Multifunctional Envelope-type Nano Device as non-viral gene delivery system for cancer therapy

多功能信封型纳米装置作为癌症治疗的非病毒基因传递系统

• 批准号: 20015003
• 负责人: HARASHIMA Hideyoshi
• 金额: $ 10.24万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20015003/
• 关键词: がん; 遺伝子治療; siRNA; ワクチン; MEND; デリバリーシステム; 多機能性エンベロープ型ナノ構造体; PPD; エンドソーム脱出; 抗腫瘍効果

In this study, we developed a multifunctional envelope-type nano device (MEND) as a non-viral siRNA delivery system for cancer, which can induce the knockdown of tumor specific genes and anti-tumor effect with no toxicity. First, we measured antigen presentation of OVA encapsulated R8-MEND in dendritic cell (DC). As a result, R8-MEND showed specific MHC class I presentation, although showed low MHC class II presentation. Moreover, mice subcutaneously immunized by R8-MEND were showed significant antitumor effect compared with control mice. Next, we prepared GALA/DMEND encapsulating siRNA core condensed with protamine. To investigate antitumor effects, we immunized DCs which were silenced SOCS1 by GALA/DMEND to mice. As a result, SOCS1- silenced DC significantly suppressed tumor growth compared with control DC. Therefore, we succeeded in enhancing antitumor effect by silencing SOCS1 of DC with GALA/DMEND. For systemic siRNA delivery, HT1080 cells were s.c. inoculated into nude mice. After i.v. injection to tumor-bearing mice, GALA/PEG-MEND exhibited high systemic stability and accumulated in tumor tissue. Target □-actin expression in tumor tissue was knockdowned more than 60% after administration of GALA/PEG-MEND (4mg siRNA/kg), which resulted in suppression of tumor growth (特願2010-39667). Serum level of ALT remained normal value, and body weight was unchanged after i.v. administration of GALA/PEG-MEND. These results suggested that GALA/PEG-MEND should be a valuable siRNA delivery system for in vivo tumor and siRNA therapeutics.

In this study, we developed a multifunctional envelope-type nano device (MEND) as a non-viral siRNA delivery system for cancer, which can induce the knockdown of tumor specific genes and anti-tumor effect with no toxicity. First, we measured antigen presentation of OVA encapsulated R8-MEND in dendritic cell (DC). As a result, R8-MEND showed specific MHC class I presentation, although showed low MHC class II presentation. Moreover, mice subcutaneously immunized by R8-MEND were showed significant antitumor effect compared with control mice. Next, we prepared GALA/DMEND encapsulating siRNA core condensed with protamine. To investigate antitumor effects, we immunized DCs which were silenced SOCS1 by GALA/DMEND to mice. As a result, SOCS1- silenced DC significantly suppressed tumor growth compared with control DC. Therefore, we succeeded in enhancing antitumor effect by silencing SOCS1 of DC with GALA/DMEND. For systemic siRNA delivery, HT1080 cells were s.c. inoculated into nude mice. After i.v. injection to tumor-bearing mice, GALA/PEG-MEND exhibited high systemic stability and accumulated in tumor tissue. Target □-actin expression in tumor tissue was knocked down more than 60% after administration of GALA/PEG-MEND (4mg siRNA/kg), which resulted in suppression of tumor growth (Special Request 2010 - 39667). Serum level of ALT remained normal value, and body weight was unchanged after i.v. administration of GALA/PEG-MEND. These results suggested that GALA/PEG-MEND should be a valuable siRNA delivery system for in vivo tumor and siRNA therapeutics.

项目成果

Nanoparticles for ex vivo siRNA delivery to dendritic cells for cancer vaccines: Programmed endosomal escape and dissociation

• DOI: 10.1016/j.jconrel.2010.01.012
• 发表时间: 2010-05-10
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Akita, Hidetaka;Kogure, Kentaro;Harashima, Hideyoshi
• 通讯作者: Harashima, Hideyoshi

脂質膜構造体

脂质膜结构

• 发表时间: 2009

Efficient MHC class I presentation by controlled intracellular trafficking of antigens in octaarginine-modified liposomes

• DOI: 10.1038/mt.2008.122
• 发表时间: 2008-08-01
• 期刊: MOLECULAR THERAPY
• 影响因子: 12.4
• 作者: Nakamura, Takashi;Moriguchi, Rumiko;Harashima, Hideyoshi
• 通讯作者: Harashima, Hideyoshi

An artificial virus-like nano carrier system: Enhanced endosomal escape of nano-particles via synergisitic action of pH-sensitive fusogenic peptide derivatives.

人工病毒样纳米载体系统：通过 pH 敏感的融合肽衍生物的协同作用增强纳米颗粒的内体逃逸。

• 发表时间: 2008
• 期刊: Anal.Bioanal.Chem. 391
• 作者: K.Sasaki;S.Chaki;Y.Nakamura;K.Kogure;H.Hamada;M.Ueno;S.Futaki;H.Harashima
• 通讯作者: H.Harashima

Multi-layered nano particles for penetrating the endosome and nuclear membrane via a steo-wise membrane fusion process.

多层纳米颗粒通过立体膜融合过程穿透核内体和核膜。

• 发表时间: 2009
• 期刊: Biomaterials 30
• 作者: H.Akita;A.Kudo;A.Minoura;M.Yamaguchi;IA.Khalil;R.Moriguchi;T.Masuda;R.Danev;K.Nagayama;K.Kogure;H.Harashima
• 通讯作者: H.Harashima