Oral Presentation Australian & New Zealand Society of Magnetic Resonance Conference 2017

Characterising the Binding of 2-Nitroimidazole: A Proton NMR Study (#25)

Dj Wijesekera 1 , Scott A Willis 1 , Abhishek Gupta 1 , Allan M Torres 1 , Gang Zheng 1 , William S Price 1
  1. Nanoscale Organisation and Dynamics, School of Science and Health, Western Sydney University, Campbelltown, New South Wales, Australia

Tumor hypoxia is known to limit the effectiveness of current radiotherapy treatments, and is of significant interest in oncology [1]. Conventionally, tumor hypoxia has been quantified through electrode measurements of intratumoral pO2 [2]. However, this method is highly-invasive, time consuming and technically difficult. Despite a wide array of methods aimed at maximising the effects of radiotherapy by either minimising or eliminating the treatment-limiting hypoxic tumor fraction [3-5], a robust method capable of non-invasively quantifying tumor hypoxia is yet to be developed. Nitroimidazole derivatives are known to target tissue hypoxia [6]. Their application in hypoxia-sensitive MRI contrast agents could potentially lead to quantitative measurements of tumor hypoxia. However, the binding of nitroimidazole to macromolecules must first be characterised in vitro to differentiate between the targeting ability of its derivatives. To this end, the binding of 2-nitroimidazole to bovine serum albumin (BSA) was characterised via NMR diffusion and relaxation studies. Diffusion, T1 and T2 measurements of 2-nitroimidazole in BSA solutions were obtained using the pulsed-gradient stimulated-echo (PGSTE) [7], inversion recovery [8] and Carr-Purcell-Meiboom-Gill (CPMG) [9] sequences, respectively. The two-site exchange Kärger model was then simultaneously fitted to the diffusion and relaxation data of the 24 samples, comprising 8 different ligand concentrations and 3 different protein concentrations. The binding was quantified by the number of binding sites and the binding association constant, which were determined to be 67 ± 6 and 137 ± 31 M-1, respectively.

  1. W.J. Koh, J.S. Rasey, M.L. Evans, J.R. Grierson, T.K. Lewellen, M.M. Graham, K.A. Krohn, T.W. Griffin, Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole, Int. J. Radiation Oncol. Biol. Phys., 22 (1991) 199-212.
  2. P. Kolstad, Intercapillary distance, oxygen tension and local recurrence in cervix cancer, Scand. J. Clin. Lab. Invest., 21 (1968) 145-157.
  3. L.S. Mortensen, S. Buus, M. Nordsmark, L. Bentzen, O.L. Munk, S. Keiding, J. Overgaard, Identifying hypoxia in human tumors: A correlation study between 18F-FMISO PET and the eppendorf oxygen-sensitive electrode, Acta. Oncol., 49 (2010) 934-940.
  4. I.N. Fleming, R. Manavaki, P.J. Blower, C. West, K.J. Williams, A.L. Harris, J. Domarkas, S. Lord, C. Baldry, F.J. Gilbert, Imaging tumour hypoxia with positron emission tomography, Br. J. Cancer, 112 (2015) 238-250.
  5. S. Rey, L. Schito, M. Koritzinsky, B.G. Wouters, Molecular targeting of hypoxia in radiotherapy, Adv. Drug Delivery Rev., 109 (2017) 45-62.
  6. A. Nunn, K. Linder, H.W. Strauss, Nitroimidazoles and imaging hypoxia, Eur. J. Nucl. Med., 22 (1995) 265-280.
  7. J.E. Tanner, Use of the stimulated echo in NMR diffusion studies, J. Chem. Phys., 52 (1970) 2523-2526.
  8. R.L. Vold, J.S. Waugh, M.P. Klein, D.E. Phelps, Measurement of spin relaxation in complex systems, J. Chem. Phys., 48 (1968) 3831-3832.
  9. H.Y. Carr, E.M. Purcell, Effects of diffusion on free precession in nuclear magnetic resonance experiments, Phys. Rev., 94 (1954) 630-638.