# Chemoprotection and imaging for aminoglycoside and chemotherapy toxicities

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2021 · —

## Abstract

The toxic side effects of many commonly used therapeutic agents can result in drug dose reduction or
discontinuation, limiting the use of these effective and inexpensive agents in the clinic. Protecting against dose
limiting toxicities would improve patient quality of life and has the potential to improve therapeutic outcomes by
increasing compliance with treatment regimens and allowing increased treatment times and doses. With
previous VA funding, we have been investigating mechanisms to decrease or eliminate the toxic side effects of
cancer chemotherapy for two decades and have moved from basic research to Phase III clinical trials. Our
research has demonstrated that delayed administration of the thiol chemoprotective agents sodium thiosulfate
(STS) and N-acetylcysteine (NAC) is an effective strategy to reduce the cochlear, renal and bone marrow
toxicities of the platinum-based chemotherapy agents cisplatin and carboplatin without decreasing their anti-
tumor efficacy. This proposal will expand our chemoprotection strategy to aminoglycoside antibiotics that are
commonly used in the VA patient population for the treatment of serious infections. Additionally, we will test the
hypothesis that inflammation following activation of the innate immune response in the cochlea will enhance
the ototoxic side effects of cisplatin chemotherapy and aminoglycoside antibiotics. To investigate the
mechanisms underlying toxicity and chemoprotection, we will test novel magnetic resonance imaging (MRI)
techniques using the iron oxide nanoparticle contrast agent ferumoxytol. Ferumoxytol is taken up by
macrophages and activated microglial cells over the course of 24 hours, providing a non-invasive marker of
inflamed tissues. We hypothesize that ferumoxytol enhancement on MRI will provide a quantifiable biomarker
to measure inflammation in the cochlea and the impact of inflammation on ototoxic stimuli, as well as the
impact of chemoprotection on these processes. In Aim 1 we will evaluate innate immune system enhancement
of cisplatin ototoxicity using generalized systemic inflammation versus localized acute neuroinflammation. We
will evaluate the magnitude of ototoxicity and inflammatory cell infiltration into the cochlea, and determine
whether thiol chemoprotection blocks the enhanced cisplatin toxicity. We will investigate high-resolution MRI
with ferumoxytol to assess inflammation and cisplatin ototoxicity and determine the impact of STS and NAC on
these processes. In Aim 2 we will assess chemoprotection for endotoxemia-potentiated aminoglycoside
ototoxicity. We will use ferumoxytol MRI to assess cochlear vessel permeability and inflammation. Our overall
goals are to develop chemoprotection strategies against the side effects of therapeutics and imaging
biomarkers to improve detection and management of inflammation, ultimately improving long-term outcomes
for VA patients.

## Key facts

- **NIH application ID:** 10046284
- **Project number:** 5I01BX003897-04
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** EDWARD A. NEUWELT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046284

## Citation

> US National Institutes of Health, RePORTER application 10046284, Chemoprotection and imaging for aminoglycoside and chemotherapy toxicities (5I01BX003897-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10046284. Licensed CC0.

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