Development of non-invasive retina-targeted siRNA delivery system for overcoming a blood-retina barrier

• Project/Area Number: 16K01397
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biomedical engineering/Biomaterial science and engineering
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Takashima Yuuki 東京薬科大学, 薬学部, 准教授 (70236214)
• Research Collaborator: Fukuhara Takeshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: siRNA delivery / リポソーム / モノクローナル抗体 / 網膜 / 点眼 / モノクロ―ナル抗体 / イムノリポソーム / 網膜色素上皮細胞 / ナノキャリア / 点眼剤 / 薬物送達システム / siRNAデリバリー

Outline of Final Research Achievements

The objective is to prepare the non-invasive retina-targeted nanocarriers for siRNA delivery to suppress the production of vascular endothelium growth factor which cause retina disease leading to late-blindness. The monoclonal antibody (mAb) which has specific internalizing ability to retinal pigment epithelium (RPE) was produced and followed by modification to liposomes which encapsulate complexes of siRNA and multifunctional peptide. The mAb-modified liposome shows small particle size which is permeable to retina through choroid. In addition, the mAb-liposomes was extremely accumulated in the isolated retinal membrane by eye drop to rat.

Academic Significance and Societal Importance of the Research Achievements

眼には血液網膜関門等の高度なバリア機能が在るため、網膜への薬物送達は容易ではなく、中途失明や視力低下を起こす網膜疾患に対しては硝子体内への直接注射等の侵襲的な薬物治療がなされる。本研究において、標的とする網膜に指向性を示すモノクローナル抗体を組み込んだ微小キャリアを設計し、通常困難とされる点眼投与によって病因タンパク質の産生を細胞レベルで阻害する核酸の送達が可能であることを明らかとした。本研究での知見は患者の身体的・精神的負担を軽減する薬物治療への貢献が期待される。

Research Products

• [Presentation] 網膜指向型モノクローナル抗体修飾リポソームの作製及び網膜移行性評価 (2018)
  • Author(s): 西田祥伍、高島由季、山内文太、藤井寛、瀬上慶祐、安達裕太、金沢貴憲、茨木ひさ子、瀬田康生、福原武志
  • Organizer: 第34回日本DDS学会
• [Presentation] 点眼による網膜への核酸送達のためのモノクローナル抗体複合ナノ粒子の設計 (2018)
  • Author(s): 山内文太、高島由季、西田祥伍、藤井寛、瀬上慶祐、茨木ひさ子、瀬田康生、福原武志
  • Organizer: 第43回製剤・創剤セミナー
• [Presentation] 網膜を指向するモノクローナル抗体修飾リポソーム点眼剤の設計 (2018)
  • Author(s): 清水菜央、高島由季、西田祥伍、山内文太、藤井寛、瀬上慶祐、安達裕太、茨木ひさ子、瀬田康生、福原武志
  • Organizer: 第62回日本薬学会関東支部大会
• [Presentation] Preparation of RPE-targeted nanocomplex for siRNA delivery to posterior segment of the eye (2018)
  • Author(s): Yuuki Takashima, Keisuke Segami, Yutaka Fujii, Yuta Adachi, Hisako Ibaraki, Takanori Kanazawa, Yasuo Seta
  • Organizer: 11th PBP World Meeting
  • Int'l Joint Research
• [Presentation] Preparation of RPE-targeted nanocomplex for siRNA delivery to posterior segment of the (2018)
  • Author(s): Yuuki Takashima, Keisuke Segami, Yutaka Fujii, Yuta Adachi, Hisako Ibaraki, Takanori Kanazawa, Yasuo Seta
  • Organizer: 11th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical
  • Int'l Joint Research
• [Presentation] Neovascularization-suppressive effect in rat retina after eye drop of anti VEGF-siRNA (2017)
  • Author(s): Yuuki Takashima, Yuta Adachi, Hisako Ibaraki, Takanori Kanazawa, Yasuo Seta
  • Organizer: 30 Years of Drug Delivery Research
  • Int'l Joint Research
• [Presentation] 抗VEGF-siRNA搭載リポソーム点眼剤による網膜疾患ラットにおける血管新生抑制効果 (2017)
  • Author(s): 藤井 寛、高島由季、安達裕太、茨木ひさ子、金沢貴憲、瀬田康生
  • Organizer: 第6回医薬工3大学包括連携推進シンポジウム