in inhibiting the apoptosis process of tumor cells. Down-regulating the expression of survivin gene by small interfering RNA (siRNA) offers a promising method for anti-tumor therapy. However, lack of appropriate siRNA delivery vector has significantly hindered the successful application of survivin-targeted siRNA in anti-tumor therapy. The purpose of this study was to use polysaccharide vector TAT-g-CS we synthesized to deliver functional siRNA and evaluate its in vivo anti-tumor activity. TAT-g-CS vector was firstly synthesized and well structurally characterized. MTT assay showed that TAT-g-CS vector exhibited good biocompatibility . TAT-g-CS complexed with siRNA offering nanoparticles with an average particle size of 212.2 nm and a polydispersity index of 0.121, and the zeta potential of the nanoparticles was +18.58 mV. Results from reporter gene assay suggested that luciferase-targeted siRNA when delivered by TAT-g-CS could down-regulate the expression of luciferase gene with 75.3% reduction. Most importantly, we use siRNA Sur targeting survivin gene to assess the in vitro and in vivo delivery capacity of TAT-g-CS and its anti-tumor effects. Our results demonstrated that TAT-g-CS/siRNA Sur nanoparticles not only strongly inhibited the in vitro proliferation of 4T1-Luc tumor cells via inducing cell apoptosis, but also effectively inhibited the in vivo growth and metastasis of malignant breast tumor, which suggested that TAT-g-CS/siRNA nanoparticle was a highly efficient non-viral system for siRNA delivery, especially for anti-tumor therapy based on siRNA therapeutics.
研究领域:
癌症生物学
·
药学
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Cuifeng Wang,Jiamin Wu,Zhongjuan Wang,Zeping Yang,Zhi Li,Huihui Deng,Long Li,Xiao Peng,Min Feng
Many human cancer cells exhibit an oncogenetic-driven addiction to glutamine (Gln) as rapidly proliferating cancer cells consume Gln at a dramatically increased rate compared to normal cells. Tumor cells, therefore, compete with host cells for Gln, which causes Gln to flux from normal tissues to the tumor. We have developed and characterized a Gln macromolecular analog polyglutamine (PGS) for the delivery of gene regulators , such as siRNAs, in our previous works. Here, we hypothesize that PGS can utilize the Gln transporter SLC1A5 to specifically deliver therapeutic compounds to Gln-addicted cancer cells. Compared to human lung fibroblast HLF cells, cisplatin-resistant human lung adenocarcinoma A549/DDP cells significantly overexpress SLC1A5, which has a high binding affinity to PGS, as confirmed through molecular docking analysis. Due to the differences in Gln metabolism between malignant and normal cells, PGS/siRNA complexes were remarkably increased in cancer cells, especially when cells were deprived of Gln, which mirrors the conditions that are commonly found in a tumor microenvironment . Furthermore, we identified that chemical and genetic inhibition of Gln transporter SLC1A5 reduced the cellular internalization of PGS/siRNA complexes, suggesting a critical role for SLC1A5 in PGS uptake in cells. In turn, PGS upregulated SLC1A5 expression. Increased uptake of PGS complexes profoundly decreased intracellular Gln levels. Decreased Gln caused a moderate reduction in cell growth. To restore drug sensitivity and further enhance anti-tumor effects, the hybrid siRNAs anti-Survivin and anti-MDR1 (siSM), as model therapeutics, were administered through the PGS delivery system, which resulted in knockdown of Survivin and MDR1 and further sensitized cancer cells to the drug cisplatin (DDP). Since PGS complexes administered i.v. mostly accumulated in the lung parenchyma, a lung orthotopic tumor model was established to evaluate their inhibitory effects on tumors in the lungs. PGS/siSM comparably decreased the rate of tumor growth, while concurrent administration of PGS/siSM and DDP enhanced this effect and insignificantly improved life span. Consistent with our hypothesis, this study demonstrated that PGS mimicked Gln in the SLC1A5 pathway and selectively ferried therapeutics to Gln-addicted cancer cells. Our findings identified a new lung cancer targeting strategy based on Gln metabolism and can be used as a drug/gene delivery system.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2026
·Vol. 193
·期 1
·58
·
IF 5.3
Yin Zhaojiang,Zhang Jing,Li Binghui,Fan Hao,Wang Mei,Cui Hanfeng
A dual-mode sensor based on intramolecular catalytic hairpin assembly strategy (intra-CHA) is proposed for Survivin mRNA detection. Intra-CHA, a triplex complex of tetraferrocene-labeled H1/H2, shortens H1-H2 distance and increases their local concentrations, accelerating reaction by 2.8-fold vs. free-CHA. Ruthenium-based covalent organic frameworks (RuCOFs) with Ru(dcbpy) 3 2+ as luminophore has dual fluorescence-electrochemiluminescence (FL-ECL) properties. EDTA-incorporated RuCOFs@EDTA expands active sites, enhancing ECL efficiency 8-fold. Intra-CHA system is covalently conjugated to RuCOFs@EDTA through amide bond linkages. Target mRNA-triggered strand displacement reactions induce structural reconfiguration of the intra-CHA probes, resulting in controlled spatial segregation of tetraferrocene from the RuCOFs@EDTA interface. This results in the recovery of FL and ECL signals, enabling rapid and highly sensitive detection of Survivin mRNA. Experimental results show that the detection limits reach 0.04 fM (in the FL mode) and 0.009 fM (in the ECL mode) respectively, with excellent selectivity, stability, and reproducibility. The system has been successfully applied to detect Survivin mRNA in actual serum samples, providing a novel strategy for Survivin mRNA detection and paving the way for developing future diagnostic strategies for early cancer screening. Graphical
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CYTOTECHNOLOGY
·
2025
·Vol. 77
·期 4
·1-12
·
IF 1.7
Bu Xiao-fen,Li Jun,Zhu Hong
Liver cancer exhibits a covert onset, high propensity for recurrence and metastasis, ultimately leading to unfavourable prognosis and increased mortality. Glycyrrhizin (GL) exhibits diverse pharmacological activities and can serve as an autophagy inducer, thereby demonstrating its potential anticancer efficacy against various cancer cell types. The impact of GL on apoptosis, migration, the STAT3/Survivin pathway, and autophagy was analysed by administering GL to human hepatocellular carcinoma cell lines. Human liver cancer cell lines were treated with 3-MA (an autophagy inhibitor) and colivelin (STAT3 agonist) to analyze glycyrrhetin's effects on autophagy, angiogenesis, and the STAT3/Survivin pathway. The GL group showed significant decreases in cell proliferation, migration, and levels of p-STAT3, Survivin, LC3-I, P62, and VEGF-A compared to controls. Conversely, apoptosis rates and expressions of LC3-II and Beclin1 increased. In the 3-MA group, proliferation, migration, p-STAT3, Survivin, LC3-I, P62, and VEGF-A were higher than in controls, but apoptosis rates and LC3-II and Beclin1 levels were lower. Colivelin inhibited GL's effects, while GL countered 3-MA's actions. Supernatants from various cell groups also yielded similar results in Human umbilical vein endothelial cells (HUVECs). Thus, GL has ability to hinder the STAT3/Survivin signalling pathway, consequently fostering autophagy and delaying the onset and progression of liver cancer cell.
研究领域:
癌症生物学
·
药理学
·
细胞生物学
·
分子生物学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2026
·
IF 6.8
Zhou Cheng,Honghui Huang,Shiying Li,Yefan Peng,Yehui Lu,Ming Huang,Huijie Zhang,Wei Sun
As an inhibitor of apoptosis protein, survivin attracts growing interest as a oncotarget because it is highly expressed in various cancers but lacks expression in normal tissues. Although silencing survivin mRNA using antisense oligonucleotides (ASO) presents a potential strategy for lung cancer treatment, the application of ASO is constrained by multiple barriers, including rapid enzymatic degradation, limited cellular internalization and non-specific tissue distribution. To overcome these challenges, we engineered a novel glyco-nanocarrier by chemically modifying glycogen. Glycogen was aminated (NG) and further conjugated with baclofen (Bac-NG), a ligand and agonist for GABAB receptors overexpressed in lung cancer cells. Bac-NG demonstrated excellent biocompatibility and efficiently complexed with survivin ASO through electrostatic interactions, protecting it from nuclease degradation. Bac-NG significantly improved the internalization of ASO in A549 cells via GABAB receptor-mediated endocytosis. Consequently, Bac-NG/ASO effectively inhibited A549 cell proliferation by triggering apoptosis. This study highlights the therapeutic promise of Bac-NG/ASO for targeted gene therapy in lung cancer
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2016
·
IF 4.32
Ping Sun,Wei Huang,Mingji Jin,Qiming Wang,Bo Fan,Lin Kang,Zhonggao Gao
Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis.
研究领域:
癌症治疗
·
药学
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSCIENCE REPORTS
·
2019
·Vol. 39
·期 1
·
IF 2.535
Chen Gang,Chen Weicheng,Ye Ming,Tan Weiqiang,Jia Bing
Neuroblastoma is the most common tumor in children, with a very poor prognosis. It is urgent to identify novel biomarkers to treat neuroblastoma, together with surgery, chemotherapy, and radiation. Human tripartite motif 59 (TRIM59), a member of the TRIM family, has been reported to participate in several human tumors. However, the exact role of TRIM59 in neuroblastoma is unknown. In the present study, real-time PCR and Western blot were used to measure mRNA and protein levels of TRIM59 in four neuroblastoma cell lines and in neuroblastoma tissues. Lentiviruses targeting TRIM59 were used to up/down-regulate TRIM59 expression levels. Cell Counting Kit-8 and Annexin-V/PI were used to analyze cell proliferation and apoptosis in neuroblastoma cell lines. Our data showed that TRIM59 knockdown inhibits cell proliferation while inducing apoptosis in SH-SY5Y and SK-N-SH neuroblastoma cell lines. TRIM59 knockdown up-regulated expression of Bax and Bim and down-regulated levels of Survivin, β-catenin, and c-myc. Interestingly, the inhibition of cell proliferation caused by TRIM59 knockdown could be blocked by LiCl, which is an agonist of Wnt/β-catenin signaling pathway. In contrast, TRIM59 overexpression could increase cell proliferation, up-regulate Survivin, β-catenin and c-myc, down-regulate Bax and Bim, and these effects could be blocked by XAV939, which is an inhibitor of Wnt/β-catenin signaling pathway. In addition, TRIM59 was up-regulated and positively related with β-catenin in neuroblastoma tissues. In conclusion, TRIM59 was up-regulated in neuroblastoma, and TRIM59 knockdown inhibited cell proliferation by down-regulating the Wnt/β-catenin signaling pathway in neuroblastoma.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2014
·Vol. 12
·期 1
·1-12
·
IF 4.078
Wang Qing,Zhang Chunlei,Shen Guangxia,Liu Huiyang,Fu Hualin,Cui Daxiang
Background Fluorescent carbon dots (Cdots) have attracted increasing attention due to their potential applications in sensing, catalysis, and biomedicine. Currently, intensive research has been concentrated on the synthesis and imaging-guided therapy of these benign photoluminescent materials. Meanwhile, Cdots have been explored as nonviral vector for nucleic acid or drug delivery by chemical modification on purpose.Results We have developed a microwave assisted one-step synthesis of Cdots with citric acid as carbon source and tryptophan (Trp) as both nitrogen source and passivation agent. The Cdots with uniform size show superior water solubility, excellent biocompatibility, and high quantum yield. Afterwards, the PEI (polyethylenimine)-adsorbed Cdots nanoparticles (Cdots@PEI) were applied to deliver Survivin siRNA into human gastric cancer cell line MGC-803. The results have confirmed the nanocarrier exhibited excellent biocompatibility and a significant increase in cellular delivery of siRNA, inducing efficient knockdown for Survivin protein to 6.1%. In addition, PEI@Cdots complexes mediated Survivin silencing, the arrested cell cycle progression in G1 phase as well as cell apoptosis was observed.Conclusion The Cdots-based and PEI-adsorbed complexes both as imaging agents and siRNA nanocarriers have been developed for Survivin siRNA delivery. And the results indicate that Cdots-based nanocarriers could be utilized in a broad range of siRNA delivery systems for cancer therapy.
研究领域:
纳米技术
·
生物医学
·
癌症治疗
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
·
2026
·Vol. 40
·期 1
·52
·
IF 3.1
Lu JiaHao,Zhao ChenHao,Qiu YingQI,Shen Li-Qun,Zhu Hua,Zhang Miao
Survivin, a multifunctional regulator of mitosis and apoptosis, plays a central role in cancer progression and therapy resistance, making it an attractive target for anticancer drug development. In this study, a series of 4,6-diphenyl-3-cyanopyridine derivatives were designed and synthesized as potential survivin inhibitors through an integrated strategy combining 3D-QSAR modeling, molecular docking, molecular dynamics simulations, and biological evaluation. The CoMFA and CoMSIA models established reliable structure–activity relationships and provided contour-map-based guidance for rational molecular optimization. Newly designed derivatives displayed enhanced antiproliferative effects against melanoma cells, and computational analyses revealed that the most promising compound showed stable and preferential binding within the BIR domain of survivin, particularly in its dimeric form. These findings demonstrate the effectiveness of contour-guided optimization in discovering novel survivin-targeting scaffolds and highlight 4,6-diphenyl-3-cyanopyridine derivatives as promising leads for further anticancer drug development. Future studies will focus on improving selectivity, clarifying the inhibition mechanism at the molecular level, and evaluating in vivo efficacy.
✓ 已验证
DOI
PubMed
高影响因子
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