Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T1 contrast

Journal name:
Nature Nanotechnology
Volume:
5,
Pages:
815–821
Year published:
DOI:
doi:10.1038/nnano.2010.203
Received
Accepted
Published online

Abstract

Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties to improve relaxivity and to enhance image contrast. Here, we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r1 was observed: Magnevist, r1  14 mM−1 s−1/Gd3+ ion (~8.15 × 10+7 mM−1 s−1/construct); gadofullerenes, r1  200 mM−1 s−1/Gd3+ ion (~7 × 10+9 mM−1 s−1/construct); gadonanotubes, r1  150 mM−1 s−1/Gd3+ ion (~2 × 10+9 mM−1 s−1/construct). These relaxivity values are about 4 to 50 times larger than those of clinically available gadolinium-based agents (~4 mM−1 s−1/Gd3+ ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behaviour of the Gd3+ ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents.

At a glance

Figures

  1. The new MRI nanoconstructs.
    Figure 1: The new MRI nanoconstructs.

    ac, Schematic showing Magnevist (a), GFs (b) and debundled GNTs (c). d,e, Scanning electron micrographs of quasi-hemispherical (H-SiMP: diameter, 1.6 µm; thickness, ~0.6 µm) (d) and discoidal (D-SiMP: diameter, 1.0 µm; thickness, 0.4 µm) particles (e). f, Cartoons showing Magnevist, GFs and GNTs (left to right) entrapped within the porous structure of the SiMPs. The geometrical confinement of the Gd-based CAs within the nanopores enhances the T1 contrast by altering both the inner- and outer-sphere contributions.

  2. Concentration of Gd3+ ions in the SiMP nanoconstruct as determined by ICP-OES analysis.
    Figure 2: Concentration of Gd3+ ions in the SiMP nanoconstruct as determined by ICP-OES analysis.

    a, Graph comparing the single-step (grey bars) and sequential (black bars) loading procedures for two different volumes of the GNT solution exposed to the SiMPs (200 µl and 300 µl). For sequential loading, SiMPs were exposed multiple times (numbers after the slash sign) to 100-µl stock solutions of GNTs. No statistically significant differences were observed between the two procedures. b, Graph showing the amount of Gd3+ ions within H-SiMPs as a function of the volume of GNT solution exposed.

  3. MRI characterization of the nanoconstruct by a benchtop relaxometer.
    Figure 3: MRI characterization of the nanoconstruct by a benchtop relaxometer.

    The longitudinal relaxivity, r1, of the six new MRI nanoconstructs is compared with the corresponding Gd-based CAs (1.41 T and 37 °C). See Supplementary Fig. S3 for the tabular form of the data. Data are presented as mean ± s.d. (n ≥ 4). Student's t-test is used to estimate the P-values between the two groups.

  4. MRI characterization of the H-SiMP/GNT nanoconstruct in a clinical scanner.
    Figure 4: MRI characterization of the H-SiMP/GNT nanoconstruct in a clinical scanner.

    a, Inversion recovery fits for SiMPs (black squares) and SiMP/GNT (black circles) nanoconstructs were acquired using an inversion recovery pulse sequence and plotted as a function of their inversion time Tinv (time at which the signal is completely suppressed). b, Inversion recovery phantoms for SiMP and SiMP/GNT nanoconstruct, clearly showing faster recovery for the nanoconstruct. Data were obtained using a 1.5 T commercial clinical scanner with TR = 7,500 ms and TE = 20 ms.

  5. Calculated longitudinal relaxivity for the SiMP/MAG and SiMP/GF nanoconstructs.
    Figure 5: Calculated longitudinal relaxivity for the SiMP/MAG and SiMP/GF nanoconstructs.

    The experimental NMRD profile for MAG (dots)6 is compared with three curves (solid lines) derived from SBM Theory for different values of the parameter τR (54, 270 and 540 ps) (a) and τD (40, 180 and 400 ps) (b). c, Calculated maximum longitudinal relaxivity r1 of the SiMP/MAG nanoconstructs as a function of the governing parameters τR and τD. All other parameters are listed in g. d,e, The experimental NMRD profile for GF (dots)23 is compared with four curves (solid lines) derived from SBM Theory for different values of the parameter τR (3, 5, 10 and 100 ns) (d) and τD (200, 550 and 2,000 ps) (e). f, Calculated maximum longitudinal relaxivity r1 of the SiMP/GF nanoconstructs as a function of the governing parameters τR and τD. All other parameters are listed in h. The magnetic properties in g and h are derived from the best fitting of the experimental NMRD profiles.

  6. NMRD profiles for the GNT and SiMP/GNT constructs.
    Figure 6: NMRD profiles for the GNT and SiMP/GNT constructs.

    ac, Graph showing comparisons of experimental (dotted line)9 NMRD profiles and best fitting curves (solid lines) derived from SBM Theory for q = 1 and 3, τm = 0.9 and 6 ns (a), q = 2, 4 and 6, and τm = 1.5 (b), q = 2, τm = 1, 1.5 and 2.9 ns (c). d, All other parameters as derived from the best fitting of the experimental NMRD.

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Author information

  1. These authors contributed equally to this work

    • Jeyarama S. Ananta &
    • Biana Godin

Affiliations

  1. Department of Chemistry, Smalley Institute for Nanoscale Science and Technology, Center for Biological and Environmental Nanotechnology, Rice University, Houston, Texas 77251-1892, USA

    • Jeyarama S. Ananta,
    • Richa Sethi &
    • Lon J. Wilson
  2. Department of Nanomedicine and Biomedical Engineering, University of Texas Health Sciences Center at Houston, Houston, Texas, USA

    • Biana Godin,
    • Xuewu Liu,
    • Rita E. Serda,
    • Mauro Ferrari &
    • Paolo Decuzzi
  3. Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Federale de Lausanne, EPFL-BCH, CH-1015 Lausanne, Switzerland

    • Loick Moriggi &
    • Lothar Helm
  4. Department of Bioengineering, Rice University, Houston, Texas 77251-1892, USA

    • Ramkumar Krishnamurthy &
    • Mauro Ferrari
  5. Department of Radiology, St. Luke's Episcopal Hospital, Houston, Texas, USA

    • Raja Muthupillai
  6. TDA Research Inc. Wheat Ridge, Colorado 80033, USA

    • Robert D. Bolskar
  7. Department of Experimental Therapeutics, the University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    • Mauro Ferrari
  8. BioNEM—Center of Bio-Nanotechnology and Engineering for Medicine, University of Magna Graecia, Catanzaro, Italy

    • Paolo Decuzzi
  9. Present address: The Methodist Hospital Research Institute, 6565 Fannin St., Houston, Texas 77030, USA (B.G., X.L., R.E.S., M.F. and P.D.)

    • Biana Godin,
    • Xuewu Liu,
    • Rita E. Serda,
    • Mauro Ferrari &
    • Paolo Decuzzi
  10. These authors shared senior authorship

    • Mauro Ferrari,
    • Lon J. Wilson &
    • Paolo Decuzzi

Contributions

J.S.A. designed the experimental plan, performed all the experiments and helped in writing the manuscript. B.G. designed the experimental plan, developed the protocols for loading, and helped in the loading experiments and in writing the manuscript. R.S. helped in performing the loading experiments and the ICP analysis. L.M. performed MRI characterization. X.L coordinated the microfabrication of the SiMPs and performed their surface modification. R.E.S. performed the SEM analysis. R.K. and R.M. performed the MRI characterization in clinical scanners. R.D.B. manufactured the GFs. L.H. helped in performing the MRI characterization of the GNT, provided input on the original draft and revisions. M.F. provided input on the original draft and revisions. L.J.W. conceived the idea, designed the experimental plan and helped in writing the manuscript. P.D. conceived the idea, designed the experimental plan, wrote the manuscript and performed all the numerical calculations. All the authors discussed the results and commented on the manuscript.

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The authors declare no competing financial interests.

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