| Project/Area Number |
07672351
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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 |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
TAKAKURA Yoshinobu Kyoto University, Fac.Pharm.Sci., Associate Professor, 薬学部, 助教授 (30171432)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIKAWA Makiya Kyoto University, Fac.Pharm.Sci., Assistant Professor, 薬学部, 助手 (40273437)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Antisense oligonucleotide / In vivo disposition / Intracellular trafficking / Pharmacokinetics / Liver / Dclivery systems / Sugar-recognition system / poly (L-lysine) / poly(L-lysine) / クリアランス / c-myc / phosphorothioate |
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| Research Abstract |
Antisense oligonucleotides have been expected as a novel class of chemotherapeutic agents for the treatment of cancer, viral infections and genetic disorders because of their potentials to inhibit gene expression in a sequence-specific manner. To achieve therapeutic effect in vivo, it is necessary to control the in vivo disposition characteristics as well as intracellular pharmacokinetics of oligonucleotides. The purpose of this project was to develop delivery systems which can control in vivo pharmacokinetics and subsequent intracellular trafficking of antisense oligonucleotides. We used 20 mer phosphodiester (PO) and its phosphorothioate (PS) derivative, complimentary to the human c-myc mRNA,as model antisense molecules. The basic pharmacokinetics of the model oligonucleotides were studied at whole body, organ, cellular and subcellular levels. The in vivo studies and organ perfusion experiments have demonstrated that the oligonucleotides underwent rapid elimination by the liver and kidney as well as degradation by nucleases after systemic administration. In vitro experiments using a variety of cultured cells in combination with confocal laser microscopy have clarified the intracellular fate of oligonucleotides. On a basis of these findings, we assessed the feasibility of macromolecular carriers, galactosylated and mannosylated poly (L-lysine), which can control both in vivo disposition and intracellular pharmacokinetics of oligonucleotides.
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