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JBIC Journal of Biological Inorganic Chemistry

, Volume 19, Issue 2, pp 215–227 | Cite as

Characterisation and evaluation of paramagnetic fluorine labelled glycol chitosan conjugates for 19F and 1H magnetic resonance imaging

  • Elena De Luca
  • Peter Harvey
  • Kirsten H. Chalmers
  • Anurag Mishra
  • P. Kanthi Senanayake
  • J. Ian Wilson
  • Mauro Botta
  • Marianna Fekete
  • Andrew M. Blamire
  • David Parker
Original Paper
Part of the following topical collections:
  1. Topical Issue on Metal-Based MRI Contrast Agents

Abstract

Medium molecular weight glycol chitosan conjugates have been prepared, linked by an amide bond to paramagnetic Gd(III), Ho(III) and Dy(III) macrocyclic complexes in which a trifluoromethyl reporter group is located 6.5 Å from the paramagnetic centre. The faster relaxation of the observed nucleus allows modified pulse sequences to be used with shorter acquisition times. The polydisperse materials have been characterised by gel permeation chromatography, revealing an average molecular weight on the order of 13,800 (Gd), 14,600 (Dy) and 16,200 (Ho), consistent with the presence of 8.5, 9.5 and 13 complexes, respectively. The gadolinium conjugate was prepared for both a q = 1 monoamide tricarboxylate conjugate (r 1p 11.2 mM−1 s−1, 310 K, 1.4 T) and a q = 0 triphosphinate system, and conventional contrast-enhanced proton MRI studies at 7 T were undertaken in mice bearing an HT-29 or an HCT-116 colorectal tumour xenograft (17 μmol/kg). Enhanced contrast was observed following injection in the tail vein in tumour tissue, with uptake also evident in the liver and kidney with a tumour-to-liver ratio of 2:1 at 13 min, and large amounts in the kidney and bladder consistent with predominant renal clearance. Parallel experiments observing the 19F resonance in the holmium conjugate complex using a surface coil did not succeed owing to its high R 2 value (750 Hz, 7 T). However, the fluorine signal in the dysprosium triphosphinate chitosan conjugate [R 1/R 2 = 0.6 and R 1 = 145 Hz (7 T)] was sharper and could be observed in vivo at −65.7 ppm, following intravenous tail vein injection of a dose of 34 μmol/kg.

Keywords

Contrast agents Fluorine Tumour uptake MRI Imaging 

Abbreviations

DO3A

1,4,7-Tricarboxymethyl-1,4,7,10-tetraazacyclododecane

GPC

Gel permeation chromatography

MRI

Magnetic resonance imaging

MS

Mass spectrometry

NMM

N-Methylmorpholine

NMRD

Nuclear magnetic relaxation dispersion

TBTU

Tetramethyluronium tetrafluoroborate

PDI

Polydispersity index

MRSI

Magnetic resonance spectroscopic imaging

Notes

Acknowledgments

We thank the Engineering and Physical Sciences Research Council and Cancer Research UK for support, Andrei Batsanov for determination of the X-ray crystal structure and Alan Kenwright for certain NMR relaxation experiments in vitro.

Supplementary material

775_2013_1028_MOESM1_ESM.pdf (164 kb)
Supplementary material (PDF 164 kb)

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Copyright information

© SBIC 2013

Authors and Affiliations

  • Elena De Luca
    • 1
  • Peter Harvey
    • 1
  • Kirsten H. Chalmers
    • 1
  • Anurag Mishra
    • 1
  • P. Kanthi Senanayake
    • 1
  • J. Ian Wilson
    • 2
  • Mauro Botta
    • 3
  • Marianna Fekete
    • 3
  • Andrew M. Blamire
    • 2
  • David Parker
    • 1
  1. 1.Department of ChemistryDurham UniversityDurhamUK
  2. 2.Northern Institute for Cancer Research, and Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUK
  3. 3.Dipartimento di Scienze e Innovazione TecnologicaUniversità del Piemonte Orientale “Amedeo Avogadro”AlessandriaItaly

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