New treatment strategy for acute lower limb ischemia by using nano-micell

• Project/Area Number: 16K10652
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: The University of Tokyo
• Principal Investigator: KOYAMA HIROYUKI 東京大学, 医学部附属病院, 登録研究員 (10241994)
• Co-Investigator(Kenkyū-buntansha): 宮原 拓也 東京大学, 医学部附属病院, 助教 (20704943) ; 三浦 裕 東京大学, 大学院工学系研究科(工学部), 客員研究員 (40557980) ; 保科 克行 東京大学, 医学部附属病院, 講師 (90571761)
• 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: Nano-micelle / ischemia / ナノ粒子 / 虚血肢モデル / PICsome / 血管再生医療 / 急性下肢虚血 / ドラッグデリバリー

Outline of Final Research Achievements

There are many unsolved problems in angiogenesis therapy for inoperable severe peripheral artery disease. In this study, we attempted to develop a drug delivery system to the collateral circulation site by polyion complex type nanoparticles as new angiogenesis therapy. The present study revealed that precise adjustment of the particle size can control the accumulation efficiency at the target site in systemic administration. Furthermore, we succeeded in synthesizing particles containing IL-1β as a drug, which can be expected to promote collateral circulation. However, the accumulation of the particles at the target site was weak, and it was inferred that the factor is attributed to the difference in the particle stability in blood. In the future, reexamination of the molecular design of drug-containing nanoparticles and optimization of the particle adjustment conditions are desired.

Academic Significance and Societal Importance of the Research Achievements

下肢虚血に対する薬剤投与は、静脈注射での力価では毒性がでる可能性があるため、出来る限り低容量が望ましい。その点ナノミセルを用いたドラッグデリバリーでは、病変部のみに集積し、同部でreleaseされるため効率的である。ただ内包する薬剤とナノミセルとの相性があり、サイズ、電荷など、臨床応用に向けてまだハードルがある。今回の成果で、内包化の最適化が示され、今後の臨床応用への重要なデータを示すことができた。

Research Products

• [Journal Article] Proresolving Lipid Mediators Resolvin D1 and Protectin D1 Isomer Attenuate Neointimal Hyperplasia in the Rat Carotid Artery Balloon Injury Model. (2019)
  • Author(s): Makino Y, Miyahara T, Nitta J, Miyahara K, Seo A, Kimura M, Suhara M, Akai A, Akagi D, Yamamoto K, Hoshina K.
  • Journal Title: Journal of Surgical Research Volume: 233 Pages: 104-110
  • DOI: 10.1016/j.jss.2018.07.049
  • Peer Reviewed / Open Access
• [Journal Article] Targeting ability of self-assembled nanomedicines in rat acute limb ischemia model is affected by size (2018)
  • Author(s): Suhara Masamitsu、Miura Yutaka、Cabral Horacio、Akagi Daisuke、Anraku Yasutaka、Kishimura Akihiro、Sano Masaya、Miyazaki Takuya、Nakamura Noriko、Nishiyama Ayako、Kataoka Kazunori、Koyama Hiroyuki、Hoshina Katsuyuki
  • Journal Title: Journal of Controlled Release Volume: 286 Pages: 394-401
  • DOI: 10.1016/j.jconrel.2018.07.049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stenotic lesion level did not affect outcomes of carotid endarterectomy (2017)
  • Author(s): Masamitsu Suhara, Katsuyuki Hoshina, Atsushi Akai, Toshihiko Isaji, Daisuke Akagi, Kota Yamamoto, Takuya Miyahara and Toshiaki Watanabe
  • Journal Title: Asian Cardiovascular & Thoracic Annals Volume: 25 Issue: 4 Pages: 271-275
  • DOI: 10.1177/0218492317703269
  • Peer Reviewed / Open Access
• [Presentation] 急性下肢虚血下の側副血行路形成に対するナノ粒子を利用したドラッグデリバリーシステムの有用性 (2017)
  • Author(s): 須原正光、保科克行
  • Organizer: 第58回日本脈管学会総会
• [Presentation] 間歇性跛行症状に対し治療された症例の中期予後の検討 (2016)
  • Author(s): 須原 正光, 赤木 大輔, 保科 克行, 瀬尾 明彦, 木村 賢, 牧野 能久, 根元 洋光, 白須 拓郎, 芳賀 真, 望月 康晃, 松倉 満, 宮原 拓也, 山本 晃太, 渡邉 聡明
  • Organizer: 第44回日本血管外科学会総会
  • Place of Presentation: 大阪