| 研究開始時の研究の概要 |
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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| 研究実績の概要 |
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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