Free Radical Research publication: S-nitrosylated l-serine-modified dendrimer as a kidney-targeting nitric oxide donor for prevention of renal ischaemia/reperfusion injury

In this paper, the MOLECUBES γ-CUBE and X-CUBE were used to investigate the preventive effect of SNO-Ser-PAMAM on renal ischaemia/reperfusion injury.

Free Radical Research. 2019; 1029-2470 (Online). doi: 10.1080/10715762.2019.1697437

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.

SPECT/CT imaging of 111In-labeled SNO-Ser-PAMAM 4h after intravenous injection in mouse. (A) 3D imaging, (B) sagittal plane, (C) coronal plane and (D) transverse plane.