In Vivo Positive Magnetic Resonance Imaging Applications of Poly(methyl vinyl ether-alt-maleic acid)-coated Ultra-small Paramagnetic Gadolinium Oxide Nanoparticles

Abstract

The study of ultra-small paramagnetic gadolinium oxide (Gd₂O₃) nanoparticles (NPs) as in vivo positive (T₁) magnetic resonance imaging (MRI) contrast agents is one of the most attractive fields in nanomedicine. The performance of the Gd₂O₃ NP imaging agents depends on the surface-coating materials. In this study, poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) was used as a surface-coating polymer. The PMVEMA-coated paramagnetic ultra-small Gd₂O₃ NPs with an average particle diameter of 1.9 nm were synthesized using the one-pot polyol method. They exhibited excellent colloidal stability in water and good biocompatibility. They also showed a very high longitudinal water proton spin relaxivity (r₁) value of 36.2 s^-1mM^-1 (r₂/r₁ = 2.0; r₂ = transverse water proton spin relaxivity) under a 3.0 tesla MR field which is approximately 10 times higher than the r₁ values of commercial molecular contrast agents. High positive contrast enhancements were observed in in vivo T₁ MR images after intravenous administration of the NP solution sample, demonstrating its potential as a T₁ MRI contrast agent.

Keywords: T1 magnetic resonance imaging; contrast agent; paramagnetic; poly (methyl vinyl ether-alt-maleic acid); ultra-small Gd2O3 nanoparticle.

Figure 1

(a) HRTEM image (dotted circles indicate PMVEMA-coated ultra-small Gd₂O₃ NPs). (b) Log-normal function fit to the observed particle diameter distribution. (c) Log-normal function fit to the observed hydrodynamic diameter distribution. (d) Photograph of an aqueous solution sample, showing good colloidal stability. (e) Tyndall effect, indicating a colloidal dispersion: the left vial containing the solution sample showed laser light scattering by the PMVEMA-coated NP colloids (indicated with an arrow), whereas the right vial containing triple-distilled water did not.

Figure 2

XRD patterns before (bottom spectrum) and after (top spectrum) TGA. All peaks in the XRD pattern after TGA were assigned with (hkl) Miller indices of cubic Gd₂O₃; only the intense peaks were representatively assigned. The estimated lattice constant, a = 10.815 Å.

Figure 3

(a) FT-IR absorption spectra of the PMVEMA-coated ultra-small Gd₂O₃ NPs (bottom spectrum labeled as “Sample”) and free PMVEMA (top spectrum): the subscript “s” indicates a symmetric stretch and “as” indicates an antisymmetric stretch. (b) Surface-coating structure of PMVEMA on the Gd₂O₃ NP surface (one C.B. is presented at the figure, but numerous C.B.s exist between PMVEMA and the Gd₂O₃ NP). (c) TGA curve of the powder sample.

Figure 4

In vitro cellular cytotoxicity results of the PMVEMA-coated ultra-small Gd₂O₃ NPs in DU145 cells, showing negligible cellular toxicities at Gd-concentrations as high as 500 μM.

Figure 5

M–H curve of the PMVEMA-coated ultra-small Gd₂O₃ NPs at T = 300 K, showing paramagnetism. The M value is the net M value of the Gd₂O₃ NPs only without PMVEMA, which was estimated using their net mass obtained from the TGA curve.

Figure 6

Plots of 1/T₁ and 1/T₂ as a function of the Gd-concentration. The slopes correspond to r₁ and r₂ values, respectively.

Figure 7

(a) In vivo T₁ MR images of a mouse under a 3.0 tesla MR field before (labeled as “Pre”) and after intravenous administration of the solution sample into the mouse’s tail: the small circles indicate ROIs and the dotted circles indicate the liver and kidneys. The administration dose was ~0.1 mmol Gd/kg. (b) SNR plots of the ROIs in the liver and kidneys of the mouse as a function of time (SNR: signal-to-noise ratio; ROI: region-of-interest).

Figure 8

Reaction scheme for the one-pot polyol synthesis of PMVEMA-coated ultra-small Gd₂O₃ NPs and the molecular structure of PMVEMA.