Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.790913
Keywords
nanomedicine; pharmacology; acute kidney injury; drug repurposing; cisplatin; redox scavenger
Categories
Funding
- NIDDK [R01-DK114321, R01DK113088]
- NCI [R01-CA215719, P30-CA008748]
- NIH [GC230452, P30DK079312, S10RR27699, F31-CA213814, R25CA020449]
- American Cancer Society Research Scholar Grant [GC230452]
- Pershing Square Sohn Cancer Research Alliance
- Expect Miracles Foundation-Financial Services Against Cancer
- Anna Fuller Fund
- Louis V. Gerstner Jr Young Investigator's Fund
- Frank A. Howard Scholars Program
- Cycle for Survival
- Alan and Sandra Gerry Metastasis Research Initiative
- Commonwealth Foundation for Cancer Research
- Experimental Therapeutics Center
- Imaging and Radiation Sciences Program
- Center for Molecular Imaging and Nanotechnology of Memorial Sloan Kettering Cancer
- Ovarian Cancer Research Fund [370463]
- American Heart Association [17POST33650043]
- City College of New York Grove School of Engineering, PSC-CUNY [ENHC-51-75]
- Oak Ridge Associated Universities
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The use of kidney-selective mesoscale nanoparticles (MNP) to deliver the reactive oxygen species scavenger edaravone improved renal function and reduced tubular epithelial cell damage and death in a mouse model of cisplatin-induced acute kidney injury (CI-AKI).
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.
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