Innovative Magnetic Nanoparticles for PET/MRI Bimodal Imaging

Abstract

Superparamagnetic iron oxide nanoparticles were developed as positron emission tomography (PET) and magnetic resonance imaging (MRI) bimodal imaging agents. These nanoparticles (NPs), with a specific nanoflower morphology, were first synthesized and simultaneously functionalized with 3,4-dihydroxy-l-phenylalanine (LDOPA) under continuous hydrothermal conditions. The resulting NPs exhibited a low hydrodynamic size of 90 ± 2 nm. The functional groups of LDOPA (-NH₂ and -COOH) were successfully used for the grafting of molecules of interest in a second step. The nanostructures were modified by poly(ethylene glycol) (PEG) and a new macrocyclic chelator MANOTA for further ⁶⁴Cu radiolabeling for PET imaging. The functionalized NPs showed promising bimodal (PET and MRI) imaging capability with high r ₂ and r ₂* (T ₂ and T ₂* relaxivities) values and good stability. They were mainly uptaken from liver and kidneys. No cytotoxicity effect was observed. These NPs appear as a good candidate for bimodal tracers in PET/MRI.

Figure 1

(a) XRD pattern, (b) Raman spectra, (c) transmission electron microscopy (TEM) image, and (d) TEM diameter distribution of Fe₃O₄–LDOPA NPs.

Figure 2

Fourier transform infrared spectra collected from 4000 to 750 cm^–1 on Fe₃O₄–LDOPA, Fe₃O₄–LDOPA–PEG, and Fe₃O₄–LDOPA–PEG–MANOTA NPs.

Figure 3

XPS spectra of curve-fitted C 1s, N 1s, and O 1s peaks recorded on (a) Fe₃O₄–LDOPA, (b) Fe₃O₄–LDOPA–PEG, and (c) Fe₃O₄–LDOPA–PEG–MANOTA NPs.

Figure 4

Zetametry of Fe₃O₄–LDOPA, Fe₃O₄–LDOPA–PEG, and Fe₃O₄–LDOPA–PEG–MANOTA NPs.

Figure 5

DLS measurements of Fe₃O₄–LDOPA and Fe₃O₄–LDOPA–PEG–MANOTA NPs in PBS (0.1 M).

Figure 6

Cytotoxicity of HepG2 cells in the resazurin assay after exposure to different concentrations (μg mL^–1) of Fe₃O₄–LDOPA–PEG–MANOTA NPs for 24 h. Results are expressed as mean ± standard deviation (three independent experiments). Statistical difference was checked using a one-way analysis of variance (ANOVA) followed by a Dunnett test (p < 0.05).

Figure 7

Whole-body PET imaging of Fe₃O₄–LDOPA–PEG–MANOTA–⁶⁴Cu NPs on mouse 1 and 24 h after injection with a scale up at 24 h. Labels: B = bladder, DS = digestive system, Li = liver, and Lu = lungs.

Figure 8

Evaluation of the injected dose (Fe₃O₄–LDOPA–PEG–MANOTA–⁶⁴Cu) per gram (tissue) in blood circulation on three mice during 2 h following intravenous injection.

Figure 9

Evaluation of the biodistribution of Fe₃O₄–LDOPA–PEG–MANOTA–⁶⁴Cu NPs 48 h after intravenous injection in mice. Values represent the mean ± standard deviation of the percentage of the injected dose per gram of tissue in different organs (n = 4).

Figure 10

(a) Three-dimensional (3D) T₂*-weighted MR images and (b) PET imaging of renal cortex at different time of injection: before injection (pre-iv) for MRI, after 1 h (1 h post-iv), and 24 h (24 h post-iv) after injection of Fe₃O₄–LDOPA–PEG–MANOTA–⁶⁴Cu NPs in a mouse.

Figure 11

Schematic view of the conjugation chemistry between Fe₃O₄–LDOPA NPs with PEG and p-NCS-Bz-MANOTA.