BIOMATERIALS
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2018
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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
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药学
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分子生物学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Weina Fan,Jian Huang,Fanglin Tian,Xin Hong,Kexin Zhu,Yuning Zhan,Xin Li,Xiangyu Wang,Xin Wang,Li Cai,Ying Xing
Alternative splicing (AS) generates protein diversity and is exploited by cancer cells to drive tumor progression and resistance to many cancer therapies, including chemotherapy. SNRPA is first identified as a spliceosome-related gene that potentially modulates resistance to platinum chemotherapy. Both the knockout or the knockdown of SNRPA via CRISPR/Cas9 and shRNA techniques can reverse the resistance of cisplatin-resistant lung adenocarcinoma (LUAD) cells to cisplatin. SNRPA overexpression enhanced the resistance of cisplatin-sensitive LUAD cells. Gene Ontology (GO) analysis reveals that SNRPA is associated with DNA damage repair. Depletion of SNRPA induced ERCC1 exon 8 skipping and reduced ERCC1–XPF complex formation, whereas SNRPA overexpression exerted the opposite effect. siRNAs targeting isoforms containing ERCC1 exon 8 [ERCC1-E8 (+)] reversed SNRPA-enhanced cisplatin resistance and DNA damage repair. Furthermore, the IGF2BP protein, an m 6 A reader, and the ELAVL1 protein, an RNA stabilizer recruited by IGF2BP1, are found to bind to the SNRPA mRNA. ELAVL1 promoted cisplatin resistance, DNA repair and ERCC1-E8 (+) expression in an SNRPA-dependent manner. In a mouse xenograft model, SNRPA- KO CRISPR enhanced the sensitivity of LUAD cells to cisplatin. Overall, this study illuminates the role of SNRPA in platinum-based drug resistance, thereby providing a novel avenue to potentially enhance chemosensitivity and improve the prognosis of patients with LUAD.
研究领域:
癌症生物学
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分子生物学
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遗传学
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药理学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Wenjie Wang,Muhammad Adeel Ghafar,Lu Liuyang,Inzamam Ul Haq,Li Cui,Huizhu Yuan,Liande Wang
RNA pesticides have emerged as a promising alternative to conventional chemical pesticides due to their high specificity and minimal environmental impact. However, the instability of RNA molecules in the environment and the challenges associated with their effective delivery to target pests limit their broader application. This study addresses these challenges by developing a dual delivery system using chitosan (CS) and Metal–Organic Frameworks (MOFs) to enhance the delivery and efficacy of double-stranded RNA (dsRNA) and cycloxaprid against Diaphorina citri, a vector of citrus greening disease. The CS-MOF nanoparticles were synthesized and characterized using scanning electron microscopy (SEM) and dynamic light scattering (DLS). Insect bioassays demonstrated that the codelivery system significantly improved insecticidal activity, achieving over 80% mortality in D. citri within 2 days. The results indicate that the encapsulation of dsRNA within MOFs enhances its stability, while the controlled release properties of the nanoparticles improve the efficacy of cycloxaprid. This novel approach shows great potential in overcoming the limitations of RNA pesticides and offers a sustainable solution for pest management in agriculture. Future research should optimize the delivery system, conduct field trials, and explore its applicability to other agricultural pests.
研究领域:
农业科学
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分子生物学
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农药科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2020
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IF 2.365
Zhongjuan Wang,Yueqin Liang,Yanqiu Liu,Hongying Xia,Jianqi Liu,Xingfang Jin,Zhongkun Li
Multi-drug resistance (MDR) is one of the major challenges in the successful chemotherapy of non-small cell lung cancer (NSCLC). Although RNA interference (RNAi) has been widely used to silence resistance-related genes, the effect remains unsatisfactory. In this study, we attempted to overcome MDR of NSCLC by simultaneously interfering with two RNAs that have different functions. A new pH-triggered polyglutamate brush polymer dimethylmaleic anhydride-poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (DMA-mPEG-b-PG-g-spermine, DPPGS) was designed and synthesized. The DPPGS/small interfering RNA (siRNA) complex nanoparticles (DPPGSN) were prepared. The results demonstrated that DPPGSN could be transformed from a negatively charged form into a positively charged form in the slightly acidic tumor extracellular environment. The siRNA targeting MDR1 mRNA (siMDR1) and siRNA targeting survivin mRNA (siSurvivin) could be efficiently co-delivered by DPPGS to simultaneously interfere with two genes (p < 0.01). Furthermore, DPPGS co-delivery of siMDR1 and siSurvivin lowered the IC50 value of cisplatin (DDP) in A549/DDP (p < 0.01) cells and increased the apoptosis rate of the cells (p < 0.01). Therefore, co-delivery of siMDR1 and siSurvivin using DPPGS would be a promising approach for overcoming MDR of NSCLC.
研究领域:
肿瘤学
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药剂学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
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2022
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IF 0
Zhiwei Li,Jiaqi Bu,Xinyu Zhu,Hao Zhou,Kaiqun Ren,Paul K. Chu,Limin Li,Xiang Hu,Xiaofeng Ding
Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3 + and cytotoxic CD8 + T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance reactive oxygen species (ROS) accumulation, and improved HCC ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor ferroptosis and reveal an effective therapy to treat advanced HCC patients.
研究领域:
肿瘤学
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分子生物学
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免疫学
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药理学
✓ 已验证
DOI
PubMed
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