| Project/Area Number |
21KK0197
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 90:Biomedical engineering and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
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| Co-Investigator(Kenkyū-buntansha) |
小嶋 基寛 国立研究開発法人国立がん研究センター, 臨床開発センター, ユニット長 (30338470)
持田 祐希 公益財団法人川崎市産業振興財団(ナノ医療イノベーションセンター), ナノ医療イノベーションセンター, 主任研究員 (60739134)
喜納 宏昭 公益財団法人川崎市産業振興財団(ナノ医療イノベーションセンター), ナノ医療イノベーションセンター, 主幹研究員 (70283067)
中川 泰宏 東京工業大学, 物質理工学院, 助教 (90831264)
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| Project Period (FY) |
2021-10-07 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2021)
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| Budget Amount *help |
¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
Fiscal Year 2024: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2023: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | Nanomedicine / CAFs / Tumor microenvironments / Immunotherapy / Polymeric nanocarriers / Polymeric micelles / Antibody ligands / Tranilast / Fibroblasts |
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| Outline of Research at the Start |
CAF targeting has potential for developing novel strategies for cancer therapy. Here, we will develop nanomedicines overcoming current CAF targeting issues by collaboration between research groups in Japan (nanomedicine and clinical cancer) and Cyprus University (tumor biomechanics).
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| Outline of Annual Research Achievements |
In this project, we aim to develop nanomedicines for targeting cancer associated fibroblasts (CAFs). These nanomedicines are based on polymeric nanocarriers equipped with ligands and drugs for reprogramming or killing CAFs. In this first part of the project, we have prepared the platform polymer based on azide-terminated multi-arm PEG for ligand installation and a poly(aspartic) acid for drug conjugation. Moreover, we have prepared anti-Fap Fab' from whole antibodies as a ligand for targeting CAFs. These antibodies where modified with maleimide-DBCO for conjugation to the polymeric carriers via click chemistry. In addition, we have been discussing our progress thoroughly with our collaborators in Cyprus University via online meetings. We have sent our first samples (tranilast-loaded micelles) for modifying the tumor CAFs and promoting chemoimmmunotherapy in breast tumors. The results showed that the tranilast-loaded micelles, but not free tranilast, can inhibit TGF-b in CAFs, leading to the improved activity of doxorubicin-loaded liposomes (Doxil) and immune checkpoint antibodies. The combination of the three drugs eradicated the tumors. Based on these results, we have submitted our first publication to Nature Commun., and received positive commments from the reviewers. We are now preparing the revision. Also, we are preparing a publication on the polymer synthesis and another publication on the role of solid stress and CAFs in human pancreatic tumors by doing a retrospective study. The later publication will help us decide our strategies in mice.
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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
We have successfully synthesized polymers in high amount to provide to the Japanese team members and the group at Cyprus University. Moreover, we have prepared the ligands. This progress is as planned. Unfortunately, because of the war in Ukraine, we have decided to postpone our visit to Cyprus University, which was originally planned for May, to November.
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| Strategy for Future Research Activity |
In the next year, we will evaluate the nanomedicines in in vitro and in vivo experiments. We will conjugate drugs to the nanocarriers for killing (cyclopamine)and for reprogramming (all-trans retinoic acid (ATRA)) CAFs. The nanomedicines will be modified with ligands (anti-Fap Fab' and commercial cyclic RGD peptide). By using fluorescent-labeled nanomedicines, we will study their ability to target CAFs isolated from mouse and human pancreatic tumors in vitro. We will also study the pharmacokinetics, tumor accumulation, and intratumoral microdistribution of fluorescent-labeled nanomedicines in KPC tumors. Moreover,in vivo CAF targeting will be studied by immunohistochemistry and FACS. Then, we will study the effect of the treatments on the mechanical and immune properties of the tumor microenvironment (TME). To test the mechanical changes, we will learn the methods to measure the interstitial fluid pressure (IFP) and the Young modulus at Cyprus University. The tumors treated with the nanomedicines will also be assessed to identify genes related to tumor vascularization and mechanical TME, e.g. VEGFR and Ang1, by RT-PCR. The results will be correlated with clinical data by measuring the stiffness of human PC and histologically assessing the levels of collagen, hyaluronan and CAFs. Moreover, changes in the phenotype of CAFs will be evaluated by immunohistochemsitry and FACS. In addition, we will do the experiments for the revision of our first manuscript on tranilast-loaded micelles.
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