Edaravone-Loaded Mesoscale Nanoparticles Treat Cisplatin-Induced Acute Kidney Injury

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. In our prior work, we developed a highly-selective kidneytargeted mesoscale nanoparticle (MNP) that accumulates primarily in the renal proximal tubular epithelial cells while exhibiting no toxicity. Here, we found that MNPs exhibit renal-selective targeting in multiple mouse models of tumor growth with virtually no tumor accumulation. We then evaluated the therapeutic efficacy of MNPs loaded with the reactive oxygen species scavenger edaravone in a mouse model of CI-AKI. We found a marked and significant therapeutic effect with this approach as compared to free drug or empty control MNPs, including improved renal function, histology, and diminution of oxidative stress. These results indicated that renal-selective MNP edaravone delivery holds substantial potential in the treatment of acute kidney injury among patients undergoing cisplatin-based chemotherapy. 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 US alone, it is estimated that the annual costs related to AKI are up to $24 billion 1 . The incidence of AKI is increasing at a rapid pace 2,3 , which is attributable to several factors including shifts in demographics, severity of underlying diseases, and expansion of invasive and complex medical procedures 4,5 . AKI can result from a variety of insults including volume depletion, septicemia, hypotension, and commonly used drugs including antibiotics and chemotherapeutic agents.Cisplatin is a widely used chemotherapy in the treatment of a variety of cancers including ovarian, head and neck, bladder, testicular, and lung, among others 6,7 . A significant side effect of cisplatin therapy is the occurrence of AKI in approximately 33% of patients 8,9 . Indeed, it has been reported that about 20% of all AKI incidences are caused by cisplatin 7,10 . The development of AKI in these patients can result in the interruption of chemotherapy or a change to less effective chemotherapies 8,9 . There is therefore a critical need to develop novel strategies to prevent or treat AKI induced by cisplatin. This would also have a direct impact on the oncologic outcomes of these patients whose treatment otherwise cannot be completed, or other less-effective chemotherapeutic agents must be used 11 .There has been significant overall progress in our understanding of the epidemiology, pathophysiology and outcomes of AKI. Despite such substantial advances, almost no meaningful progress has been made in the ...

Targeting the Kidneys at the Nanoscale: Nanotechnology in Nephrology

“… 97 , 101 , 106 , 107 Interestingly, kidney-specific targeting has been demonstrated in nude and nod-scid gamma mice bearing flank and orthotopic lung tumors in work designed to avoid NP localization to tumors in chemotherapy-associated AKI. 109 It should be noted that most studies have been performed in mice to date, with one initial work in rats.…”