Augmentation of EPR effect and therapeutic effect of nanomedicine by improving tumor microenvironment

• Project/Area Number: 16K08217
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Sojo University
• Principal Investigator: 方 軍 崇城大学, 薬学部, 准教授 (20412736)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: EPR効果 / 一酸化窒素 / 一酸化炭素 / ナノメディシン / DDS / 腫瘍微小環境 / ニトログリセリン / アルギニン / ヒドロキシウレア / ドラッグデリバリー / 腫瘍

Outline of Annual Research Achievements

本年度、平成２８年度と平成２９年度の研究成果を踏まえ、マウス皮下移植がんモデル（S180, C26, B16)を用いてNOドナーとCO産生薬による組織内NO,COの産生及び腫瘍血流の変化を検討した。また、CO産生薬により最近本研究室で開発されたPDTナノプローブ（pHPMA結合したピロフェオフォルバイト,P-PyF）の腫瘍イメージング効果とPDT治療効果の増強について検討を行った。期間中に以下のことが明らかになった。
１、各種NOドナーの投与により、S180腫瘍モデルにおいて、腫瘍特異的なNOの産生が認められた。正常組織において、顕著なNOの増加が見られなかった。
２、ミセル型COドナーSMA/CORM2、長い血中半減期を示し、EPR効果により腫瘍選択的に集積し、COを放出することが確認され、肝臓などの正常臓器におけるCOの産生がほとんど見られなかった。高分子型CO産生誘導剤PEG-heminもより腫瘍選択的にCO産生を誘導することが認められた。SMA/CORM2とPEG-heminによる腫瘍内CO産生のピークはそれぞれ投与後2時間と24時間であることがわかり、高分子抗がん薬との併用治療プロトコール（タイミング）を確立した。
３、蛍光イメージング装置（SAI-1000）を用い、S180腫瘍モデルにおいて腫瘍血管造影を行った結果、CO産生薬投与により腫瘍血流の回復と増加が認められた。
４、CO産生薬とP-PyFとの併用により、より顕著な腫瘍イメージングが得られた。PDT治療効果も2-3倍増強された。
以上の結果より、CO産生薬SMA/CORM2とPEG-heminはEPR効果増強剤になる可能性が強く示唆され、その臨床への応用が期待されている。

Research Products

• [Int'l Joint Research] Inst. Macromolecular Chemistry, AS CR(チェコ)
• [Int'l Joint Research] Inst. Macromolecular Chemistry, AS CR(チェコ)
• [Int'l Joint Research]
• [Int'l Joint Research] Inst. Macromolecular Chemistry, AS CR(チェコ)
• [Journal Article] Augmentation of the Enhanced Permeability and Retention Effect with Nitric Oxide-Generating Agents Improves the Therapeutic Effects of Nanomedicines. (2018)
  • Author(s): Islam, W., Fang, J., Imamura, T., Etrych, T., Subr, V., Ulbrich K., & Maeda, H.
  • Journal Title: Mol Cancer Ther. Volume: 17 Pages: 2643-2653
  • DOI: 10.1158/1535-7163.mct-18-0696
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-(2-hydroxypropyl)methacrylamide polymer conjugated pyropheophorbide-a, a promising tumor-targeted theranostic probe for photodynamic therapy and imaging. (2018)
  • Author(s): Fang J, Subr V, Islam W, Hackbarth S, Islam R, Etrych T, Ulbrich K, Maeda H.
  • Journal Title: Eur J Pharm Biopharm. Volume: 130 Pages: 165-176
  • DOI: 10.1016/j.ejpb.2018.06.005
  • Peer Reviewed / Int'l Joint Research
• [Presentation] がんセラノスティックスを目指したHPMAポリマー結合型Pyropheophorbide-aの開発 (2018)
  • Author(s): 方 軍、Vladimr Subr、Waliul Md. Islam、Steffen Hackbarth、Tomas Etrych、Karel Ulbrich、前田 浩
  • Organizer: 第34回日本DDS学会
• [Presentation] N-(2-Hydroxypropyl)methacrylamide polymer conjugated pyropheophorbide-a, a promising tumor-targeted theranostic probe for photodynamic therapy and imaging. (2018)
  • Author(s): Jun Fang, Vladimr Subr, Waliul Islam, Steffen Hackbarth, Tomáš Etrych, Karel Ulbrich, Hiroshi Maeda.
  • Organizer: International Conference on Medicinal Chemistry & Drug Design.
  • Int'l Joint Research / Invited
• [Presentation] Polymeric pyropheophorbide-a, a promising tumor-targeted theranostic probe for photodynamic therapy and imaging. (2018)
  • Author(s): Jun Fang, Waliul Islam, Hiroshi Maeda.
  • Organizer: 77th Annual Meeting of the Japanese Cancer Association.
• [Presentation] Augmentation of tumor-targeted PDT by using nitric oxide generating agents. (2017)
  • Author(s): Jun Fang
  • Organizer: International symposium of polymer therapeutics focusing the EPR effect and its Future Development
  • Int'l Joint Research / Invited
• [Presentation] Characterization and evaluation of photodynamic effect of HPMA copolymer based nanoprobes. (2017)
  • Author(s): Jun Fang, Waliul Islam, Vladmimir Subr, Karel Ulbrich, Hiroshi Maeda
  • Organizer: Trilateral, Japan-Israel-Czech Republic, International Symposium of Polymer Therapeutics Focusing on the Targeted Nanomedicines
  • Int'l Joint Research / Invited
• [Presentation] 一酸化窒素産生薬を用いるEPR効果増強法の検討 (2017)
  • Author(s): 方軍、Waliul Islam、Tomas Etrych、Petr Chytil、Karel Ulbrich、前田浩
  • Organizer: 第33回日本DDS学会
• [Presentation] Nitric oxide generating agents enhance tumor-targeted photodynamic therapy by modulating tumor microenvironment (2017)
  • Author(s): Jun Fang, Waliul Md. Islam, Hiroshi Maeda
  • Organizer: 第76回日本癌学会
• [Presentation] Augmentation of tumor-targeted photodynamic therapy and imaging by modulating tumor microenvironment using nitric oxide generating agents. (2017)
  • Author(s): Jun Fang, Waliul Md. Islam, Vladmimir Subr, Tomas Etrych, Karel Ulbrich, Hiroshi Maeda.
  • Organizer: The 44th Annual Meeting and Exposition of the Controlled Release Society
  • Int'l Joint Research
• [Presentation] Photodynamic therapy and imaging based on tumor-targeted nanoprobe, pHPMA-conjugated zinc protoporphyrin, and its augmentation. (2016)
  • Author(s): Jun Fang, Hideaki Nakamura, Vladmimir Subr, Karel Ulbrich, Hiroshi Maeda.
  • Organizer: International Conference on Pharmaceutical Chemistry
  • Place of Presentation: Frankfurt, Germany
  • Year and Date: 2016-09-05
  • Int'l Joint Research
• [Presentation] Photodynamic therapy and imaging based on tumor-targeted nanoprobe, pHPMA-conjugated zinc protoporphyrin, and its augmentation. (2016)
  • Author(s): Jun Fang, Hideaki Nakamura, Vladmimir Subr, Karel Ulbrich, Hiroshi Maeda.
  • Organizer: 11th International Symposium on Polymers Therapeutics From Laboratory to Clinical Practice.
  • Place of Presentation: The Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain
  • Year and Date: 2016-05-23
  • Int'l Joint Research