title: Off-resonance saturation MRI of superparamagnetic nanoprobes: theoretical models and experimental validations.
abstract: Off-resonance saturation (ORS) is a new magnetic resonance imaging (MRI) method that has shown greatly improved contrast sensitivity for the detection of cancer-specific biomarkers by superparamagnetic nanoprobes in vivo. However, quantitative understanding of the ORS contrast mechanism and its dependence on the structural parameters of superparamagnetic nanoprobes are still lacking. Here we propose a quantitative model of ORS contrast and its experimental validation by superparamagnetic polymeric micelles (SPPM) with precisely controlled structural properties. Size selected, monodisperse Fe₃O₄ nanoparticles (6.1 ± 0.2 nm) were used to form a series of SPPM nanoprobes with specifically controlled corona thickness using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxypoly(ethylene glycol) (DSPE-PEG) with different PEG molecular weights. Transmission electron microscopy and dynamic light scattering showed that SPPM were uniform in size. The average hydrodynamic diameters of SPPM with PEG lengths of 0.55, 1, 2, and 5 kD were 16.6 ± 2.8, 18.4 ± 2.9, 24.1 ± 3.4, and 28.9 ± 3.4 nm, respectively. MRI experiments at 7 T determined that r₂ values of SPPM with 0.55, 1, 2, and 5 kD PEG as corona were 201 ± 3, 136 ± 8, 107 ± 5, and 108 ± 8 FemM⁻¹s⁻¹, respectively. ORS intensity from Z-spectra of SPPM showed a significant correlation with the inverse of T₂ relaxation rates (1/T₂, s⁻¹) of the SPPM nanoprobes regardless of the PEG corona thickness. These data provide the fundamental understanding of the structure-property relationships between the SPPM nanostructures and ORS sensitivity, which offers useful mechanistic insights for the future improvement of SPPM nanoprobes in cancer molecular imaging applications.
authors.affiliation: Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States.
authors.forename: Chalermchai
authors.initials: C
authors.lastname: Khemtong
authors.forename: Osamu
authors.initials: O
authors.lastname: Togao
authors.forename: Jimin
authors.initials: J
authors.lastname: Ren
authors.forename: Chase W
authors.initials: CW
authors.lastname: Kessinger
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: A Dean
authors.initials: AD
authors.lastname: Sherry
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D005290:Ferric Compounds / Q000032:analysis*; D007089:Image Enhancement / Q000379:methods*; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics; D008956:Models, Chemical; D049329:Nanostructures / Q000032:analysis*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D005290:Ferric Compounds; C000499:ferric oxide