Development of a novel carrier for tumor associated macrophage and its application to cancer immunotherapy

• Project/Area Number: 15K15185
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Kumamoto University
• Principal Investigator: MARUYAMA TORU 熊本大学, 薬学部, 教授 (90423657)
• Co-Investigator(Kenkyū-buntansha): 異島 優 徳島大学, 大学院医歯薬学研究部(薬学系), 准教授 (00457590) ; 渡邊 博志 熊本大学, 薬学部, 准教授 (70398220)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ドラッグデリバリーシステム / ドラックデリバリー / ドラッグデリバリー

Outline of Final Research Achievements

We have been constructed the albumin DDS platform that is albe to create albumin dervaties with active targeting potency and multiple functions. The purpose of the present study is to attempt a developement of novel immunotherapy which convert M2 type tumor associated macrophage to its M1 type. To achive this strategy, it must be nessesary to construct a novel DDS system to TAM. Here, we originally develop a TAM tardeting carrier based on recombinant mannosylated albumin with PEGlation (PEGlated Man-HSA). Actually, this carrier preferentially distributed to tumor tissues and simultaneously reduced the distribution to liver. Using albumin fusion technology, M1-inducers were attached to PEGlated Man-HSA, and it retained M1 inducing ability. Administration of M1-PEGlated Man-HSA caused the alternation of TAM phenotype from M2 type to M1 like type, and hence, suppresed the tumor growth significantly. Thus, M1-PEGlated Man-HSA has a potential as a novel immunotherapy against cancer.

Research Products

• [Journal Article] The down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism (2017)
  • Author(s): Sugimoto R, Watanabe H, Ikegami K, Enoki Y, Imafuku T, Sakaguchi Y, Murata M, Nishida K, Miyamura S, Ishima Y, Tanaka M, Matsushita K, Komaba H, Fukagawa M, Otagiri M, Maruyama T
  • Journal Title: Kidney Int Volume: 91 Pages: 658-670
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease (2016)
  • Author(s): Shibata A, Ishima Y, Ikeda M, Sato H, Imafuku T, Chuang VTG, Ouchi Y, Abe T, Watanabe H, Ishida T, Otagiri M, Maruyama T
  • Journal Title: Biochem Biophys Res Comm Volume: 479 Pages: 578-583
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Carbon monoxide-bound hemoglobin-vesicles ameliorates multi-organ injuries induced by severe acute pancreatitis in mice via their anti-inflammatory and anti-oxidant properties (2016)
  • Author(s): Nagao S, Taguchi K, Sakai H, Yamasaki K, Watanabe H, Otagiri M, Maruyama T
  • Journal Title: Int J Nanomedicine Volume: 11 Pages: 5611-5620
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of a new type of nano-sized carbon monoxide donor on treating mice with experimentally induced colitis (2016)
  • Author(s): Nagao S, Taguchi K, Miyazaki Y, Wakayama T, Chuang VT, Yamasaki K, Watanabe H, Sakai H, Otagiri M, Maruyama T
  • Journal Title: J Control Release Volume: 234 Pages: 49-58
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1 (2016)
  • Author(s): Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, Ishima Y, Kotani S, Nakajima M, Tanaka M, Matsushita K, Fukagawa M, Otagiri M, Maruyama T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 32084-32084
  • DOI: 10.1038/srep32084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Influence of Molecular Structure on O2-Binding Properties and Blood Circulation of Hemoglobin‒Albumin Clusters (2016)
  • Author(s): Yamada K, Yokomaku K, Haruki R, Taguchi K, Nagao S, Maruyama T, Otagiri M, Komatsu T
  • Journal Title: PLoS One Volume: 19 Issue: 2 Pages: 1-12
  • DOI: 10.1371/journal.pone.0149526
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biological Responsiveness and Metabolic Performance of Liposome-Encapsulated Hemoglobin (Hemoglobin-Vesicles) in Apolipoprotein E-Deficient Mice after Massive Intravenous Injection (2015)
  • Author(s): Taguchi K, Nagao S, Yamasaki K, Sakai H, Seo H, Maruyama T, Otagiri M
  • Journal Title: Biol Pharm Bull Volume: 38 Pages: 1606-16
  • NAID: 130005101572
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] S-Nitrosated human serum albumin dimer as novel nano EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes (2015)
  • Author(s): Kinoshita R, Ishima Y, Ikeda M, Kragh-Hansen U, Fang J, Nakamura H, Chuang VTG, Tanaka R, Maeda H, Kodama A, Watanabe H, Maeda H, Otagiri M, Maruyama T
  • Journal Title: J Control Release Volume: 217 Pages: 1-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia (2015)
  • Author(s): Hashimoto M, Taguchi K, Ogaki S, Watanabe H, Kinoshita M, Nishikawa K, Takeoka S, Ikeda Y, Handa M, Otagiri M, Maruyama T
  • Journal Title: J Pharm Sci Volume: 105 Pages: 3968-76
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Safety Evaluation of Hemoglobin-Albumin Cluster "HemoAct" as a Red Blood Cell Substitute. (2015)
  • Author(s): Haruki R, Kimura T, Iwasaki H, Yamada K, Kamiyama I, Kohno M, Taguchi K, Nagao S, Maruyama T, Otagiri M, Komatsu T.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 12778-12778
  • DOI: 10.1038/srep12778
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Renoprotective effect of long acting thioredoxin by modulating oxidative stress and macrophage migration inhibitory factor against rhabdomyolysis-associated acute kidney injury. (2015)
  • Author(s): Nishida K, Watanabe H, Ogaki S, Kodama A, Tanaka R, Imafuku T, Ishima Y, Giam Chuang VT, Toyoda M, Kondoh M, Wu Q, Fukagawa M, Otagiri M, Maruyama T.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 14471-14471
  • DOI: 10.1038/srep14471
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Repeated Injections of Adenosine Diphosphate-Encapsulated Liposomes Coated with a Fibrinogen γ-Chain Dodecapeptide Developed as a Synthetic Platelet Substitute on Accelerated Blood Clearance in a Healthy and an Anticancer Drug-Induced Thrombocytopenia Rat Model (2015)
  • Author(s): Taguchi K, Hashimoto M, Ogaki S, Watanabe H, Takeoka S, Ikeda Y, Handa M, Otagiri M, Maruyama T
  • Journal Title: J Pharm Sci Volume: 104 Pages: 3084-9
  • Peer Reviewed / Int'l Joint Research
• [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 VT, 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 Pages: 255-263
  • Peer Reviewed / Int'l Joint Research
• [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 VTG, Taguchi K, Inatsu A, Kinoshita M, Tanaka M, Sasaki Y, Otagiri M, Maruyama T
  • Journal Title: J Pharm Exp Ther Volume: 352 Pages: 244-57
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy via 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 Pages: 194-200
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Long-acting albumin-thioredoxin fusion protein prevents AKI-associated acute lung injury (2016)
  • Author(s): Kento Nishida, Hiroshi Watanabe, Masafumi Fukagawa and Toru Maruyama
  • Organizer: Kidney Week-ASN 2016
  • Place of Presentation: USA：Chicago McCormick Place
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] Downregulation of ABCG2, a Urate Exporter, by Parathyroid Hormone Enhances Urate Accumulation in Secondary Hyperparathyroidism (2016)
  • Author(s): Hiroshi Watanabe, Ryusei Sugimoto, Motoko Tanaka, Hirotaka Komaba, Masafumi Fukagawa and Toru Maruyama
  • Organizer: Kidney Week-ASN 2016
  • Place of Presentation: USA：Chicago McCormick Place
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] Molecular mechanism of uremic toxin induced-skeletal muscle atrophy in chronic kidney disease (2016)
  • Author(s): Hiroshi Watanabe, Yuki Enoki, Riho Arake, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa and Toru Maruyama
  • Organizer: The 2nd Asian Conference for Frailty and Sarcopenia
  • Place of Presentation: Japan, Nagoya
  • Year and Date: 2016-11-04
  • Int'l Joint Research
• [Presentation] Therapeutic application of a new type of nano-sized carbon monoxide donor in colitis model mice (2016)
  • Author(s): Saori Nagao(D3), Kazuaki Taguchi, Hiromi Sakai, Masaki Otagiri, Toru Maruyama
  • Organizer: 2016 Controlled Release Society Annual Meeting & Exposition
  • Place of Presentation: Washington State Convention Center,USA
  • Year and Date: 2016-07-17
  • Int'l Joint Research
• [Presentation] S-Nitrosated human serum albumin dimer as a novel nano EPR enhancer applied to nanotechnology based anticancer drugs (2016)
  • Author(s): Ryo Kinoshita , Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda,Masaki Otagiri, Toru Maruyama
  • Organizer: 2016 Controlled Release Society Annual Meeting & Exposition
  • Place of Presentation: Washington State Convention Center,USA
  • Year and Date: 2016-07-17
  • Int'l Joint Research
• [Presentation] S-Nitrosated human serum albumin dimer as novel nano EPR enhancer applied to nano-anticancer drugs (2015)
  • Author(s): Ryo Kinoshita, Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Organizer: Asian Federation for Pharmaceutical Sciences 2015
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-11-25
  • Int'l Joint Research
• [Presentation] Anti-tumor effect of Poly-S-nitrosated Human Serum Albumin is enhanced by phosphodiesterase 5 inhibitors (2015)
  • Author(s): Mayumi Ikeda, Yu Ishima, Ryo Kinoshita, Hiroshi Watanabe, Tsuyoshi Ikeda, Masaki Otagiri, Toru Maruyama
  • Organizer: Asian Federation for Pharmaceutical Sciences 2015
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-11-25
  • Int'l Joint Research
• [Presentation] 新規ナノEPR増強剤である一酸化窒素付加アルブミンダイマーを用いた高分子抗癌剤治療の効率化 (2015)
  • Author(s): 木下 遼、異島 優、池田 真由美、方 軍、前田 浩、渡邊 博志、 小田切 優樹、丸山 徹
  • Organizer: 第22回日本血液代替物学会年次大会
  • Place of Presentation: 熊本：熊本大学薬学部
  • Year and Date: 2015-10-22
• [Presentation] Poly-S-二トロソ化ヒト血清アルブミンのHIF-1alpha抑制効果 (2015)
  • Author(s): 異島 優、井上 亜希、小田切 優樹、渡邊 博志、丸山 徹
  • Organizer: 第31回 日本DDS学会学術集会
  • Place of Presentation: 東京：京王プラザホテル
  • Year and Date: 2015-07-02
• [Presentation] 急性及び慢性肝炎モデルマウスにおけるCD68+/CD206+クッパ―細胞由来活性酸素種を標的としたナノ抗酸化アルブミンの治療効果 (2015)
  • Author(s): 前田 仁志、一水 翔太、渡邊 博志、異島 優、小田切 優樹、丸山 徹
  • Organizer: 第31回 日本DDS学会学術集
  • Place of Presentation: 東京：京王プラザホテル
  • Year and Date: 2015-07-02