Research Title

Although several new compounds are expected for effective medicine according to recent development of various techniques in the field of biotechnology and life science, their practical use is limited owing to the low bioavailability and short half-life in the body. Therefore, we have been studying the behavior of a drug in the body (the process of absorption, distribution, metabolism and excretion) for controlling the disposition characteristics of a drug. In particular, we focus on the administration route and have been carrying out a research for clinical application.

Drug Targeting to the Liver Utilizing the Absorption from the Liver Surface

Liver plays an important role in drug disposition in the body, so that there is an increasing interest in improving treatment of liver diseases. It is desired that the administered drug distributes largely into the target site in the liver, as proposed to treat liver diseases e.g. localized tumor. Normal routes of drug administration by intravenous and oral administration route have difficulty in achieving a local site of action in the liver by inadequate delivery into liver as well as toxicity in other organs. Although the direct way of drug application to the liver surface should yield local drug distribution for drug delivery to the target site in liver (Fig. 1), the drug absorption from the liver surface has not been reported in literature.
We have analyzed pharmacokinetically the absorption of organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in-vivo employing a cylindrical diffusion cell (Fig. 2). The main purpose of this research is to obtain the information concerning the absorption mechanism from liver surface membrane, and to attain the effective drug targeting to the liver. Furthermore, we are examining the changes in absorption characteristics in the deseased state (CCl4- or D-galactosamine-treated rat) and the differences in the drug absorption from the peritoneal cavity with the injection site, for clinical application.

Cell Specific Gene Delivery to the Liver by Cationic Liposome as a Non-viral Vector

Cationic liposomes have been considered as a potential non-viral vector for gene delivery because they possess low immunogenicity, unlike viral vectors. The gene transfer efficiency of cationic liposomes is lower than that of viral vectors but recent advances have shown that it is possible to enhance the gene expression levels of cationic liposomes. The main problem with cationic liposomes seems to be the lack of organ or cell selectivity because the lung has the highest level of gene expression after intravenous injection. Applying cell-specific targeting technology to liposomes would improve in vivo gene delivery and reduce any unexpected side effects.
Both liver parenchymal and non-parenchymal cells exclusively express large numbers of high affinity asialoglycoprotein and mannose receptors, respectively. Receptor-mediated gene delivery systems are able to introduce foreign DNA into specific cell types in vivo. However, we have confirmed that not only the nature of the ligands grafted to carriers but also the overall physicochemical properties of the complexes need to be optimized for effective cell-selective targeting of plasmid DNA. Therefore, we attempt to develop a gene delivery system based on the physicochemical properties of plasmid DNA/glycosylated cationic complexes.