NISHIGORI Hideo Faculty of Pharmaceutical Sciences, Teikyo University, Professor, 薬学部, 教授 (90050517)
ARANO Yasushi Graduate School of Pharmaceutical Sciences, Chiba University, Professor, 大学院・薬学研究院, 教授 (90151167)
|Budget Amount *help
¥6,900,000 (Direct Cost : ¥6,900,000)
Fiscal Year 2004 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 2003 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 2002 : ¥2,900,000 (Direct Cost : ¥2,900,000)
We have already obtained high tumor accumulation by using radionuclide-encapsulating liposomes, therefore, we consider that the most important task of this research is not to allow radionuclides accumulate in normal tissues, such as liver, spleen, or bone marrow.
1. We developed a radiolabelling method that will permit liposomes encapsulate enough amount of ^<186>Re/^<188>Re and ^<90>Y, which are suitable nuclides for radiotherapy. For this method, we newly prepared MRP20, a lipophilic chelating agent, and ethylenedicysteine (CD), a hydrophilic one. Labeling methods and choice of ligand are very important, because they may largely affect non-specific accumulation in normal tissues as described below.
2. Use of carriers such as liposomes or lipid spheres permitted fine control of radionuclide biodistribution. In case of liposomes, it accumulated in the tumor in large quantity and also in the liver and spleen, and then released radionuclides there. Following behavior of released-nuclides w
as dominated by their chelating ligands. From results of detailed examination on subcellular distribution, it was cleared that ^<67>Ga and ^<111>In (maybe also ^<90>Y) transferred from cytosol to lysosome and remained there for a long time owing to their own nature, however, chelation to high-affinity ligands dramatically altered their behavior. Nuclide-ligand complexes were present in cytosol and went out of the cell. These results suggest that high-affinity ligands are essential for reduction of radiation exposure to normal tissues, and further suggested that ligand design, such as leading of excretion by membrane transporter, may make it possible to remove radionuclides in normal tissues actively.
3. Preparation of external stimulus-responsible drug carrier was tried. By pulling the "trigger", destruction of carriers in the blood circulation and following release encapsulated-radionuclides were planed. Some promising results have been obtained, however, modification of carriers led to decrease tumor accumulation largely. Further examinations are under way. Less