L-cysteine and l-serine modified dendrimer with multiple reduced thiols as a kidney-targeting reactive oxygen species scavenger to prevent renal ischemia/reperfusion injury

Abstract

L-cysteine (Cys)-and L-serine (Ser)-modified, third-generation polyamidoamine (PAMAM) dendrimer with multiple reduced thiols (Ser-PAMAM-Cys) was synthesized as a kidney-targeting reactive oxygen species (ROS) scavenger to help prevent renal ischemia/reperfusion injury. Ser-PAMAM-Cys effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and ROS (hydrogen peroxide and hydroxyl radical) in phosphate-buffered saline (PBS). In addition, ~64% of 111 In-labeled Ser-PAMAM-Cys accumulated in mouse kidney 3 h after intravenous administration. An in vivo imaging system (IVIS) study indicated that near-infrared fluorescence dye (NIR)-labeled Ser-PAMAM-Cys specifically accumulated in the kidney. In a mouse renal ischemia/reperfusion injury model, increases in the kidney damage markers creatinine (Cre) and blood urea nitrogen (BUN) were significantly inhibited by intravenous Ser-PAMAM-Cys administration. In contrast, Cys injection had no statistically significant effect of preventing Cre or BUN elevation relative to the control. Ser-PAMAM-Cys also effectively downregulated the inflammatory factors NGAL, IL-18, ICAM-1, and VCAM-1 in the renal ischemia/reperfusion injury model. These results indicate that Ser-PAMAM-Cys is a promising kidney-targeting ROS scavenger which could prevent ischemia/reperfusion-induced renal failure.