Development of siRNA delivery system tot tumor vesssels: optimization of intracellular trafficking and pharmacokinetics

• Project/Area Number: 25893001
• Research Category: Grant-in-Aid for Research Activity start-up
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: SAKURAI Yu 北海道大学, 薬学研究科(研究院), その他 (00707234)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: siRNA / リポソーム / アクティブターゲティング / 血管新生阻害療法 / がん治療 / 腫瘍血管内皮細胞 / ドラッグデリバリーシステム / がん / ドラッグデリバリー

Outline of Final Research Achievements

Angiogenesis is indispensable for a progression of cancer via a supplement with oxygen and nutrients. I developed a nanocarrier for delivering small interfering RNA (siRNA) to tumor endothelial cells (TECs). I called the carrier “RGD-MEND”. SiRNA is encapsulated in lipid envelope of RGD-MEND, and further cyclic RGD, which recognize TECs, is displayed on the surface of RGD-MEND. When the formulated siRNA to inhibit a growth of TECs was administered into tumor bearing-mice via the tail vein, tumor growth was significantly inhibited. In addition, mRNA expression level or the target gene was reduced by siRNA injection.

Research Products

• [Journal Article] The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus (2015)
  • Author(s): Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S, Watanabe T, Iijima S, Sakurai Y, Watashi K, Tsutsumi S, Sato Y, Akita H, Wakita T, Rice CM, Harashima H, Kohara M, Tanaka Y, Takaoka A
  • Journal Title: Immunity Volume: 42 Pages: 123-132
  • DOI: 10.1016/j.immuni.2014.12.016
  • NAID: 120005822521
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Construction of an aptamer modified liposomal system targeted to tumor endothelial cells (2014)
  • Author(s): Ara MN, Matsuda T, Hyodo M, Sakurai Y, Ohga N, Hida K, Harashima H
  • Journal Title: Biol Pharm Bull Volume: 37 Pages: 1742-1749
  • NAID: 130004703894
  • Peer Reviewed
• [Journal Article] Ligand density at the surface of a nanoparticle and different uptake mechanism: two important factors for successful siRNA delivery to liver endothelial cells (2014)
  • Author(s): Akhter A, Hayashi Y, Sakurai Y, Ohga N, Hida K, Harashima H
  • Journal Title: Int J Pharm Volume: 475 Pages: 227-237
  • DOI: 10.1016/j.ijpharm.2014.08.048
  • Peer Reviewed
• [Journal Article] An aptamer ligand based liposomal nanocarrier system that targets tumor endothelial cells. (2014)
  • Author(s): Ara MN, Matsuda T, Hyodo M, Sakurai Y, Hatakeyama H, Ohga N, Hida K, Harashima H
  • Journal Title: Biomaterials Volume: 35 Pages: 7110-7120
  • DOI: 10.1016/j.biomaterials.2014.04.087
  • NAID: 120005512022
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Improvement of doxorubicin efficacy using liposomal anti-polo-like kinase 1 siRNA in human renal cell carcinomas (2014)
  • Author(s): Sakurai Y, Hatakeyama H, Akita H, Harashima H.
  • Journal Title: Mol Pharm Volume: in press Pages: 2713-2719
  • DOI: 10.1021/mp500245z
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system. (2014)
  • Author(s): Yu Sakurai, Hiroto Hatakeyama, Yusuke Sato, Mamoru Hyodo, Hidetaka Akita, Noritaka Ohga, Kyoko Hida, Hideyoshi Harashima
  • Journal Title: Journal of Controlled Release Volume: 173 Pages: 110-118
  • DOI: 10.1016/j.jconrel.2013.10.003
  • NAID: 120005476193
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 腫瘍血管内皮細胞へのアクティブターゲティング型siRNAデリバリーシステム (2013)
  • Author(s): 櫻井遊、畠山浩人、秋田秀万、大賀則孝、樋田京子、原島秀吉
  • Organizer: 第23回アンチセンスシンポジウム
  • Place of Presentation: 徳島大学 大塚講堂、徳島
• [Presentation] 腫瘍血管内皮細胞へのin vivo siRNA導入法の確立 (2013)
  • Author(s): 2) 櫻井遊、畠山浩人、佐藤悠介、兵藤守、秋田英万、大賀則孝、樋田京子、原島秀吉
  • Organizer: 第21回日本血管生物医学会
  • Place of Presentation: 千里阪急ホテル、大阪
• [Presentation] Development of an in vivo Active siRNA Delivery System to Tumor Endothelial Cells using Cyclic RGD-modified Liposomal siRNA (2013)
  • Author(s): 1) Y. Sakurai, H. Hatakeyama, Y. Sato, M. Hyodo, H. Akita, H. Harashima
  • Organizer: 9 th Annual Meeting of Oligonucleotide Therapeutics Society
  • Place of Presentation: Royal Continental Hotel、ナポリ、イタリア
• [Remarks] 未来創剤学研究室
  • URL: http://www.pharm.hokudai.ac.jp/mirai/
• [Remarks] 薬剤分子設計学研究室
  • URL: http://www.pharm.hokudai.ac.jp/yakusetu/
• [Remarks] 未来創剤学研究室
  • URL: http://www.pharm.hokudai.ac.jp/mirai/