Interaction of Gd(III) MRI contrast agents with membranes: a review of recent EPR studies

Rational development of new selective paramagnetic contrast agents (PCAs) requires a detailed understanding of their interactions with biological macromolecules. This report shows how some of these interactions can be studied with electron paramagnetic resonance (EPR) through examples of Gd3+ complexes interactions with model phospholipid membranes. It is shown that the spin label EPR method can be used to detect: (i) presence and possible location of lipophilic contrast agents in the model membranes, (ii) changes and distortions in membrane organization upon interaction with the PCAs, and (iii) changes in the local polarity of the bilayer and its phase behavior due to addition of Gd3+ complexes. This work demonstrates that interaction of Gd3+ complexes with phospholipid bilayers can be observed directly from changes in their continuous wave (CW) EPR spectra obtained at frequencies higher than X-band (9.5 GHz), where signals arising from aqueous and lipid-bound Gd3+ complexes become resolved. Analysis of frequency dependence of the effective g-factors of the EPR signal provides estimates of zero-field splitting (ZFS) parameter for these complexes at physiological conditions and information on how this parameter is affected by interaction with lipids. Multifrequency EPR experiments at high magnetic fields are also useful in providing data on the frequency dispersion of electronic relaxation caused mainly by a modulation of the electron-electron dipolar interaction (ZFS) of these high spin ions.