Rapamycin PFC Nanoparticles Pre‐Treatment Mitigates Cisplatin Induced Acute Kidney Injury

Abstract

Cisplatin, belonging to the class of platinum‐containing anti‐cancer drugs, is widely used in a variety of cancers, including sarcomas, lymphomas, small cell lung cancer, squamous cell carcinoma of the head and neck, bladder cancer, testicular cancer, cervical cancer and ovarian cancer. Despite its chemotherapeutic efficacy, cisplatin induces acute kidney injury (AKI) in approximately one‐third of treated patients, which further impairs their quality of life, and thwarts successful outcomes of cisplatin treatment. Although it is known that early enhancement of autophagy and inhibition of cisplatin induced inflammation is beneficial in mitigating cisplatin induced AKI, treatment targeting both mechanisms remains to be developed. Accordingly, our hypothesis is that rapamycin PFC nanoparticles could serve this purpose via rapamycin targeting of mTOR signaling to induce autophagy and inhibit its downstream NF‐κB signaling pathway, a convergent gate keeper in inflammation. Rapamycin delivery by PFC nanoparticles enables sufficient drug delivery to the site of injury with minimum systemic exposure as well as sustained local drug release.Fluorescence microscopic images demonstrated the delivery of rapamycin PFC nanoparticles to the kidneys, where they remained for 24 hours following i.v. injection (n=3). Therefore, we performed rapamycin PFC nanoparticles (1 ml/kg) treatment 24 hours before cisplatin injection (10 mg/kg) (n=5). Mice receiving cisplatin injection only (n=5) and mice receiving no injection (n=5) served as controls. On the day of rapamycin PFC nanoparticles and cisplatin injections as well as 24, 48, and 72 hours after the cisplatin injection, blood was collected from each mouse for a BUN test to assess kidney function. The results (Fig. A) illustrated that cisplatin treatment induced mild kidney function impairment, which was mitigated by rapamycin PFC nanoparticles pre‐treatment. Furthermore, using proximal tubule cells (NRK‐52E), we demonstrated that the benefit of rapamycin PFC nanoparticles pre‐treatment could come from 1) enhancing autophagy (Fig. B), where p62 level was reduced in the groups with the rapamycin nanoparticles treatment regardless of cisplatin treatment; 2) preventing cisplatin induced inflammation (Fig. C) through NF‐κB signaling pathway activation, where p65 upregulation was only observed in the group receiving cisplatin treatment alone; and 3) inhibiting apoptosis (Fig. C), where rapamycin pre‐treatment inhibited cisplatin induced Bax expression.In conclusion, rapamycin PFC nanoparticles pretreatment could potentially mitigate cisplatin induced AKI in cancer patients.Support or Funding InformationThis work was supported by the NIH grant R01 DK102691.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.