Iron-doped calcium phytate nanoparticles as a bio-responsive contrast agent in 1H/31P magnetic resonance imaging

Abstract

We present the MR properties of a novel bio-responsive phosphorus probe doped with iron for dual proton and phosphorus magnetic resonance imaging (¹H/³¹P-MRI), which provide simultaneously complementary information. The probes consist of non-toxic biodegradable calcium phytate (CaIP₆) nanoparticles doped with different amounts of cleavable paramagnetic Fe³⁺ ions. Phosphorus atoms in the phytate structure delivered an efficient ³¹P-MR signal, with iron ions altering MR contrast for both ¹H and ³¹P-MR. The coordinated paramagnetic Fe³⁺ ions broadened the ³¹P-MR signal spectral line due to the short T₂ relaxation time, resulting in more hypointense signal. However, when Fe³⁺ was decomplexed from the probe, relaxation times were prolonged. As a result of iron release, intensity of ¹H-MR, as well as the ³¹P-MR signal increase. These ¹H and ³¹P-MR dual signals triggered by iron decomplexation may have been attributable to biochemical changes in the environment with strong iron chelators, such as bacterial siderophore (deferoxamine). Analysing MR signal alternations as a proof-of-principle on a phantom at a 4.7 T magnetic field, we found that iron presence influenced ¹H and ³¹P signals and signal recovery via iron chelation using deferoxamine.

Figure 1

Homogeneity of ¹H/³¹P radiofrequency solenoid coil measured using a water phantom and ¹H-MRI on a 4.7 T scanner: (a) ¹H/³¹P radiofrequency solenoid coil with 500-µL tube suitable for high SNR measurement; (b) axial plane, with scale bar representing 10 mm; signal intensity is represented by a colour scale (dB) reflecting signal attenuation—from red (highest signal) to blue (lowest signal).

Figure 2

MR results for phantoms at different iron doping concentrations measured on a 4.7 T scanner: (a) ¹H-MRI and (b) ³¹P-MRI for calcium phytate nanoparticles doped with 0–13.6 mmol L⁻¹ Fe³⁺ and 2.73 mmol L⁻¹ Fe³⁺ probe with DFOA, with scale bar representing 10 mm and dotted line showing quantified region of interest for phosphorus signal; (c) ³¹P-MRS comparison of 2.73 mmol L⁻¹ Fe³⁺ probes with and without DFOA chelation.

Figure 3

Relative (a) ¹H-MRI and (b) ³¹P-MRI signal intensity (SI) dependence of calcium phytate probes doped with different iron concentrations (c^Fe = 0–13.6 mmol L⁻¹) measured on a 4.7 T scanner. Error bars represent standard deviation of mean signal intensity.

Figure 4

Results of alamarBlue cell viability assay, represented as a percentage of the resazurin reduction by HepG2 and Caco-2 cells comparing to the control cells after a 24-h incubation with the 2.04 mmol L⁻¹ Fe³⁺ probe with the calcium phytate concentration of 0.22–0.89 mg mL⁻¹.