Abstract: TH-PO098
Treatment of Cisplatin-Induced AKI with Renal Selective Nanotherapy
Session Information
- AKI: Inflammation, New Technologies, Omics
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Jaimes, Edgar A., Memorial Sloan-Kettering Cancer Center, New York, New York, United States
- Williams, Ryan M., Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Mercer, Elizabeth, Indiana University School of Medicine, Evansville, Indiana, United States
- Heller, Daniel A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
Background
Acute kidney injury (AKI) occurs in up to 30% of patients treated with cisplatin and up to 25% of patients in intensive care. AKI is linked to increased morbidity and mortality. Unfortunately there are no effective interventions for the treatment or prevention of AKI in humans. In prior work, we developed mesoscale nanoparticles (MNPs) that selectively localize to the kidneys primarily to the proximal tubular epithelium. We hypothesize that these MNPs can be used a delivery platform of small molecules for the treatment of AKI.
Methods
We synthesized nanoparticles from poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) which were encapsulated with the reactive oxygen species scavenger edaravone. The particles are approximately 400 nm in diameter with a negative surface charge. AKI was induced wit cisplatin induction (25 mg/kg IP) followed by intravenous injection of therapeutic MNPs (50mg/kg) loaded with edaravone(3.9 mcg/100 mg MNP) or the free drug alone 24 hours after induction of AKI. Mice were sacrificed after 72 hours.
Results
Compared to cisplatin alone, mice treated with drug-encapsulating MNPs had a significant reduction in serum creatinine. We stained for the renal injury marker NGAL, DNA-damage induced protein p53, TUNEL for apoptosis, and nitrotyrosine for oxidative stress. In each, we found significantly increased injury and staining in mice with cisplatin alone or cisplatin plus dose-matched free drug, with reduced or baseline levels in mice receiving therapeutic MNPs.
Conclusion
These studies demonstrate the therapeutic efficacy of our MNP as a delivery system of drugs to the proximal tubules for the treatment of cisplatin induced AKI. This approach may result in the development of novel therapeutic strategies for patients affected by AKI of different etiologies.
a) Electron micrograph of MNPs. b) MNP localization to the kidneys c) Serum creatinine in mice treated with therapeutic nanoparticles or edaravone
Funding
- Other NIH Support