title: Application of high-resolution magic-angle spinning NMR spectroscopy to define the cell uptake of MRI contrast agents.
abstract: A new method, based on proton high-resolution magic-angle spinning ((1)H HR-MAS) NMR spectroscopy, has been employed to study the cell uptake of magnetic resonance imaging contrast agents (MRI-CAs). The method was tested on human red blood cells (HRBC) and white blood cells (HWBC) by using three gadolinium complexes, widely used in diagnostics, Gd-BOPTA, Gd-DTPA, and Gd-DOTA, and the analogous complexes obtained by replacing Gd(III) with Dy(III), Nd(III), and Tb(III) (i.e., complexes isostructural to the ones of gadolinium but acting as shift agents). The method is based on the evaluation of the magnetic effects, line broadening, or induced lanthanide shift (LIS) caused by these complexes on NMR signals of intra- and extracellular water. Since magnetic effects are directly linked to permeability, this method is direct. In all the tests, these magnetic effects were detected for the extracellular water signal only, providing a direct proof that these complexes are not able to cross the cell membrane. Line broadening effects (i.e., the use of gadolinium complexes) only allow qualitative evaluations. On the contrary, LIS effects can be measured with high precision and they can be related to the concentration of the paramagnetic species in the cellular compartments. This is possible because the HR-MAS technique provides the complete elimination of bulk magnetic susceptibility (BMS) shift and the differentiation of extra- and intracellular water signals. Thus with this method, the rapid quantification of the MRI-CA amount inside and outside the cells is actually feasible.
authors.affiliation: Bracco Imaging S.p.A. Centro Ricerche Milano, via E. Folli, 50-20134 Milan, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Calabi
authors.forename: Goffredo
authors.initials: G
authors.lastname: Alfieri
authors.forename: Luca
authors.initials: L
authors.lastname: Biondi
authors.forename: Mario
authors.initials: M
authors.lastname: De Miranda
authors.forename: Lino
authors.initials: L
authors.lastname: Paleari
authors.forename: Stefano
authors.initials: S
authors.lastname: Ghelli
mesh_terms: D002463:Cell Membrane Permeability; D003287:Contrast Media / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000378:metabolism*; D005583:Fourier Analysis; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008536:Meglumine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C064572:gadobenic acid; D008536:Meglumine; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D019786:Gadolinium DTPA