Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

Abstract

Magnetic resonance imaging (MRI) is a highly valuable non-invasive imaging tool owing to its exquisite soft tissue contrast, high spatial resolution, lack of ionizing radiation, and wide clinical applicability. Contrast agents (CAs) can be used to further enhance the sensitivity of MRI to obtain information-rich images. Recently, extensive research efforts have been focused on the design and synthesis of high-performance inorganic nanoparticle-based CAs to improve the quality and specificity of MRI. Herein, the basic rules, including the choice of metal ions, effect of electron motion on water relaxation, and involved mechanisms, of CAs for MRI have been elucidated in detail. In particular, various design principles, including size control, surface modification (e.g. organic ligand, silica shell, and inorganic nanolayers), and shape regulation, to impact relaxation of water molecules have been discussed in detail. Comprehensive understanding of how these factors work can guide the engineering of future inorganic nanoparticles with high relaxivity. Finally, we have summarized the currently available strategies and their mechanism for obtaining high-performance CAs and discussed the challenges and future developments of nanoparticulate CAs for clinical translation in MRI.

Fig. 1

Inner sphere, secondary sphere, and outer sphere can influence relaxation rates of MRI CAs.

Fig. 2

Factors influencing relaxation of MRI CAs: size, surface, and shape effects at the nanoscale.

Fig. 3

(a) TEM images of oleate-stabilized NaGdF₄ NPs of varied particle sizes (scale bar is the same for all images). (b) Plots of 1/T₁ versus Gd³⁺ concentration for varied NaGdF₄ NPs in water (1.5 T). Reproduced with permission from ref. . Copyright 2011, American Chemical Society. (c) R₁ relaxivity of aqueous solutions containing NaGdF₄ NPs of different sizes or Gd–DTPA with different concentrations of Gd³⁺. Reproduced with permission from ref. . Copyright 2013, American Chemical Society. (d) Magnetic resonance angiography of rabbits within 3 min after injection of ultra-small NaGdF₄ nanodots or Magnevist. AA: abdominal aorta; IVC: inferior vena cava. (e) Transverse cross-sectional images of rabbit atherosclerotic plaques before and after injection of ultra-small NaGdF₄ nanodots or Magnevist at the same dosage (13 mg Gd per kg). Reproduced with permission from ref. . Copyright 2014, Wiley-VCH.

Fig. 4

(a) TEM images of MnO NPs of varied sizes (7, 15, 20, and 25 nm) in water. (b) T₁-weighted MR image of MnO NPs in a 3.0 T clinical MRI system. Reproduced with permission from ref. . Copyright 2007, Wiley-VCH. Size-dependent T₁-weighted MR images and relaxivities of water-dispersible spherical (c) and tetrahedral (d) Mn₃O₄ NPs at varied Mn²⁺ concentrations. (e) The r₁ and r₂ values and r₂/r₁ ratios of Mn₃O₄ MPs from c and d. Reproduced with permission from ref. . Copyright 2012, Wiley-VCH.

Fig. 5

(a) Field-dependent magnetization curves at 300 K for iron oxide NPs of varied sizes. (b) Description of spin canting effect (canting layer = 0.9 nm) in iron oxide NPs of varied sizes. Red and black colors represent magnetic cores and magnetically disordered shells. (c) Plots of 1/T₁ over concentration of iron oxide NPs of 3 nm and 12 nm diameter. (d) T₁-weighted MR images of MCF-7 cell pellets after 24 h incubation with iron oxide NPs of 3 nm and 12 nm in diameters. Reproduced with permission from ref. . Copyright 2011, American Chemical Society. (e) T₁-weighted magnetic resonance angiography (MRA) of a mouse injected with ultra-small iron oxide NPs at 7 T. (f) Five different perspectives of MRA images, which were extracted from a 3D scan, at 4 minutes post-injection. Reproduced with permission from ref. . Copyright 2017, National Academy of Sciences.

Fig. 6

(a) TEM images of iron oxide NPs of 4, 6, 9, and 12 nm. (b) Upper panel: Size-dependent T₂-weighted MR images of iron oxide NPs in aqueous solution at 1.5 T; lower panel: size-dependent changes from red to blue in color-coded MR images based on T₂ values. (c) The magnetization of iron oxide NPs measured by a SQUID magnetometer. (d) Size-dependent r₂ values of iron oxide NPs. Reproduced with permission from ref. . Copyright 2005, American Chemical Society. (e) Size-dependent T₂-weighted MR images of PVP-coated iron oxide NPs in aqueous solution with various concentrations at 7 T. (f) Plots of 1/T₂ against Fe concentration of PVP-coated iron oxide NPs. (g) Size-dependent r₂ values of iron oxide NPs. Reproduced with permission from ref. . Copyright 2010, American Chemical Society.

Fig. 7

(a) r₁ and (b) r₂ values of NaDyF₄ NPs (three different sizes) at 3 and 9.4 T. (c) (i) TEM images of 5.4, 9.8, and 20.3 nm NaDyF₄ NPs, (ii) phantom MR images of NPs at 1.0 mM Dy³⁺ concentration at 9.4 T. Reproduced with permission from ref. . Copyright 2012, American Chemical Society. (d) Schematic of the effect of size and a coating layer on the relaxation of NaDyF₄ and NaHoF₄ NPs. Reproduced with permission from ref. . Copyright 2016, American Chemical Society. (e) T₂-weighted MR images of NaHoF₄ NPs of varied sizes in aqueous solutions at 7.0 T. (f) r₂ values obtained for varied sized NaHoF₄ NPs at 1.5 T, 3.0 T, and 7.0 T. (g) Simulated curves of B²φ from Curie contribution versus diffusion correlation time (τ_D), which is related to NP size. Reproduced with permission from ref. . Copyright 2016, Elsevier Ltd.

Fig. 8

(a) A TEM image of ultra-small oleate-stabilized NaGdF₄ NPs of 3 nm diameter. (b) A representative negative-stained TEM image of DSPE– PEG-coated NP micelles. Inset: Schematic of a NaGdF₄ NP confined within a DSPE–PEG micelle. (c) r₁ values of a clinical MRI contrast agent (Dotarem) and the compact NP micelles at low (1.41 T) and high (7 T) fields. (d) Schematic and (e) r₁ values of NaGdF₄ NPs (3 nm) confined within DSPE–PEG micelles with varied PEG chain length. (f) Schematic and (g) r₁ values of NaGdF₄ NPs confined within DSPE–PEG micelles with variable core NP size (3–5 nm). Reproduced with permission from ref. . Copyright 2016, American Chemical Society. (h) r₁ and r₂ values of NaGdF₄ NPs coated with different ligands measured at 0.5 T. (i) Schematic of the strong hydrogen-bonding capacity of PAA to water molecules to improve r₁. Reproduced with permission from ref. . Copyright 2017, American Chemical Society.

Fig. 9

(a) Left panel: Chemical structures of PEGs used for exchanging the hydrophobic ligands of 3.6 nm(S: small) and 10.9 nm(L: large) iron oxide NPs; right panel: TEM images of resulting PEGylated NPs (scale bars: 50 nm); insets: photographs of aqueous solutions of PEGylated NPs at an equal Fe concentration of 20 mM. Comparison of (b) r₂ and (c) r₁ values of different kinds of PEGylated NPs. Reproduced with permission from ref. . Copyright 2014, Wiley-VCH. (d) Left panel: Schematic of three transfer approaches: ligand exchange of oleic acid with a water-soluble polymer (top), coating of individual NPs with the amphiphilic polymer (middle), and embedding into lipid micelles (bottom). Reproduced with permission from ref. . Copyright 2007, American Chemical Society. (e) Schematic of a nanoparticle with 4.8 nm iron oxide core and DSPE-PEG1000 coating. (f) T₂ relaxivity of iron oxide NPs at a constant iron concentration. (g) T₂ relaxivity of NPs on a per-particle basis. Iron oxide NPs with two core sizes, 5 and 14 nm, and five PEG sizes, 550, 750, 1000, 2000, and 5000 Da, were evaluated. Reproduced with permission from ref. . Copyright 2010, American Chemical Society.

Fig. 10

(a) Schematic illustration of coating UCNPs with dSiO₂ and mSiO₂ shells. (b) TEM images of (b) UCNP@mSiO₂ and (c) UCNP@dSiO₂ with varied shell thicknesses. Scale bar: 20 nm. (d) The plot of r₁ and r₂ versus mSiO₂ shell thickness. (e) The plot of r₁ and r₂ versus dSiO₂ shell thickness. Reproduced with permission from ref. . Copyright 2014, Wiley-VCH. (f) Schematic of the synthesis of HMnO@mSiO₂ NPs and labeling of mesenchymal stem cells. HMnO denotes hollow structure manganese oxide NPs. (g) TEM images and r₁ value of MnO–lipid PEG, MnO@dSiO₂, HMnO@mSiO₂ NPs. (h) No MRI contrast enhancement (red arrow) was detected in mice transplanted with unlabeled mesenchymal stem cells into the brain, whereas hyperintense signals (green arrows) were detected in mice transplanted with HMnO@mSiO₂-labeled mesenchymal stem cells, which were still visible 14 days after injection in the brain. The scheme and figures (with minor modifications) are licensed under the ACS AuthorChoice license. Reproduced with permission from ref. . Copyright 2011, American Chemical Society.

Fig. 11

HRTEM images of (a) FePt@Fe₂O₃ yolk–shell NPs, (b) Pt@Fe₂O₃ yolk–shell NPs, (c) FePt@Fe₃O₄ core–shell NPs obtained by the seed-growth method, and (d) γ-Fe₂O₃ hollow NPs. (e) Room-temperature field-dependent magnetization measurements of different NPs. Reproduced with permission from ref. . Copyright 2008, American Chemical Society. (f) TEM image of 16 nm iron/iron oxide core/shell NPs. (g) HRTEM image showing a core of single-crystal a-Fe and a shell consisting of multiple domains of iron oxide. (h) T₂-weighted MR images at 9.4 T of iron/iron oxide core/shell NPs and iron oxide NPs. (i) r₂ values of the core/shell and oxide NPs determined from the same samples as in (h). Reproduced with permission from ref. . Copyright 2011, Wiley-VCH.

Fig. 12

TEM images and schematic of Gd-free core (a, f and k) and core@NaGdF₄ with varied NaGdF₄ shell thicknesses of 0.2 nm (b, g, and l), 0.7 nm (c, h and m), 2.0 nm (d, i, and n), and 3.7 nm (e, j, and o). Yellow dots in l, m, n, and o represent Gd³⁺ ions. The r₁ values of silica-coated water-soluble core@NaGdF₄ NPs of various sizes are shown in the middle of the schematic illustrations. Reproduced with permission from ref. . Copyright 2011, Wiley-VCH.

Fig. 13

Shape effects on T₂ contrast. (a) TEM image (scale bar, 100 nm) and (b) higher magnification TEM image (scale bar, 20 nm) of octapod-30 NPs of uniform four-armed iron oxide NPs. (c) A cartoon showing octapod and spherical iron oxide NPs. With the same geometric core volumes, the octapod NPs have much larger effective volumes (radius, R) than the spherical NPs (radius, r). (d) Comparison of r₂ values of different iron oxide NPs. (e) In vivo sagittal MR images and (f) quantification of signal-to-background ratio (*P = 0.01) of orthotopic liver tumor models at 0, 0.5, 1, 2 and 4 h after intravenous injection of octapod-30 and spherical-16 iron oxide NPs. Reproduced with permission from ref. . Copyright 2013, Nature Publishing Group. (g and h) Top: TEM images of 16 nm iron oxide NPs (g) and 50 nm NRs (h). Bottom: Local magnetic field generated by the NRs and spherical Fe₃O₄ NPs of equivalent material volumes under an applied magnetic field of 3 T. (i) Schematic of the quantum mechanical outer sphere model of Fe₃O₄ NPs and NRs of the same material volume. Reproduced with permission from ref. . Copyright 2015, Royal Society of Chemistry.

Fig. 14

Effects of NP shape on T₁ relaxivity. (a) Schematic showing r₁ values of different kinds of MRI CAs including Gd³⁺ chelates, DNA–Gd@spheres, and DNA–Gd@stars. (b) NMRD profiles for water solutions of DNA–Gd@stars and DNA–Gd@spheres. (c) Simulated deconvolution of DNA–Gd@stars NMRD profiles into their inner, secondary, and outer sphere contributions. Reproduced with permission from ref. . Copyright 2015, American Chemical Society. (d) Schematic showing the dependence of relaxation on branch numbers of DNA–Gd@stars. Reproduced with permission from ref.. Copyright 2016, American Chemical Society.

Fig. 15

Schematic of engineering strategies to obtain high-relaxivity CAs for efficient MRI contrast enhancement.

Fig. 16

(a) Schematics showing (i) Magnevist (MAG), (ii) gadofullerenes (GF), and (iii) gadonanotubes (GNT) and cartoons showing Magnevist, GFs and GNTs entrapped within the porous structure of SiMPs. (b) r₁ values of six MRI CA nanostructures in comparison with corresponding Gd-based CAs at 1.41 T and 37 °C. Reproduced with permission from ref. . Copyright 2010, Nature Publishing Group. (c) Schematic of Gd₂O₃ confined in MSNs. Reproduced with permission from ref. . Copyright 2016, Royal Society of Chemistry. (d) TEM image of hybrid mesoporous composite nanocapsules (HMCNs). Inset: STEM image with scale bar = 100 nm. (e) Relaxivity of an aqueous suspension of HMCNs after 4 h of soaking in buffer solutions at pH 5.0 and 7.4 at 37 °C. Reproduced with permission from ref. . Copyright 2012, Elsevier Ltd.

Fig. 17

(a) TEM images, mass magnetization values, magnetic spin structures, magnetic moments, T₂-weighted images and colormaps of MnFe₂O₄, FeFe₂O₄, CoFe₂O₄, and NiFe₂O₄ NPs. Reproduced with permission from ref. . Copyright 2007, Nature Publishing Group. (b) Plots of r₂ versus Zn²⁺ doping level in (Zn_xM_1−x)Fe₂O₄ (M = Mn²⁺, Fe²⁺) NPs at 4.5 T. (c) Comparison of r₂ values of NPs, showing that Zn²⁺ doped NPs have significantly enhanced MRI contrast when compared to conventional iron oxide NPs. Reproduced with permission from ref. . Copyright 2009, Wiley-VCH.

Fig. 18

(a) Schematic of intracellular caspase-3/7-triggered aggregation of Fe₃O₄@1 NPs. (b) Plots of 1/T₂ versus metal concentration in the presence or absence of caspase-3/7. (c) In vivo T₂-weighted coronal images of Fe₃O₄@1 NPs or Fe₃O₄@1-Scr NPs in saline or DOX-treated (i.e., apoptotic) mice in 0 h (top) or 3 h (bottom) post injection. To make tumor apoptotic, about 8 mg kg⁻¹ of doxorubicin (DOX) was injected intravenously, once every 4 days three times. Reproduced with permission from ref. . Copyright 2016, American Chemical Society. (d) Schematic of ^99mTc-labeled Fe₃O₄ NPs and their responsiveness to GSH-triggering within the tumor microenvironment to form aggregates through inter-particle crosslinking reactions. (e) TEM images of the nonresponsive probe (left panel) and responsive probe (right panel) after being treated with GSH. (f) Temporal evolution of transverse relaxation rate R₂ for both the responsive probe and nonresponsive control recorded on a 3.0 T MRI scanner during incubation with GSH (inset: T₂-weighted images of probe solutions acquired at different incubation time points). Reproduced with permission from ref. . Copyright 2017, Wiley-VCH.

Fig. 19

(a) Schematic of how a degradable polymermatrix is able to control the interaction of water molecules with Gd₂O₃ NPs (purple spheres). (b) Magnetic relaxivity of Gd₂O₃ NPs encapsulated in pH-responsive materials demonstrates a jump from neutral pH to mild acidity. (c) Increasing concentrations of H₂O₂ results in corresponding increases in the T₁ relaxation rates of Gd₂O₃ NPs encapsulated in an H₂O₂-responsive polymer. Reproduced with permission from ref. . Copyright 2013, American Chemical Society.

Fig. 20

(a) Schematic of the hybrid structure of PEGMnCaP. PEGMnCaP consists of a CaP-based core and a PEG shell. The Mn²⁺ ions are trapped in the CaP core. (b) r₁ value of PEGMnCaP in physiological environments at different pH levels, with and without proteins (for example, HSA). (c) MR images of liver metastasis using 1 T MRI scanner after i.v. injection of PEGMnCaP NPs. Scale bar, 1 cm. (d) MR images of a hypoxic region within a C26 tumor at 1 T, 4 h after the i.v. injection of PEGMnCaP NPs. (e) Staining of tumor tissues with pimonidazole confirmed that the hypoxic regions (brown) are at the same location as the tumor regions with higher MRI contrast enhancement. Scale bar, 1 mm. Reproduced with permission from ref. . Copyright 2016, Nature Publishing Group. (f) Schematic of the disassembly of PEG/Mn–HMSNs through “manganese extraction” and release of Mn²⁺ component intracellularly. TEM images showing structural evolution of Mn–HMSNs after biodegradation at a GSH concentration of (g) 5.0 and (h) 10 mM at pH 5.0 for 48 h. (i) Plot of 1/T₁ versus Mn concentration for PEG/Mn–HMSN solution at varied GSH concentrations and (j) at varied pH. Reproduced with permission from ref. . Copyright 2016, American Chemical Society.

Fig. 21

(a) Schematic illustration showing the fabrication process of MnO₂/DVDMS and the reaction in GSH solution or with H₂O₂ (pH 5.5). (b) Plot of 1/T₁ versus Mn concentration for MnO₂/DVDMS (black line), MnO₂/DVDMS + GSH (red line), and MnO₂/DVDMS + H₂O₂/H⁺ (blue line) solutions. (c) T₁-weighted MR images before and after injection of MnO₂/DVDMS. (d) TEM images of MCF-7 tumor sections at 24 h after injection of MnO₂/DVDMS. Reproduced with permission from ref. . Copyright 2017, Wiley-VCH. (e) UV-vis-NIR absorption spectra and (f) plot of 1/T₁ versus Gd³⁺ concentration of PEG–Na_xGdWO₃ nanorods after oxidization with H₂O₂ for varied time periods: 1#: 0 h; 2#: 0.5 h; 3#: 1 h; 4#: 3 h. (g) Schematic of the affinity of oxygen vacancies for oxygen atoms and its impact on the interaction between water molecules and Gd³⁺ ions. Reproduced with permission from ref. . Copyright 2017, American Chemical Society.

Fig. 22

(a) Schematic representation of distance-dependent magnetic resonance tuning. (b) Schematic of a nanoscale ruler that shows a variable T₁ MRI signal, dependent on the separation distance between the paramagnetic enhancer (Gd-DOTA) and superparamagnetic quencher (i.e., 12 nm Zn_0.4Fe_2.6O₄ particle). Lower panel: T₁-weighted MR image and color map image of a solution containing the enhancer and quencher with varied separation distances. (c) A plot of r₁ values versus separation distance. (d) Schematic of modular combinations for the preparation of distance-dependent magnetic resonance sensors, operated using three different modes of interactions (cleavage, binding, and conformational changes) and subsequent T₁ MRI signal outputs. Reproduced with permission from ref. . Copyright 2017, Nature Publishing Group.

Fig. 23

(a) Columns showing r₂ values of iron oxide (IO) clusters, as well as the single IO-5 and IO-15 NPs. C1: clusters of 5 nm NPs only; C2: clusters of 15 nm NPs only; C3: clusters of mixed 5 nm NPs and 15 nm NPs. (b and c) TEM and high-resolution TEM images, as well as cartoons of clusters C6 (IO cubes) and C7 (IO nanoplates), respectively. (d) Columns showing r₂ values of IO clusters C6 and C7, as well as the single IO cubes and plates. (e and f) Simulation models and calculated stray fields for clusters C6 and C7, respectively. Color bars represent log₁₀(H_d), where H_d is the calculated stray field. Reproduced with permission from ref. . Copyright 2017, Nature Publishing Group.

Fig. 24

Summary and outlooks of designing inorganic NPs for MRI.