| Project/Area Number |
07557142
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Physical pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KAMO Naoki Hokkaido Univ., Fac.of Pharm.Sci.prof., 薬学部, 教授 (10001976)
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| Co-Investigator(Kenkyū-buntansha) |
NARA Toshifumi Hokkaido Univ., Fac.of Pharm.Sci.Instruclo, 薬学部, 助手 (30241350)
WATANABE Tohru Sando Pharmaceutical Co.Researcher, 研究員
SHUTOH Satoru Hokkaido Univ., Fac.of Pharm.Sci.Asso.Prof., 薬学部, 助教授 (70241346)
MIYAUCHI Seiji Hokkaido Univ., Fac.of Pharm.Sci.Lect., 薬学部, 講師 (30202352)
MATUDA Akira Hokkaido Univ., Fac.of Pharm.Sci.prof., 薬学部, 教授 (90157313)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1996: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1995: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Keywords | Peptide transporter / fluorescent substrate / Caco-2 / methoxylate / multi-efflux transporter / PEPT1 / anti-cancer drugs / 蛍光性輸送基質 / ダイペプチド / FITC / Caco2 / Sw620 / ザルコシン / 腸管吸収 / 膜輸送 / リゾリン脂質 / 平面脂質二分子膜 / ピレン / ロ-ダミン123 / フローレセッイン |
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| Research Abstract |
PEPT1 is a peptide-transporter that recognizes a wide variety of substances, then our investigation focused this transporter for construction of drug delivery system. Our strategy is that when we attach a drug to a substrate that is transported by a transporter whose substrate recognition is not strict, this drug may be taken up fast. As a model cell, we chosen Caco-2 cell that expresses PEPT1 as an only peptide transporter, and as a model combination of drugs and substrates, we chosen fluorescent dyes (fluorescein isocyanate and coumarin-3-carboxylic acid) and dipeptides (Val-Lys and Lys-Sar).
Initial uptake rates of these 'drugs' were proportional to the concentrations of the drug. Since the drivingforce of the transport by PEPT1 is a proton-motive-force, addition of an uncoupler, CCCP should decrease or diminish the transport. In fact, the uptake of Lys-Sar was diminished completely. The uptake rate of model drugs (the peptides with fluorescent probes), on the contrary to our expectation, increased appreciably. These facts imply that an efflux transporter may express the cell and extrude these fluorescent drugs. When substances that are considered to be transported were added, the uptake of the fluorescent drugs increased markedly. Anti-cancer drugs are expelled by this efflux transporters, hence this fact suggests that the presence of these fluorescent drugs suppress the efflux of anti-cancer drugs, which increases the availability of anticancer drugs.
In addition, we can estimate the factors that determine the substrate recognition of PEPTl, although fluorescent compounds synthesized in this study are not transported into cells.
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