| Project/Area Number | 13672385 |
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
応用薬理学・医療系薬学
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
TSUTSUMI Yasuo Osaka University, Graduate School of Pharmaceutical Sciences, Research Associate, 薬学研究科, 助手 (50263306)
|
|---|
| 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)
|
|---|
| Project Period (FY) |
2001 – 2002
|
| Project Status |
Completed(Fiscal Year 2002)
|
| 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)
|
|---|
| 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 |
|---|
| 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.
|
