Mitochondrial targeted ROS scavenger based on nitroxide for treatment and MRI imaging of acute kidney injury

摘要

Overproduction of reactive oxygen species (ROS) during oxidative stress is hallmark of acute kidney injury (AKI), which induced the damage to the renal cells and mitochondrial injury. In this contribution, we prepared mitochondrial targeted nitroxide, which linked 3-carboxy-2,2,5,5-tetramethylpyrrolidine 1-oxyl (carboxy-PROXYL) with (2-aminoethyl)triphenylphosphonium bromide (TPP), named TPP-PROXYL to eliminate the ROS in situ and image the oxidative stress reaction by MRI. 2,7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA) staining, mitochondrial membrane potential assay (JC-1) staining and transmission electron microscope (TEM) experiments were processed to verify that TPP-PROXYL could target mitochondria, scavenge the ROS, and prevent damage to mitochondria in live cells. Contrast enhanced MRI also been used to monitor these redox reaction in AKI model. TPP-PROXYL demonstrated excellent ROS T-1-weighted magnetic resonance imaging enhancement in vitro and in vivo, with r(1) value about 0.190 mM(-1) s(-1). In vivo AKI treatment experiments proved that TPP-PROXYL could improve the survival rate of mice and inhibit kidney damage. Moreover, the great ROS scavenging capability and the renal damage reduction during AKI treatment of TPP-PROXYL was verified via MR imaging technology. Collectively, this research provides TPP-PROXYL would serve as a powerful platform to realize ROS scavenging, treatment, and MR imaging of AKI.