MEMRI and tumors: a method for the evaluation of the contribution of Mn(II) ions in the extracellular compartment

• Published in: NMR in biomedicine 2015-09, Vol.28 (9), p.1104-1110
• Main Authors: Gianolio, Eliana, Arena, Francesca, Di Gregorio, Enza, Pagliarin, Roberto, Delbianco, Martina, Baio, Gabriella, Aime, Silvio
• Format: Article
• Language: English
• Subjects: Animals; calcium receptors; Cell Line, Tumor; cellular and molecular cancer imaging; DO2A; Female; Heterocyclic Compounds, 1-Ring - metabolism; Humans; Magnetic Resonance Imaging - methods; Manganese - metabolism; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; MEMRI; Mice; Mice, Inbred C57BL; molecular and cellular probes; relaxivity
• ISSN: 0952-3480; 1099-1492
• DOI: 10.1002/nbm.3349

The purpose of the work was to set‐up a simple method to evaluate the contribution of Mn2+ ions in the intra‐ and extracellular tumor compartments in a MEMRI experiment. This task has been tackled by “silencing” the relaxation enhancement arising from Mn2+ ions in the extracellular space. In vitro relaxometric measurements allowed assessment of the sequestering activity of DO2A (1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid) towards Mn2+ ions, as the addition of Ca‐DO2A to a solution of MnCl2 causes a drop of relaxivity upon the formation of the highly stable and low‐relaxivity Mn‐DO2A. It has been proved that the sequestering ability of DO2A towards Mn2+ ions is also fully effective in the presence of serum albumin. Moreover, it has been shown that Mn‐DO2A does not enter cell membranes, nor does the presence of Ca‐DO2A in the extracellular space prompt migration of Mn ions from the intracellular compartment. On this basis the in vivo, instantaneous, drop in SE% (percent signal enhancement) in T1‐weighted images is taken as evidence of the sequestration of extracellular Mn2+ ions upon addition of Ca‐DO2A. By applying the method to B16F10 tumor bearing mice, T1 decrease is readily detected in the tumor region, whereas a negligible change in SE% is observed in kidneys, liver and muscle. The relaxometric MRI results have been validated by ICP‐MS measurements. Copyright © 2015 John Wiley & Sons, Ltd. Ca‐DO2A was used as sequestering agent for manganese to set up a simple method to assess the contribution of Mn2+ ions in the intra‐ and extracellular compartments in tumors. In vitro relaxometric characterization was followed by the in vivo validation.