pH Dependence of MRI Contrast in Magnetic Nanoparticle Suspensions Demonstrates Inner-Sphere Relaxivity Contributions and Reveals the Mechanism of Dissolution

Abstract

Superparamagnetic iron oxide nanoparticles, MNPs, are under investigation as stimulus-responsive nanocarriers that can be tracked by magnetic resonance imaging. However, fundamental questions remain, including the effect of differing surface chemistries on MR image contrast efficacy (relaxivity), both initially and over time in the biological environment. The effects of pH and ligand type on the relaxivity of electrostatically and sterically stabilized spherical 8.8 nm superparamagnetic MNP suspensions are described. It is shown for the first time that across the pH ranges, within which the particles are fully dispersed, increasing acidity progressively reduces relaxivity for all ligand types. This effect is stronger for electrostatically (citrate or APTES) than for sterically stabilized (PEG5000) MNPs. NMR relaxation profiles (relaxivity as a function of 1H Larmor frequency) identified an inner-sphere effect, arising from the protonation of bare oxide or low-molecular-weight-bound species, as the cause. The suppression is not accounted for by the accepted model (SPM theory) and is contrary to previous reports of increased relaxivity at lower pH for paramagnetic iron oxide nanoparticles. We propose that the suppression arises from the orientation of water molecules, with the oxygen atom facing the surface increasingly preferred with increasing surface protonation. For APTES-stabilized MNPs, pendant amines and the silane layer confer exceptional chemical and colloidal stability at low pH. Dissolution of these particles at pH 1.8 was monitored over several months by combining in situ measurements of relaxation profiles with dynamic light scattering. It was shown that particles are magnetically intact for extended periods until they rapidly dissolve, once the silane layer is breached, in a process that is apparently second order in particle concentration. The findings are of interest for tracking MNP fate, for quantitation, and for retention of magnetic responsiveness in biological settings.

Integrative Modulation of Magnetic Resonance Transverse and Longitudinal Relaxivity in a Cell-Viable Bimagnetic Ensemble, γ-Fe2O3@ZnFe2O4

“…However, r 1 and r 2 efficiency are found to be affected by a few key parameters, such as magnetization, nanoparticle size, effective radius, inhomogeneous magnetic field gradient, related crystal phases, etc. in accordance to Solomon–Bloembergen–Morgan Theory, Outer-Sphere Diffusion Model, etc. − The water proton relaxation solely occurs at the interface of magnetic nanosystems and their respective surrounding aqueous environment. The separation of paramagnetic species with the aid of various diamagnetic layers is also observed as a contemporary idea to produce efficient relaxivity in hybrid nanosystems .…”

“…1−3 Magnetic Resonance (MR)-relaxivity provides an extent up to which a contrast agent can increase the longitudinal/transverse relaxation rate of water protons. 4,5 The transverse relaxivity (r 2 ) or longitudinal relaxivity (r 1 ) associated with an ensemble of magnetic nanosystems is considered as a significant strategy to achieve MRI-contrast efficiency. 6−8 Generally, the magnetizing effects of magnetic nanosystems (MNPs) having Neel fluctuations can impact the MR-relaxivity in bi-and tri-magnetic systems.…”

“…The proton nuclear magnetic resonance-based relaxivity in the Magnetic Resonance Imagining (MRI) technique is an excellent approach for attaining improved biomedical images. − Magnetic Resonance (MR)-relaxivity provides an extent up to which a contrast agent can increase the longitudinal/transverse relaxation rate of water protons. , The transverse relaxivity ( r 2 ) or longitudinal relaxivity ( r 1 ) associated with an ensemble of magnetic nanosystems is considered as a significant strategy to achieve MRI-contrast efficiency. − Generally, the magnetizing effects of magnetic nanosystems (MNPs) having Neel fluctuations can impact the MR-relaxivity in bi- and tri- magnetic systems. In such a multidomain framework, the boundaries of the domains divide the spin arrays of each domain resulting in modulation of MRI-contrast efficacy. , The optimized magnetic dynamics such as blocking of Neel fluctuations, because of local magnetocrystalline field, can trigger enhancement in both r 1 and r 2 .…”

Interacting Trimagnetic Ensembles for Enhanced Magnetic Resonance Transverse Relaxivity

“…The exotic behavior of magnetic nanosystems (MNPs) has been recognized as an emerging platform in the domain of the water proton diffusion mechanism in magnetic resonance imaging (MRI) relaxivity augmentation. − The water proton diffusion around the ensembles is governed by the following three conditions: motional averaging regime (MAR) model, , static dephasing regime (SDR), and echo-limiting regime (ELR) − to understand the MR transverse relaxivity. The correlation between magnetization and transverse relaxivity of MNPs in the regime of MAR is partially recognized in complex cluster structures.…”