Development of polyethylene glycol-conjugated poly-S-nitrosated serum albumin, a novel S-nitrosothiol for prolonged delivery of nitric oxide in the blood circulation in vivo
Development of polyethylene glycol-conjugated poly-S-nitrosated serum albumin, a novel S-nitrosothiol for prolonged delivery of nitric oxide in the blood circulation in vivo
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DOI：
10.1124/jpet.105.087429
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发表时间：
2005-09-01
影响因子：
3.5
通讯作者：
Hashida, M
中科院分区：
文献类型：
--
作者：
Katsumi, H;Nishikawa, M;Hashida, M
S-亚硝基硫醇是一类有趣的一氧化氮（NO）供体，用于治疗循环障碍。在这项研究中，我们开发了一种新的大分子NO供体，其中10个NO分子通过S-亚硝基硫醇键共价键合到聚乙二醇（PEG）缀合的牛血清白蛋白（BSA）（PEG-poly SNO-BSA）。在PEG-聚SNO-BSA中，阻止了巯基引入BSA过程中可能形成的分子间二硫键。电子自旋共振研究表明，PEG-聚SNO-BSA在体内血液循环中确实释放NO自由基。小鼠静脉注射In 111-PEG-聚N-琥珀酰亚胺S-乙酰硫代乙酸酯（SATA）-BSA（PEG-poly SNO-BSA的载体部分）后，其药时曲线下面积是In 111-BSA的1.7倍。在大鼠静脉注射等量NO剂量（3 μ mol NO/kg）后，PEG-聚SNO-BSA中血压降低的持续时间比经典的S-亚硝基硫醇（如S-亚硝基-N-乙酰青霉胺、S-亚硝基谷胱甘肽和NO-BSA）长2.3至3.7倍。NO从PEG-poly SNO-BSA的释放半衰期比经典的S-亚硝基硫醇长11至108倍，并且这种缓慢的NO释放速率可以解释静脉注射PEG-poly SNO-BSA后大鼠血压的持续降低。PEG-聚SNO-BSA与硝酸甘油之间无交叉耐受性。这些发现表明，新型S-亚硝基硫醇PEG-聚SNO-BSA是一种有前途的化合物，其在体内血液循环中表现出独特的持续释放NO的特性，这将有利于治疗循环障碍。
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 In-111-PEG-poly N-succinimidyl S-acetylthioacetate (SATA)-BSA, the carrier part of PEG-poly SNO-BSA, was 1.7 times greater than that of In-111-BSA after intravenous injection in mice. After intravenous injection in rats at an equivalent NO dose (3 mu mol 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.