Abstract

Nitric oxide (NO) deficiency is known to play a role in renal ischaemia/reperfusion injury; therefore, kidney-targeting NO donor is expected to prevent renal ischaemia/reperfusion injury. We therefore developed an S-nitrosylated L-serine-modified polyamidoamine dendrimer (SNO-Ser-PAMAM), in which multiple S-nitrosothiols (NO donors) were covalently bound to L-serine-modified dendrimer, as a kidney-targeting NO donor. In the pharmacokinetic study, approximately 76% of ¹¹¹In-SNO-Ser-PAMAM accumulated in the kidney after intravenous injection in mice. Furthermore, single photon emission computed tomography/computed tomography (SPECT/CT) imaging study showed that ¹¹¹In-SNO-Ser-PAMAM specifically accumulated in the renal cortex after intravenous injection. SNO-Ser-PAMAM gradually released NO over a day in plasma, indicating that SNO-Ser-PAMAM would show sustained release of NO in vivo. In a mouse model of renal ischaemia/reperfusion injury, increased plasma creatinine, a kidney damage marker, and histological changes were effectively inhibited by intravenous administration of SNO-Ser-PAMAM. These results indicate that SNO-Ser-PAMAM is a promising kidney-targeting NO donor for the efficient prevention of renal ischaemia/reperfusion injury.

摘要

已知一氧化氮 (NO) 缺乏在肾缺血/再灌注损伤中起作用；因此，肾脏靶向 NO 供体有望预防肾脏缺血/再灌注损伤。因此，我们开发了一种 S-亚硝基化 L-丝氨酸修饰的聚酰胺胺树枝状聚合物 (SNO-Ser-PAMAM)，其中多个 S-亚硝基硫醇（NO 供体）与 L-丝氨酸修饰的树枝状聚合物共价结合，作为靶向肾脏的 NO 供体. 在药代动力学研究中，小鼠静脉注射后，大约 76% 的¹¹¹ In-SNO-Ser-PAMAM 在肾脏中积累。此外，单光子发射计算机断层扫描/计算机断层扫描 (SPECT/CT) 成像研究表明，¹¹¹静脉注射后，In-SNO-Ser-PAMAM 在肾皮质中特异性积累。SNO-Ser-PAMAM 在一天内在血浆中逐渐释放 NO，表明 SNO-Ser-PAMAM 会在体内持续释放 NO 。在肾缺血/再灌注损伤的小鼠模型中，静脉注射 SNO-Ser-PAMAM 可有效抑制血浆肌酐、肾损伤标志物和组织学变化的增加。这些结果表明 SNO-Ser-PAMAM 是一种很有前途的肾脏靶向 NO 供体，可有效预防肾脏缺血/再灌注损伤。