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

Ryan M Williams,Vanessa Thompson,Elizabeth Mercer,Justin M Cheung,Elisa De Stanchina,Jaclyn M Kubala,Madeline Dorso,Daniel A Heller,Helen S Tian,Edgar A Jaimes,Lorraine J Gudas,Janki Shah

doi:10.3389/fphar.2021.790913

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.

Highlights

Acute kidney injury (AKI) is a common clinical condition associated with significant morbidity and mortality regardless of etiology or setting
To deliver the free radical scavenger edaravone to the site of Cisplatin-induced acute kidney injury (CI-AKI), we formulated kidney-targeted mesoscale nanoparticles to encapsulate the drug via nanoprecipitation as previously described (Williams et al, 2015; Williams et al, 2018)
Ctrl-mesoscale nanoparticle (MNP) exhibited an average size of 332.0 ± 7.56 nm with a polydispersity index (PDI) of 0.302. 74% of these particles fell within the 164–531 nm size range (Table 1; Figure 1A)

Summary

Introduction

Acute kidney injury (AKI) is a common clinical condition associated with significant morbidity and mortality regardless of etiology or setting. AKI affects millions of individual patients and has a large socioeconomic impact, including longer hospital stay and higher costs. In the United States alone, it is estimated that the annual costs related to AKI are up to $24 billion (Silver and Chertow, 2017). The incidence of AKI is increasing at a rapid pace (Xue et al, 2006; Goldberg and Dennen, 2008), which is attributable to several factors including shifts in demographics, severity of underlying diseases, and expansion of invasive and complex medical procedures (Hoste and Schurgers, 2008; Zappitelli, 2008). AKI can result from a variety of insults including volume depletion, septicemia, hypotension, and commonly used drugs including antibiotics and chemotherapeutic agents.

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