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EPR-effect driven tumor delivery of multifunctional boron nanomedicine for neutron capture therapy

Research Project

Project/Area Number 22KF0311
Project/Area Number (Other) 21F21407 (2021-2022)
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeMulti-year Fund (2023)
Single-year Grants (2021-2022)
Section外国
Review Section Basic Section 90120:Biomaterials-related
Research InstitutionKumamoto University

Principal Investigator

新留 琢郎  熊本大学, 大学院先端科学研究部(工), 教授 (20264210)

Co-Investigator(Kenkyū-buntansha) ISLAM WALIUL  熊本大学, 大学院先端科学研究部(工), 外国人特別研究員
Project Period (FY) 2023-03-08 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2023: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2022: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2021: ¥600,000 (Direct Cost: ¥600,000)
Keywordsmulti-functional drug / BNCT / glycolysis inhibition / EPR-effect / ER/mitochondrial stress / ホウ素中性子捕捉療法 / ホウ素 / 解糖系 / EPR効果 / 小胞体ストレス / ミトコンドリアストレス
Outline of Research at the Start

To develop an innovative boron neutron capture therapy (BNCT), we have developed a boron containing nanomicelle (SGB-complex). Firstly, we will determine the chemical structure of this complex. Secondly, we will investigate whether SGB-complex inhibits glucose metabolism, mitochondria damage and ER stress.
Finally, we will examine SGB-complex using several types of tumor-bearing mice. We also want to confirm effect of NO donors on EPR effect and irradiation of neutron on anti-tumor effect. SGB-complex strongly will be a new modality for the successful treatment of BNCT in clinic.

Outline of Annual Research Achievements

We developed a water-soluble polymer drug namely styrene maleic acid (SMA) copolymer conjugated glucosamine and boric acid (SGB-complex). Initially this drug was designed for boron neutron capture therapy, but surprisingly we discovered that this complex can inhibit the cancer cell growth even without neutron irradiation. However, the precise chemical structure of SGB-complex and the detail mechanism of showing cytotoxicity was not clearly understood. During the fellowship period, we have investigated the exact chemical structure of the SGB-complex by means of UV-vis, infra-red, circular dichroism, NMR spectroscopy and liquid chromatography masa spectroscopy. Based on accumulating data, we conclude that the -NH2 group of glucosamine bound to -COOH group of SMA polymer by amide bond, and the boric acid (BA) bound to the glucosamine via cis-diol bond.
We also investigated possible mechanisms of cell killing effect by SGB-complex, and we confirmed that SGB-complex released free BA in tumor tissue pH and liberated BA compete with phosphate in phosphorylation of glucose to glucose 1-phosphate and inhibit the glycolysis of cancer cells. According to Warburg effect, in hypoxic state of cancer cells predominantly depend on energy production by glycolysis instead of TCA cycle. It means suppression of glycolysis of cancer cell will lead it to apoptosis. Moreover, the SGB-complex induced endoplasmic reticulum stress especially in hypoxia state which mimic the tumor tissue environment and turn to apoptosis. Taken together, SGB-complex inhibits the tumor growth with multiple mechanisms.

Report

(3 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (12 results)

All 2024 2023 2022 2021 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (4 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Styrene Maleic Acid Polymer-Encapsulated Chlorophyll as a Stable Micellar Nanoprobe for Advanced Anticancer Photodynamic Therapy2023

    • Author(s)
      Islam Waliul、Tsutsuki Hiroyasu、Rahman Azizur、Harada Ayaka、Zhang Tianli、Ono Katsuhiko、Islam Rayhanul、Hossen Foysal、Niidome Takuro、Sawa Tomohiro、Fang Jun
    • Journal Title

      ACS Applied Polymer Materials

      Volume: 5 Issue: 12 Pages: 10289-10302

    • DOI

      10.1021/acsapm.3c02042

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Disulfiram encapsulated in polymer nanoparticles ameliorates thioacetamide-induced liver injury2023

    • Author(s)
      Wei Xu, Yuta Kadoya, Waliul Islam, Fumika Akizuki, Hisaaki Hirose, Shiroh Futaki, Yukio Fujiwara, Yoshihiro Komohara, Takuro Niidome
    • Journal Title

      Journal of Drug Delivery Science and Technology

      Volume: 88 Pages: 104981-104981

    • DOI

      10.1016/j.jddst.2023.104981

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural Determination of the Nanocomplex of Borate with Styrene?Maleic Acid Copolymer-Conjugated Glucosamine Used as a Multifunctional Anticancer Drug2022

    • Author(s)
      Islam Waliul、Tsutsuki Hiroyasu、Ono Katsuhiko、Harada Ayaka、Shinozaki Kozo、Niidome Takuro、Fang Jun、Sawa Tomohiro
    • Journal Title

      ACS Applied Bio Materials

      Volume: 5 Issue: 12 Pages: 5953-5964

    • DOI

      10.1021/acsabm.2c00883

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced Permeability and Retention Effect as a Ubiquitous and Epoch-Making Phenomenon for the Selective Drug Targeting of Solid Tumors2022

    • Author(s)
      Islam Waliul、Niidome Takuro、Sawa Tomohiro
    • Journal Title

      Journal of Personalized Medicine

      Volume: 12 Issue: 12 Pages: 1964-1964

    • DOI

      10.3390/jpm12121964

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of potent antipseudomonal β‐lactams by means of polycarboxylation of aminopenicillins2021

    • Author(s)
      Akter Shahinur、Migiyama Yohei、Tsutsuki Hiroyasu、Ono Katsuhiko、Hamasaki Chika、Zhang Tianli、Miyao Kenki、Toyomoto Touya、Yamamoto Keiichi、Islam Waliul、Sakagami Takuro、Matsui Hirotaka、Yamaguchi Yoshihiro、Sawa Tomohiro
    • Journal Title

      Microbiology and Immunology

      Volume: 65 Issue: 10 Pages: 449-461

    • DOI

      10.1111/1348-0421.12930

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] A stable micelle of SMA-polymer encapsulated chlorophyll shows a potent anticancer effect as a photodynamic therapy2022

    • Author(s)
      Waliul Islam, Ayaka Harada, Hiroyasu Tsutsuki, Jun Fang, Takuro Niidome, Tomohiro Sawa
    • Organizer
      The 38th annual meeting of the Japan Society of Drug Delivery System
    • Related Report
      2022 Annual Research Report
  • [Presentation] A promising strategy for cancer treatment by using SMA-polymer encapsulated chlorophyll as a photodynamic therapy2022

    • Author(s)
      Waliul Islam, Jun Fang
    • Organizer
      The 81th annual meeting of Japanese Cancer association, Yokohama
    • Related Report
      2022 Annual Research Report
  • [Presentation] Enhancement of tumor drug delivery using nitric oxide donors in advanced cancer2022

    • Author(s)
      Waliul Islam, Jun Fang, Hiroyasu Tsutsuki, Takuro Niidome, Tomohiro Sawa
    • Organizer
      Redox week : The 12th International NO Conference & The 22nd NOSJ
    • Related Report
      2022 Annual Research Report
  • [Presentation] A stable micelle of SMA copolymer encapsulated chlorophyll shows potent photodynamic effect for cancer treatment2021

    • Author(s)
      Waliul Islam, Rayhanul Islam, Jun Fang, Hiroshi Maeda
    • Organizer
      The 80th Annual Meeting of the Japanese Cancer Association
    • Related Report
      2021 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      http://www.chem.kumamoto-u.ac.jp/~niidome/

    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] BNCT: Novel anticancer agent: polymer conjugate carbohydrate complex2024

    • Inventor(s)
      Hiroshi Maeda, Waliul Islam
    • Industrial Property Rights Holder
      Hiroshi Maeda, Waliul Islam
    • Industrial Property Rights Type
      特許
    • Filing Date
      2024
    • Related Report
      2023 Annual Research Report
  • [Patent(Industrial Property Rights)] Polymer drug2022

    • Inventor(s)
      Hiroshi Maeda, Waliul Islam
    • Industrial Property Rights Holder
      Hiroshi Maeda, Waliul Islam
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2022 Annual Research Report
    • Overseas

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Published: 2022-02-08   Modified: 2024-12-25  

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