| Project/Area Number |
13672385
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Osaka University |
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Principal Investigator |
TSUTSUMI Yasuo Osaka University, Graduate School of Pharmaceutical Sciences, Research Associate, 薬学研究科, 助手 (50263306)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAGAWA Shinsaku Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (70207728)
TADANORI Mayumi Osaka University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (00098485)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | PEGylation / interleukin-6 / cytokine / Drug Delivery System / ポリエチレングリコール / プロテオーム創薬 / ドラッグデリバリーシステム / 創薬 / トランスレーショナルリサーチ / ライフサイエンス / 医療 |
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| Research Abstract |
We developed a novel method for the chemical modification of proteins with synthetic polymers to increase the therapeutic efficacy of the former in vivo. A pH-reversible amino-protective reagent, dimethylmaleic anhydride (DMMAn), was used for modification of interleukin-6 (IL-6) with polyethylene glycol (PEG). The novel PEGylated IL-6 (DmPEG-IL-6), which had been pretreated with DMMAn before PEGylation, showed up to a 140% increase in in vitro specific activity compared with PEG-IL-6 that had been synthesized by the previous method. Moreover, DmPEG-IL-6 caused thrombopoiesis more potently in mice than PEG-IL-6. The DmPEG-IL-6, having 3-4 PEG chains attached to the cytokine, showed the strongest thrombopoietic effect among the DmPEG-IL-6s with different molecular sizes that were tested. PEG-IL-6 had a 500-fold higher potency in stimulating thrombopoiesis than native IL-6, and DmPEG-IL-6 Fr.1 achieved a threefold higher thrombopoietic effect than PEG-IL-6. In addition, side-effects, such as an increase in the plasma fibrinogen level, were not observed after injection of either PEG-IL-6s or DmPEG-IL-6s. Additionally, we also found that PEGylation of tumor necrosis factor-alpha and G-CSF using DMMAn increased their specific activities. These results suggest that PEGylation with DMMAn pretreatment may become a useful means for clinical cytokine delivery.
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