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

• Published in: Frontiers in pharmacology 2022-01, Vol.12, p.790913
• Main Authors: Williams, Ryan M, Shah, Janki, Mercer, Elizabeth, Tian, Helen S, Thompson, Vanessa, Cheung, Justin M, Dorso, Madeline, Kubala, Jaclyn M, Gudas, Lorraine J, de Stanchina, Elisa, Jaimes, Edgar A, Heller, Daniel A
• Format: Article
• Language: English
• Subjects: acute kidney injury; cisplatin; drug repurposing; nanomedicine; Pharmacology; redox scavenger
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2021.790913

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.