Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury
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Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival.
High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers.
A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified.
These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.
KEY WORDSbiomarkers genistein lung injury metabolomics radiation
Acute radiation syndrome
Delayed effects of acute radiation exposure
Federal Drug Administration
False discovery rate
Flow injection analysis
Hematoxylin and eosin
High definition mass spectrometry
High-performance liquid chromatography
Multiple reaction monitoring
Principal component analysis
Partial least squares-discriminate analysis
Polyunsaturated fatty acid
Standard error of the mean
Saturated fatty acid
Total ion chromatogram
Ultra performance liquid chromatography
Extracted ion chromatogram
Whole thorax lung irradiation
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