Mitigate cisplatin induced acute kidney injury through preservation of vasculature and proximal tubule

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Abstract Since its discovery about five decades ago, cisplatin has been proven to be one of the most effective treatments for a variety of cancers and is still a widely used chemotherapy drug subscribed to 10-20% of the cancer patients. Along with its potent anti-cancer efficacy, well recognized is the toxic side effects associated with cisplatin/platinum-based chemotherapy. Cisplatin induced nephrotoxicity, as known since its early clinical trials, is not only prevalent but also severe with long lasting adverse effects. Acute kidney injury has been observed in 30% of cancer patients receiving a single dose of cisplatin chemotherapy and in 50-70% of patients receiving multiple doses. Besides disrupting effective anti-cancer treatment, cisplatin induced acute kidney injury affects those patients even after switching to other anticancer regimens. They still face increased risks of chronic kidney injury, poor prognosis, and higher mortality. Therefore, it is essential to address this unmet medical need by developing effective preventions and interventions to mitigate cisplatin induced acute kidney injury. In the kidney, cisplatin causes both vascular and proximal tubule damages through molecular events of elevated oxidative stress, inflammation, excessive wastes accumulation in cytoplasm, and apoptosis. Our preliminary results demonstrated that rapamycin perfluorocarbon (PFC) nanoparticles simultaneously enhance autophagy to facilitate clearance of wastes in cytoplasm and inhibit inflammation through mTOR-NF-κB signaling. With the rapamycin PFC nanoparticles treatment, renal function is protected, and survival rate is significantly improved in the mice receiving cisplatin. Moreover, rapamycin PFC nanoparticles have favorable pharmacokinetics and biodistribution. Comparing to free rapamycin, rapamycin PFC nanoparticles significantly reduced systemic exposure of rapamycin and its accumulation in the vital organs, such as brain. Accordingly, in this proposed study, our central hypothesis is that cisplatin induced acute kidney injury could be mitigated by preserving renal vasculature and proximal tubule through simultaneously inhibition of inflammation and enhancement of autophagy via mTOR-NF-κB signaling pathway. Therefore, following three specific aims are proposed to test the hypothesis for potential clinical translation. Specific Aim 1 will further validate the therapeutic efficacy of rapamycin PFC nanoparticles both in vitro and in vivo with regard to elucidate the molecular mechanism of therapy with regard to mTOR-NF-κB signaling pathway; Specific Aim 2 will evaluate integrated 19F and 1H BOLD MRI for non-invasive therapeutic evaluation of cisplatin induced AKI by simultaneously quantifying renal vascular injury and hypoxia. In Specific Aim 3, we will rigorously examine the safety of rapamycin PFC nanoparticles, pharmacokinetics/pharmacodynamics, clearance, and biodistribution in both control and tumor-bearing mice for clinical translation. Also, the effect of rapamycin PFC nanoparticles on tumor growth will be investigated.