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New vanadium-based magnetic resonance imaging probes: clinical potential for early detection of cancer

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Abstract

We have developed a magnetic resonance imaging (MRI) method for improved detection of cancer with a new class of cancer-specific contrast agents, containing vanadyl (VO2+)-chelated organic ligands, specifically bis(acetylacetonato)oxovanadium(IV) [VO(acac)2]. Vanadyl compounds have been found to accumulate within cells, where they interact with intracellular glycolytic enzymes. Aggressive cancers are metabolically active and highly glycolytic; an MRI contrast agent that enters cells with high glycolytic activity could provide high-resolution functional images of tumor boundaries and internal structure, which cannot be achieved by conventional contrast agents. The present work demonstrates properties of VO(acac)2 that may give it excellent specificity for cancer detection. A high dose of VO(acac)2 did not cause any acute or short-term adverse reactions in murine subjects. Calorimetry and spectrofluorometric methods demonstrate that VO(acac)2 is a blood pool agent that binds to serum albumin with a dissociation constant K d ~ 2.5 ± 0.7 × 10−7 M and a binding stoichiometry n = 1.03 ± 0.04. Owing to its prolonged blood half-life and selective leakage from hyperpermeable tumor vasculature, a low dose of VO(acac)2 (0.15 mmol/kg) selectively enhanced in vivo magnetic resonance images of tumors, providing high-resolution images of their interior structure. The kinetics of uptake and washout are consistent with the hypothesis that VO(acac)2 preferentially accumulates in cancer cells. Although VO(acac)2 has a lower relaxivity than gadolinium-based MRI contrast agents, its specificity for highly glycolytic cells may lead to an innovative approach to cancer detection since it has the potential to produce MRI contrast agents that are nontoxic and highly sensitive to cancer metabolism.

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Abbreviations

AA:

Atomic absorption

BSA:

Bovine serum albumin

ENDOR:

Electron nuclear double resonance

EPR:

Electron paramagnetic resonance

EPSI:

Echo planar spectroscopic imaging

HEPES:

N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), sodium salt

ITC:

Isothermal titration calorimetry

MRI:

Magnetic resonance imaging

PET:

Positron emission tomography

VC:

Vanadyl chelate

VO(acac)2 :

Bis(acetylacetonato)oxovanadium(IV)

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Acknowledgments

This work was supported by grants from the American Cancer Society, Illinois Division (nos. 06-18, 08-45). This work was also partially supported by grants from the National Institutes of Health (RO1 EB003108), the University of Chicago Cancer Research Center, and the Lynn S. Florsheim MRIS facility.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Center for Integrative Science, The University of Chicago, 929 East 57th Street, Chicago, IL, 60637, USA

    Devkumar Mustafi, Bo Peng & Marvin W. Makinen

  2. Department of Radiology, The University of Chicago, Chicago, IL, 60637, USA

    Sean Foxley, Gregory S. Karczmar & Marta Zamora

  3. Department of Chemistry, Northern Michigan University, Marquette, MI, 49855, USA

    John Ejnik & Heather Martin

Authors
  1. Devkumar Mustafi
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  2. Bo Peng
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Correspondence to Devkumar Mustafi.

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Mustafi, D., Peng, B., Foxley, S. et al. New vanadium-based magnetic resonance imaging probes: clinical potential for early detection of cancer. J Biol Inorg Chem 14, 1187–1197 (2009). https://doi.org/10.1007/s00775-009-0562-0

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  • DOI: https://doi.org/10.1007/s00775-009-0562-0

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