铁基纳米酶调控细胞氧化—还原环境与白血病耐药

项目来源

国家重点研发计划(NKRD)

项目主持人

张宇

项目受资助机构

东南大学

立项年度

2017

立项时间

未公开

项目编号

2017YFA0205502

项目级别

国家级

研究期限

未知 / 未知

受资助金额

730.00万元

学科

纳米科技

学科代码

未公开

基金类别

“纳米科技”重点专项

关键词

纳米酶 ; 急性髓系白血病 ; 氧化铁 ; 普鲁士蓝 ; 活性氧 ; Nanoenzyme ; Acute myeloid leukemia ; Iron oxide ; Prussian blue ; ROS

参与者

马明;窦骏;王进科

参与机构AI

东南大学

项目标书摘要:本课题成功完成了氧化铁纳米酶活性测量的国家标准的研制,已通过终审并获批准备发布;成功实现了普鲁士蓝纳米酶从40 mL体系逐级放大到3 L、10 L、50 L的宏量制备和质量控制;完成了普鲁士蓝纳米酶标准物质的研制。我们还开发了2 种高效介导AML 细胞基因转染的新型核酸载体(阳离子化多糖纳米粒和阳离子化磁性纳米颗粒核酸转染载体)。构建了尺寸为20纳米的AML耐药细胞特异性靶向磁性纳米探针,完成了AML细胞磁捕获微流控检测芯片的设计加工,完成了微流控芯片测定的荧光定量检测仪研制。另外,我们还成功构建了2种可用于细胞内 ROS调控的新型纳米酶:一种是具双靶向AML细胞的载药普鲁士蓝纳米酶,另一种是超小Pt纳米颗粒复合的靶向铁基纳米酶,两者都能实现对AML细胞的有效靶向杀伤。我们还研究发现:体外氧化铁纳米酶联合阿糖胞苷能表现出比阿糖胞苷单药更强地促进白血病癌干细胞(LSCs)凋亡;体内阿糖胞苷与氧化铁纳米酶联合用药对荷急性髓系白血病(AML)小鼠有更强的治疗效果。

Application Abstract: This project has successfully completed the development of the national standard for the measurement of iron oxide nanoenzyme activity.The macroscopical preparation and quality control of Prussian blue nanoenzyme were successfully achieved by scaling up from 40 mL system to 3 L,10 L and 50 L.The standard material of Prussian blue nanoenzyme was developed.We also developed two novel nucleic acid vectors(cationic polysaccharide nanoparticles and cationic magnetic nanoparticle nucleic acid transfection vectors)that efficiently mediate gene transfection of AML cells.An AML drug-resistant cell specific targeted magnetic nanoprobe with a size of 20 nm was constructed,the design and processing of AML cell magnetic capture microfluidic detection chip was completed,and the development of fluorescence quantitative detector for microfluidic measurement was completed.In addition,we have successfully constructed two novel nanoenzyme that can be used for intracellular ROS regulation:one is a drug-carrying Prussian blue nanoenzyme with double-targeted AML cells,and the other is a composite iron-based nanoenzyme with ultra-small Pt nanoparticles,both of which can effectively target and kill AML cells.We also found that in vitro ferric oxide nanoenzyme combined with cytosine cytosine could promote the apoptosis of leukemia cancer stem cells(LSCs)more strongly than cytosine cytosine monotherapy.The combination of cytarabine and ferric oxide nanoenzyme in vivo has a stronger therapeutic effect on mice with acute myeloid leukemia(AML).

项目受资助省

江苏省

联系人信息

张宇:zhangyu@seu.edu.cn

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  • 1.Research Progress of siRNA Nano-delivery System

    • 关键词:
    • RNA interference; siRNA drugs; nanocarriers; nano drug delivery;RNA-INTERFERENCE; ADMINISTERED SIRNA; DRUG-DELIVERY;EXTRACELLULAR-MATRIX; NANOPARTICLES; THERAPEUTICS; BARRIERS; TUMORS;CHEMOTHERAPY; DIFFUSION

    Small interfering RNA(siRNA)is the initiator of RNA interference,which stimulates the silencing ofcomplementary target mRNA.It is of great significance for gene regulation and disease treatment.It is used inviral infections,cancers,family genetic diseases and autoimmune diseases.As a new type of drug,siRNA isgradually being valued by researchers due to its high efficiency,strong specificity,and easy detection oftherapeutic effects.siRNA used as a drug alone or co-delivered with anti-tumor drugs such as chemotherapy forcancer treatment shows greater application potential than traditional drugs.siRNA drugs have the advantages ofdesignable targeting,convenient synthesis,instantaneous silencing,and strong target specificity.However,theirdelivery also faces obstacles that they are easily degraded in the blood circulation,cleared by the kidney,anddifficult to break through the vascular endothelium/cell membrane/lysosome.Therefore,designing suitablenanocarriers to help siRNA successfully deliver into cells and play a role is an important goal for the developmentof siRNA drugs,and the amout of research in this area is also increasing year by year.The precise design of thenanocarrier material type,size,structure,surface modification,etc.are important factors for the successfuldelivery of siRNA drugs.At present,the design of siRNA drug nanocarriers mainly includes4strategies:loadingsiRNA drugs on the surface of nanocarriers,co-assembly of siRNA drugs and nanocarriers,nanocarriersencapsulating siRNA drugs,and siRNA self-assembly.At this stage,the use of nanocarriers to achieve siRNAdrug delivery has made great progress.With the in-depth research and application development,the precisecontrolled preparation,precise targeted delivery and multifunctionalization of siRNA drug nanocarriers haveachieved good results.However,there are still some problems that need to be overcome by researchers.Forexample,when siRNA drugs are used in the clinic,there are still problems such as inaccurate structure design oftargeted drugs,serious off-target effects,difficulty in achieving endosome escape,and difficulties in large-scalepreparation of nanocarriers.Because of this,only3siRNA drugs have been approved for marketing,namelyOnpattro(Patisiran),Givlaari(Givosiran)and Oxlumo(Lumasiran)developed by Alnylam Pharmaceuticals.Howto prepare siRNA drugs on a large scale is a major problem facing the clinical application of siRNA drugs,and itwill become a research hotspot.At the same time,with the development of computer technology,combined withartificial intelligence,machine learning and other technologies,drug design with the aid of big data analysis isbecoming a new research and development trend.Intelligent design and precise regulation of siRNAnanomedicine,and the design of multifunctional siRNA nanomedicine that integrates targeting,tracing,and co-delivery with other drugs to achieve synergy is also one of the future development directions of siRNAnano medicine

    ...
  • 2.The Evolving Landscape of Checkpoint Inhibitor Combination Therapy in the Treatment of Advanced Hepatocellular Carcinoma

    Hepatocellular carcinoma (HCC) is one of the most common cancers and a main cause of cancer-associated death worldwide. Even with the successful launch of sorafenib for the clinical treatment of HCC in 2007, the long-term survival for patients with HCC is still suboptimal, largely due to the occurrence of primary or acquired drug resistance. With an improved understanding of the molecular pathophysiology and tumor heterogeneity of HCC, therapeutic options have been evolving rapidly in recent years. While lenvatinib, cabozantinib, regorafenib, and the monoclonal antibody ramucirumab, as well as the immune checkpoint inhibitors (ICIs) atezolizumab, nivolumab, and pembrolizumab, have all shown promise in clinical trials, ICIs, especially when administered in combination with molecular-targeted drugs or cytotoxic drugs, have drawn increased attention. Recently, ample relevant clinical studies have surfaced, particularly related to the use of ICIs and exploring the therapeutic potential of ICI combination strategies. A more thorough knowledge of novel treatment strategies should help in decision making for advanced HCC therapy. The present review summarizes the mechanisms of HCC tumorigenesis, relevant trial results for approved HCC therapies, future perspectives, and major challenges for the overall treatment of HCC.

    ...
  • 3.The Evolving Landscape of Checkpoint Inhibitor Combination Therapy in the Treatment of Advanced Hepatocellular Carcinoma

    Hepatocellular carcinoma (HCC) is one of the most common cancers and a main cause of cancer-associated death worldwide. Even with the successful launch of sorafenib for the clinical treatment of HCC in 2007, the long-term survival for patients with HCC is still suboptimal, largely due to the occurrence of primary or acquired drug resistance. With an improved understanding of the molecular pathophysiology and tumor heterogeneity of HCC, therapeutic options have been evolving rapidly in recent years. While lenvatinib, cabozantinib, regorafenib, and the monoclonal antibody ramucirumab, as well as the immune checkpoint inhibitors (ICIs) atezolizumab, nivolumab, and pembrolizumab, have all shown promise in clinical trials, ICIs, especially when administered in combination with molecular-targeted drugs or cytotoxic drugs, have drawn increased attention. Recently, ample relevant clinical studies have surfaced, particularly related to the use of ICIs and exploring the therapeutic potential of ICI combination strategies. A more thorough knowledge of novel treatment strategies should help in decision making for advanced HCC therapy. The present review summarizes the mechanisms of HCC tumorigenesis, relevant trial results for approved HCC therapies, future perspectives, and major challenges for the overall treatment of HCC.

    ...
  • 4.Polymerase chain reaction combined with fluorescent lateral flow immunoassay based on magnetic purification for rapid detection of canine parvovirus 2.

    • 关键词:
    • ;

    BACKGROUND: Canine parvovirus 2 (CPV-2) is one of the most common etiological agents that cause severe gastroenteritis in puppies. Early accurate diagnosis is important for infected dogs. In recent years, magnetic separation has become an efficient and useful tool for bioassays. In this study, polymerase chain reaction (PCR) combined with fluorescent lateral flow immunoassay (LFIA) based on magnetic purification assay was developed for the quantitative detection of CPV-2.; RESULTS: The optimum working reaction volume and reaction time for LFIA was 100muL and 2min, respectively. The PCR-LFIA assay only detected CPV-2, and did not show cross-detection of non-CPV strains. Experiments showed analytical sensitivity of 3*101 copies/muL and demonstrated the PCR-LFIA has a diagnostic agreement of 100% with conventional PCR on detection of clinical samples (22.6% positive, 14/62). Cutoff value is 146. The results were further verified by sequencing and BLAST software. The entire process from PCR step only takes ~80min.; CONCLUSIONS: This approach provides an attractive platform for rapid and quantitative detection of CPV-2, indicating great promise as a convenient molecular detection tool to facilitate disease outbreak investigations and response timely.

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  • 5.Nanozyme and Their ROS Regulation Effect in Cells

    • 关键词:
    • nanozyme; reactive oxygen; cell; redox; tumour therapy;CERIUM OXIDE NANOPARTICLES; PEROXIDASE-LIKE ACTIVITY; ENZYME-LIKEACTIVITIES; REACTIVE OXYGEN; HYDROGEN-PEROXIDE; PLATINUM NANOPARTICLES;COLORIMETRIC DETECTION; CATALYTIC-ACTIVITY; OXIDATIVE STRESS; GRAPHENEOXIDE

    With the development of nanotechnology, researchers have successfully constructed isome inorganic nanomaterials, which can mimic the catalytic activity of natural antioxidant enzymes. These nanomaterials can regulate the redox levels of cells by mimicking the catalytic processes of natural enzymes such as peroxidase,I catalase, and superoxide dismutase. This paper describes the intracellular ROS regulation 1 and oxidative stress-related diseases treatment effects of metal compounds nanozymes, noble metal nanozymes amid carbon-based nanozymes from the perspective of their enzyme-like activities. As a new type of enzyme mimic, nanozymes are expected to provide a new strategy for the treatment of diseases in the future biomedical field.

    ...
  • 6.Magnetic nanoparticles: recent developments in drug delivery system

    • 关键词:
    • Magnetic nanoparticles; drug delivery system; pharmacokinetics;biodistribution; drug loading;IRON-OXIDE NANOPARTICLES; IN-VIVO; ENHANCED PERMEABILITY; BIOMEDICALAPPLICATIONS; MACROMOLECULAR DRUGS; TARGETED DELIVERY; OXIDATIVE STRESS;CANCER-THERAPY; TUMOR; TOXICITY

    Nanostructured functional materials have demonstrated their great potentials in medical applications, attracting increasing attention because of the opportunities in cancer therapy and the treatment of other ailments. This article reviews the problems and recent advances in the development of magnetic NPs for drug delivery.

    ...
  • 7.Nanozyme and Their ROS Regulation Effect in Cells

    • 关键词:
    • nanozyme; reactive oxygen; cell; redox; tumour therapy;CERIUM OXIDE NANOPARTICLES; PEROXIDASE-LIKE ACTIVITY; ENZYME-LIKEACTIVITIES; REACTIVE OXYGEN; HYDROGEN-PEROXIDE; PLATINUM NANOPARTICLES;COLORIMETRIC DETECTION; CATALYTIC-ACTIVITY; OXIDATIVE STRESS; GRAPHENEOXIDE

    With the development of nanotechnology, researchers have successfully constructed isome inorganic nanomaterials, which can mimic the catalytic activity of natural antioxidant enzymes. These nanomaterials can regulate the redox levels of cells by mimicking the catalytic processes of natural enzymes such as peroxidase,I catalase, and superoxide dismutase. This paper describes the intracellular ROS regulation 1 and oxidative stress-related diseases treatment effects of metal compounds nanozymes, noble metal nanozymes amid carbon-based nanozymes from the perspective of their enzyme-like activities. As a new type of enzyme mimic, nanozymes are expected to provide a new strategy for the treatment of diseases in the future biomedical field.

    ...
  • 8.Magnetic nanoparticles: recent developments in drug delivery system

    • 关键词:
    • Magnetic nanoparticles; drug delivery system; pharmacokinetics;biodistribution; drug loading;IRON-OXIDE NANOPARTICLES; IN-VIVO; ENHANCED PERMEABILITY; BIOMEDICALAPPLICATIONS; MACROMOLECULAR DRUGS; TARGETED DELIVERY; OXIDATIVE STRESS;CANCER-THERAPY; TUMOR; TOXICITY

    Nanostructured functional materials have demonstrated their great potentials in medical applications, attracting increasing attention because of the opportunities in cancer therapy and the treatment of other ailments. This article reviews the problems and recent advances in the development of magnetic NPs for drug delivery.

    ...
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