Development of novel multifunctional nanoparticles based on uptake mechanism of endogenous albumin by pancreatic cancer cells

• Project/Area Number: 18H02587
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: The University of Tokushima
• Principal Investigator: ISHIMA Yu 徳島大学, 大学院医歯薬学研究部(薬学域), 准教授 (00457590)
• Co-Investigator(Kenkyū-buntansha): 石田 竜弘 徳島大学, 大学院医歯薬学研究部(薬学域), 教授 (50325271) ; 小田切 優樹 崇城大学, 薬学部, 特任教授 (80120145)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: アルブミン / 膵臓がん / ドラッグデリバリーシステム / ナノ粒子

Outline of Final Research Achievements

Many nano antitumor drugs were developed based on the enhanced permeability and retention (EPR) effect. However, these EPR effect-based therapeutic systems a less effective in malignant tumors with low vascular permeability, such as pancreatic tumors. Since the EPR effect depends on nanoparticles' size, we first determined nanoparticles' size associating with a high tumor-targeting rate in a human pancreatic tumor xenograft model with low vascular permeability. The tumor-targeted delivery and antitumor activity of PTX loaded albumin nanoparticles were significantly improved by optimizing the mean nanoparticle diameter to 30 nm. Furthermore, the nitric oxide-PTX loaded 30 nm-albumin nanoparticles treatment on model mice achieved a significantly higher survival rate than conventional therapy. These findings suggest that 30 nm-albumin nanoparticles have a high therapeutic effect against human pancreatic tumors.

Academic Significance and Societal Importance of the Research Achievements

本研究は、治療満足度の低い膵臓がんを対象としたものであり、膵臓がんへの特異的デリバリーを可能にするキャリアの開発に成功した。このキャリアは人の体に従来から存在するアルブミンを原料としていることから、免疫原性や副反応も少ない安全なものであり、アルブミンの様々な薬物を結合する特性から、複数種類の抗がん剤の搭載も可能である。臨床応用されることで、現状の膵臓がんの治療満足度の改善が見込められ、学術的意義のみならず、社会的意義も大きいと考えている。

Research Products

• [Int'l Joint Research] Monash University Malaysia(マレーシア)
• [Int'l Joint Research] Monash University Malaysia(マレーシア)
• [Journal Article] Repeated Administration of Kupffer Cells-Targeting Nanoantioxidant Ameliorates Liver Fibrosis in an Experimental Mouse Model (2020)
  • Author(s): Maeda H, Minayoshi Y, Ichimizu S, Mizuta Y, Nagasaki T, Matsusaka K, Oshiro S, Oniki K, Saruwatari J, Ishima Y, Watanabe H, Otagiri M, Maruyama T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 1 Pages: 93-101
  • DOI: 10.1248/bpb.b19-00599
  • NAID: 130007779193
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin (2020)
  • Author(s): Tsukigawa Kenji、Imoto Shuhei、Yamasaki Keishi、Nishi Koji、Tsutsumi Toshihiko、Yokoyama Shoko、Ishima Yu、Otagiri Masaki
  • Journal Title: Pharmaceuticals Volume: 14 Issue: 1 Pages: 22-22
  • DOI: 10.3390/ph14010022
  • 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] Carbon monoxide rescues the developmental lethality of experimental rat models of rhabdomyolysis-induced acute kidney injury (2020)
  • Author(s): Taguchi K, Ogaki S, Nagasaki T, Yanagisawa H, Nishida K, Maeda H, Enoki Y, Matsumoto K, Sekijima H, Ooi K, Ishima Y, Watanabe H, Fukagawa M, Otagiri M, Maruyama T
  • Journal Title: J Pharmacol Exp Ther Volume: 372(3) Issue: 3 Pages: 355-365
  • DOI: 10.1124/jpet.119.262485
  • Peer Reviewed / Open Access
• [Journal Article] Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon. (2020)
  • Author(s): El Sayed, M.M., Takata, H., Shimizu, T., Kawaguchi, Y., Abu Lila, A.S., Elsadek, N.E., Alaaeldin, E., Ishima, Y., Ando, H., Kamal, A., Sarhan, H.A., Ishida, T.
  • Journal Title: J. Conrol. Release Volume: 323 Pages: 102-109
  • DOI: 10.1016/j.jconrel.2020.04.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] S-Nitrosated alpha-1-acid glycoprotein exhibits antibacterial activity against multidrug-resistant bacteria strains and synergistically enhances the effect of antibiotics (2019)
  • Author(s): Ishima Yu、Watanabe Kaori、Chuang Victor T. G.、Takeda Iyo、Kuroda Teruo、Ogawa Wakano、Watanabe Hiroshi、Iwao Yasunori、Ishida Tatsuhiro、Otagiri Masaki、Maruyama Toru
  • Journal Title: FASEB BioAdvances Volume: 1 Issue: 3 Pages: 137-150
  • DOI: 10.1096/fba.1018
  • NAID: 120007153321
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment (2019)
  • Author(s): Ishima Yu、Mimono Ai、Tuan Giam Chuang Victor、Fukuda Tetsuya、Kusumoto Kohshi、Okuhira Keiichiro、Suwa Yoshiaki、Watanabe Hiroshi、Ishida Tatsuhiro、Morioka Hiroshi、Maruyama Toru、Otagiri Masaki
  • Journal Title: IUBMB Life Volume: 72 Issue: 4 Pages: 641-651
  • DOI: 10.1002/iub.2203
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell-penetrating mechanism of intracellular targeting albumin: Contribution of macropinocytosis induction and endosomal escape (2019)
  • Author(s): Ichimizu Shota、Watanabe Hiroshi、Maeda Hitoshi、Hamasaki Keisuke、Ikegami Komei、Chuang Victor Tuan Giam、Kinoshita Ryo、Nishida Kento、Shimizu Taro、Ishima Yu、Ishida Tatsuhiro、Seki Takahiro、Katsuki Hiroshi、Futaki Shiroh、Otagiri Masaki、Maruyama Toru
  • Journal Title: Journal of Controlled Release Volume: 304 Pages: 156-163
  • DOI: 10.1016/j.jconrel.2019.05.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distribution of Polysulfide in Human Biological Fluids and Their Association with Amylase and Sperm Activities (2019)
  • Author(s): Ikeda Mayumi、Ishima Yu、Chuang Victor T. G.、Sakai Maki、Osafune Hiroki、Ando Hidenori、Shimizu Taro、Okuhira Keiichiro、Watanabe Hiroshi、Maruyama Toru、Otagiri Masaki、Akaike Takaaki、Ishida Tatsuhiro
  • Journal Title: Molecules Volume: 24 Issue: 9 Pages: 1689-1689
  • DOI: 10.3390/molecules24091689
  • NAID: 120006995454
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of SAPK/JNK signaling pathway in copper enhanced zinc-induced neuronal cell death. (2019)
  • Author(s): Tanaka KI1, Shimoda M1, Kasai M1, Ikeda M2, Ishima Y2, Kawahara M
  • Journal Title: Toxicol Sci. 2019 Feb 15. pii: kfz043. doi: 10.1093/toxsci/kfz043. [Epub ahead of print] Volume: Feb15 Issue: 1 Pages: 043-043
  • DOI: 10.1093/toxsci/kfz043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel S-sulfhydrated human serum albumin preparation suppresses melanin synthesis, (2018)
  • Author(s): Ikeda M, Ishima Y, Kinoshita R, Chuang VTG, Tasaka N, Matsuo N, Watanabe H, Shimizu T, Ishida T, Otagiri M, Maruyama T,
  • Journal Title: Redox Biology Volume: 14 Pages: 354-360
  • DOI: 10.1016/j.redox.2017.10.007
  • NAID: 120007029979
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity. (2018)
  • Author(s): Tanaka KI, Shimoda M, Chuang VTG, Nishida K, Kawahara M, Ishida T, Otagiri M, Maruyama T, Ishima Y.
  • Journal Title: Int J Pharm. Volume: 535 Issue: 1-2 Pages: 140-147
  • DOI: 10.1016/j.ijpharm.2017.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic Fusion of Type-I Interferon to a Recombinant Albumin Mutant with polymannosylated N-linked oligosaccharide attached is a Novel and Superior Kupffer Cell Targeting Agent for the Treatment of Hepatitis. (2018)
  • Author(s): Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T.
  • Journal Title: Drug Delivery Volume: 25 Issue: 1 Pages: 1067-1077
  • DOI: 10.1080/10717544.2018.1464083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery (2018)
  • Author(s): Ichimizu Shota、Watanabe Hiroshi、Maeda Hitoshi、Hamasaki Keisuke、Nakamura Yuka、Chuang Victor Tuan Giam、Kinoshita Ryo、Nishida Kento、Tanaka Ryota、Enoki Yuki、Ishima Yu、Kuniyasu Akihiko、Kobashigawa Yoshihiro、Morioka Hiroshi、Futaki Shiro、Otagiri Masaki、Maruyama Toru
  • Journal Title: Journal of Controlled Release Volume: 277 Pages: 23-34
  • DOI: 10.1016/j.jconrel.2018.02.037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual therapeutic effects of an albumin-based nitric oxide donor on two experimental models of chronic kidney disease (2018)
  • Author(s): Oshiro S, Ishima Y, Maeda H, Honda N, Bi J, Kinoshita R, Ikeda M, Iwao Y, Imafuku T, Nishida K, Miyamura S, Watanabe H, Otagiri M, Maruyama T
  • Journal Title: J Pharm Sci Volume: 107 Issue: 3 Pages: 848-855
  • DOI: 10.1016/j.xphs.2017.10.023
  • Peer Reviewed / Int'l Joint Research
• [Presentation] アルブミン結合型パクリタキセル製剤であるAbraxaneの新たな腫瘍移行機序の発見 (2020)
  • Author(s): 濵眞壱、安藤英紀、清水太郎、異島優、石田竜弘
  • Organizer: 日本薬剤学会第35年会
• [Presentation] PEG修飾タンパクのPEG鎖長や修飾数が及ぼす抗PEG抗体産生と血中滞留性低下への影響 (2020)
  • Author(s): 福田悠花、中島祟樹、長野一也、異島優、石田竜弘
  • Organizer: 日本薬剤学会第35年会
• [Presentation] ヒト生体液におけるポリスルフィドプールの発見とその生理学的意義 (2020)
  • Author(s): 異島優、池田真由美、石田竜弘
  • Organizer: 第47回日本毒性学会学術年会
  • Invited
• [Presentation] 生体液中の活性イオウ分子種含有タンパク質の同定と生理学的意義の解明 (2020)
  • Author(s): 長船裕輝、池田真由美、安藤英紀、清水太郎、異島優、石田竜弘
  • Organizer: 第93回日本生化学会大会
• [Presentation] 酸化型ポリスルフィドタンパク質によるユニークな抗酸化作用機構 (2020)
  • Author(s): 異島優、池田真由美、田坂菜々美、石田竜弘
  • Organizer: 第73回日本酸化ストレス学会・第20回日本NO学会合同学術集会
  • Invited
• [Presentation] Functional Elucidation of Polysulfides In Serum Albumin and Development of Biomimetic Donor of Polysulfides. (2019)
  • Author(s): Ikeda, M., Ishima, Y., Watanabe, H., Maruyama, T., Otagiri, M., Ishida, T.
  • Organizer: 2019 CRS Annual Meeting & Exposition.
  • Int'l Joint Research
• [Presentation] Quantitative determination of polysulfide in plasma proteins and biological human fluids using a novel Sulfide elimination from polysulfide (SEP) method. (2019)
  • Author(s): Ishima, Y.
  • Organizer: The 1st International Conference on Persulfide and Sulfur Metabolism in Biology and Medicine
  • Int'l Joint Research / Invited
• [Presentation] Human albumin based drug delivery: SNO-albumin dimer for cancer therapeutic application. (2019)
  • Author(s): Otagiri, M., Ishima, Y., Taguchi, K., Maruyama, T.
  • Organizer: 17th International Symposium on Blood Substitutes & Oxygen Therapeutics
  • Int'l Joint Research / Invited
• [Presentation] 血清アルブミンの酸化ストレス応答を模倣した新規抗酸化剤の設計 (2019)
  • Author(s): 池田真由美、異島優、清水太郎、安藤英紀、奥平桂一郎、渡邊博志、丸山徹、小田切優樹、石田竜弘
  • Organizer: 日本薬剤学会第34年会
• [Presentation] 難治性膵臓がんへの高い移行性を有するアルブミンナノ粒子の開発 (2019)
  • Author(s): 平川尚樹、異島優、木下遼、清水太郎、丸山徹、奥平桂一郎、石田竜弘
  • Organizer: 日本薬剤学会第34年会
• [Presentation] ヒト血清アルブミンに存在するポリスルフィドによるユニークな酸化ストレス応答 (2019)
  • Author(s): 池田真由美、異島優、酒井真紀、清水太郎、安藤英紀、渡邊博志、丸山徹、小田切優樹、石田竜弘
  • Organizer: 第19回日本NO学会学術集会
• [Presentation] 亜鉛(Zn)/銅(Cu)の神経細胞死におけるSAPK/JNK経路の関与 (2019)
  • Author(s): 田中健一郎、下田実可子、廣木美果、久保田真帆、池田真由美、異島優、川原正博
  • Organizer: 第46回日本毒性学会学術年会
• [Presentation] 慢性肝障害治療に対する肝クッパー細胞指向性1型インターフェロンの有用性評価 (2019)
  • Author(s): 皆吉勇紀、前田仁志、渡邊博志、異島優、小田切優樹、丸山徹
  • Organizer: 第35回日本DDS学会学術集会
• [Presentation] 抗体医薬を用いたがん治療に対するEPR増強剤SNO-HSA-dimerの効果 (2019)
  • Author(s): 異島優、木下遼、池田真由美、丸山徹、小田切優樹、石田竜弘
  • Organizer: 第35回日本DDS学会学術集会
• [Presentation] 細胞膜透過型アルブミンの細胞内移行機序の解明～マクロピノサイトーシス誘導とエンドソーム脱出経路～ (2019)
  • Author(s): 一水翔太、渡邊博志、前田仁志、清水太郎、異島優、石田竜弘、二木史朗、小田切優樹、丸山徹
  • Organizer: 第35回日本DDS学会学術集会
• [Presentation] アルブミン研究の新展開～新たな生体防御機構解明へ～ (2019)
  • Author(s): 異島優
  • Organizer: 九重セミナー第43回西日本薬剤学研究会
  • Invited
• [Presentation] 難治性膵臓がんにおけるアルブミンナノ粒子のサイズ最適化の検討 (2019)
  • Author(s): 異島優、木下遼、平川尚樹、石田竜弘、小田切優樹、丸山徹
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] EPR増強剤の併用は膵臓癌に対するnab-パクリタキセルの治療効果を増強する (2019)
  • Author(s): 丸山徹、木下遼、前田仁志、渡邊博志、小田切優樹、異島優
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] Development of a novel tumor microenvironment-targeted drug deliver carrier (2019)
  • Author(s): 水田夕稀、前田仁志、皆吉勇紀、一水翔太、木下遼、異島優、渡邊博志、小田切優樹、馬場秀夫、丸山徹
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] 内因性アルブミン輸送システムを介した膵臓がんへのアルブミン標的化 (2019)
  • Author(s): 異島優
  • Organizer: 日本薬物動態学会第34回年会
  • Invited
• [Presentation] A Novel S-Sulfhydrated Human Serum Albumin Preparation Suppresses Melanin Synhtesis. (2018)
  • Author(s): Ikeda, M., Tasaka, N., Shimizu, T., Ishima, Y., Ishida, T.
  • Organizer: 5th World Congress on Hydrogen Sulfide in Biology&Medicine
  • Int'l Joint Research
• [Presentation] アルブミン製剤中のサルフェン硫黄含有量の差異と抗酸化能の評価 (2018)
  • Author(s): 酒井真紀、池田真由美、今福匡司、清水太郎、丸山徹、小田切優樹、異島優、石田竜弘
  • Organizer: 第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会
• [Presentation] 生物由来健康食品に含まれる活性イオウ分子種の検出 (2018)
  • Author(s): 長船裕輝、池田真由美、酒井真紀、清水太郎、異島優、石田竜弘
  • Organizer: 第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会
• [Presentation] ポリスルフィド付加血清アルブミンによるメラニン産生の抑制 (2018)
  • Author(s): 池田真由美、清水太郎、丸山徹、小田切優樹、異島優、石田竜弘
  • Organizer: 第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会
• [Presentation] 新規腫瘍DDSキャリアである共有結合型アルブミンナノ粒子の有用性評価 (2018)
  • Author(s): 木下遼、異島優、渡邊博志、清水太郎、石田竜弘、小田切優樹、丸山徹
  • Organizer: 日本薬剤学会第33年会
• [Presentation] 新規抗菌剤SNO-AGPの多剤耐性菌に対する克服効果 (2018)
  • Author(s): 異島優、渡辺佳織、小田切優樹、石田竜弘、丸山徹
  • Organizer: 日本薬剤学会第33年会
• [Presentation] アルブミン付加製剤の基礎と未来 (2018)
  • Author(s): 異島優
  • Organizer: 第34回日本DDS学会学術集会
  • Invited
• [Presentation] 共有結合型アルブミンナノ粒子をキャリアとしたナノDDS抗がん剤の開発及び有用性評価 (2018)
  • Author(s): 平川尚樹、木下遼、異島優、清水太郎、丸山徹、奥平桂一郎、石田竜弘
  • Organizer: 第34回日本DDS学会学術集会
• [Presentation] 多剤耐性菌および真菌に対するS‐ニトロソ化Alpha1―酸性糖蛋白質の効果 (2018)
  • Author(s): 異島優、石田竜弘, 金城雄樹、丸山徹、小田切優樹
  • Organizer: 医療薬学フォーラム 2018
  • Invited
• [Presentation] 生体液中の活性イオウ分子種の検出と機能解明 (2018)
  • Author(s): 池田真由美、異島優、渡邊博志、赤池孝章、丸山徹、小田切優樹、石田竜弘
  • Organizer: 第40回生体膜と薬物の相互作用シンポジウム
• [Presentation] 共有結合型アルブミンナノ粒子を用いたセラノスティックナノDDS抗がん剤の開発 (2018)
  • Author(s): 平川尚樹、異島優、木下遼、清水太郎、丸山徹、奥平桂一郎、石田竜弘
  • Organizer: 第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] 一酸化窒素を利用した血管透過性制御とがん治療応用 (2018)
  • Author(s): 異島優、木下遼、池田真由美、丸山徹、小田切優樹、石田竜弘
  • Organizer: 日本薬学会第139年会
  • Invited
• [Remarks] 徳島大学薬学部 薬物動態制御学
  • URL: https://www.tokushima-u.ac.jp/ph/faculty/labo/ykz/