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Pharmaceutical Research

, Volume 34, Issue 12, pp 2698–2709 | Cite as

Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury

  • Jace W. Jones
  • Isabel L. Jackson
  • Zeljko Vujaskovic
  • Michael D. Kaytor
  • Maureen A. Kane
Research Paper

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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 WORDS

biomarkers genistein lung injury metabolomics radiation 

Abbreviations

ARS

Acute radiation syndrome

CID

Collision-induced dissociation

DEARE

Delayed effects of acute radiation exposure

FDA

Federal Drug Administration

FDR

False discovery rate

FIA

Flow injection analysis

H&E

Hematoxylin and eosin

HDMSE

High definition mass spectrometry

HPLC

High-performance liquid chromatography

LC

Liquid chromatography

LD

Lethal dose

MCM

Medical countermeasure

MRM

Multiple reaction monitoring

NMDA

N-methyl-D-aspartate

PC

Glycerophosphatidylcholine

PCa

Diacyl glycerophosphatidylcholine

PCA

Principal component analysis

PCe

Ether glycerophosphatidylcholine

PCho

Phosphocholine

PE

Glycerophosphoethanolamine

PLS-DA

Partial least squares-discriminate analysis

PUFA

Polyunsaturated fatty acid

sem

Standard error of the mean

SFA

Saturated fatty acid

SM

Sphingomyelin

TIC

Total ion chromatogram

UPLC

Ultra performance liquid chromatography

XIC

Extracted ion chromatogram

WTLI

Whole thorax lung irradiation

Supplementary material

11095_2017_2200_MOESM1_ESM.docx (2.6 mb)
ESM 1 (DOCX 2622 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Jace W. Jones
    • 1
  • Isabel L. Jackson
    • 2
  • Zeljko Vujaskovic
    • 2
  • Michael D. Kaytor
    • 3
  • Maureen A. Kane
    • 1
  1. 1.School of Pharmacy, Department of Pharmaceutical SciencesUniversity of MarylandBaltimoreUSA
  2. 2.School of Medicine, Division of Translational Radiation Sciences Department of Radiation OncologyUniversity of MarylandBaltimoreUSA
  3. 3.Humanetics CorporationEdinaUSA

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