Abstract 2032: Renal tubule-targeted supportive care nanotherapy for cisplatin-induced acute kidney injury

Abstract

Abstract Acute kidney injury (AKI) develops in up to 30% of patients who receive cisplatin-based chemotherapy. In this setting, AKI can result in delays in completion of treatment and/or the need to switch to other potentially less effective therapeutic regimens. Despite its high incidence and associated increased morbidity and mortality, there is no effective pharmacologic intervention to treat AKI of any etiology, including AKI resulting from cisplatin or any other nephrotoxic treatments. In the case of cisplatin-induced AKI, it is also imperative that any pharmacologic intervention that could be effective for AKI will not interfere with the systemic chemotherapeutic effects of cisplatin. In prior studies (Nano Letters, 2015), we reported the development of mesoscale nanoparticles (MNPs), composed of poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) that localize to the kidneys with a high affinity, primarily to the proximal tubules (the site of injury in AKI), and persist at that location for up to a week. Herein, we encapsulated a small molecule reactive oxygen species scavenger, (edaravone) in the MNPs. Experiments were performed in male C57BL/6 mice with cisplatin-induced AKI (25 mg/kg IP). To assess therapeutic efficacy, tail vein injections of 50 mg/kg edaravone-containing MNPs, 50 mg/kg empty control MNPs, or 30 mg/kg free edaravone were performed 24 hours after cisplatin injection (n=6-8 per group). Mice were euthanized at 72 hours post-cisplatin administration, and kidney and serum were saved for analysis. In a separate group of mice bearing metastatic small cell lung cancer, fluorescent MNPs were injected to determine whether MNPs still localize to the kidneys rather than to the tumor as has been described for other types of nanoparticles. Mice receiving cisplatin had a ~5 fold increase in serum creatinine and severe acute tubular necrosis as compared to controls. In contrast to mice receiving cisplatin alone, mice receiving edaravone-containing MNPs along with cisplatin had normal creatinine and histology similar to controls. Neither treatment with free edaravone nor empty MNPs resulted in a significant improvement in renal function or severity of tubular necrosis in mice with cisplatin-induced AKI. In the presence of AKI, the distribution of MNPs was still highly selective to the renal proximal tubules. In mice with metastatic lung tumors, we determined that MNPs maintain their specific renal distribution and do not localize to tumors as has been described with other smaller nanoparticle systems. These studies demonstrate that edaravone-containing MNPs can be an effective treatment for cisplatin-induced AKI while avoiding the possible therapeutic abatement associated with tumor deposition of reactive oxygen species scavengers. We anticipate that these studies will constitute the basis for the development of novel strategies for the treatment and prevention of cisplatin-induced AKI in humans. Citation Format: Daniel A. Heller, Edgar Jaimes, Ryan Williams, Janki Shah. Renal tubule-targeted supportive care nanotherapy for cisplatin-induced acute kidney injury [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2032.