| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Research Abstract |
Liposomes with ligands bonded to their external membrane surface have beenstudied in order to provide a method for delivering drugs or genes selectively to a target region. Transferrin N-glutaryl-dioleoyl-Phosphatidylethanolamine (Tf-NGPE) liposomes were designed as intracellular targeting carriers of chemotherapeutic drugs into tumors. This study showed that the intratumoral delivery of a platinum (Pt)-based anticancer drug, oxaliplatin (L-OHP), using Tf-NGPE liposomes varied depending on the 24-hr variation in the expression of transferrin receptors on tumor cells. Colon 26 tumor-bearing mice were housed under standardized light/dark cycle conditions (lights on at 07:00 h, off at 19:00 h) with food and water ad libitum. The growth of tumor cells implanted in mice was more severely inhibited by intravenous injection of Tf-NGPE liposome encapsulated with L-OHP (L-OHP : 7.5 mg/kg) in the early dark phase than when it was injected in the early light phase. The dosing-time dependency of the anti-tumor effect was parallel to that of Pt incorporation into tumor DNA. Luciferase reporter and chromatin immunoprecipitation analyses revealed that c-Myc regulated the 24-hr oscillation of type 1 transferrin receptor (TfR1) expression in tumor cells, which underlay the dosing-time-dependent changes in the internalization of Tf-NGPE liposome-delivered L-OHP into the tumor cells. These results suggested that intratumoral delivery of chemotherapeutic drug using Tf-NGPE liposomes is enhanced by administering the drug when tumor expression of TfR1 is abundant. The potent therapeutic efficacy of such an intracellular targeting drug delivery system (DDS) could be enhanced by optimizing the dosing schedule.
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