Cell Death & Disease
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2024
·Vol. 15
·期 7
·1-17
·
IF 8.1
Wang Yuying,Su Kunqi,Wang Chang,Deng Tao,Liu Xiaofeng,Sun Shiqi,Jiang Yang,Zhang Chunfeng,Xing Baocai,Du Xiaojuan
Chemotherapeutic efficacy is seriously impeded by chemoresistance in more than half of hepatocellular carcinoma (HCC) patients. However, the mechanisms involved in chemotherapy-induced upregulation of chemoresistant genes are not fully understood. Here, this study unravels a novel mechanism controlling nuclear acetyl-CoA production to activate the transcription of chemoresistant genes in HCC. NAT10 is upregulated in HCC tissues and its upregulation is correlated with poor prognosis of HCC patients. NAT10 is also upregulated in chemoresistant HCC cells. Targeting NAT10 increases the cytotoxicity of chemotherapy in HCC cells and mouse xenografts. Upon chemotherapy, NAT10 translocates from the nucleolus to the nucleus to activate the transcription of CYP2C9 and PIK3R1 . Additionally, nuclear acetyl-CoA is specifically upregulated by NAT10. Mechanistically, NAT10 binds with ACLY in the nucleus and acetylates ACLY at K468 to counteract the SQSTM1-mediated degradation upon chemotherapy. ACLY K468-Ac specifically accumulates in the nucleus and increases nuclear acetyl-CoA production to activate the transcription of CYP2C9 and PIK3R1 through enhancing H3K27ac. Importantly, K468 is required for nuclear localization of ACLY. Significantly, ACLY K468-Ac is upregulated in HCC tissues, and ablation of ACLY K468-Ac sensitizes HCC cells and mouse xenografts to chemotherapy. Collectively, these findings identify NAT10 as a novel chemoresistant driver and the blockage of NAT10-mediated ACLY K468-Ac possesses the potential to attenuate HCC chemoresistance.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Guoxin Tan,Jiayang Li,Dandan Liu,Hao Pan,Renfang Zhu,Yue Yang,Weisan Pan
Gene therapy is a promising approach to many diseases, however, the barriers in the gene delivery restrict its application. Therefore, in the present study, an efficient non-viral gene vector (PRHF/N/D) for overcoming the barriers in gene delivery was prepared. The synthesized PRHF integrated the advantages of PAMAM and amino acids, which could improve the cellular uptake, enhance the endosomal escape ability and minimize cytotoxicity. To further enhance nuclear entry of carrier, the nuclear localization signal (NLS) peptide was selected to add in the PRHF/D polyplexes. The PRHF/N/D polyplexes demonstrated good condensation capacity, wonderful pDNA protection and low toxicity. Moreover, the PRHF/N/D polyplexes showed the excellent transfection efficiency than P/D. PRHF/N/D further improve transfection capability than PRHF/D in the presence of NLS. After 4 h of incubation, the mean fluorescence intensity of PRHF/N/D was also higher than the P/D and PRHF/D complexes. We then investigated the intracellular dissociation, the DNA is able to disassemble from PRHF/N/D gene carriers. Taken together, we exhibited that this PRHF/N/D polyplexes has the potential for use in the gene delivery.
研究领域:
药剂学
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分子生物学
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基因治疗
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DOI
PubMed
高影响因子
AAPS PHARMSCITECH
·
2022
·Vol. 24
·期 1
·1-14
·
IF 4.026
Wang Xiaoling,Du Jiangyue,Zhou Feng,Ye Qing,Chen Ying,Sun Dujuan,Chen Haimin,Lv Yuanyuan,Sun Xiaoyi
Adequate delivery of therapeutic agents to their intended molecular targets is crucial in tumor therapy. Versatile drug carriers need to overcome the challenges coming from the systemic circulation, membrane barriers, and endo-lysosomal degradation. Herein, hyaluronic acid-conjugated polydopamine (HA-PDA)-shelled mesoporous silica nanoparticles encapsulated with doxorubicin (MSNs-DOX) were successfully fabricated for targeted tumor therapy. Compared with reported studies focusing on the pH-sensitive release in tumors, we especially revealed the significant role of lysosomal release in DOX nuclear accumulation. After active targeting and CD44-mediated endocytosis in tumor cells, the PDA layer of the nanoparticles would be peeled off to trigger drug release owing to MSNs gatekeeper in acidic lysosomes. Subsequently, DOX molecules passively diffused into nuclei. The intracellular DOX transportation was evidenced by DOX accumulation in nuclei, lysosomal location of nanoparticles, and lysosome acidification inhibition test. After discharging of the cargoes from nanoparticles, PDA shells from residual nanoparticles were able to produce localized hyperthermia under NIR irradiation entrapped in lysosomes, inducing synergistic chemo-photothermal effect. Under NIR treatment, HA-PDA@MSNs-DOX presented a prominent tumor inhibition rate without obvious side effects. This study indicated the potent nuclear delivery and synergetic chemo-photothermal therapy achieved by HA-PDA-shelled MSNs. Graphical Abstract
研究领域:
癌症治疗
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纳米医学
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药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2016
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IF 7.441
Wenjun Zhang,Feihu Wang,Yun Wang,Jining Wang,Yanna Yu,Shengrong Guo,Rongjun Chen,Dejian Zhou
A thiolated pH-responsive DNA conjugated gold nanorod (GNR) was developed as a multifunctional nanocarrier for targeted, pH-and near infrared (NIR) radiation dual-stimuli triggered drug delivery. It was further passivated by a thiolated poly(ethylene glycol)-biotin to improve its cancer targeting ability by specific binding to cancer cell over-expressed biotin receptors. Doxorubicin (DOX), a widely used clinical anticancer drug , was conveniently loaded into nanocarrier by intercalating inside the double-stranded pH-responsive DNAs on the GNR surface to complete the construction of the multifunctional nanomedicine . The nanomedicine can rapidly and effectively release its DOX payload triggered by an acidic pH environment (pH ~ 5) and/or applying an 808 nm NIR laser radiation. Compared to free DOX, the biotin-modified nanomedicine displayed greatly increased cell uptake and significantly reduced drug efflux by model multidrug resistant (MDR) breast cancer cell lines (MCF-7/ADR). The application of NIR radiation further increased the DOX release and facilitated its nuclear accumulation. As a result, this new DNA-GNR based multifunctional nanomedicine exerted greatly increased potency (~ 67 fold) against the MDR cancer cells over free DOX.
研究领域:
纳米技术
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癌症治疗
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药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
Advanced Science
·
2021
·Vol. 8
·期 18
·2100950
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IF 16.806
Xiaoli Liu,Yifan Zhang,Yu Guo,Wangbo Jiao,Xiao Gao,Wee Siang Vincent Lee,Yanyun Wang,Xia Deng,Yuan He,Ju Jiao,Ce Zhang,Guoqing Hu,Xing-Jie Liang,Haiming Fan
Effective delivery of anticancer drugs into the nucleus for pharmacological action is impeded by a series of intratumoral transport barriers. Despite the significant potential of magnetic nanovehicles in electromagnetic field (EF)-activated drug delivery, modularizing a tandem magnetoresponsive activity in a one-nanoparticle system to meet different requirements at both tissue and cellular levels remain highly challenging. Herein, a strategy is described by employing sequential EF frequencies in inducing a succession of magnetoresponses in the magnetic nanovehicles that aims to realize cascaded tissue penetration and nuclear accumulation. This nanovehicle features ferrimagnetic vortex-domain iron oxide nanorings coated with a thermo-responsive polyethylenimine copolymer (PI/FVIOs). It is shown that the programmed cascading of low frequency (L f )-EF-induced magnetophoresis and medium frequency (M f )-EF-stimulated magneto-thermia can steer the Doxorubicin (DOX)-PI/FVIOs to the deep tissue and subsequently trigger intracellular burst release of DOX for successful nuclear entry. By programming the order of different EF frequencies, it is demonstrated that first-stage L f -EF and subsequent M f -EF operation enables DOX-PI/FVIOs to effectively deliver 86.2% drug into the nucleus in vivo . This nanodelivery system empowers potent antitumoral activity in various models of intractable tumors, including DOX-resistant MCF-7 breast cancer cells, triple-negative MDA-MB-231 breast cancer cells, and BxPC-3 pancreatic cancer cells with poor permeability.
研究领域:
纳米技术
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生物医学工程
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癌症研究
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药物递送系统
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材料科学
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DOI
PubMed
高影响因子
PARTICLE & PARTICLE SYSTEMS CHARACTERIZATION
·
2021
·Vol. 38
·期 11
·2100193
·
IF 3.31
Shuang Qi,Zhihui Jin,Yuanjun Hou,Chao Li,Xuesong Wang,Qianxiong Zhou
Ru(II) complexes with weak ligand fields may undergo light-induced ligand dissociation, and the resulted Ru(II) aqua complexes may bind with biomolecules such as DNA, showing potential as photoactivated chemotherapy (PACT) agents. However, Ru(II) complexes with efficient PACT activity are still rare. Some Ru(II) complexes exhibit efficient photoinduced ligand dissociation but poor cytotoxicity. It is speculated that the low nuclear accumulation levels may account for their low PACT efficacy. In order to confirm this hypothesis, the almost noncytotoxic [Ru(7-OCH 3 -dppz)(4-OCH 3 -py) 4 ](PF 6 ) 2 (Ru1) is loaded on nucleus-targeted C 5 N 2 nanoparticles (NPs). Compared with the free Ru1, Ru1–C 5 N 2 NPs exhibit significantly increased cellular uptake and nuclear accumulation. Therefore, Ru1–C 5 N 2 NPs show efficient PACT activity toward various cancer cell lines (including cisplatin-resistant one) with half maximal inhibitory concentration (IC 50 ) values of 0.18 × 10 −6 –0.29 × 10 −6 m and phototoxicity index (IC 50 dark /IC 50 light ) values above 137 under both normoxic and hypoxic conditions. Moreover, Ru1–C 5 N 2 NPs also exhibit efficient PACT activity toward cisplatin-resistant 3D multicellular tumor spheroids upon two-photon irradiation (800 nm). The same strategy is also feasible to greatly improve the PACT activity of [Ru(7-OCH 3 -dppz)(py) 4 ] 2+ , which itself only has a medium effect. The results may provide new sights for developing efficient Ru(II) PACT agents.
研究领域:
化学
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药学
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肿瘤学
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材料科学
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生物医学工程
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产品关联
DOI
高影响因子
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