Development of Biomimetic DDS to improve healthy longevity and its application to the treatment for sarcopenia

• Project/Area Number: 20K21485
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Maruyama Toru 熊本大学, 大学院生命科学研究部(薬), 教授 (90423657)
• Co-Investigator(Kenkyū-buntansha): 渡邊 博志 熊本大学, 大学院生命科学研究部(薬), 准教授 (70398220) ; 前田 仁志 熊本大学, 大学院生命科学研究部(薬), 助教 (80791483)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2020: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: サルコペニア / 健康寿命 / ミオスタチン / アルブミン / ドラッグデリバリーシステム / バイオミメティック / 筋萎縮因子 / アルブミン融合技術 / チオレドキシン / グレリン / sActRIIB / バイオミメティクDDS

Outline of Research at the Start

健康長寿社会を実現するためには健康寿命の延伸が必須であり、そのためには“サルコペニア”対策が鍵を握る。本研究では、筋萎縮阻害因子のバイオミメティックな薬物送達システム(DDS）を開発し、4種類の筋萎縮モデル動物を用いて有用性を評価する。筋萎縮阻害因子としては、チオレドキシン、グレリン、sActRⅡB(筋萎縮因子ミオスタチン阻害剤）の3種類を選択するとともに、血中滞溜性に富み、筋組織への移行性も高い一酸化窒素付加ヒト血清アルブミンダイマーをDDS担体として用いる。本ハイブリッド融合体はバイオミメティックDDSとして、優れた筋萎縮抑制・筋力維持作用を発揮することが期待される。

Outline of Final Research Achievements

pDNA fused with HSA dimer and muscle atrophy inhibitor was prepared, and then the fusion protein was expressed in yeast, and purified by several chromatographic methods. Then, an S-nitroso compound was prepared with isoamyl nitrite. We examined the pharmacokinetics of the fusion protein in mice and found that the retention in blood significantly increased and the muscle distribution was significantly enhanced compared with the muscular atrophy inhibitor alone. We also evaluated the pharmacological effect of the fusion protein against muscle atrophy model animals and found that the decrease in body weight and skeletal muscle weight was significantly suppressed, and the muscle strength and muscular endurance were recovered compared with the saline group.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は廃用症候群の予防など他の疾患治療へも応用可能である。例えば、癌に代表される消耗性疾患の場合、カヘキシアと呼ばれる骨格筋萎縮を呈し、 QOLの低下はもとより予後を悪化させる。カヘキシアは高頻度でサルコペニアを合併するため、本融合体の開発はカヘキシア対策にも有望である。加えて、宇宙空間では、重力の低下に伴い、筋委縮や筋力低下が生じやすくなり、5～11日間の滞在で約20%程度の筋肉が減少する。そのため、近い将来に実現する宇宙時代では、この筋肉萎縮・筋力消失への対策も切望されているが、サルコペニア治療薬の開発はこれら宇宙科学への貢献も期待できる。

Research Products

• [Journal Article] Effects of Uremic Toxins on the Binding of Aripiprazole to Human Serum Albumin (2021)
  • Author(s): Koji Nishi, Keiki Sakurama, Hiroshi Watanabe, Toru Maruyama, Keishi Yamasaki, Masaki Otagiri
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 44 Issue: 3 Pages: 437-441
  • DOI: 10.1248/bpb.b20-00929
  • NAID: 130007993459
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2021-03-01
  • Peer Reviewed / Open Access
• [Journal Article] Cysteinylated albumin as a potential biomarker for the progression of kidney disease in patients with type 2 diabetes (2021)
  • Author(s): Imafuku T, Watanabe H, Oniki K, Yoshida A, Kato H, Nakano T, Tokumaru K, Fujita I, Arimura N, Maeda H, Sakamoto Y, Kondo N, Morita A, Saruwatari J, Tanaka M, Matsushita K, Wada T, Fukagawa M, Otagiri M, Fitzgerald ML, Jinnouchi H, Maruyama T.
  • Journal Title: Diabetes Care Volume: 26 Issue: 6 Pages: e115-e117
  • DOI: 10.2337/dc20-3003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An acute phase protein alfa1-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action (2021)
  • Author(s): Hiroshi Watanabe*,#, Rui Fujimura*, Yuto Hiramoto*, Ryota Murata, Kento Nishida, Jing Bi, Tadashi Imafuku, Hisakazu Komori, Hitoshi Maeda, Ayumi Mukunoki, Toru Takeo, Naomi Nakagata, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Sci Rep. Volume: 12;11(1) Issue: 1 Pages: 7953-7953
  • DOI: 10.1038/s41598-021-87217-8
  • Peer Reviewed / Open Access
• [Journal Article] Reduction-responsive and multi-drug deliverable albumin nanoparticles: an antitumor drug to Abraxane_ against human pancreatic tumor-bearing mice (2021)
  • Author(s): Naoki Hirakawa, Yu Ishima, Ryo Kinoshita, Ryuto Nakano, Victor Tuan Giam Chuang, Hidenori Ando, Taro Shimizu, Keiichiro Okuhira, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida
  • Journal Title: ACS Applied Bio Materials Volume: 268 Issue: 5 Pages: 4302-4309
  • DOI: 10.1021/acsabm.1c00110
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reduction-responsive and multi-drug deliverable albumin nanoparticles: an antitumor drug to Abraxane_ against human pancreatic tumor-bearing mice (2021)
  • Author(s): Naoki Hirakawa, Yu Ishima, Ryo Kinoshita, Ryuto Nakano, Victor Tuan Giam Chuang, Hidenori Ando, Taro Shimizu, Keiichiro Okuhira, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida
  • Journal Title: ACS Applied Bio Materials Volume: 4,5 Pages: 4302-4309
  • DOI: 10.1016/j.lfs.2020.118991
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Cinacalcet on the Redox Status of Albumin in Secondary Hyperparathyroidism Patients Receiving Hemodialysis (2020)
  • Author(s): Imafuku Tadashi、Tanaka Motoko、Tokunaga Koki、Miyamura Shigeyuki、Kato Hiromasa、Tanaka Shoma、Nakano Takehiro、Hirata Kenshiro、Kadowaki Daisuke、Maeda Hitoshi、Matsushita Kazutaka、Otagiri Masaki、Komaba Hirotaka、Fukagawa Masafumi、Watanabe Hiroshi、Maruyama Toru
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 10 Pages: 1583-1590
  • DOI: 10.1248/bpb.b20-00472
  • NAID: 130007920876
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-10-01
  • Peer Reviewed / Open Access
• [Journal Article] Drug Delivery System for Refractory Cancer Therapy <i>via</i> an Endogenous Albumin Transport System (2020)
  • Author(s): Ishima Yu、Maruyama Toru、Otagiri Masaki、Ishida Tatsuhiro
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 68 Issue: 7 Pages: 583-588
  • DOI: 10.1248/cpb.c20-00026
  • NAID: 130007867325
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2020-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Effects of surface-deacetylated chitin nanofibers on non-alcoholic steatohepatitis model rats and their gut microbiota (2020)
  • Author(s): Goto Miwa、Iohara Daisuke、Michihara Akihiro、Ifuku Shinsuke、Azuma Kazuo、Kadowaki Daisuke、Maruyama Toru、Otagiri Masaki、Hirayama Fumitoshi、Anraku Makoto
  • Journal Title: International Journal of Biological Macromolecules Volume: 164 Pages: 659-666
  • DOI: 10.1016/j.ijbiomac.2020.07.184
  • Peer Reviewed / Open Access
• [Journal Article] Systemic and sustained thioredoxin analogue prevents acute kidney injury and its-associated distant organ damage in renal ischemia reperfusion injury mice (2020)
  • Author(s): Kento Nishida*, Hiroshi Watanabe*,#, Masako Miyahisa, Yuto Hiramoto, Hiroto Nosaki, Rui Fujimura, Hitoshi Maeda, Masaki Otagiri, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Sci Rep Volume: 26;10(1): Issue: 1 Pages: 20635-20635
  • DOI: 10.1038/s41598-020-75025-5
  • Peer Reviewed / Open Access
• [Journal Article] The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models (2020)
  • Author(s): Abdullah-Al-Shoeb Mohammad、Sasaki Kenta、Kikutani Saori、Namba Nanami、Ueno Keiichi、Kondo Yuki、Maeda Hitoshi、Maruyama Toru、Irie Tetsumi、Ishitsuka Yoichi
  • Journal Title: Antioxidants Volume: 9 Issue: 10 Pages: 965-965
  • DOI: 10.3390/antiox9100965
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin (2020)
  • Author(s): Yamasaki Keishi、Sakurama Keiki、Nishi Koji、Watanabe Hiroshi、Maruyama Toru、Seo Hakaru、Otagiri Masaki、Taguchi Kazuaki
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 109 Issue: 9 Pages: 2919-2924
  • DOI: 10.1016/j.xphs.2020.06.011
  • Peer Reviewed / Open Access
• [Journal Article] Indoxyl sulfate contributes to adipose tissue inflammation through the activation of NADPH oxidase (2020)
  • Author(s): Shoma Tanaka*, Hiroshi Watanabe*,#, Takehiro Nakano, Tadashi Imafuku, Hiromasa Kato, Kai Tokumaru, Nanaka Arimura, Yuki Enoki, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Toxins (Basel) Volume: 5;12(8): Issue: 8 Pages: 502-502
  • DOI: 10.3390/toxins12080502
  • Peer Reviewed / Open Access
• [Journal Article] Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects (2020)
  • Author(s): Hiroshi Watanabe*,#, Masako Miyahisa*, Mayuko Chikamatsu*, Kento Nishida, Yuki Minayoshi, Mei Takano, Shota Ichimizu, Yoshihiro Kobashigawa, Hiroshi Morioka, Hitoshi Maeda, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: J Control Release Volume: 10;324: Pages: 522-531
  • DOI: 10.1016/j.jconrel.2020.05.036
  • Peer Reviewed / Open Access
• [Journal Article] A synthetic retinoic acid receptor agonist Am80 ameliorates renal fibrosis via inducing the production of alpha-1-acid glycoprotein (2020)
  • Author(s): Watanabe Hiroshi、Bi Jing、Murata Ryota、Fujimura Rui、Nishida Kento、Imafuku Tadashi、Nakamura Yuka、Maeda Hitoshi、Mukunoki Ayumi、Takeo Toru、Nakagata Naomi、Kurauchi Yuki、Katsuki Hiroshi、Tanaka Motoko、Matsushita Kazutaka、Fukagawa Masafumi、Maruyama Toru
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11424-11424
  • DOI: 10.1038/s41598-020-68337-z
  • Peer Reviewed / Open Access
• [Journal Article] Advanced oxidation protein products contribute to renal tubulopathy via perturbation of renal fatty acids (2020)
  • Author(s): Imafuku, T., Watanabe, H., Satoh, T., Matsuzaka, T., Inazumi, T., Kato, H., Tanaka, S., Nakamura, Y., Nakano, T., Tokumaru, K., Maeda, H., Tanaka, M., Matsushita, K., Tsuchiya, S., Sugimoto, Y., Shimano, H., Fukagawa, M., and Maruyama, T.
  • Journal Title: Kidney360 Volume: 1 Issue: 8 Pages: 781-796
  • DOI: 10.34067/kid.0000772019
  • Peer Reviewed / Open Access
• [Journal Article] Changes in redox state of albumin before and after kidney transplantation in patients with end-stage renal disease (2020)
  • Author(s): Ryota Tanaka, Tadashi Imafuku, Yosuke Suzuki, Kento Nishida, Kotaro Matsusaka, Toshitaka Shin, Yuhki Sato, Yu Ishima, Hiroshi Watanabe, Hiromitsu Mimata, Toru Maruyama, Hiroki Itoh
  • Journal Title: Clin Biochem Volume: 81 Pages: 20-26
  • DOI: 10.1016/j.clinbiochem.2020.04.010
  • Peer Reviewed / Open Access
• [Journal Article] In vivo evaluation of drug dialyzability in a rat model of hemodialysis. (2020)
  • Author(s): Fukunaga M, Kadowaki D, Mori M, Hagiwara S, Narita Y, Saruwatari J, Tanaka R, Watanabe H, Yamasaki K, Taguchi K, Ito H, Maruyama T, Otagiri M, Hirata S.
  • Journal Title: PLoS One Volume: 15 Issue: 6 Pages: 20-26
  • DOI: 10.1371/journal.pone.0233925
  • Peer Reviewed / Open Access
• [Journal Article] The<I> DsbA-L</I> gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties. (2020)
  • Author(s): Kentaro Oniki, Hirofumi Nohara, Ryunosuke Nakashima, Yui Obata, Narumi Muto, Yuki Sakamoto, Keiko Ueno-Shuto, Tadashi Imafuku, Yu Ishima, Hiroshi Watanabe, Toru Maruyama, Koji Otake, Yasuhiro Ogata, Mary Ann Suico, Hirofumi Kai, Tsuyoshi Shuto, and Junji Saruwatari.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5973-5973
  • DOI: 10.1038/s41598-020-62872-5
  • Peer Reviewed / Open Access
• [Journal Article] α1-acid glycoprotein attenuates adriamycin-induced nephropathy via CD163 expressing macrophages induction (2020)
  • Author(s): Fujimura Rui、Watanabe Hiroshi、Nishida Kento、Fujiwara Yukio、Koga Tomoaki、Bi Jing、Imafuku Tadashi、Kobayashi Kazuki、Komori Hisakazu、Miyahisa Masako、Maeda Hitoshi、Tanaka Motoko、Matsushita Kazutaka、Wada Takashi、Fukagawa Masafumi、Maruyama Toru
  • Journal Title: Kidney360 Volume: ー Issue: 5 Pages: 343-353
  • DOI: 10.34067/kid.0000782019
  • Peer Reviewed / Open Access
• [Presentation] 物質共生マテリアルであるアルブミンを基盤としたバイオミメティックな機能分子設計 (2021)
  • Author(s): 丸山徹
  • Organizer: 日本薬剤学会 第36年会
  • Invited