Letter pubs.acs.org/NanoLett
Water-Dispersible Ferrimagnetic Iron Oxide Nanocubes with Extremely High r2 Relaxivity for Highly Sensitive in Vivo MRI of Tumors Nohyun Lee,†,§ Yoonseok Choi,‡,§ Youjin Lee,† Mihyun Park,† Woo Kyung Moon,‡ Seung Hong Choi,*,‡ and Taeghwan Hyeon*,† †
World Class University Program of Chemical Convergence for Energy and Environment, Institute of Chemical Processes, and School of Chemical and Biological Engineering, Seoul National University, Seoul, 151-744, Korea ‡ Diagnostic Radiology, Seoul National University Hospital, and the Institute of Radiation Medicine, Medical Research Center, Seoul National University, 28, Yeongeon-dong, Jongno-gu, Seoul, 110-744, Korea S Supporting Information *
ABSTRACT: The theoretically predicted maximum r 2 relaxivity of iron oxide nanoparticles was achieved by optimizing the overall size of ferrimagnetic iron oxide nanocubes. Uniform-sized iron oxide nanocubes with an edge length of 22 nm, encapsulated with PEG-phospholipids (WFION), exhibited high colloidal stability in aqueous media. In addition, WFIONs are biocompatible and did not affect cell viability at concentrations up to 0.75 mg Fe/ml. Owing to the enhanced colloidal stability and the high r2 relaxivity (761 mM−1 s−1), it was possible to successfully perform in vivo MR imaging of tumors by intravenous injection of 22-nm-sized WFIONs, using a clinical 3-T MR scanner. KEYWORDS: Nanoparticle, nanomedicine, iron oxide, magnetic resonance imaging, contrast agent, colloidal stability
M
volume, size control of nanoparticles is critical for achieving high relaxivity.30 A previous report shows that the r2 relaxivity of superparamagnetic iron oxide nanoparticles increased with the size of the nanoparticles.31 For magnetic nanoparticles smaller than 30 nm, fast diffusion averages the magnetic field due to iron oxide nanoparticles (motional averaging regime, MAR).32,33 In this MAR, the relaxivity of nanoparticles is dependent on their size. For large-sized nanoparticles, the diffusion effect becomes small, and nanoparticles can be regarded as randomly distributed stationary objects (static dephasing regime, SDR). In the SDR, nanoparticles are predicted to exhibit the highest r2 relaxivity, which is independent of their size.34,35 However, iron oxide nanoparticles in the SDR are ferrimagnetic, and their magnetic dipole interaction results in poor colloidal stability.36,37 The severe agglomeration of ferrimagntic iron oxide nanoparticles precludes their in vivo applications because their circulation time is very short, and they can sometimes cause organ damage because of capillary occlusion.38 An alternative method to avoid ferrimagnetic dipole interaction is controlled clustering of multiple superparamagnetic iron oxide nanoparticles using larger templates such as silica and polymers because the T2 contrast effect also increases with an increasing number of
agnetic nanoparticles have received enormous attention in various research areas because of their unique magnetic properties, facile surface modification, and biocompatibility.1−6 Magnetic nanoparticles have been used as contrast agents for magnetic resonance imaging (MRI),7−11 drug delivery vehicles,12−14 hyperthermia agents,15,16 and for magnetic separation.17−19 Among them, MRI is one of the key applications of magnetic nanoparticles because the inherently low sensitivity of MRI can be improved by magnetic nanoparticles.20−22 Magnetic nanoparticles accelerate spin− spin relaxation of adjacent protons by producing a magnetic field, resulting in signal attenuation in T2-weighted MR images.23 Among the various magnetic nanomaterials available, iron oxide nanoparticles have been most widely used as T2 MRI contrast agents because they are biologically well tolerated and benign.24,25 Several iron oxide nanoparticle-based MRI contrast agents including Feridex and Resovist have been approved for clinical use. However, these iron oxide nanoparticles, which are prepared by coprecipitation, are relatively polydisperse, and their magnetic property and relaxivity are difficult to control. Owing to significant recent advances in synthetic methods for nanocrystals, including the well-known thermal decomposition process, uniform and highly crystalline iron oxide nanocrystals with sizes ranging from a few nanometers to tens of nanometers are now available for various medical applications.26−29 Because the T2 contrast effect of iron oxide nanoparticles is dependent on their magnetic moment, which is proportional to their © 2012 American Chemical Society
Received: March 16, 2012 Revised: May 2, 2012 Published: May 10, 2012 3127
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Figure 1. (a) TEM image of 22 nm WFIONs dispersed in water. The average size of WFIONs is 22 ± 2.6, and their shape is cubic (inset: HRTEM image). (b) Picture showing high colloidal stability of WFIONs in water. The nanoparticles are not aggregated even in the external magnetic field. (c) DLS data for WFIONs in water. Hydrodynamic diameter of WFIONs is 43 ± 10 nm. (d) M−H curves of ferrimagnetic iron oxide nanoparticles. Whereas saturation magnetization is independent of the nanoparticle size, remnant magnetization and coercivity decrease with their decreasing size.
nanoparticles in the aggregates.34,35,39,40 However, to date, maximum r2 relaxivity could not be realized because the fraction of magnetic nanoparticles in the clusters is relatively small. Therefore, the dispersible single core magnetic nanoparticles in SDR are highly desirable. Herein, we report on the successful preparation of water-dispersible ferrimagnetic iron oxide nanocubes (WFIONs) and demonstrate highly sensitive in vivo MR imaging of tumors. Ferrimagnetic iron oxide nanocubes (FIONs) were synthesized using a previously reported method.36 The transmission electron microscopy (TEM) image shows that cube-shaped nanoparticles were obtained with an average size of 22 ± 2.6 nm (Figure 1a). Because as-synthesized nanoparticles are very hydrophobic, FIONs were transferred to aqueous media by encapsulation with polyethylene glycol-phospholipid (PEGphospholipid). The encapsulated nanoparticles showed excellent colloidal stability in water. Furthermore, they did not aggregate even in an external magnetic field (Figure 1b), and the hydrodynamic diameter in deionized water, measured with dynamic light scattering (DLS), was 43 ± 10 nm (Figure 1c). In addition, the hydrodynamic diameters of WFIONs were 51 ± 6.5 and 52 ± 10.9 nm in phosphate buffered saline (PBS) and culture media containing 10% fetal bovine serum (FBS), respectively (Figure S1a,b, Supporting Information). WFIONs did not exhibit significant change in their hydrodynamic diameter even after keeping in aqueous media for 48 h, demonstrating their high colloidal stability in biological media
(Figure S1c, Supporting Information). The high colloidal stability of WFIONs could be attributed to both the stabilization by long PEGs and the reduced remnant magnetization. As shown in Figure 1d, the saturation magnetization of 22 nm WFIONs was very similar to that of the larger-sized nanocubes because the portion of canted spins on the surface of nanoparticles is very small in this size range. However, coercivity and remnant magnetization of single-domain magnetic nanoparticles decrease with decreasing size (Figure 1d). The remnant magnetization and coercivity of 22 nm WFIONs are ca. 5 emu/g Fe and ca. 14 Oe, respectively, at room temperature. Recently, colloidally stable ferromagnetic Fe/Fe3O4 nanoparticles with relatively small coercivity and remnant magnetization were reported, demonstrating that the magnetic dipole interaction between nanoparticles can be overcome using suitable surfactants.41,42 Compared to these core/shell Fe/Fe3O4 nanoparticles, the coercivity and remnant magnetization of WFIONs are smaller, whereas the core size is larger. In addition to the small remnant magnetization, the stabilization by long PEG chains is critical for achieving colloidal stability in aqueous media. The measured hydrodynamic diameter of the as-synthesized ferrimagnetic iron oxide nanoparticles in chloroform was 99 ± 24 nm (Figure S1d, Supporting Information), and these nanoparticles were aggregated in the presence of an external magnetic field. When the nanoparticles were dispersed in water using charge repulsion by encapsulation with cetyltrimethylammonium 3128
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Figure 2. MR contrast effect of ferrimagnetic iron oxide nanoparticles on changes in size. (a) T2-weighted MR images of ferrimagnetic iron oxide nanoparticles at various concentrations of iron at 3 T and (b) their color-coded images. (c) Plots of R2 values of ferrimagnetic iron oxide nanoparticles and (d) comparison of their r2 values.
bromide (CTAB), the hydrodynamic diameter was 96 ± 24 nm (Figure S1e, Supporting Information), which is still larger than that of WFIONs encapsulated with PEG-phospholipids. Subsequently, the r2 relaxivities of WFIONs and larger ferrimagnetic iron oxide nanoparticles were measured using a 3T clinical MR scanner. Given that the ferrimagnetic iron oxide nanoparticles larger than 30 nm are not colloidally stable, these nanoparticles were dispersed in 1% agarose to prevent sedimentation during the measurement. Dispersion in agarose did not affect the T2 relaxation process, and the r2 values of WFIONs dispersed in water and agarose were nearly identical (Figure S2, Supporting Information).43 The T2-weighted MR images show that 22-nm-sized WFIONs produced stronger T2 contrast effect than the larger nanocubes (Figure 2a,b). The r2 values of iron oxide nanoparticles with sizes of 22, 28, 32, 42, and 49 nm were 761, 740, 532, 343, and 296 s−1 mM−1, respectively (Figure 2c,d). In general, the r2 values of magnetic nanoparticles increase with increasing size. However, as shown in Figure 2d, the r2 values of 22-nm- and 28-nm-sized WFIONs are very similar, and the r2 values decreased for the nanoparticles larger than 30 nm. According to theoretical studies, the highest r2 relaxivity is expected to be achieved for spherical single-core iron oxide nanoparticles with diameters ranging from 30 to 300 nm, and multicore iron-oxidenanoparticle clusters ranging in size from 30 to 120 nm.34,35 The core volume of cube-shaped WFIONs with an edge dimension of 22 nm is similar to that of spherical nanoparticles with a diameter of 30 nm. The hydrodynamic diameters of 22nm- and 28-nm-sized ferrimagnetic nanoparticles are 44 and 56 nm, respectively, demonstrating that the WFIONs are in the
static dephasing regime (SDR) where the highest r2 value is expected to appear. In the SDR, the r2 value of the nanoparticle is given by r2 =
3 8π 2 3 A N0 γMs 81 106Z
(1)
where A is the lattice parameter, N0 is the Avogadro constant, Z is the number of formula units per unit cell, γ is the gyromagnetic ratio, and Ms is the saturation magnetization. As shown in eq 1, the r2 value in the SDR is dependent solely on the saturation magnetization. The r2 value of the 22-nmsized WFIONs with a saturation magnetization of 106 emu/g Fe is calculated to be approximately 800 s−1 mM−1, which is very similar to the measured r2 value of 22 nm WFIONs (761 s−1 mM−1). To the best of our knowledge, this is the first report on the preparation of dispersible single-core iron oxide nanoparticles in the SDR. Iron oxide nanoparticles larger than 30 nm aggregate because of their strong magnetic dipole moments, and the overall size becomes larger than 200 nm. The hydrodynamic diameters of 32-, 42-, and 49-nm-sized ferrimagnetic iron oxide nanoparticles are 261, 378, and 534 nm, respectively, which are beyond the SDR (Figure S3, Supporting Information). Because these large aggregates of magnetic nanoparticles generate a very strong magnetic field, the nearby water protons are completely dephased and they are unable to contribute to the MR signal. Consequently, for these large aggregates, the r2 relaxivity decreases with increasing nanoparticle size (referred to as the “Luz-Meiboom” regime).32,33 3129
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The cytotoxicity of WFIONs was evaluated with a 3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay using the B16F10 melanoma cell line. No appreciable toxicity was observed up to a very high concentration of 0.75 mg Fe/ml, demonstrating the high biocompatibility of WFIONs (Figure 3a). Although bare iron oxide nanoparticles
Figure 4. In vivo MR Images of the tumor site before (a) and 1 h after (b) intravenous injection of WFIONs (arrows indicate the tumor sites). After administration of WFIONs, the MR signal of the tumor is significantly attenuated.
Supporting Information). Since 15 nm superparamagnetic iron oxide nanoparticles have similar surface property to WFIONs, the significant MR signal change of the tumor by WFIONs can be attributed to their superior contrast effect. To confirm the accumulation of WFIONs at the tumor site, the mouse was sacrificed after the MR imaging, and sections of the tumor were observed with a fluorescence microscope (Figure S7, Supporting Information). The fluorescence image shows the accumulation of RITC-labeled WFIONs throughout the tumor site. In addition to the tumor, MR signal attenuation can be observed in the liver, spleen, bone marrow, and lymph nodes owing to the clearance of the nanoparticles by macrophages (Figure S6, Supporting Information). The signal decrease in the lymph nodes demonstrates that WFIONs can also be used for the detection of lymph node metastases.48−50 When the tissue sections were examined using fluorescence microscope, a very small amount of WFIONs was observed in the lung, indicating that large agglomerates did not form during the circulation (Figure S7, Supporting Information). In addition, hematoxylin and eosin (H&E) stains of major organs showed no evidence of any adverse effect due to WFIONs (Figure S8, Supporting Information). In summary, the theoretically predicted maximum of r2 relaxivity was achieved by optimizing the overall size of ferrimagnetic iron oxide nanoparticles. WFIONs with an edge length of 22 nm, encapsulated with PEG-phospholipids, exhibited high colloidal stability in aqueous media. In addition, WFIONs did not affect cell viability at concentrations up to 0.75 mg Fe/ml. Owing to the enhanced colloidal stability and the high r2 relaxivity (761 mM−1 s−1), it was possible to successfully perform in vivo MR imaging of tumors by intravenous injection of 22-nm-sized WFIONs using a clinical 3-T MR scanner. Compared to commercialized T2 MRI contrast agents such as Feridex, WFIONs provide a superior T2 contrast effect, and their overall size is smaller (Table S1, Supporting Information). When combined with suitable targeting ligands, WFIONs will be able to play critical roles in the early diagnosis and detection of tumor metastasis.
Figure 3. (a) In vitro cytotoxicity test of WFIONs. The viability of the B16F10 cells was determined by MTT assay after incubation with various concentrations of WFIONs for 24 h (n = 3). (b) T2-weighted MR image of dispersed cells in agarose. The cells were incubated with various concentrations of WFIONs for 24 h.
are toxic owing to free radicals generated by the Fenton reaction, nanoparticles coated with appropriate surfactants are known to be much less toxic.44 The cellular uptake of WFIONs was confirmed using a confocal laser scanning microscope (CLSM) after the incubation of the cells with rhodamine-Bisothiocyanate (RITC)-labeled WFIONs for 24 h. The WFIONs were readily internalized by the cells without any treatment to enhance cellular uptake,45,46 and they were observed in the cytoplasm as red fluorescence (Figure S4, Supporting Information). The T2-weighted MR images of B16F10 cells incubated with various concentrations of nanoparticles were acquired with a 3-T clinical MR scanner. The MR signal intensities of the cells were clearly attenuated as the concentration of WFIONs increased (Figure 3b). Nanoparticles are able to accumulate at the tumor sites due to their leaky vascular structure and poor lymphatic drainage, which is referred to as the enhanced permeation and retention (EPR) effect.47 However, colloidal stability is critical for the successful delivery of nanoparticles because large aggregates of nanoparticles are rapidly cleared by the reticuloendothelial system (RES), preventing the particles from accumulating at the tumor sites. To demonstrate the in vivo MR imaging of tumors, WFIONs were injected intravenously into a nude mouse with melanoma, and T2-weighted MR imaging was performed using a clinical 3-T MR scanner. In the MR images, signal attenuation at the tumor site was clearly observed 1 h after the injection, demonstrating the passive targeting of WFIONs (Figure 4). When Feridex or 15 nm spherical superparamagnetic iron oxide nanoparticle was administered, signal changes of the tumors were marginal (Figure S5,
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ASSOCIATED CONTENT
S Supporting Information *
Experimental details, DLS data of 22 nm ferrimagnetic iron oxide nanoparticles in various condition and larger-sized nanoparticles, relaxivity of WFIONs in water and in agarose, confocal microscope image of cells incubated with WFIONs, in vivo MR images after administration of Feridex and 15 nm iron oxide nanoparticles, in vivo MR images of lymph nodes, fluorescence images and H&E images of the selected tissues are 3130
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included. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: (T.H.)
[email protected]; (S.H.C.) verocay@radiol. snu.ac.kr. Author Contributions §
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS T.H. acknowledges financial support by the National Research Foundation (NRF) of Korea through Strategic Research (20100029138), Global Research Laboratory (2011-0021628), and World Class University (R31-10013) Programs. S.H.C acknowledges financial support from the Korea Healthcare technology R&D Projects, Ministry for Health, Welfare, and Family Affairs (A112028).
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