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Abstract: FR-PO1013

Mesoscale Nanoparticles Treat Cisplatin-Induced AKI and Avoid Tumor Accumulation

Session Information

  • Onco-Nephrology: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Onco-Nephrology

  • 1500 Onco-Nephrology

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, 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

Acute kidney injury (AKI) develops in ~ 30% of patients who receive cisplatin-based chemotherapy. In this setting, AKI can result in delays in completion of treatment or the need to switch to other therapeutic regimens. Despite its high incidence there is no effective pharmacologic intervention for AKI. In cisplatin-induced AKI, it is imperative that any intervention effective for AKI will not interfere with the chemotherapeutic effects of cisplatin. In prior work (Nano Letters 2015) we developed mesoscale nanoparticles (MNPs) that localize to the kidneys with high affinity, primarily to the proximal tubules.

Methods

We synthesized nanoparticles from PLGA-PEG and encapsulated the small molecule reactive oxygen species scavenger edaravone. Experiments were performed in C57 mice with cisplatin-induced AKI (25 mg/kg IP). To assess therapeutic efficacy, IV injections of 50 mg/kg edaravone-containing MNPs, control MNPs, or 30 mg/kg free edaravone were performed 24 hours after cisplatin. Mice were euthanized at 72 hours post-cisplatin. In a separate group of mice bearing metastatic small cell lung cancer, fluorescent MNPs were injected to determine whether MNPs localization.

Results

Compared to mice receiving cisplatin alone, mice receiving edaravone-containing MNPs had normal sCr and normal renal histology. Neither free edaravone nor empty MNPs improved sCr or histology. 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 smaller nanoparticle systems.

Conclusion

These studies confirm the likelihood of successful AKI therapy in the context of cisplatin-induced AKI, while avoiding the possible therapeutic abatement associated with tumor deposition of ROS 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.

Funding

  • NIDDK Support