Construction of an Innovative Bone Marrow Delivery System of Anticancer Drug for Control of Malignant Tumors' Bone Metastasis

• Project/Area Number: 25670085
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Sojo University
• Principal Investigator: OTAGIRI Masaki 崇城大学, 薬学部, 教授 (80120145)
• Co-Investigator(Kenkyū-buntansha): MARUYAMA Toru 熊本大学, 薬学部, 教授 (90423657) ; WATANABE Hiroshi 熊本大学, 薬学部, 准教授 (70398220)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルブミン / リポソーム / 骨髄指向性 / デリバリーシステム / 体内動態解析 / 薬力学的評価 / 抗がん剤 / 腫瘍治療効果

Outline of Final Research Achievements

This research aims to construct an anticancer drug delivery system using bone marrow-directed liposome as a carrier, and explore its clinical application in malignant tumors’ bone metastasis treatment. The drug was incorporated in the bone marrow directed liposome for physicochemical, pharmacological efficacy and pharmacokinetic properties examinations. As such, erythropoietin (EPO) liposome was produced to effectively and selectively deliver EPO to its site of action in bone marrow. The formulation characteristics, transferability to bone marrow, and hematopoietic effect were being examined. In comparison to EPO alone which did not demonstrate any desirable effects, liposome formulation was found to have produced significant site directed delivery improvement effect.

Research Products

• [Journal Article] Cross-linked human serum albumin dimer has the potential for use as a plasma retaining-agent for the fatty acid-conjugated antidiabetic drugs. (2015)
  • Author(s): Taguchi K, Chuang VTG, Yamasaki K, Urata Y, Tanaka R, Anraku M, Seo H, Kawai K, Maruyama T, Komatsu T, Otagiri M
  • Journal Title: J Pharm Pharmacol. Volume: 67 Issue: 2 Pages: 255-263
  • DOI: 10.1111/jphp.12338
  • Peer Reviewed
• [Journal Article] Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nano-antioxidant for the treatment of two acute hepatitis models. (2015)
  • Author(s): Maeda H, Hirata K, Watanabe H, Ishima Y, Chuang VT, Taguchi K, Inatsu A, Kinoshita M, Tanaka M, Sasaki Y, Otagiri M, Maruyama T.
  • Journal Title: J Pharmacol Exp Ther Volume: 352 Issue: 2 Pages: 244-257
  • DOI: 10.1124/jpet.114.219493
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a model of acetaminophen-induced hepatotoxicity in different weekly-aged ICR mice. (2015)
  • Author(s): Taguchi K, Tokuno M, Yamasaki K, Kadowaki D, Seo H, Otagiri M
  • Journal Title: Lab Anim. Volume: -
  • Peer Reviewed
• [Journal Article] Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin. (2015)
  • Author(s): Tsukigawa K, Liao L, Nakamura H, Fang J, Greish K, Otagiri M, Maeda H.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 3 Pages: 270-278
  • DOI: 10.1111/cas.12592
  • Peer Reviewed
• [Journal Article] Effect of different chemical bonds in pegylation of zinc protoporphyrin that affects drug release, intracellular uptake, and therapeutic effect in the tumor. (2015)
  • Author(s): Tsukigawa K, Nakamura H, Fang J, Otagiri M, Maeda H
  • Journal Title: Eur J Pharm Biopharm. Volume: 89 Pages: 259-270
  • DOI: 10.1016/j.ejpb.2014.12.016
  • Peer Reviewed
• [Journal Article] Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide. (2015)
  • Author(s): Ishima Y, Inoue A, Fang J, Kinoshita R, Ikeda M, Watanabe H, Maeda H, Otagiri M, Maruyama T.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 2 Pages: 194-200
  • DOI: 10.1111/cas.12577
  • Peer Reviewed / Open Access
• [Journal Article] Interactions of Linezolid with Two Major Serum Proteins, Human Serum Albumin and Alpha-1 Acid Glycoprotein. (2015)
  • Author(s): Taguchi K, Yamasaki1 K, Shiga A, Otagiri M, Seo H.
  • Journal Title: J. Pharmacol Clin Toxicol. Volume: 3 Pages: 1045-1045
  • Peer Reviewed
• [Journal Article] N-acetyl-Lmethionine is a superior protectant of human serum albumin against photooxidation and reactive oxygen species compared to N-acetyl-L-tryptophan (2014)
  • Author(s): Kouno Y, Anraku M, Yamasaki K, Okayama Y, Iohara D, Ishima Y, Maruyama T, Kragh-Hansen U, Hirayama F, Otagiri M
  • Journal Title: Biochim Biophys Acta Volume: (in press) Issue: 9 Pages: 2806-2812
  • DOI: 10.1016/j.bbagen.2014.04.014
  • Peer Reviewed
• [Journal Article] Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis. (2014)
  • Author(s): Nagao S, Taguchi K, Sakai H, Tanaka R, Horinouchi H, Watanabe H, Kobayashi K, Otagiri M, Maruyama T.
  • Journal Title: Biomaterials. Volume: 35 Issue: 24 Pages: 6553-6562
  • DOI: 10.1016/j.biomaterials.2014.04.049
  • Peer Reviewed
• [Journal Article] Tuning of Poly-S-Nitrosated Human Serum Albumin as Superior Antitumor Nanomedicine (2014)
  • Author(s): Ishima Y, Fang J, Kragh-Hansen U, Yin H, Liao L, Katayama N, Watanabe H, Kai T, Suenaga A, Maeda H, Otagiri M, Maruyama T
  • Journal Title: J Pharm Sci Volume: 103 Issue: 7 Pages: 2184-2188
  • DOI: 10.1002/jps.24020
  • Peer Reviewed
• [Journal Article] Carbon monoxide-bound red blood cell resuscitation ameliorates hepatic injury induced by massive hemorrhage and red blood cell resuscitation via hepatic cytochrome P450 protection in hemorrhagic shock rats. (2014)
  • Author(s): Ogaki S, Taguchi K, Watanabe H, Ishima Y, Otagiri M, Maruyama T.
  • Journal Title: J Pharm Sci. Volume: 103 Issue: 7 Pages: 2199-2206
  • DOI: 10.1002/jps.24029
  • Peer Reviewed
• [Journal Article] Effects of chitosan on oxidative stress and related factors in hemodialysis patients. (2014)
  • Author(s): Anraku M, Tanaka M, Hiraga A, Nagumo K, Imafuku T, Maezaki Y, Iohara D, Uekama K, Watanabe H, Hirayama F, Maruyama T, Otagiri M
  • Journal Title: Carbohydr Polym Volume: 112 Pages: 152-157
  • DOI: 10.1016/j.carbpol.2014.05.078
  • Peer Reviewed
• [Journal Article] Therapeutic impact of erythropoietin-encapsulated liposomes targeted to bone marrow on renal anemia. (2014)
  • Author(s): Miyazaki Y, Taguchi K, Sou K, Watanabe H, Ishima Y, Miyakawa T, Mitsuya H, Fukagawa M, Otagiri M, Maruyama T.
  • Journal Title: Mol Pharm. Volume: 11 Issue: 11 Pages: 4238-4248
  • DOI: 10.1021/mp500453a
  • Peer Reviewed
• [Journal Article] Therapeutic Impact of Human Serum Albumin-Thioredoxin Fusion Protein on Influenza Virus-Induced Lung Injury Mice. (2014)
  • Author(s): Tanaka R, Ishima Y, Enoki Y, Kimachi K, Shirai T, Watanabe H, Chuang VT, Maruyama T, Otagiri M.
  • Journal Title: Front Immunol Volume: 5 Pages: 561-561
  • DOI: 10.3389/fimmu.2014.00561
  • Peer Reviewed / Open Access
• [Journal Article] Albumin Fusion Prolongs the Antioxidant and Anti-Inflammatory Activities of Thioredoxin in Mice with Acetaminophen-Induced Hepatitis. (2014)
  • Author(s): Tanaka R, Ishima Y, Maeda H, Kodama A, Nagao S, Watanabe H, Chuang VT, Otagiri M, Maruyama T.
  • Journal Title: Mol Pharm. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity. (2014)
  • Author(s): Kodama A, Watanabe H, Tanaka R, Kondo M, Chuang VT, Wu Q, Endo M, Ishima Y, Fukagawa M, Otagiri M, Maruyama T.
  • Journal Title: Biochim Biophys Acta. Volume: 1840 Issue: 3 Pages: 1152-1162
  • DOI: 10.1016/j.bbagen.2013.12.007
  • Peer Reviewed
• [Journal Article] Poly-s-nitrosated albumin as a safe and effective multifunctional antitumor agent : characterization, biochemistry and possible future therapeutic applications (2013)
  • Author(s): Ishima Y, Kragh-Hansen U, Maruyama T, Otagiri M
  • Journal Title: Biomed Res Int Volume: 2013 Pages: 353892-353892
  • DOI: 10.1155/2013/353892
  • Peer Reviewed
• [Journal Article] Effect of albumin on transthyretin and amyloidogenic transthyretin Val30Met disposition and tissue deposition in familial amyloidotic polyneuropathy. (2013)
  • Author(s): Taguchi K, Jono H, Kugimiya-Taguchi T, Nagao S, Su Y, Yamasaki K, Mizuguchi M, Maruyama T, Ando Y, Otagiri M.
  • Journal Title: Life Sci. Volume: 18 Issue: 25-26 Pages: 1017-22
  • DOI: 10.1016/j.lfs.2013.10.031
  • Peer Reviewed
• [Journal Article] Albumin-drug interaction and its clinical implication. (2013)
  • Author(s): Yamasaki K, Chuang VT, Maruyama T, Otagiri M.
  • Journal Title: Biochim Biophys Acta. Volume: 1830 Issue: 12 Pages: 5435-43
  • DOI: 10.1016/j.bbagen.2013.05.005
  • Peer Reviewed
• [Journal Article] Redox properties of serum albumin. (2013)
  • Author(s): Anraku M, Chuang VT, Maruyama T, Otagiri M.
  • Journal Title: Biochim Biophys Acta. Volume: 1830 Issue: 12 Pages: 5465-5472
  • DOI: 10.1016/j.bbagen.2013.04.036
  • Peer Reviewed
• [Journal Article] UW solution improved with high anti-apoptotic activity by S-nitrosated human serum albumin. (2013)
  • Author(s): Ishima Y
  • Journal Title: Nitric Oxide. Volume: 印刷中 Pages: 36-42
  • DOI: 10.1016/j.niox.2013.01.004
  • Peer Reviewed
• [Journal Article] Albumin domain II mutant with high bilirubin binding affinity has a great potential as serum bilirubin excretion enhancer for hyperbilirubinemia treatment. (2013)
  • Author(s): Minomo A
  • Journal Title: Biochim Biophys Acta. Volume: 印刷中 Issue: 4 Pages: 141-8
  • DOI: 10.1016/j.bbagen.2013.01.006
  • Peer Reviewed
• [Presentation] S-ニトロソ化α1-酸性タンパク質による抗生物質の多剤耐性克服と機序解明 (2014)
  • Author(s): 丸山 徹
  • Organizer: 第36回 生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 徳島大学 大塚講堂（徳島県徳島市）ほか
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] Therapeutic Applications of Albumin-Thioredoxin Fusion Protein. (2014)
  • Author(s): Masaki Otagiri
  • Organizer: 10th European Symposium on Biochemical Engineering Sciences and 6th International Forum on Industrial Bioprocesses Lille
  • Place of Presentation: Lille (France)
  • Year and Date: 2014-09-07 – 2014-09-10
  • Invited
• [Presentation] Pharmacokinetics of serum albumin variants. (2014)
  • Author(s): M.Otagiri
  • Organizer: Innovation workshop on Albumin: The next generation protein therapeutics 2014
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2014-07-12
  • Invited
• [Presentation] NO付加型ヒト血清アルブミンの臨床応用へのアプローチ (2014)
  • Author(s): 異島 優
  • Organizer: 第14回日本NO学会学術集会
  • Place of Presentation: ホテルニューオータニ佐賀（佐賀県佐賀市）
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] インフルエンザ肺炎モデルマウスに対するヒト血清アルブミン－チオレドキシン融合タンパク質の有効性評価 (2014)
  • Author(s): 異島優
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本・ホテル日航熊本他
• [Presentation] Development of recombinant serum albumin. (2013)
  • Author(s): Masaki Otagiri
  • Organizer: The International Liver Congress 2013 48th annual meeting of the European association for the study of the liver
  • Place of Presentation: オランダ・アムステルダム
  • Invited
• [Presentation] Albumin-Thioredoxin Fusion Protein is Effective in Suppressing Lung Injury. (2013)
  • Author(s): Masaki Otagiri
  • Organizer: 9th Retrometabolism Based Drug Design and Targeting Conferenece
  • Place of Presentation: アメリカ・オーランド
  • Invited
• [Presentation] Poly-S-nitrosated Human Serum Albumin inhibits the Expression of P-glycoprotein Transporter in Human Multidrug-resistant Tumor (2013)
  • Author(s): Yu Ishima
  • Organizer: the 5th Asian Arden conference
  • Place of Presentation: 愛知・Aichi Gakuin University
• [Presentation] PRECLINICAL STUDIES OF HEMOGLOBIN-VESICLES AS AN ARTIFICIAL OXYGEN CARRIER IN NON-HUMAN PRIMATE. (2013)
  • Author(s): Kazuaki Taguchi
  • Organizer: 日本薬物動態学会 第28回年会
  • Place of Presentation: 東京・タワーホール船堀
• [Presentation] THERAPEUTIC IMPACT OF HUMAN SERUM ALBUMIN-THIOREDOXIN FUSION PROTEIN, LONG-ACTING ANTI-OXIDATIVE AND ANTI-INFLAMMATORY MODULATOR, AGAINST ACETAMINOPHEN-INDUCED ACUTE LIVER FAILURE (2013)
  • Author(s): Ryota Tanaka
  • Organizer: 日本薬物動態学会 第28回年会
  • Place of Presentation: 東京・タワーホール船堀
• [Presentation] Preclinical studies of hemoglobin-vesicles as an artificial oxygen carrier in non-human primate. (2013)
  • Author(s): Kazuaki Taguchi
  • Organizer: The XIVth International Symposium on Blood Substitutes and Oxygen Therapeutics.
  • Place of Presentation: 中国・成都
• [Presentation] The effect of N-acetyl-methionine on photo-stability of albumin products. (2013)
  • Author(s): Makoto Anraku
  • Organizer: Asian Federation for Pharmaceutical Sciences 2013
  • Place of Presentation: 韓国・済州島
• [Book] 薬剤学実験法必携マニュアル Ⅱ生物薬剤学 4.薬物分布実験 タンパク結合：血漿・組織タンパク結合 (2014)
  • Author(s): 小田切 優樹、 丸山 徹
  • Total Pages: 423
  • Publisher: 南江堂
• [Book] ACHUTE PHASE PROTEINS (2013)
  • Author(s): Masaki Otagiri
  • Total Pages: 180
  • Publisher: INTECH
• [Book] HUMAN SERUM ALBUMIN (2013)
  • Author(s): Masaki Otagiri
  • Total Pages: 510
  • Publisher: Sojo University Publishing Center