遺伝子医薬品の体内動態および細胞取り込み機構の解明に基づくデリバリー戦略の確立
阐明基因药物的药代动力学和细胞摄取机制,建立递送策略
基本信息
- 批准号:11672257
- 负责人:
- 金额:$ 2.3万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:1999
- 资助国家:日本
- 起止时间:1999 至 2000
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Plasmid DNA (pDNA) has become an important class of macromolecular agent suitable for non-viral gene therapy as well as DNA vaccination. In vivo application of pDNA is thought to be safer than that of viruses because there is less potential for adverse effects. However, concerns have been raised since there is increasing evidence suggesting that bacterial, but not mammalian, DNA activates immune competent cells, especially macrophages. However, the cellular uptake mechanism of pDNA by macrophages is not yet fully understood. In order to elucidate the mechanism, the binding and uptake of pDNA were studied in vitro using cultured Chinese hamster ovary cells expressing the class A scavenger receptor (SRA) and peritoneal macrophages from SRA-knockout mice. We found that pDNA binding and uptake in mouse peritoneal macrophages are mediated by a specific mechanism to some defined polyanions based on three-dimtensional structure of polyanions. Furthermore, we investigated the cytokine secretion induced by pDNA containing unmethylated CpG motifs complexed with cationic liposomes. A significant amount of tumor necrosis factor-α (TNF-α) was produced from the macrophages upon stimulation with the complex. However methylated pDNA and calf thymus DNA complexed with the cationic liposomes could induce TNF-α and IL-6 production, indicating that these responses were not dependent on CpG motifs. These results suggest that pDNA becomes active to stimulate the cultured macrophages in vitro through CpG motif independent manner when it is combined with the liposome formulations. These findings would be an important basis for optimization of pDNA delivery in gene therapy and DNA vaccination.
质粒DNA(pDNA)已成为一类重要的大分子药物,适用于非病毒基因治疗以及DNA疫苗接种。pDNA的体内应用被认为比病毒更安全,因为产生不良反应的可能性较小。然而,由于越来越多的证据表明细菌DNA(而不是哺乳动物DNA)激活免疫活性细胞,尤其是巨噬细胞,因此引起了人们的担忧。然而,巨噬细胞对pDNA的细胞摄取机制尚未完全了解。为了阐明机制,使用表达A类清道夫受体(SRA)的培养的中国仓鼠卵巢细胞和来自SRA敲除小鼠的腹腔巨噬细胞在体外研究pDNA的结合和摄取。我们发现小鼠腹腔巨噬细胞对pDNA的结合和摄取是通过一种基于聚阴离子三维结构的特定机制来介导的。此外,我们研究了含有未甲基化CpG基序的pDNA与阳离子脂质体复合诱导的细胞因子分泌。巨噬细胞经复合物刺激后产生大量的肿瘤坏死因子-α(TNF-α)。而甲基化pDNA和小牛胸腺DNA与阳离子脂质体复合后可诱导TNF-α和IL-6的产生,表明这些反应不依赖于CpG基序。这些结果表明,当pDNA与脂质体制剂组合时,pDNA通过CpG基序非依赖性方式变得有活性以刺激体外培养的巨噬细胞。这些发现将为基因治疗和DNA疫苗接种中优化pDNA递送提供重要依据。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Yoshinobu Takakura: "Characterization of plasmid DNA binding and uptake by peritoneal macrophages from class A scavenger receptor knockout mice."Pharmaceutical Research. 16(4). 503-508 (1999)
Yoshinobu Takakura:“A 类清道夫受体敲除小鼠腹腔巨噬细胞对质粒 DNA 结合和摄取的表征。”药物研究。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Naoki Kobayashi: "Hepatic Uptake and Gene Expression Mechanisms Following Intravenous Administration of Plasmid DNA by conventional and Hydrodynamics-based Procedures."The Journal of Pharmacology and Experimental Therapeutics. (in press).
Naoki Kobayashi:“通过常规和基于流体动力学的程序静脉注射质粒 DNA 后的肝脏摄取和基因表达机制。”药理学和实验治疗学杂志。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Toshihide Takagi: "Effect of Cationic Liposomes on Intracellular Trafficking and Efficacy of Antisense Oligonucleotides in Mouse Peritoneal Macrophages"Journal of Drug Targeting. 7. 363-371 (2000)
Toshihide Takagi:“阳离子脂质体对细胞内运输的影响和反义寡核苷酸在小鼠腹膜巨噬细胞中的功效”药物靶向杂志。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Toshihide Takagi: "Effect of cationic liposomes on intracellular trafficking and efficacy of antisense oligonucleotides in mouse peritoneal macrophages."Journal of Drug Targeting. 7(5). 363-371 (2000)
Toshihide Takagi:“阳离子脂质体对细胞内运输的影响以及反义寡核苷酸在小鼠腹膜巨噬细胞中的功效。”药物靶向杂志。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Yoshinobu Takakura: "Characterization of plasmid DNA binding and uptake by peritoneal macropages from class A scavenger receptor knockout mice."Pharmaceutical Research. 16. 503-508 (1999)
Yoshinobu Takakura:“A 类清道夫受体敲除小鼠腹膜巨页的质粒 DNA 结合和摄取的表征。”药物研究。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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TAKAKURA Yoshinobu其他文献
TAKAKURA Yoshinobu的其他文献
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{{ truncateString('TAKAKURA Yoshinobu', 18)}}的其他基金
Optimization of cytokine gene therapy based on the regulation of transcription/translation, pharmacokinetics, and cellular response.
基于转录/翻译、药代动力学和细胞反应调节的细胞因子基因治疗的优化。
- 批准号:
24390008 - 财政年份:2012
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Design and delivery of plasmid vector for spatiotemporal control of the expression of therapeutic protein and siRNA
用于时空控制治疗蛋白和 siRNA 表达的质粒载体的设计和递送
- 批准号:
21390009 - 财政年份:2009
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of all inclusive anti tumor immunotherapy based on engineered protein and nucleic acid
基于工程蛋白和核酸的全包式抗肿瘤免疫疗法的开发
- 批准号:
19390041 - 财政年份:2007
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Design and delivery of nucleic acid drugs for optimization of DNA vaccination
用于优化 DNA 疫苗接种的核酸药物的设计和递送
- 批准号:
17390041 - 财政年份:2005
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Establishment of novel delivery strategies to dendritic cells and optimization of DNA vaccination
树突状细胞新型递送策略的建立和 DNA 疫苗接种的优化
- 批准号:
15390048 - 财政年份:2003
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of plasmid DNA delivery methods to antigen presenting cells for optimized DNA vaccination
开发质粒 DNA 递送至抗原呈递细胞的方法,以优化 DNA 疫苗接种
- 批准号:
13470514 - 财政年份:2001
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of local drug disposition analysis and delivery methods in human solid tumors
人类实体瘤局部药物分布分析和递送方法的开发
- 批准号:
12557212 - 财政年份:2000
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of Gene Delivery Systems to Intestinal Epithelial Cells as a Target
以肠上皮细胞为靶标的基因传递系统的开发
- 批准号:
09672324 - 财政年份:1997
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of Delivery Systems for the Control of Pharmacokinetics and Intracellular Trafficking of Antisense Drugs
开发用于控制反义药物的药代动力学和细胞内运输的递送系统
- 批准号:
07672351 - 财政年份:1995
- 资助金额:
$ 2.3万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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