AUTHOR=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. TITLE=Kidney-Targeted Redox Scavenger Therapy Prevents Cisplatin-Induced Acute Kidney Injury JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.790913 DOI=10.3389/fphar.2021.790913 ISSN=1663-9812 ABSTRACT=

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.