Abstract: PO0217
Peritubular Transcytosis Enables Mesoscale Nanoparticle Treatment of AKI
Session Information
- AKI Mechanisms - 3
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Williams, Ryan, City College of New York, New York, New York, United States
- Shah, Janki, Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Heller, Daniel A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
Background
In prior studies we demonstrated that mesoscale nanoparticles (MNP) localize to the kidneys up to 26-fold more than to any other organ and that they specifically target the renal tubular epithelium. In this study we investigated the mechanism of MNP localization to the renal tubules and evaluated this platform’s potential for therapeutic delivery in a model of cisplatin-induced acute kidney injury (AKI).
Methods
We synthesized ~400 nm diameter MNPs from the biocompatible polymers poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG). MNPs were encapsulated with a fluorescent far-red dye or the reactive oxygen species scavenger edaravone. Male C57BL/6 mice, were sacrificed 30 minutes after injection for immune-electron microscopy studies . We also performed intravital microscopy to visualize the transit of MNPs in Cx3crgfp/+ C57BL/6 mice with GFP-expressing renal macrophages. We also evaluated their therapeutic potential in a cisplatin-induced AKI (25 mg/kg IP) model. 24 hours following cisplatin, mice received edaravone-loaded MNPs or appropruate controls. Serum creatinine and histology were analyzed 72 hours following cisplatin.
Results
We found that MNPs localize to the proximal tubular eoithelium via transcytosis from the peritubular capillaries. We observed MNPs flowing in these capillaries and in transit across the tubular interstitium. We also found that transcytosis of MNPS was not facilitated by macrophage uptake. Finally, we found that therapeutic MNPs use this mechanism to localize to the proximal tubules of mice with cisplatin-induced AKI (Figure).
Conclusion
These studies characterized transcytosis from the peritubular capillaries as the mechanism of particle localization to the kidneys and portend the development of additional therapeutic targeting tools for renal diseases.
Funding
- NIDDK Support