Project/Area Number |
21K05302
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
|
Research Institution | Institute of Physical and Chemical Research |
Principal Investigator |
張 宗哲 国立研究開発法人理化学研究所, 開拓研究本部, 特別研究員 (00774853)
|
Project Period (FY) |
2021-04-01 – 2024-03-31
|
Project Status |
Granted (Fiscal Year 2022)
|
Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
Keywords | Sialyltransferase / Prodrug / Acrolein / In vivo synthesis / Gold metal / Immunotherapy / Metal catalysis / Sialic acid / Glycoalbumin |
Outline of Research at the Start |
Cancer is the second leading cause of death globally, and is responsible for about 10 million deaths per year. The research could innovate the cancer immunotherapy to achieve efficiently cancer therapy for life extension and reduce numbers and death number.
|
Outline of Annual Research Achievements |
One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. Therapies are being proposed and tested in animal models that aim to decrease sialic acid on cancer cells that are crucial for maintaining the inflammatory environment in tumors. However, sialyltransferase inhibitors that have been reported to reduce the amount of sialic acid are not selective for cancer cells and could cause side effects such as kidney dysfunction and weight loss. Recently our laboratory found that acrolein is expressed in large amounts in cancer cells. Furthermore, our laboratory has developed a prodrug that can be activated selectively by the reaction with acrolein of cancer cells. Herein, this author attempted to deliver a sialyltransferase inhibitor selectively to the cancer cells by using the [3+2] cycloaddition of azide and acrolein. A prodrug was synthesized by conjugating the hydroxyl group of the sialyltransferase inhibitor with 2, 6-diisopropylphenyl azide via a carbonyl linker. The prodrug reacts with endogenous to give a diazo compound, which subsequently cleave the linker and release of the sialyltransferase inhibitor only in cancer cells.
|
Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We have succeeded in finding a specific cancer targeting method, that is, targeting acrolein expressed by cancer cells by [3+2] cycloaddition of azide and acrolein. With the targeting system, a prodrug composed of a sialyltransferase inhibitor with 2, 6-diisopropylphenyl azide could be able to release the inhibitor to cancer cells via endogenous acrolein. Therefore, we think the system can succeefully inhibit tumors in vivo.
|
Strategy for Future Research Activity |
In the next step, administration of the prodrug to A549 (lung cancer) and B16F10 (mouse-derived malignant melanoma) cells to reduce fsialic acid on the cancer cells surface will be examined. After that, experiments using a mouse model to examine whether the prodrug can efficiently inhibit tumor growth while reducing the side effects will proceed.
|