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

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $411,674

## Abstract

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,...

## Key facts

- **NIH application ID:** 10644372
- **Project number:** 7R01DK125322-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Hua Pan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,674
- **Award type:** 7
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10644372

## Citation

> US National Institutes of Health, RePORTER application 10644372, Mitigate cisplatin induced acute kidney injury through preservation of vasculature and proximal tubule (7R01DK125322-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10644372. Licensed CC0.

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