Size and Compositional Effects on Contrast Efficiency of

Article pubs.acs.org/JPCC

Size and Compositional Effects on Contrast Efficiency of Functionalized Superparamagnetic Nanoparticles at Ultralow and Ultrahigh Magnetic Fields Wei Wang,†,‡ Victor Pacheco,§,⊥ Hans-Joachim Krause,‡ Yi Zhang,‡ Hui Dong,*,∥ Rudolf Hartmann,§ Dieter Willbold,§,⊥ Andreas Offenhaü sser,‡ and Zhongwei Gu*,† †

National Engineering Research Center for Biomaterials, Sichuan University, 610064 Chengdu, China Peter Grünberg Institute (PGI-8), Research Center Jülich, 52425 Jülich, Germany § Institute of Complex Systems (ICS-6), Research Center Jülich, 52425 Jülich, Germany ∥ State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, 200050 Shanghai, China ⊥ Institute of Physical Biology, Heinrich-Heine-University, Düsseldorf, Germany ‡

S Supporting Information *

ABSTRACT: Magnetic resonance imaging (MRI) systems at ultralow and ultrahigh field have been developed for biomedical imaging. We synthesized and functionalized superparamagnetic (SPM) nanoparticles (NPs) and studied the spin−lattice (T1) and spin−spin (T2) relaxation time of protons in water surrounding these NPs at ultralow and at ultrahigh magnetic fields. In these fields, size and compositional effects of SPM NPs were observed contributing to the spin−lattice (r1) and spin−spin (r2) relaxivities as well as r2/r1 ratios. These results reveal the relationship between magnetic characteristics of SPM NPs and relaxation behavior of water proton at ultralow or ultrahigh field.

1. INTRODUCTION Magnetic resonance imaging (MRI) is one of the most prevalent noninvasive diagnostic tools to provide high spatial resolution tomographic images by measuring proton relaxation processes of water in biological systems.1−3 In the past decade, MRI systems at ultralow magnetic field4−6 (typically lower than 1 mT) and at ultrahigh field7,8 (3 T and more) have been developed for biomedical imaging and exhibited special imaging properties with considerable novel potential for human imaging applications. Ultralow field MRI has proven to exhibit substantially greater T1-weighted contrast,9 thus allowing the possibility of simultaneous imaging in conjunction with magnetoencephalography (MEG).10 In addition, high-resolution T2-weighed imaging can be obtained in ultrahigh field MRI systems.11,12 In MRI systems, superparamagnetic (SPM) nanoparticles (NPs) are typically employed as contrast agents to shorten proton spin−lattice (T1) or spin−spin (T2) relaxation time of specific targets, thus enhancing visualization of the difference between normal and abnormal tissue.13,14 A lot of research effort in recent years has been focused on studying the different properties of SPM NPs, e.g., size, shape, and composition, on T1- or T2-weighed contrast efficiency at medical field (0.47 to 3 T).15−19 These studies revealed that spin−spin relaxation rate (R2 = 1/T2) was roughly proportional to the size of SPM NPs. © 2012 American Chemical Society

In addition, the composition effects were observed to noticeably influence their R2 at 1.5 T.16,20,21 However, little attention has been paid to the contrast efficiency of SPM NPs at either ultralow or ultrahigh fields.22,23 In our previous work,24 a considerable enhancement of T1 and T2 contrast efficiency of ultrasmall superparamagnetic iron oxide nanoparcticles (USPIOs) has been revealed at ultralow and ultrahigh field, respectively. Unfortunately, the mechanism of the proton relaxation of SPM NPs in these systems remains unclear. Therefore, it is necessary to examine the relationship between SMP NPs characteristics and relaxation behavior of surrounding water protons. In this study, SPM NPs with different core size and composition were synthesized and transferred to aqueous solution. The r1 and r2 relaxivities, as well as r2/r1 ratios of these SPM NPs, were investigated at ultralow (T1@10 mT and T2@ 212 μT) and at ultrahigh field (14.1 T). These results demonstrated the size and compositional effects on the T1 and T2 contrast efficiency of SPM NPs at ultralow and ultrahigh field. Received: March 22, 2012 Revised: July 18, 2012 Published: July 18, 2012 17880

dx.doi.org/10.1021/jp302758h | J. Phys. Chem. C 2012, 116, 17880−17884

The Journal of Physical Chemistry C

Article

Figure 1. TEM images of synthesized and functionalized SPM NPs for 6 nm Fe3O4 (a,e), 10 nm Fe3O4 (b,f), 6 nm CoFe2O4 (c,g), and 6 nm MnFe2O4 (d,h). (a−d) Particles in hexane and (e−h) in water. The scale bar is 20 nm.

ultralow field were measured with our homemade MRI system utilizing a high-temperature radio frequency superconducting quantum interference device (SQUID).24,27 The high field values were acquired with a 600 MHz Varian INOVA spectrometer. The r1 and r2 relaxivities and r2/r1 ratios, which constitute a measure of the contrast effect, were then calculated as the slopes of the inverse relaxation times against metal concentration.

2. EXPERIMENTAL SECTION 2.1. Chemicals. Iron(III) acetylacetonate (99%), cobalt(II) acetylacetonate, Mn(II) acetylacetonate, hexane (>98%), ethanol, benzylether (99%), oleic acid (90%), 1,2-hexadecanediol (90%), oleylamine (70%), and meso-2,3-dimercaptosuccinic acid (meso-DMSA) were purchased from Sigma-Aldrich. All reactants were used in the synthesis without further purification. 2.2. Synthesis of SPM NPs. Four kinds of SPM NPs, namely, Fe3O4 (particle sizes of 6 and 10 nm), CoFe2O4 (6 nm), and MnFe2O4 (6 nm), were synthesized using the modified thermal decomposition method reported by Sun et al.25 2.3. Surface Modification. SPM NPs were subsequently functionalized with hydrophilic meso-DMSA via ligand exchange method26 and transferred into aqueous solution. In a glass container under ambient conditions, 30 mg of SPM NPs were dissolved in 3 mL toluene. Subsequently, a solution of 30 mg of meso-DMSA in 3 mL of dimethyl sulfoxide (DMSO) was added to the mixture and shaken for 48 h. For complete ligand exchange, another 30 mg of meso-DMSA was added in the solution and stirred for 12 h. Finally, the precipitated SPM NPs were successively mixed and magnetically separated with acetone and hexane several times to remove free oleic acid molecules. The resulting SPM NPs were redispersed in 3 mL of Milli-Q water. Monodisperse SPM NPs were obtained after the solution passed through a 0.2 μm syringe filter. 2.4. Physical Characterization. A physical characterization of the SPM NPs was performed by transmission electron microscopy (TEM), physical property measurement system (PPMS), and inductively coupled plasma optical emission spectrometry (ICP-OES). TEM images were obtained on a JEOL JEM 2000 EX II instrument equipped with a field emission gun electron source. The magnetization of the MNPs was investigated on a PPMS-9T instrument up to maximum field strength of 2 T at 300 K. Dynamic light scattering (DLS) experiments were carried out using a DynaPro dynamic light scattering system from Protein Solutions (Lakewood, NJ, USA) with a 3 mm path length and a 45 μL quartz cuvette. 2.5. T1 and T2 Relaxation Measurements in Ultralow and Ultrahigh Field. The T1 and T2 relaxation times at

3. RESULTS AND DISCUSSION TEM images (Figure 1) show that both synthesized SPM NPs and functionalized SPM NPs were uniform and well dispersed in hexane and water with narrow size distribution. The hysteresis loops (see Figure 2) illustrate that all of the SPM

Figure 2. Hysteresis loops of the meso-DMSA-functionalized SPM NPs measured at 300 K.

NPs maintain their superparamagnetic properties after mesoDMSA functionalization. The increase of the size of functionalized Fe3O4 NPs from 6 to 10 nm results in an enhancement of their saturation magnetization (Ms) from 30 ± 2.4 emu/g to 37 ± 2.8 emu/g, respectively. The replacement of Fe by Mn (MnFe2O4 NPs) leads to the highest Ms (41 ± 2.6 emu/g) of all SPM NPs. In addition, the value observed for CoFe2O4 NPs (27 ± 2.2 emu/g) was lower than that of 6 nm Fe3O4 NPs (30 ± 1.8 emu/g). In principle, the r2 value of SPM NPs is 17881



Article

for these SPM NPs are small and vary slightly at ultrahigh field. The r1 value of 6 nm MnFe2O4, 10 nm Fe3O4, 6 nm Fe3O4, and 6 nm CoFe2O4 NPs dropped sharply to only 2.61 ± 0.10, 1.77 ± 0.19, 2.08 ± 0.18, and 1.42 ± 0.11 mM−1 s−1, respectively. At high field, the 1/T2 is roughly proportional to the square of the Ms value of the particle, which can be tuned with respect to size, shape, composition, and crystallinity.28−30 These results can be expressed using Ayant’s model.31−33

proportional to the square of their saturation magnetization Ms and related to the T2 contrast efficiency. Table 1 shows the size distribution of these SPM NPs before and after meso-DMSA modification, as measured with TEM Table 1. Diameters of Different SPM NPs in Hexane (Oleic Acid Coated) and in Water (meso-DMSA Coated), Measured by TEM and by Dynamic Light Scattering (DLS) TEM (nm) surface coating

oleic acid

MnFe2O4 Fe3O4 Fe3O4 CoFe2O4

6±1 10 ± 1 6±1 6±1

1/T1 = cμ2 {9L2(x)JA ( 2ωIτD )}

DLS (nm) oleic acid 10 13 10 10

± ± ± ±

2 2 2 2

meso-DMSA 32 38 32 32

± ± ± ±

1/T2 = cμ2 {4.5JA ( 2ωIτD ) + 6JA (0)}

3 4 4 4

with JA (z) =

and DLS. Because of the hydrophilic meso-DMSA coating, the size of the functionalized SPM NPs increases to about 30 nm, indicating lower nonspecific uptake and longer circulation time in in vivo applications. The values of r1 and r2 and of the r2/r1 ratio of these SPM NPs at 14.1 T are depicted in Figure 3a,b and Table 2. The r2 value measured for 10 nm Fe3O4 NPs (241 ± 12 mM−1 s−1) was two times larger than the value obtained from 6 nm Fe3O4 particles (121 ± 8 mM−1 s−1). Moreover, the contrast efficiency of same size SPM NPs with different composition was measured at 14.1 T. As shown in Figure 4, MnFe2O4 NPs exhibited the highest r2 (423 ± 20 mM−1s−1), which is 3.5 times and 4.2 times higher than the values of Fe3O4 and CoFe2O4 NPs (100 ± 9 mM−1 s−1), respectively. However, the r1 values

1+ 1+z+

z2 2

+

5z 8

z3 6

+

+

z2 8

4z 4 81

+

z5 81

+

z6 648

where c = ((32π/40500)γ2NA[M])/r3, ωI is the proton Larmor frequency, τD the translational correlation time, r the particle radius, NA the Avogadro number, μ the magnetic moment of the particle, and γ the proton gyromagnetic ratio. Consistent with the magnetization results (see Figure 2), the MnFe2O4 NPs generate the highest 1/T2 and r2 values, resulting in the highest contrast enhancement effects at 14.1 T. These results are well correlated with the previous studies of magnetic NPs as T2-weighted contrast agents at 1.5 T13,19 and other ultrahigh field strengths.16,34,35 Thu,s the r2/r1 ratio, which is indicative to the effectiveness of the T2-weighted contrast agent, is enhanced to a high level at ultrahigh filed.

Figure 3. Spin−lattice (1/T1) and spin−spin (1/T2) relaxation rates for functionalized 6 nm Fe3O4, 10 nm Fe3O4, 6 nm CoFe2O4, and 6 nm MnFe2O4 NPs, as a function of metal concentration, at ultrahigh field (a,b) and ultralow field (c,d) field, respectively. 17882



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Table 2. T1 and T2 Relaxivities,a r1 and r2, and r2/r1 Ratios for SPM NPs at Ultralow (212 μT for T2 and 10 mT for T1) and Ultrahigh (14.1 T) Magnetic Fields ultrahigh field (14.1 T) r2

sample MnFe2O4 (6 nm) Fe3O4 (10 nm) Fe3O4 (6 nm) CoFe2O4 (6 nm) a

423 241 121 100

± ± ± ±

r1 20 12 8 9

2.61 1.77 2.08 1.42

± ± ± ±

0.10 0.19 0.18 0.11

ultralow field (10 mT and 212 μT) r2/r1

r2 (212 μT)

r1 (10 mT)

r2/r1 (212 μT)b

162 136 58 70

51.1 21.3 10.8 39.3

± ± ± ±

16.1 ± 0.9 9.4 ± 0.4 12.9 ± 0.7 10.0 ± 0.5

3.2 2.3 0.8 3.9

2.6 1.8 2.1 1.4

Values in mM−1 s−1. bThe r1 at 10 mT was equal to the value at 212 μT.17,22

Figure 4. Spin−lattice (r1) and spin−spin (r2) relaxivities of SPM NPs at ultrahigh field (a) and ultralow field (b).

core ions ratio in the case of smaller size NPs.39 Moreover, their r2 values were similar and dramatically decreased as compared to the values at ultrahigh field, resulting in a r2/r1 ratio of 6 nm Fe3O4 NPs (0.83), which is considerably lower than the value of 10 nm Fe3O4 NPs (2.25). These results suggest that the T1weighted efficiency is noticeably enhanced with decreasing NP size at ultralow field.

As can be seen from Table 2 and Figure 4a, the r2/r1 ratio of 10 nm Fe3O4 NPs (136) is much higher than the ratio of 6 nm Fe3O4 NPs (58.2). Furthermore, the r2/r1 ratio exhibited from MnFe2O4 NPs is around two times higher than that of Fe3O4 and CoFe2O4. The higher r2 values and extremely high r2/r1 ratios of 10 nm Fe3O4 and 6 nm MnFe2O4 indicate that the contrast efficiency of these SPM NPs is related to their sizes and compositions at ultrahigh fields. At ultralow field, the 1/T1 and 1/T2 can be expressed by the Freed relaxation functions:32,33,36

4. CONCLUSIONS In conclusion, the size and compositional effects of contrast efficiency of SPM NPs were studied at ultralow and ultrahigh fields. At ultrahigh field, the SPM NPs with large size or those doped by high magnetic moment metals exhibited high r2 values and extremely high r2/r1 ratios, indicating an excellent T2 contrast efficiency. Simultaneously, at ultralow field, the size also influenced the r1 values and r2/r1 ratios. The SPM NPs with smaller size exhibited higher r1 values but lower r2/r1 ratios, indicating the excellent T1 contrast efficiency of smaller size NPs at ultralow field. These results provide a perspective for potential applications of proper SPM NPs as T1- or T2weighted contrast agents in ultralow or ultrahigh field MRI systems.

1/T1 = 10cμ2 JF (ωI , τD , τN) 1/T2 = cμ2 {8JF (ωI , τD , τN) + 2JF (0, τD , τN)}

with 1 ⎛ ⎞ 1 + 4 Ω1/2 ⎜ ⎟ JF (ωI , τD , τN) = R exp⎜ 4 1 3/2 ⎟ 1/2 + Ω + Ω + Ω 1 ⎝ ⎠ 9 9

Ω = iωIτD + τD/τN

At ultralow field, the magnetic moment is free to flip from one anisotropy direction to the other.32 The Néel relaxation, determined by the core size and Ms, and water diffusion modulated the T1 and T2 relaxation times, indicating that the r1 and r2 values were related to the size and composition effects.37,38 High r1 and low r2 values, as well as low r2/r1 ratios are expected for SPM NPs, which agree with the experimental results given in Table 2 and Figure 4b. The r1 of MnFe2O4 (16.1 ± 0.9 mM−1 s−1) is 1.25 times higher than the value of Fe3O4 (12.9 ± 0.7 mM−1 s−1) and 1.61 times higher than that for CoFe2O4 NPs (10.0 ± 0.5 mM−1 s−1) at 10 mT, resulting from compositional effects. It is interesting to observe that the r1 of 10 nm Fe3O4 (9.4 ± 0.4 mM−1 s−1) is significantly lower than the value of 6 nm Fe3O4 (12.9 ± 0.7 mM−1 s−1). This result can be explained by the increasing ratio of surface ions to

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ASSOCIATED CONTENT

S Supporting Information *

IR spectrum of as-synthesized and modified SPM NPs; the relationship of measured r2 effects and the squared saturated magnetization of SPM NPs at 14.1 T. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*(Z.G.) Phone: +86 28 8541 0653. Fax: +86 28 8541 0703. Email: [email protected]. (H.D.) Phone: +86 21 6251 10708503. Fax: +86 21 6251 1070-8507. E-mail: [email protected]. ac.cn. 17883



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Notes

(24) Wang, W.; Dong, H.; Pacheco, V.; Willbold, D.; Zhang, Y.; Offenhaeusser, A.; Hartmann, R.; Weirich, T. E.; Ma, P.; Krause, H. J.; et al. J. Phys. Chem. B 2011, 115, 14789−14793. (25) Sun, S.; Zeng, H.; Robinson, D. B.; Raoux, S.; Rice, P. M.; Wang, S. X.; Li, G. J. Am. Chem. Soc. 2004, 126, 273−279. (26) Jun, Y.-W.; Huh, Y.-M.; Choi, J.-S.; Lee, J.-H.; Song, H.-T.; Kim, S.; Yoon, S.; Kim, K.-S.; Shin, J.-S.; Suh, J.-S.; et al. J. Am. Chem. Soc. 2005, 127, 5732−5733. (27) Dong, H.; Zhang, Y.; Krause, H. J.; Xie, X. M.; Braginski, A. I.; Offenhausser, A. Supercond. Sci. Technol. 2009, 22 (12), 125022. (28) Cheon, J.; Lee, J. H. Acc. Chem. Res. 2008, 41, 1630−1640. (29) Vestal, C. R.; Zhang, Z. J. Chem. Mater. 2002, 14, 3817−3822. (30) Nasongkla, N.; Bey, E.; Ren, J.; Ai, H.; Khemtong, C.; Guthi, J. S.; Chin, S. F.; Sherry, A. D.; Boothman, D. A.; Gao, J. Nano Lett. 2006, 6, 2427−2430. (31) Ayant, Y.; Belorizky, E.; Aluzon, J.; Gallice, J. J. Phys. 1975, 36, 991−1004. (32) Laurent, S.; Forge, D.; Port, M.; Roch, A.; Robic, C.; Vander Elst, L.; Muller, R. N. Chem. Rev. 2008, 108, 2064−2110. (33) Gossuin, Y.; Gillis, P.; Hocq, A.; Vuong, Q. L.; Roch, A. Wiley Interdiscip Rev.: Nanomed. Nanobiotechnol. 2009, 1, 299−310. (34) Roca, A. G.; Veintemillas-Verdaguer, S.; Port, M.; Robic, C.; Serna, C. J.; Morales, M. P. J. Phys. Chem. B 2009, 113, 7033−7039. (35) Das, G. K.; Johnson, N. J. J.; Cramen, J.; Blasiak, B.; Latta, P.; Tomanek, B.; van Veggel, F. C. J. M. J. Phys. Chem. Lett. 2012, 3, 524− 529. (36) Freed, J. H. J. Phys. Chem. 1978, 68, 4034−4037. (37) Petoral, R. M.; Söderlind, F.; Klasson, A.; Suska, A.; Fortin, M. A.; Abrikossova, N.; Selegård, L. A.; Käll, P.-O.; Engström, M.; Uvdal, K. J. Phys. Chem. C 2009, 113, 6913−6920. (38) Abbasi, A. Z.; Gutiérrez, L. A.; del Mercato, L. L.; Herranz, F.; Chubykalo-Fesenko, O.; Veintemillas-Verdaguer, S.; Parak, W. J.; Morales, M. P.; González, J. S. M.; Hernando, A.; et al. J. Phys. Chem. C 2011, 115, 6257−6264. (39) Kim, B. H.; Lee, N.; Kim, H.; An, K.; Park, Y. I.; Choi, Y.; Shin, K.; Lee, Y.; Kwon, S. G.; Na, H. B.; et al. J. Am. Chem. Soc. 2011, 133, 12624−12631.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research work was supported by the National Basic Research Program of China (National 973 program, no. 2011CB606206), the China Scholarship Council (CSC), and the German Helmholtz Association. The authors thank F. Dorn and T. E. Weirich (Central Facility for Electron Microscopy, RWTH Aachen University) for TEM imaging and H. Lippert (Central Division of Analytical Chemistry, Forschungszentrum Jülich) for the ICP-OES measurements.

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REFERENCES

(1) Moonen, C. T.; van Zijl, P. C.; Frank, J. A.; Le Bihan, D.; Becker, E. D. Science 1990, 250, 53−61. (2) Bowtell, R. Nature 2008, 453, 993−994. (3) Yip, C. Y.; Fessler, J. A.; Noll, D. C. Magn. Reson. Med. 2006, 56, 1050−1059. (4) Lee, S. K.; Mossle, M.; Myers, W.; Kelso, N.; Trabesinger, A. H.; Pines, A.; Clarke, J. Magn. Reson. Med. 2005, 53, 9−14. (5) Clarke, J.; Hatridge, M.; Mossle, M. Annu. Rev. Biomed. Eng. 2007, 9, 389−413. (6) Kraus, R. H., Jr.; Volegov, P.; Matlachov, A.; Espy, M. Neuroimage 2008, 39, 310−317. (7) Lupo, J. M.; Li, Y.; Hess, C. P.; Nelson, S. J. Curr. Opin. Neurol. 2011, 24, 605−615. (8) Kangarlu, A.; Baudendistel, K. T.; Heverhagen, J. T.; Knopp, M. V. Radiology 2004, 44, 19−30. (9) Busch, S.; Hatridge, M.; Mossle, M.; Myers, W.; Wong, T.; Muck, M.; Chew, K.; Kuchinsky, K.; Simko, J.; Clarke, J. Magn. Reson. Med. 2012, 67, 1138−1145. (10) Zotev, V. S.; Matlashov, A. N.; Volegov, P. L.; Savukov, I. M.; Espy, M. A.; Mosher, J. C.; Gomez, J. J.; Kraus, R. H., Jr. J. Magn. Reson. 2008, 194, 115−120. (11) Shajan, G.; Hoffmann, J.; Balla, D. Z.; Deelchand, D. K.; Scheffler, K.; Pohmann, R. NMR Biomed. 2012, DOI: 10.1002/ nbm.2786. (12) Trattnig, S.; Mamisch, T. C.; Noebauer, I. Z. Rheumatol. 2006, 65, 681−687. (13) Weissleder, R.; Elizondo, G.; Wittenberg, J.; Rabito, C. A.; Bengele, H. H.; Josephson, L. Radiology 1990, 175, 489−493. (14) Bulte, J. W. M.; Kraitchman, D. L. NMR Biomed. 2004, 17, 484− 499. (15) Pinho, S. L. C.; Laurent, S.; Rocha, J.; Roch, A.; Delville, M.-H.; Mornet, S.; Carlos, L. D.; Vander Elst, L.; Muller, R. N.; Geraldes, C. F. G. C. J. Phys. Chem. C 2011, 116, 2285−2291. (16) Lee, J. H.; Huh, Y. M.; Jun, Y. W.; Seo, J. W.; Jang, J. T.; Song, H. T.; Kim, S.; Cho, E. J.; Yoon, H. G.; Suh, J. S.; et al. Nat. Med. 2007, 13, 95−99. (17) Bulte, J. W. M.; Brooks, R. A.; Moskowitz, B. M.; Bryant, L. H.; Frank, J. A. Magn. Reson. Med. 1999, 42, 379−384. (18) Gillis, P.; Koenig, S. H. Magn. Reson. Med. 1987, 5, 323−345. (19) Xiao, L.; Li, J.; Brougham, D. F.; Fox, E. K.; Feliu, N.; Bushmelev, A.; Schmidt, A.; Mertens, N.; Kiessling, F.; Valldor, M.; et al. ACS Nano 2011, 5, 6315−6324. (20) Seo, W. S.; Lee, J. H.; Sun, X. M.; Suzuki, Y.; Mann, D.; Liu, Z.; Terashima, M.; Yang, P. C.; McConnell, M. V.; Nishimura, D. G.; et al. Nat. Mater. 2006, 5, 971−976. (21) Jang, J.-T.; Nah, H.; Lee, J.-H.; Moon, S. H.; Kim, M. G.; Cheon, J. Angew. Chem., Int. Ed. 2009, 48, 1234−1238. (22) Bulte, J. W. M.; Vymazal, J.; Brooks, R. A.; Pierpaoli, C.; Frank, J. A. J. Magn. Reson. Imaging 1993, 3, 641−648. (23) Corot, C.; Robert, P.; Idee, J. M.; Port, M. Adv. Drug Delivery Rev. 2006, 58, 1471−1504. 17884


Size and Compositional Effects on Contrast Efficiency of

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