Development of PEGylated Histone Deacetylase Inhibitor Having Prolonged Blood Retention and EPR effect

• Project/Area Number: 24590152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kansai University
• Principal Investigator: NAGAOKA Yasuo 関西大学, 化学生命工学部, 教授 (90243039)
• Co-Investigator(Kenkyū-buntansha): HATTORI Yoshiyuki 星薬科大学, 薬学部, 准教授 (90350222)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ヒストン脱アセチル化酵素阻害剤 / HDAC / PEG / 抗がん剤 / ナノ粒子 / EPR効果 / Vorinostat / SAHA / プロドラッグ

Outline of Final Research Achievements

Since the hydroxamate type histone deacetylase inhibitor (HDI) like SAHA is readily degraded in physiological conditions, it has low bioavailability and is not applicable to the solid cancer so far. In order to overcome this drawback, we protected hydroxamic acid moiety with a polyethylene glycol (PEG) peptide conjugate and form micelle expecting to provide stealth effect and EPR (enhanced permeability and retention) effect to prolong the blood retention and to enhance the drug accumulation to the cancer tissue. PEG-peptide-SAHA is synthesized with coupling of SAHA with PEG-peptide prepared by solid-phase method. Micelles, whose average diameter is 40 nm, were formed and the molecules in the micelles were linked each other with S-S bonds to stabilize them. Retention of the molecule in blood, as well as anti-proliferative activity of PEG-peptide-SAHA micelle was higher than that of intact SAHA, indicating that PEGylated SAHA can efficiently act as prodrug of HDI.

Research Products

• [Journal Article] Influence of the carbamate fungicide benomyl on the gene expression and activity of aromatase in the human breast carcinoma cell line MCF-7 (2015)
  • Author(s): Yasuyuki Kawaratani , Takeshi Matsuoka , Yoshiyuki Hirata , Naofumi Fukata , Yasuo Nagaoka , Shinichi Uesato
  • Journal Title: Environmental Toxicology and Pharmacology Volume: 39 Issue: 1 Pages: 292-299
  • DOI: 10.1016/j.etap.2014.11.032
  • Peer Reviewed / Open Access
• [Journal Article] Synergistic Antitumor Effect of a Combination of Paclitaxel and Carboplatin with Nobiletin from Citrus depressa on Non-Small-Cell Lung Cancer Cell Lines (2014)
  • Author(s): S. Uesato, H. Yamashita, R. Maeda, Y. Hirata, M. Yamamoto, S. Matsue, Y. Nagaoka, M. Shibano, M. Taniguchi, K. Baba, M. Ju-Ichi
  • Journal Title: Planta. Med. Volume: 80 Issue: 06 Pages: 452-457
  • DOI: 10.1055/s-0034-1368321
  • Peer Reviewed
• [Journal Article] Induction of melanogenesis by 4'-O-methylated flavonoids in B16F10 melanoma cells (2013)
  • Author(s): I. Horibe, Y. Satoh, Y. Shiota, A. Kumagai, N. Horike, H. Takemori, S. Uesato, S. Sugie, K. Obata, H. Kawahara, Y. Nagaoka.
  • Journal Title: J. Nat. Med. Volume: 67 Issue: 4 Pages: 705-710
  • DOI: 10.1007/s11418-012-0727-y
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of new orally bioavailable 2-amino-5-(thiophen-2-yl)benzamide-series histone deacetylase inhibitors, possessing an aqueous soluble functional group as a surface recognition domain (2012)
  • Author(s): Y. Hirata, M. Hirata, Y. Kawaratani, M. Shibano, M. Taniguchi, M. Yasuda, Y. Ohmomo, Y. Nagaoka, K. Baba, S. Uesato
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 5 Pages: 1926-1930
  • DOI: 10.1016/j.bmcl.2012.01.053
  • Peer Reviewed
• [Presentation] PEG化ヒストン脱アセチル化酵素阻害剤の抗がん活性 (2015)
  • Author(s): 上條洋士、木村元気、服部善之、住吉孝明、上里新一、長岡康夫
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学他（神戸）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Enhanced Effect of Histone Deacetylase Inhibitors on Expression of Therapeutic shRNA Gene Targeting Proto-Oncogenic Factor, CDC6 (2014)
  • Author(s): Hiroto Aihara, Mariko Kobayashi, Hiromi Yoshino, Yoshihisa Hirata, Shinichi Uesato, Takaaki Sumiyoshi, Yasuo Nagaoka
  • Organizer: 50th International Conference on Medicinal Chemistry
  • Place of Presentation: フランス（ルーアン）
  • Year and Date: 2014-07-02 – 2014-07-04
• [Presentation] ANTITUMOR EFFECT OF PEGYLATED HISTONE DEACETYLASE INHIBITOR (2013)
  • Author(s): Hiroto Kamijo, Mariko Kobayashi, Mako Tamano, Yukihiro Yoshimoto, Shinichi Uesato, and Yasuo Nagaoka
  • Organizer: 49th International Conference on Medicinal Chemistry
  • Place of Presentation: Nice, France
• [Presentation] ENHANCED EFFECT OF HISTONE DEACETYLASE INHIBITORS ON THE EXPRESSION OF LIPOFECTED GENES (2012)
  • Author(s): M. Kobayashi, H. Yoshino, H. Kamijo, K. Mizushima, S. Matsue, S. Uesato, Y. Nagaoka
  • Organizer: 48th International Conference on Medicinal Chemistry (RICT 2012)
  • Place of Presentation: Poitiers, France