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

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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.

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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

References

  1. Dorr H, Meineke V. Acute radiation syndrome caused by accidental radiation exposure - therapeutic principles. BMC med. 2011;9:126.

    Article  PubMed  PubMed Central  Google Scholar 

  2. MacVittie TJ, Farese AM, Jackson W III. The hematopoietic syndrome of the acute radiation syndrome in rhesus macaques: a systematic review of the lethal dose response relationship. Health Phys. 2015;109(5):342–66.

    Article  CAS  PubMed  Google Scholar 

  3. Van Dyk J, Keane TJ, Kan S, Rider WD, Fryer CJ. Radiation pneumonitis following large single dose irradiation: a re-evaluation based on absolute dose to lung. Int J Radiat Oncol Biol Phys. 1981;7(4):461–7.

    Article  PubMed  Google Scholar 

  4. Mah K, Van Dyk J. Quantitative measurement of changes in human lung density following irradiation. Radiother Oncol. 1988;11(2):169–79.

    Article  CAS  PubMed  Google Scholar 

  5. Day RM, Barshishat-Kupper M, Mog SR, McCart EA, Prasanna PG, Davis TA, et al. Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat res. 2008;49(4):361–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Calveley VL, Jelveh S, Langan A, Mahmood J, Yeung IW, Van Dyk J, et al. Genistein can mitigate the effect of radiation on rat lung tissue. Radiat res. 2010;173(5):602–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang Z, Kulkarni K, Zhu W, Hu M. Bioavailability and pharmacokinetics of genistein: mechanistic studies on its ADME. Anti Cancer Agents med Chem. 2012;12(10):1264–80.

    Article  CAS  Google Scholar 

  8. Ha CT, Li XH, Fu D, Xiao M, Landauer MR. Genistein nanoparticles protect mouse hematopoietic system and prevent proinflammatory factors after gamma irradiation. Radiat res. 2013;180(3):316–25.

    Article  CAS  PubMed  Google Scholar 

  9. Jackson IL, Zodda A, Gurung G, Pavlovic R, Kaytor MD, Kuskowski MA, Vujaskovic Z. BIO 300, a nanosuspension of Genistein, mitigates pneumonitis/fibrosis following high dose radiation exposure in the C57L/J murine model. Br J Pharmacol 2017. (in review).

  10. Jackson IL, Xu P, Hadley C, Katz BP, McGurk R, Down JD, et al. A preclinical rodent model of radiation-induced lung injury for medical countermeasure screening in accordance with the FDA animal rule. Health Phys. 2012;103(4):463–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Product development under the animal rule: Guidance for industry. U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). 2015. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm399217.pdf.

  12. Guidance for industry and FDA staff: Qualification process for drug development tools. U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). 2014. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm230597.pdf.

  13. Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.

    Article  Google Scholar 

  14. Jones JW, Carter CL, Li F, Yu J, Pierzchalski K, Jackson IL, et al. Ultraperformance convergence chromatography-high resolution tandem mass spectrometry for lipid biomarker profiling and identification. Biomed Chromatogr. 2017;31(3):e3822. doi:10.1002/bmc.3822.

    Article  Google Scholar 

  15. Tyburski JB, Patterson AD, Krausz KW, Slavik J, Fornace AJ Jr, Gonzalez FJ, et al. Radiation metabolomics. 1. Identification of minimally invasive urine biomarkers for gamma-radiation exposure in mice. Radiat res. 2008;170(1):1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ossetrova NI, Sandgren DJ, Blakely WF. Protein biomarkers for enhancement of radiation dose and injury assessment in nonhuman primate total-body irradiation model. Radiat Prot Dosim. 2014;159(1–4):61–76.

    Article  CAS  Google Scholar 

  17. Jones JW, Scott AJ, Tudor G, Xu PT, Jackson IL, Vujaskovic Z, et al. Identification and quantitation of biomarkers for radiation-induced injury via mass spectrometry. Health Phys. 2014;106(1):106–19.

    Article  CAS  PubMed  Google Scholar 

  18. Biomarkers Used as Outcomes in Development of FDA-Approved Therapeutics (October 2007–December 2015) [10/18/2016]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm483052.htm.

  19. Mukherjee D, Coates PJ, Lorimore SA, Wright EG. Responses to ionizing radiation mediated by inflammatory mechanisms. J Pathol. 2014;232(3):289–99.

    Article  CAS  PubMed  Google Scholar 

  20. Fleckenstein K, Zgonjanin L, Chen L, Rabbani Z, Jackson IL, Thrasher B, et al. Temporal onset of hypoxia and oxidative stress after pulmonary irradiation. Int J Radiat Oncol Biol Phys. 2007;68(1):196–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carter CL, Jones JW, Farese AM, MacVittie TJ, Kane MA. Inflation-fixation method for Lipidomic mapping of lung biopsies by matrix assisted laser desorption/ionization-mass spectrometry imaging. Anal Chem. 2016;88(9):4788–94.

    Article  CAS  PubMed  Google Scholar 

  22. Xia J, Wishart DS. Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis. Curr Protoc Bioinformatics. 2016;55(14.10):1–14.

    Google Scholar 

  23. Castro-Perez J, Roddy TP, Nibbering NM, Shah V, McLaren DG, Previs S, et al. Localization of fatty acyl and double bond positions in phosphatidylcholines using a dual stage CID fragmentation coupled with ion mobility mass spectrometry. J am Soc Mass Spectrom. 2011;22(9):1552–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lisa M, Cifkova E, Holcapek M. Lipidomic profiling of biological tissues using off-line two-dimensional high-performance liquid chromatography-mass spectrometry. J Chromatogr a. 2011;1218(31):5146–56.

    Article  CAS  PubMed  Google Scholar 

  25. Houjou T, Yamatani K, Nakanishi H, Imagawa M, Shimizu T, Taguchi R. Rapid and selective identification of molecular species in phosphatidylcholine and sphingomyelin by conditional neutral loss scanning and MS3. Rapid Commun Mass Spectrom. 2004;18(24):3123–30.

    Article  CAS  PubMed  Google Scholar 

  26. Pannkuk EL, Fornace AJ Jr, Laiakis EC. Metabolomic applications in radiation biodosimetry: exploring radiation effects through small molecules. Int J Radiat Biol. 2017;12:1–26.

  27. Brunelli L, Caiola E, Marabese M, Broggini M, Pastorelli R. Comparative metabolomics profiling of isogenic KRAS wild type and mutant NSCLC cells in vitro and in vivo. Sci Report. 2016;6:28398.

    Article  CAS  Google Scholar 

  28. Schnackenberg LK, Pence L, Vijay V, Moland CL, George N, Cao Z, et al. Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice. J Appl Toxicol. 2016;36(11):1486–95.

    Article  CAS  PubMed  Google Scholar 

  29. Qiu Y, Zhou B, Su M, Baxter S, Zheng X, Zhao X, et al. Mass spectrometry-based quantitative metabolomics revealed a distinct lipid profile in breast cancer patients. Int J Mol Sci. 2013;14(4):8047–61.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Conlon TM, Bartel J, Ballweg K, Gunter S, Prehn C, Krumsiek J, et al. Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema. Clin Sci (Lond.). 2016;130(4):273–87.

    Article  CAS  Google Scholar 

  31. Carter CL, Jones JW, Barrow K, Kieta K, Taylor-Howell C, Kearney S, et al. A MALDI-MSI approach to the characterization of radiation-induced lung injury and medical countermeasure development. Health Phys. 2015;109(5):466–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu G. Amino acids: metabolism, functions, and nutrition. Amino Acids. 2009;37(1):1–17.

    Article  Google Scholar 

  33. Orlando GF, Wolf G, Engelmann M. Role of neuronal nitric oxide synthase in the regulation of the neuroendocrine stress response in rodents: insights from mutant mice. Amino Acids. 2008;35(1):17–27.

    Article  CAS  PubMed  Google Scholar 

  34. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, et al. Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 2009;37(1):153–68.

    Article  CAS  PubMed  Google Scholar 

  35. Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, et al. Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling. Mol Pharmacol. 2005;67(5):1470–84.

    Article  CAS  PubMed  Google Scholar 

  36. Said SI, Berisha HI, Pakbaz H. Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S a. 1996;93(10):4688–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li Y, Liu Y, Peng X, Liu W, Zhao F, Feng D, et al. NMDA receptor antagonist attenuates bleomycin-induced acute lung injury. PLoS One. 2015;10(5):e0125873.

    Article  PubMed  PubMed Central  Google Scholar 

  38. da Cunha AA, Pauli V, Saciura VC, Pires MG, Constantino LC, de Souza B, et al. N-methyl-D-aspartate glutamate receptor blockade attenuates lung injury associated with experimental sepsis. Chest. 2010;137(2):297–302.

    Article  PubMed  Google Scholar 

  39. da Cunha AA, Nunes FB, Lunardelli A, Pauli V, Amaral RH, de Oliveira LM, et al. Treatment with N-methyl-D-aspartate receptor antagonist (MK-801) protects against oxidative stress in lipopolysaccharide-induced acute lung injury in the rat. Int Immunopharmacol. 2011;11(6):706–11.

    Article  PubMed  Google Scholar 

  40. Tang F, Yue S, Luo Z, Feng D, Wang M, Qian C, et al. Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury. Pediatr Pulmonol. 2005;40(5):437–44.

    Article  PubMed  Google Scholar 

  41. Engelmann B, Brautigam C, Thiery J. Plasmalogen phospholipids as potential protectors against lipid peroxidation of low density lipoproteins. Biochem Biophys res Commun. 1994;204(3):1235–42.

    Article  CAS  PubMed  Google Scholar 

  42. Harwood JL. Lung surfactant. Prog Lipid res. 1987;26(3):211–56.

    Article  CAS  PubMed  Google Scholar 

  43. Griese M. Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999;13(6):1455–76.

    Article  CAS  PubMed  Google Scholar 

  44. Finkelstein JN. Physiologic and toxicologic responses of alveolar type II cells. Toxicology. 1990;60(1–2):41–52.

    Article  CAS  PubMed  Google Scholar 

  45. Agrawal A, Kale RK. Radiation induced peroxidative damage: mechanism and significance. Indian J Exp Biol. 2001;39(4):291–309.

    CAS  PubMed  Google Scholar 

  46. Catala A. Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids. 2009;157(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  47. Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012;1822(9):1442–52.

    Article  CAS  PubMed  Google Scholar 

  48. Niaudet C, Bonnaud S, Guillonneau M, Gouard S, Gaugler MH, Dutoit S, et al. Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis. Cell Signal. 2017;33:10–21.

    Article  CAS  PubMed  Google Scholar 

  49. Corre I, Guillonneau M, Paris F. Membrane signaling induced by high doses of ionizing radiation in the endothelial compartment. Relevance in radiation toxicity. Int J Mol Sci. 2013;14(11):22678–96.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene. 2003;22(37):5897–906.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. School of Pharmacy, Department of Pharmaceutical Sciences, University of Maryland, 20 N. Pine Street, Baltimore, Maryland, 21201, USA

    Jace W. Jones & Maureen A. Kane

  2. School of Medicine, Division of Translational Radiation Sciences Department of Radiation Oncology, University of Maryland, Baltimore, 21201, Maryland, USA

    Isabel L. Jackson & Zeljko Vujaskovic

  3. Humanetics Corporation, Edina, 55435, Minnesota, USA

    Michael D. Kaytor

Authors
  1. Jace W. Jones
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  2. Isabel L. Jackson
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  3. Zeljko Vujaskovic
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  4. Michael D. Kaytor
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  5. Maureen A. Kane
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Correspondence to Maureen A. Kane.

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Jones, J.W., Jackson, I.L., Vujaskovic, Z. et al. Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury. Pharm Res 34, 2698–2709 (2017). https://doi.org/10.1007/s11095-017-2200-9

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  • DOI: https://doi.org/10.1007/s11095-017-2200-9

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