Biography
Professor, Department of Materials Science, University of Tsukuba
Concurrent Professor, Department of Medical Science, University of Tsukuba
Center for Research in Isotopes and Environmental Dynamics (CRiED), University of Tsukuba
e-mail: happyhusband@nagalabo.jp
url: http://www.ims.tsukuba.ac.jp/~nagasaki_lab/index.htm
Yukio Nagasaki graduated University of Tokyo in 1982 and received Ph.D. in Department of Industrial Chemistry, Faculty of Engineering, University of Tokyo in 1987. Since 1987, he became Research associate in Department of Industrial Chemistry, Research associate, Assistant Professor and Professor in Department of Materials Science, Science University of Tokyo. He moved to University of Tsukuba in 2004 as a professor.
His research interest is directed to the creation of new functional materials by a novel polymerization technique. End-functionalized poly(ethylene glycol) (PEG) as surface modifier and novel nanoparticles as intelligent drug vehicle are his main targets for novel material design. He is also interested in creating high performance biointerfaces, including non-fouling and certain bio-recognition characters. They have found that the PEG bonded chain surface with a mixture of long and short chains almost completely reduces nonspecific protein adsorption (Uchida et al., Ana. Chem., 77, 1075, 2005). The antibody/PEG co-immobilized surface increased the PEG linked chain density and surface antibody reactivity (Nagasaki et al., J. Coll. Int. Sci., 307, 524, 2007). This immunochemical enhancement effect is expected to be three phenomena that create a highly functional surface of highly versatile biomaterial.
Recently, Nitroxide Radical Containing Nanoparticles (RNP) with the ability of scavenging ROS to reduce oxidative stress activity was developed (Yoshitomi et al., Bioconjugate Chemistry, 20, 2792 (2009)). Using RNP, ROS damage due to cerebral ischemia reperfusion is effectively reduced (Marushima et al., Neurosurgery, 2011). RNP is also effective not only for the Alzheimer’s disease, but also for cancer, and ulcerative colitis. Antiinflammation by nanoparticles is very promising.
In the process of these research on biofunctional materials at Science University of Tokyo and University of Tsukuba, he made surface modification of protein modification polymers and diagnostic particles, which were commercialized from Nippon Oil&Fat and JSR, respectively. In addition, a high efficient cell culture dish was commercialized from Toyogosei Industry Co., Ltd. As described above, antioxidative nanoparticle is now developing and start to collaborate with several companies. He wishes to commercialize them near future.
Abstract
Design of molecular self-assembling drugs
Reactive oxygen species (ROS) is known to play a variety of roles at many important event opportunities in vivo. However, overproduction of ROS causes serious adverse side effects in the body. Many drugs have been applied to reduce excessively produced ROS. However, low molecular weight (LMW) antioxidants spread nonspecifically to the whole body and are internalized in healthy cells. Since the organism acquires energy via the mitochondrial electron transport chain, such LMW antioxidants suppress this type of normal redox reaction and cause severe damage to normal organs and the body. In order to improve selective antioxidant properties in vivo, we started to focus on novel design of effective antioxidant drugs. Our concept of drug design is to avoid side effects such as inevitable toxicity of small molecules and to create safe and effective drugs by molecular assembly. To create this concept, we synthesized a redox amphiphilic block copolymer, forms self-assembling nanoparticles in an aqueous media. Our idea is to prevent mitochondrial damage of healthy cells by preventing cellular uptake by self-assembly structure of antioxidant. The nitroxide radical, which is one of the strongest antioxidants, covalently conjugated as a side chain of the hydrophobic segment in the block copolymer were compartmentalized into the solid core of the micelle and was named nitroxide radical containing nanoparticles (RNPN). Because RNPN is hardly incorporated into healthy cells, unlike LMW antioxidants, its in vivo toxicity has become extremely low. Since RNPN has pH-sensitive disassembling properties, it collapses at pH-reducing tumors and sites of inflammation. We have confirmed that this particle can be applied for versatile oxidative stress related diseases such as cerebral, renal and myocardial ischemia reperfusion injuries, cerebral hemorrhage, cancer, ulcerative colitis and Alzheimer’s disease and it is promising as a novel antioxidant self-assembling nanodrugs. From these results, we are proposing new concept, “molecular assemble drugs”. Namely, even though conventional low molecular weight drugs, which are high effective in vitro, cannot be effective or even appear strong toxicity in vivo, their self-assembling and/or complexation with other molecules can exert selective pharmacological activity, avoiding possible adverse effects to normal cells and tissues. Based on this concept, we have designed self-assembling drugs based on amino acid for novel cancer therapy, acute liver injury and Parkinson’s diseases. Most recently, we started new molecular-assembling drug based on short chain fatty acids for cancer therapy and diet effect. This concept of self-assembling drug is highly anticipated as a new drug target.