TY - JOUR T1 - Development of Polyethylene Glycol-Conjugated Poly-<em>S</em>-Nitrosated Serum Albumin, a Novel <em>S</em>-Nitrosothiol for Prolonged Delivery of Nitric Oxide in the Blood Circulation in Vivo JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1117 LP - 1124 DO - 10.1124/jpet.105.087429 VL - 314 IS - 3 AU - Hidemasa Katsumi AU - Makiya Nishikawa AU - Fumiyoshi Yamashita AU - Mitsuru Hashida Y1 - 2005/09/01 UR - http://jpet.aspetjournals.org/content/314/3/1117.abstract N2 - 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. Electron spin resonance study indicated that PEG-poly SNO-BSA does release the NO radical in the blood circulation in vivo. The area under the concentration-time curve of 111In-PEG-poly N-succinimidyl S-acetylthioacetate (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 of NO per kilogram), the duration of reduction in the blood pressure was 2.3 to 3.7 times longer in PEG-poly SNO-BSA than in classic S-nitrosothiols such as S-nitroso-N-acetyl penicillamine, S-nitrosoglutathione, and NO-BSA. The release half-life of NO from PEG-poly SNO-BSA was 11 to 108 times longer than those of the classic 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. The American Society for Pharmacology and Experimental Therapeutics ER -