| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥570,000)
Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
In this study, we aim to develop a novel polymeric albumin preparation with prolonged half-life by using site-directed mutagenesis and redox reaction. First, to obtain fundamental information regarding which amino acid residues in albumin are involved in its elimination, the pharmacokinetics and antioxidant activity of 26 genetic variants of albumin, as well as oxidized and glycated albumins were examined. As a result, we found that when two amino acid residues, namely, Glu 570 and Lys 573, in domain III were mutated to Arg, one Arg was added to the N-terminal and domain II were glycosylated, the half-life of albumin was increased. On the basis of these results, we performed multiple mutations to albumin and the mutant was further polymerized. The polymeric recombinant albumin mutant was correctly folded, as evidenced by the similarity of the patterns in the far- and near-UV circular dichroism spectra of mutant and native albumin. In addition, the plasma levels of the polymeric albumin mutant after intravenous bolus injection to rats exhibited two-phase profiles, and the half-life was longer than that of native albumin. Furthermore, the polymeric albumin showed a reduction in edema against paw edema mouse models because of its high molecular weight. These results indicate the potential for development of the new polymeric recombinant albumin preparation with prolonged half-life, but further investigation is needed to ensure the safety of the albumin preparation.
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