| Project/Area Number |
12470507
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | University of Shizuoka |
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Principal Investigator |
OKU Naoto University of Shizuoka, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (10167322)
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| Co-Investigator(Kenkyū-buntansha) |
TAKI Takao Otsuka Pharmaceutical Co., Ltd., Molecular Medical Science Institute, Director General, 分子医科学研究所, 所長 (10046295)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2000: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Keywords | Cancer / Angiogenesis / Neovessel / Cancer treatment / Phage displayed library / Liposome / Drug delivery system / Targeting |
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| Research Abstract |
In this study, novel peptides specifically homing to angiogenic vasculature were successfully isolated from a phage-displayed peptide library. The results of homing studies with phage particle and liposomal formulation indicate that PRP and WRP sequences in pentadecapeptides are important for the targeting to angiogenic sites. One of selected peptides, ASSSYPLIHWRPWAR, suppressed in vivo anagiogenesis possibly through the inhibition of endothelial cell migration. Moreover, ASSSYPLIHWRPWAR and its fragment peptides containing WRP suppressed tumor growth. Moreover, WRP is clearly revealed to be a minimum and essential sequence for the activity. In therapeutic experiments, modification of liposomes with APRPG enhanced the anti-tumor activity of ADM and reduced the toxicity of the drug due to targeting effect. It is considered that ADM damages neovascular endthelial cells, since PRP-LipADM is expected to bind these growing cells efficiently from the results of both confocal observation and
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histochemical staining. The results of therapeutic experiment with DPP-CNDAC support this idea. Since lipophilic drugs should be delivered to the cells as liposomal form, the therapeutic efficacy reflects the damage of the cells to which liposome accesses rather than change in local concentration of the agent in tumor tissue. The therapeutic efficacy of PRP-LipCN is superior to LipCN, suggesting that the destruction of angiogenic endothelial cells is superior to the direct destruction of tumor cells in the tumor treatment. In fact, the bulk accumulation of DPP-CNDAC-containing liposomes in the tumor tissue was not so much different between APRPG-liposome and non-modified liposome. From the results obtained in this study, it would be expected that PRP-Lip could deliver anticancer agents for anti-neovascular therapy, or anti-angiogenic agents for tumor dormancy therapy. It is considered that APRPG may be useful for human cancer treatment, since PRP-Lip and PRPGAPLAGSWPGTS have affinity for VEGF-stimulated HUVECs and human tumor angiogenic endothelia respectively. Less
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