Development of Gene Therapy with Nanotechnology derived Intelligent Drug Deliver Systems

利用纳米技术衍生的智能药物输送系统开发基因治疗

• 批准号: 15390389
• 负责人: YANAGIE Hironobu
• 金额: $ 9.47万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390389/
• 关键词: Polyethyleneimine; anionic PEG complex; JTS-1; Drug Delivery System; Gene Therapy; Multidrug resistant gene; Targeting; Drug Delivery System; JTS-1; DNAマクロアレイ; トランスポーター; JTS-1、4 DDS

We develop polyion complex with DNA and polycation for gene delivery systems. Polyethyleneimine was selected for polycation that have protonsponde effect on transfection to cancer cells. Polyethylene-glycol binding carboxyl chain was also used for coating the cationic charged DNA/polycation complex. To increase the transfection efficacy, we also examined pH sensitive peptide, JTS-1 that constructed with analysis of Influenza virus. Polyethyleneimine and DNA complex showed 1 × 10^9 IU/mg luciferase activity. In case of coating the DNA/polyion complex with PEG-C, the luciferase activity was increase to 3 × 10^9 IU/mg, because of the compaction and incresent of stability with addition of PEG-C to complex, so the transfection efficacy was increased. When addition of JTS-1 to the DNA/polyethyleneimine/lactose-binding PEG-C complex, it is easily to escape the lysis of lysosome and transfect the DNA to cytoplasm, and 6 × 10^9 IU/mg luciferase activity was obtained. Increasing of transfection efficacy of β-gal gene by intratumor injection of β-gal DNA plasmid/Polyethyleneimine/lactose-binding PEG-C/JTS-1 complex on gastric cancer tumor bearing mice model.According to the analysis of DNA microarray with ancer cell lines that were sensitive or resistant to Oxaliplatin or Cisplatin, Tubrin specific Chaperon E gene and CBP/P300-interacting transactivator (CITED2) gene were increased on Oxaliplatin or Cisplatin resistant cancer cells.

我们开发了用于基因传递系统的DNA和聚阳离子的聚离子复合物。选择聚乙烯亚胺作为对癌细胞转染具有质子应答作用的聚阳离子。聚乙二醇结合羧基链也被用于涂覆带阳离子电荷的DNA/聚阳离子复合物。为了提高转染效率，我们还检测了通过分析流感病毒构建的pH敏感肽JTS-1。聚乙烯亚胺和DNA复合物显示1 × 10^9 IU/mg荧光素酶活性。用PEG-C包被DNA/聚离子复合物，由于PEG-C的加入使复合物致密化，稳定性提高，荧光素酶活性提高到3 × 10^9 IU/mg，从而提高了转染效率。当将JTS-1加入到DNA/聚乙烯亚胺/乳糖结合的PEG-C复合物中时，很容易逃避溶酶体的裂解，将DNA转移到细胞质中，获得6 × 10^9IU/mg的荧光素酶活性。瘤内注射β-gal DNA质粒/聚乙烯亚胺/乳糖结合PEG-C/JTS-1复合物提高β-gal基因对胃癌荷瘤小鼠的转染效率根据对奥沙利铂或顺铂敏感或耐药的肿瘤细胞系的DNA微阵列分析，肿瘤特异性伴侣E基因和CBP/P300相互作用反式激活因子（CITED 2）基因在奥沙利铂或顺铂耐药的癌细胞上增加。

项目成果

Kazuo Maruyama: "Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin."Pharmaceutical Research. 25. 275-279 (2003)

Kazuo Maruyama：“通过带有聚乙二醇偶联转铁蛋白的脂质体靶向大鼠缺血后脑内皮。”药物研究。

Kazuo Maruyama: "Intracellular targeting of sodium mercaptoundecahydrododecaborate (BHS) to solid tumors by transferring-PEG liposomes, for boron neutron-capture therapy (BNCT)"J.Control.Release. (in press). (2004)

Kazuo Maruyama：“通过转移 PEG 脂质体将巯基十一氢十二硼酸钠 (BHS) 细胞内靶向实体瘤，用于硼中子捕获疗法 (BNCT)”J.Control.Release。

Intracellular targeting of sodium mercaptoundecahydrododecaborate(BSH)to solid tumors by transferring-PEG liposomes, for boron neutron-capture therapy (BNCT)

通过转移 PEG 脂质体将巯基十一氢十二硼酸钠 (BSH) 细胞内靶向实体瘤，用于硼中子俘获疗法 (BNCT)

• 发表时间: 2004
• 期刊: J.Control.Release Vol.98 No.2
• 作者: Hironobu Yanagie;Kazuo Maruyama
• 通讯作者: Kazuo Maruyama

Intracellular targeting of sodium mercaptoundecathydrododecaborate(BHS)to solid tumors by transferring-PEG liposomes,for boron neutron-capture therapy (BNCT)

通过转移 PEG 脂质体将巯基十一氢十二硼酸钠 (BHS) 细胞内靶向实体瘤，用于硼中子俘获疗法 (BNCT)

• 发表时间: 2004
• 期刊: J.Control.Release 98,(2)
• 作者: Matsumoto S;et al.;Yoden E;Matsumoto K. et al.;Zamora CA;松本慎一;Matsumoto K;Yamamoto T;Kuroki H;Kazuo Maruyama
• 通讯作者: Kazuo Maruyama

Involvement of OCTNI(SLC22A4)in pH-Dependent Transport of Organic Cation

OCTNI(SLC22A4) 参与 pH 依赖性有机阳离子运输

• 发表时间: 2003
• 期刊: Molecular Phamaceutics Vol.11 No.1
• 作者: Ikumi Tamai