Abstract: TH-PO308

Renal Selective Mesoscale Nanoparticles to Treat AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

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
  • Shah, Janki, MSKCC, NY, 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) accounts for 1% of hospital admissions and up to 25% of patients in intensive care develop AKI. As many as 25% of these patients require renal replacement therapy and have high mortality rates. Despite the incidence and associated morbidities, there are no proven or effective therapies for AKI of different etiologies including cisplatin induced AKI, which occurs in 30% of patients receiving this chemotheraputic agent.

Methods

We synthesized nanoparticles from poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) encapsulating an antioxidant small molecule. The particles are 400 nm in diameter with a negative surface charge and when injected systemically they accumulate predominantly in the proximal tubules as we have shown (Williams, Nanoletters, 2015). Therapy experiments were performed in a mouse model (C57BL6, N = 4 to 6) of cisplatin induced AKI ( 25 mg/kg I.P.). MNPs (0.2 mg/kg nano-encapsulated drug) were injected IV 24 hours after AKI induction with cisplatin. Mice were sacrificed at 72 hours post-injury and blood urea nitrogen and creatinine measurements, and kidneys were fixed and saved for histology.

Results

MNPs exhibited significant therapeutic efficacy in cisplatin-induced AKI. In vivo, MNPs caused a significant decrease in serum biomarkers and histopathological hallmarks of AKI. AKI mice treated with therapeutic MNPs exhibited a 50% decrease in blood urea nitrogen and an 80% decrease in creatinine, with a marked decrease in tubular necrosis as assessed in PAS stained slides.

Conclusion

These studies demonstrate that targeted delivery of small molecules to the proximal tubule is an effective method of treatment for AKI. In future studies we will investigate the mechanisms of localization and optimization of therapy. This novel strategy may result in the development of novel strategies for the treatment and prevention of AKI of different etiologies.


In vivo AKI therapy with anti-oxidant-loaded nanoparticles. AKI mice treated with MNPs 24 hours after cisplatin administration. (A) BUN and (B) creatinine measurements show significant decrease in injury with MNP treatment.

Funding

  • Other NIH Support