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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 18, 2005; DOI: 10.1124/jpet.105.087429

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Received for publication April 6, 2005.
Revised May 16, 2005.
Accepted for publication May 17, 2005.

Development of PEGylated poly S-nitrosated serum albumin, a novel S-nitrosothiol for prolonged delivery of nitric oxide in the blood circulation in vivo

Hidemasa Katsumi 1, Makiya Nishikawa 1, Fumiyoshi Yamashita 1, Mitsuru Hashida 1*

1 Kyoto University Graduate School of Pharmaceutical Sciences

* Address correspondence to: E-mail: hashidam{at}pharm.kyoto-u.ac.jp

Abstract

S-nitrosothiols are an interesting class of nitric oxide (NO) donors used for the treatment of circulation disorders. In this study, we developed a novel macromolecular NO donor, in which 10 NO molecules were covalently bound to polyethylene glycol (PEG)-conjugated bovine serum albumin (BSA) through S-nitrosothiol linkages (PEG-poly SNO-BSA). Intermolecular disulfide linkages possibly formed during the introduction of thiol groups to BSA were prevented in PEG-poly SNO-BSA. ESR study indicated that PEG-poly SNO-BSA does release the NO radical in the blood circulation in vivo. The AUC of 111In-PEG-poly SATA-BSA, the carrier part of PEG-poly SNO-BSA, was 1.7 times greater than that of 111In-BSA after intravenous injection in mice. After intravenous injection in rats at an equivalent NO dose (3 µmol NO/kg), the duration of reduction in the blood pressure was 2.3-3.7 times longer in PEG-poly SNO-BSA than in classical S-nitrosothiols such as S-nitroso-N-acethyl penicillamine, S-nitrosoglutathione and NO-BSA. The release half life of NO from PEG-poly SNO-BSA was 11-108 times longer than those of the classical S-nitrosothiols examined, and this slow release rate of NO would explain the sustained reduction in the blood pressure after intravenous injection of PEG-poly SNO-BSA in rats. No cross-tolerance between PEG-poly SNO-BSA and nitroglycerin was also observed. These findings indicate that the novel S-nitrosothiol, PEG-poly SNO-BSA, is a promising compound that exhibits unique characteristics of sustained release of NO in the blood circulation in vivo, which would be beneficial for the treatment of circulation disorders.


Key words: blood pressure, circulation, controlled release, distribution, drug delivery, nitric oxide


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Y. Ishima, T. Sawa, U. Kragh-Hansen, Y. Miyamoto, S. Matsushita, T. Akaike, and M. Otagiri
S-Nitrosylation of Human Variant Albumin Liprizzi (R410C) Confers Potent Antibacterial and Cytoprotective Properties
J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 969 - 977.
[Abstract] [Full Text] [PDF]


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