| Project/Area Number |
22KF0311
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| Project/Area Number (Other) |
21F21407 (2021-2022)
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| Research Category |
Grant-in-Aid for JSPS Fellows
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| Allocation Type | Multi-year Fund (2023)
Single-year Grants (2021-2022) |
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| Section | 外国 |
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| Review Section |
Basic Section 90120:Biomaterials-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
新留 琢郎 熊本大学, 大学院先端科学研究部(工), 教授 (20264210)
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| 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
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| Project Period (FY) |
2023-03-08 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| 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)
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| Keywords | multi-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 |
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| 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.
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| 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.
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