| Project/Area Number |
23KJ1297
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| Research Category |
Grant-in-Aid for JSPS Fellows
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| Allocation Type | Multi-year Fund |
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| Section | 国内 |
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| Review Section |
Basic Section 90120:Biomaterials-related
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| Research Institution | Kyoto University |
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Principal Investigator |
HUO WENTING 京都大学, 工学研究科, 特別研究員(DC2)
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| Project Period (FY) |
2023-04-25 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2024: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2023: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | drug delivery / tetraphenylethene |
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| Outline of Research at the Start |
Gene therapy is a powerful tool which has the potential to cure diseases permanently. But it's still not widely available to patients because it's hard to get the negatively charged gene molecules into the right cells. Therefore, it's urgent to develop efficient delivery strategies for gene therapy.
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| Outline of Annual Research Achievements |
Molecules like oligonucleotides struggle to cross cell membranes due to their polar and charged nature. To overcome this, we developed a light-triggered twistable tetraphenylethene derivative, TPE-C-N, which facilitates their entry into cells through an endocytosis-independent pathway. This method successfully transports peptides and oligonucleotides with molecular weights from 1000 to 5000 Daltons. This new intracellular delivery method proposed can transport both negatively and positively charged molecule without the need for additional chemical modifications and does not require the inefficient endosomal escape. It is foreseeable that this research will inject new vitality into the development of drug delivery systems.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
In this research, our goal is to enhance the delivery efficiency of oligonucleotide therapeutics from 0.1% to approximately 10%. To achieve this, we developed a new strategy that utilizes intramolecular motions to disturb the cell membrane. Tetraphenylethene (TPE) is notable because its central double bond is planar in ground states but becomes twisted in excited states. Consequently, we chose TPE as the light-triggered, twistable backbone. To attach to cell membranes, the TPE backbone was functionalized with hydrophobic anchors. Optimizing the molecular design to balance solubility and membrane attachment required considerable effort. Ultimately, we synthesized TPE-C-N, which successfully increased the delivery efficiency of oligonucleotide therapeutics from 0.1% to approximately 10%.
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| Strategy for Future Research Activity |
In 2024, we plan to develop delivery systems based on various molecular backbones capable of photoinduced intramolecular motions, thereby comprehensively validating the universality of our proposed delivery strategy. To date, we have achieved significant progress in creating light-controllable drug delivery systems using tetraphenylethene. However, the mechanisms by which these systems disturb cell membranes remain unclear. Exploring new molecular backbones will help establish this novel light-controlled delivery system, addressing the gap in the delivery of negatively charged therapeutics. To refine the molecular design, including the twist angle and displacement associated with intramolecular motions, it is essential to study other molecular backbones featuring diverse motion models.
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