Drug Delivery System

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

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.

Research on gene delivery for future gene therapy (Gene Unit)

Although the development of genetic medicines for intractable diseases such as congenital gene defects and cancer is strongly desired, few gene delivery methods satisfy both efficacy and safety. The Gene Unit has been researching the development and evaluation of gene transfer methods and mechanistic analysis.

1. Formulation design and evaluation of lipid-based nanoparticles based on Design of Experiments and AI
2. Powderization of lipid-calcium carbonate nanoparticles
3. Evaluation of in vivo fate of gene carriers based on tissue optical clearing
4. Elucidation of transfection mechanism based on oxidative stress

{Representative Publications]

1. Okami K, Fumoto S, et al., One-Step Formation Method of Plasmid DNA-Loaded, Extracellular Vesicles-Mimicking Lipid Nanoparticles Based on Nucleic Acids Dilution-Induced Assembly. Cells. (2024) 13(14):1183. PMID: 39056764.
2. Hu D, Fumoto S, et al., Diffusion coefficient of cationic liposomes during lipoplex formation determines transfection efficiency in HepG2 cells. Int J Pharm. (2023) 637:122881. PMID: 36963641.
3. Fumoto S, et al., A pH-Adjustable Tissue Clearing Solution That Preserves Lipid Ultrastructures: Suitable Tissue Clearing Method for DDS Evaluation. Pharmaceutics. (2020) 12(11):1070. PMID: 33182398.
4. Peng JQ, Fumoto S, et al., Targeted co-delivery of protein and drug to a tumor in vivo by sophisticated RGD-modified lipid-calcium carbonate nanoparticles. J Control Release. (2019) 302:42-53. PMID: 30926479.

Research on individual drug therapy in case of disease state and several therapies (ADME Unit)

There is an optimal range of concentrations (therapeutic range) within which a drug must be administered to show a beneficial effect. Below the therapeutic range, the drug shows no effect (ineffective), while above the therapeutic range it causes adverse events. However, pharmacokinetics are subject to change due to the patient's disease and concomitant medications, and individual optimization of drug therapy is necessary. We analyze the factors that affect the pharmacokinetics of drugs during pathological conditions (liver and renal diseases, peritoneal disorders) and during various types of treatment (hypothermia and hyperthermia). In addition, we are analyzing the relationship between underlying diseases and concomitant medications and the occurrence of adverse events by utilizing the medical information database, which contains drug information such as adverse events and therapeutic effects caused by the use of drugs in actual clinical practice.