Kidney-Targeted Redox Scavenger Therapy Prevents Cisplatin-Induced Acute Kidney Injury.

Cisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. We investigated a drug delivery strategy to improve the pharmacokinetics of an approved therapy that does not normally demonstrate appreciable efficacy in CI-AKI, as a preventive intervention. In prior work, we developed a kidney-selective mesoscale nanoparticle (MNP) that targets the renal proximal tubular epithelium. Here, we found that the nanoparticles target the kidneys in a mouse model of CI-AKI with significant damage. We evaluated MNPs loaded with the reactive oxygen species scavenger edaravone, currently used to treat stroke and ALS. We found a marked and significant therapeutic benefit with edaravone-loaded MNPs, including improved renal function, which we demonstrated was likely due to a decrease in tubular epithelial cell damage and death imparted by the specific delivery of edaravone. The results suggest that renal-selective edaravone delivery holds potential for the prevention of acute kidney injury among patients undergoing cisplatin-based chemotherapy.
Competing Interests: DH is a cofounder and officer with equity interest in Goldilocks Therapeutics, Inc., LipidSense, Inc., and Nirova BioSense, Inc. DH is a member of the scientific advisory boards of Concarlo Holdings, LLC, Nanorobotics, Inc., and Mediphage Bioceuticals, Inc. RW is a scientific advisor with equity interest in Goldilocks Therapeutics, Inc. EJ is a cofounder and chief medical officer with equity interest in Goldilocks Therapeutics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Williams, Shah, Mercer, Tian, Thompson, Cheung, Dorso, Kubala, Gudas, de Stanchina, Jaimes and Heller.)