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

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K15185
• Research Institution: Kumamoto University
• Principal Investigator: 丸山 徹 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
• Keywords: ドラックデリバリー

Outline of Annual Research Achievements

増殖/再発/転移といった難治性癌に対する新規治療法戦略として、M2 マクロファージ様細胞で ある腫瘍関連マクロファージ(TAM)が注目され、TAM を M1 様細胞へ表現型転換することで、癌細胞を取り巻く悪性化微小環境の改善と、M1 様細胞による癌細胞死を誘導する”TAM の re-education”療法が有望視されている。本研究では、TAM 表面にマンノース受容体が高発現していることに着目し、より効率的な“re-education”療法を実践すべく、マクロファージ表面 の CD206 を選択的に認識する高マンノース糖鎖含有組換え型アルブミンを TAM 標的化担体として用い、これにアルブミン工学を駆使して M1 誘導剤を付加した結合体を創製することを企図した。昨年度は、平成 27 年度に作製した rMan-HSA-M1 誘導剤の M1 誘導能を in vitro 実験系でスクリーニングした。その結果、M2 化マクロファージ及びTAM様細胞に対して、 rMan-HSA-M1 誘導剤は M1 誘導能を有していることが判明した。次に、 rMan-HSA-M1 誘導剤の体内動態特性を担癌マウスで検討したところ、腫瘍への優先的な分布が確認された。さらに、rMan-HSA-M1 誘導剤投与群では、TAM様細胞の減少とM1様細胞の増加が認められ、それに伴い腫瘍サイズの縮小と肺への転移抑制が観察された。rMan-HSA-M1 誘導剤を繰り返し投与しても体重や生化学的及び血液学的パラメータへの影響は認められなかった。これらの結果から、rMan-HSA-M1 誘導剤はTAMの極性転換により腫瘍組織の微小環境を改善する“re-education”療法を実現するユニークな抗癌剤としての可能性を見出すことができた。

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 Pages: -
  • DOI: 10.1038/srep32084
  • Peer Reviewed / Open Access / 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 – 2016-11-20
  • 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 – 2016-11-20
  • 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 – 2016-11-05
  • 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 – 2016-07-20
  • 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 – 2016-07-20
  • Int'l Joint Research