Development of formulation for gene therapy utilizing epigenetic effect of HDAC inhibitors

• Project/Area Number: 15K08035
• 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)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); 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); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヒストン脱アセチル化酵素阻害剤 / HDAC / ナノ粒子 / Vorinostat / SAHA / 遺伝子治療 / EPR効果 / PEG / プロドラッグ / vorinostat

Outline of Final Research Achievements

Histone deacetylase (HDAC) inhibitors in nature have activity to enhance the gene expression owing to the improvements in the processes of intracellular DNA delivery and intranucleus DNA transcription caused by hyper acetylation of cytosolic microtubules and core histone proteins. We therefore evaluated several types of HDAC inhibitors as enhancer of the gene expression for lipofection. In this study, we developed an efficient formulation for gene therapy in which an HDAC inhibitor, SAHA, is hybridized. The formulation is composed of PEGylated poly-lysine and PEG-SAHA.

Research Products

• [Journal Article] The Importance of 11alpha-OH, 15-oxo, and 16-en Moieties of 11α-Hydroxy-15-oxo-kaur-16-en-19-oic Acid in Its Inhibitory Activity on Melanogenesis (2017)
  • Author(s): Kuroi Azusa、Sugimura Koji、Kumagai Ayako、Kohara Arihiro、Nagaoka Yasuo、Kawahara Hidehisa、Yamahara Minori、Kawahara Nobuo、Takemori Hiroshi、Fuchino Hiroyuki
  • Journal Title: Skin Pharmacology and Physiology Volume: 30 Issue: 4 Pages: 205-215
  • DOI: 10.1159/000475471
  • Peer Reviewed / Open Access
• [Journal Article] Simple chronic colitis model using hypopigmented mice with a Hermansky-Pudlak syndrome 5 gene mutation (2016)
  • Author(s): Y. Itoh, Y. Nagaoka, Y. Katakura, H. Kawahara and H. Takemori
  • Journal Title: Pigment Cell Melanoma Res. Volume: 29 Issue: 5 Pages: 578-582
  • DOI: 10.1111/pcmr.12504
  • Peer Reviewed
• [Journal Article] Callicarpa longissima extract, carnosol-rich, potently inhibits melanogenesis in B16F10 melanoma cells (2016)
  • Author(s): M. Yamahara, K. Sugimura, A. Kumagai, H. Fuchino, A. Kuroi, M. Kagawa, Y. Itoh, H. Kawahara, Y. Nagaoka, O. Iida, N. Kawahara, H. Takemori, H. Watanabe
  • Journal Title: J. Nat. Med. Volume: 70 Issue: 1 Pages: 28-35
  • DOI: 10.1007/s11418-015-0933-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Identification of aldehydes as lipid peroxidation end-product in hair and scalp formed under the hair bleaching or UV irradiation conditions (2017)
  • Author(s): D. Fukuzaki, Y. Kokuwano, S. Kitayama, T. Sumiyoshi, Y. Nagaoka
  • Organizer: The 12th International Symposium in Science and Technology 2017
  • Int'l Joint Research
• [Presentation] Design and synthesis of PEGylated peptide micellar formulation for cancer gene therapy (2017)
  • Author(s): T. Inada, M. Katsuragi, G. Kimura, T. Sumiyoshi, Y. Nagaoka
  • Organizer: The 12th International Symposium in Science and Technology 2017
  • Int'l Joint Research
• [Presentation] Effect of histone deacetylase inhibitors on transfection of IFN-beta anti-cancer therapeutic gene into human breast cancer cells (2017)
  • Author(s): R. Sueyoshi, R. Nishimura, T. Sumiyoshi, Y. Nagaoka
  • Organizer: The 12th International Symposium in Science and Technology 2017
  • Int'l Joint Research
• [Presentation] Epigenetic Control of Therapeutic Gene Expression in Breast Cancer Cells with Histone Deacetylase Inhibitors (2016)
  • Author(s): R. Nishimura, H. Aihara, M. Katsuragi, Y. Fukushima, S. Uesato, T. Sumiyoshi, Y. Nagaoka
  • Organizer: The 11th International Symposium in Science and Technology 2016
  • Place of Presentation: 関西大学（大阪府）
  • Year and Date: 2016-07-26
  • Int'l Joint Research
• [Presentation] Design and Synthesis of PEGylated Hydroxamic Acid-Type Histone Deacetylase Inhibitor Prodrugs Having Targeting Ability to Cancer Tissue (2016)
  • Author(s): G. Kimura, H. Aihara, H. Kamijo, M. Katsuragi, T. Inada, S. Uesato, T. Sumiyoshi, Y. Nagaoka
  • Organizer: Design and Synthesis of PEGylated Hydroxamic Acid-Type Histone Deacetylase Inhibitor Prodrugs Having Targeting Ability to Cancer Tissue, The 11th International Symposium in Science and Technology 2016
  • Place of Presentation: 関西大学（大阪府）
  • Year and Date: 2016-07-26
  • Int'l Joint Research
• [Presentation] Enhanced Effect of Histone Deacetylase Inhibitors on Expression of Therapeutic shRNA Gene Targeting Proto-Oncogenic Factor, Cdc6 (2016)
  • Author(s): M. Noor, H. Aihara, R. Nishimura, M. Katsuragi, Y. Nagaoka
  • Organizer: The 11th International Symposium in Science and Technology 2016
  • Place of Presentation: 関西大学（大阪府）
  • Year and Date: 2016-07-26
  • Int'l Joint Research
• [Presentation] Histone Deacetylase Inhibitors as Lipofection Enhancer (2016)
  • Author(s): S. Mashi, T. Sumiyoshi, Y. Nagaoka
  • Organizer: The 11th International Symposium in Science and Technology 2016
  • Place of Presentation: 関西大学（大阪府）
  • Year and Date: 2016-07-26
  • Int'l Joint Research
• [Presentation] IFN-β発現遺伝子を用いたがん遺伝子治療に対するヒストン脱アセチル化酵素阻害剤の併用効果 (2016)
  • Author(s): 相原浩人、西村伶、木村元気、住吉孝明、長岡康夫
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] ヒストン脱アセチル化酵素阻害剤の遺伝子増強作用を利用したがん遺伝子治療の効率化 (2016)
  • Author(s): 西村伶、末吉燎平、上里新一、住吉孝明、長岡康夫
  • Organizer: 第66回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪薬科大学（大阪府）
• [Presentation] Design and Synthesis of PEGylated Hydroxamic Acid-Type Histone Deacetylase Inhibitor Prodrugs Having Targeting Ability to Cancer Tissues (2015)
  • Author(s): Genki Kimura, Hiroto Aihara, Hiroto Kamijo, Mizuki Katsuragi, Yuya Fukushima, Shinichi Uesato, Takaaki Sumiyoshi, Yasuo Nagaoka
  • Organizer: The 2015 International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: 米国（ホノルル）
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Neuroprotective Effect of Biflavones Isolated from Leaves of Sciadopitys verticillata (2015)
  • Author(s): Yasuaki Tanaka, Yoshihisa Hirata, Daiki Iibata, Shintaro Kitayama, Mako Tamano, Yukihiro Yoshimoto, Naofumi Fukata, Takaaki Sumiyoshi, Yasuo Nagaoka,
  • Organizer: The 2015 International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: 米国（ホノルル）
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Combination of Histone Deacetylase Inhibitors and Lipofection-Mediated INF-β Gene Therapy (2015)
  • Author(s): Rei Nishimura, Hiroto Aihara, Mizuki Katsuragi, Yuya Fukushima, Shinichi Uesato, Takaaki Sumiyoshi, Yasuo Nagaoka
  • Organizer: The 2015 International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: 米国（ホノルル）
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Remarks] 医薬品工学研究室
  • URL: http://pharm.life-bio.kansai-u.ac.jp/