| Project/Area Number |
06452376
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | Department of Pharmacutics, Faculty of Pharmaceutical Sciences, University of Tokyo, |
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Principal Investigator |
TERASAKI Tetsuya University of Tokyo, Department of Pharmaceutics, Associate Professor., 薬学部, 助教授 (60155463)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAZAKI Masayo Toho University, Department of Biopharmaceutics, Associate Professor., 薬学部, 講師 (40240741)
KATO Yukio University of Tokyo, Department of Phrmaceutics, Research Associate., 薬学部, 助手 (30251440)
SUGIYAMA Yuichi University of Tokyo, Department of Pharmaceutics, Professor., 薬学部, 教授 (80090471)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 1995: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥4,800,000 (Direct Cost: ¥4,800,000)
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| Keywords | Blood-brain barrier / Poliovirus / Virus receptor / Cell adhesion molecule / Drug delivery / Tumor cells / Organ tropism / Transport carrier / ウイルス感染 / モノクローナル抗体 / トランスジェニックマウス |
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| Research Abstract |
Poliovirus receptor considered to be a member of cell adhesion molecule is known to be a determinant for the central nervous system selective infection of poliovirus. In colorectal cancer, sialyl lewice X (sLe^x), a ligand of selectin, is considered to be a determinant for the hepatic metastatis. In the present study, we have examined to find new strategies of brain selective delivery by elucidating the organ specific virus infection and tumor metastasis. Poliovirus was inoculated intravenously to the transgenic mouse expressing poliovirus receptor gene (Tg21) and its native type (ICR). The blood-brain barrier (BBB) permeability clearance of Mahoney, a toxic strain, in Tg21 was very similar to that of Sabin 1, a vaccine strain. These BBB permeability clearances were approximately 100-folds greater than that of 1251-albumin, Moreover, very similar results were obtained for the study of ICR,suggesting that there would be a different determinat factor for the significant BBB permeation of poliovirus. In the study of metastasis, we have found that the first-pass effect plays an important role for the initial distribution of cancer cells. No significant difference was observed for the initial distribution in the liver between cells expressing diferent level of sLe^x. Interestingly. the extent of sLe^x expression in the plasma membrane of cells was suggested to be a determinant for the adhesion and the invasion following an initial distribution. In the present study, we have also found that several efflux transporters are responsible for the significantly restricted distribution of drugsinthebrain.
In conclusion, the present study suggest that, in addition to the differential expression of cell adhesion molecule, the enhancement of tinitial association to the brain capillary and the lack of recognition by the efflux transporters at the brain capilary are important for the brain selective drug delivery.
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