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GdDO3NI, a nitroimidazole-based T 1 MRI contrast agent for imaging tumor hypoxia in vivo

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Abstract

Tumor hypoxia is known to affect sensitivity to radiotherapy and promote development of metastases; therefore, the ability to image tumor hypoxia in vivo could provide useful prognostic information and help tailor therapy. We previously demonstrated in vitro evidence for selective accumulation of a gadolinium tetraazacyclododecanetetraacetic acid monoamide conjugate of 2-nitroimidazole (GdDO3NI), a magnetic resonance imaging T 1-shortening agent, in hypoxic cells grown in tissue culture. We now report evidence for accumulation of GdDO3NI in hypoxic tumor tissue in vivo. Our data show that GdDO3NI accumulated significantly (p < 0.05) in the central, poorly perfused regions of rat prostate adenocarcinoma AT1 tumors (threefold higher concentration than for the control agent) and showed better clearance from well-perfused regions and complete clearance from the surrounding muscle tissue. Inductively coupled plasma mass spectroscopy confirmed that more GdDO3NI than control agent was retained in the central region and that more GdDO3NI was retained in the central region than at the periphery. These results show the utility of GdDO3NI to image tumor hypoxia and highlight the potential of GdDO3NI for application to image-guided interventions for radiation therapy or hypoxia-activated chemotherapy.

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Abbreviations

DOTA:

Tetraazacyclododecanetetraacetic acid

GdDO3ABA:

Gadolinium tetraazacyclododecanetetraacetic acid (n-butyl)monoamide

GdDO3NI:

Gadolinium tetraazacyclododecanetetraacetic acid monoamide conjugate of 2-nitroimidazole

GdDTPA:

Gadolinium diethylenetriaminepentaacetic acid

GdHPDO3A:

Gadolinium 10-(2-hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid

ICP-MS:

Inductively coupled plasma mass spectrometry

MR:

Magnetic resonance

MRI:

Magnetic resonance imaging

PET:

Positron emission tomography

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Acknowledgments

This research was supported in part by grants from the Norman Hackerman ARP grant (010019-0056-2007), the National Institutes of Health (R21CA132096, R01CA139043 and R01CA115531), the Southwestern Small Animal Imaging Research Program (U24 CA126608), and the Robert A. Welch Foundation (AT-584). MRI experiments were performed at the Advanced Imaging Research Center with support from a National Institutes of Health National Institute of Biomedical Imaging and Bioengineering resource grant (P41EB015908). We would like to thank Li Liu and Abhijit Bugde for helpful advice.

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Author notes

  1. Praveen K. Gulaka

    Present address: Samsung Electronics, Suwon, South Korea

Authors and Affiliations

  1. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Praveen K. Gulaka, Ralph P. Mason & A. Dean Sherry

  2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Federico Rojas-Quijano, Zoltan Kovacs & A. Dean Sherry

  3. School of Biological and Health Systems Engineering, Arizona State University, Phoenix, AZ, 85287-9709, USA

    Vikram D. Kodibagkar

Authors
  1. Praveen K. Gulaka
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  2. Federico Rojas-Quijano
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  3. Zoltan Kovacs
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  4. Ralph P. Mason
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  5. A. Dean Sherry
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Correspondence to Vikram D. Kodibagkar.

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Responsible Editor: Valerie C. Pierre.

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Gulaka, P.K., Rojas-Quijano, F., Kovacs, Z. et al. GdDO3NI, a nitroimidazole-based T 1 MRI contrast agent for imaging tumor hypoxia in vivo. J Biol Inorg Chem 19, 271–279 (2014). https://doi.org/10.1007/s00775-013-1058-5

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  • DOI: https://doi.org/10.1007/s00775-013-1058-5

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