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50 nm) also increase the particle size.16,20 By contrast, the current method of

Fig. 6 Schematic presentation of magnetic modulation of scattering of light (A and B) by nanoeyes (iron oxide core was incubated in oxalic acid for 9.5 h), (C) intensity time series for nanoeyes under darkfield microscope.

12806 | J. Mater. Chem., 2012, 22, 12802–12809

Fig. 7 (A) Radioluminescence spectra of nanoeyes (iron oxide core was incubated in oxalic acid for 9.5 h) and nanorice excited by X-ray, (B) fluorescence spectra of nanoeyes (iron oxide core was incubated in oxalic acid for 9.5 h) and nanorice excited by 480 nm light.

partial dissolving the iron oxide core reduces the quenching while maintaining the total nanoparticle size and volume. We expect that carefully controlling dissolution time will allow optimization of the optical and magnetic properties. In addition, a hollow space is formed around the iron oxide core in the nanoeyes which could serve to encapsulate drugs for drug delivery applications (see Fig. S4B, ESI†). We expect that low molecular weight drugs can be loaded into the hollow space of the particles. Although the hollow nanorice obtained by completely dissolving the iron oxide are paramagnetic, brightly luminescent, and have a large internal space for encapsulation, their magnetic moment is weak compared to the solid nanorice and nanoeyes, especially at low fields. As a result, they separate only very slowly with typical permanent magnet-generated magnetic fields and field gradients. The nanorice particles with a solid iron oxide core respond rapidly to magnetic fields but display only weak fluorescence and negligible radioluminescence. In addition, there is not much space within the core for dye and drug encapsulation. By partially dissolving the iron oxide core, nanoeyes are formed which display magnetophoresis and radioluminescence. Their bright luminescence under UV (365 nm) and X-ray irradiation is shown in Fig. 8 Compared with the UV fluorescence, the X-ray luminescence of the nanoeyes provides a background-free image which can be used for deep tissue imaging. The hollow regions in the nanoeyes could also be used for indicator dye and drug encapsulation for theranostic applications. To test whether the

Fig. 8 Photograph of hollow nanorice under (A) UV light (365 nm) and (B) X-ray luminescence.

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pores in the Gd2O3 shell were large enough for small molecules to diffuse through, we incubated the nanoparticles in a solution of bromocresol blue dye, encapsulated the dye and particle with 10 nm silica layer, and washed and separated the particles via centrifugation. The dye could indeed be encapsulated (see Fig. 4S, ESI†), while a control, the solid core particles could not encapsulate dye. We are currently developing coatings to control the dye release rate.

Magnetic luminescent nanoparticles as T2 contrast agent It is useful to have contrast agents that provide both radioluminescence and MRI contrast in order to validate measurements, and to provide complimentary information (e.g. molecular information with functional XLT spectroscopy using indicators and tissue contrast with MRI). Our magnetic radioluminescent particles are expected to serve as T2 and T2* contrast agents because of their strong magnetic moment in static MRI fields. This is consistent with recent work showing that gadolinium oxide nanoparticles have higher relaxivities compared with gadolinium chelates.27,45,46 Fig. 9 shows T2 and T2* weighted images after 4 ms and 1.5 ms, respectively. The decrease with echo time was fit to an exponential in order to calculate the relaxation rate, R2 ¼ 1/T2 and R2* ¼ 1/T2* at each concentration. These relaxation rates are shown as a function of concentration in Fig. 10 and S5 (see Table S1† for the molar concentration of Gd and Fe in 0.8, 0.4, 0.1, and 0.05 mg ml1 of solution, ESI†). The curves are approximately linear, although there is some evidence of saturation at the highest concentration, 0.8 mg ml1. Fitting the points up to 0.4 mg ml1 (2.6–3 mM), the relaxivities, r2 and r2* are 69 mM1 s1 and 274 mM1 s1 respectively for the nanorice; 58 mM1 s1 and 120 mM1 s1 for the nanoeyes, and 46 mM1 s1 and 112 mM1 s1 for the hollow nanorice. The relaxivity is calculated based on the total molar concentration of both Gd3+ and Fe3+. For comparison with other literature we have also calculated r2 and r2* using the molar concentrations of just Gd3+

Fig. 9 T2 and T2*-weighted images of nanorice, nanoeyes (iron oxide core was incubated in oxalic acid for 9.5 h), and hollow nanorice at echo time of 4 ms and 1.5 ms, respectively. Group A: T2-weighted images of nanorice with concentration of 0.8 mg ml1, 0.4 mg ml1, 0.1 mg ml1, and 0.05 mg ml1. Group B: T2-weighted images of nanoeyes with concentration of 0.8 mg ml1, 0.4 mg ml1, 0.1 mg ml1, and 0.05 mg ml1. Group C: T2-weighted images of hollow nanorice with concentration of 0.8 mg ml1, 0.4 mg ml1, 0.1 mg ml1, and 0.05 mg ml1. Group A*: T2-weighted images of nanorice with concentration of 0.8 mg ml1, 0.4 mg ml1, 0.1 mg ml1, and 0.05 mg ml1. Group B*: T2*-weighted images of nanoeyes with concentration of 0.8 mg ml1, 0.4 mg ml1, 0.1 mg ml1, and 0.05 mg ml1. Group C*: T2-weighted images of hollow nanorice with concentration of 0.8 mg ml1, 0.4 mg ml1, 0.1 mg ml1, and 0.05 mg ml1.

This journal is ª The Royal Society of Chemistry 2012

Fig. 10 The relaxation rate curves as a function of concentration. Black squares: nanorice, blue triangles: nanoeyes (iron oxide core was incubated in oxalic acid for 9.5 h), red circles: hollow nanorice. Error bars represent the standard deviation.

and Fe3+, and the total mass concentration in mg ml1 (see Table S2, ESI†). For all particles, r2* is larger than r2 because r2 includes contributions from local static field inhomogeneities caused by the magnetic moment of the particles. The difference between r2 and r2* may provide more specificity towards the contrast agents, especially for the nanorice which display a factor of 4 increased relaxivity. The iron oxide core significantly increased the relaxivities, with the solid core providing the highest relaxivity and the hollow core the least. Previous work showed that ultrasmall Gd2O3 nanoparticles (1–10 nm)26,28,29,47 and hollow nanoparticles with thin Gd2O3 shell (10 nm)30 served as good T1 contrast agents and moderate T2 contrast agents. In contrast, our spindle-shaped nanoparticles with a 40 nm Gd2O3:Eu shell worked better as a T2 contrast agents. This may be due to low water exchange efficiency inside of the porous Gd2O3 nanoparticles, which is consistent with earlier work by using the porous Gd2O3 nanoparticles (200 nm in diameter).30 Compared to FDA-approved iron oxide nanoparticle contrast agents such as Ferumoxtran (Resovist, 65 mM1 s1), cross-linked iron oxide particle (CLIO-Tat, 62 mM1 s1), and water soluble iron oxide (WSIO, 78 mM1 s1), our nanorice, nanoeyes, and hollow nanorice had similar T2 relaxivities.48–51 However, these T2 relaxivities were several times higher than typical gadolinium chelates (Gd-DTPA, 4.9 mM1 s1)52 and Gd2O3 nanoparticles (14.1–16.9 mM1 s1).52–54 Most importantly, the contrast is sufficient for many drug delivery applications. For example, 5–10 mg ml1 is a typical magnetic particle concentration in tumors for magnetic hyperthermia,55 while our particles have several times faster relaxation rates than the gel even at the lowest concentrations of 50 mg ml1 (R2 is 37.7 s1 for the nanorice, 29.3 s1 for nanoeyes, and 20.0 s1 for the hollow rice, compared to 5.1  0.1 s1 for the unloaded gel). Nanoparticle cytotoxicity assay Previous studies toxicity of 80 nm iron oxide nanoparticles found no acute or subacute toxic effects by histologic or serologic studies in rats or beagle dogs which received a total of 3 mmol Fe kg1.56 In order to study the potential cytotoxicity of the rare earth elements in the magnetic imaging probles (nanorice, J. Mater. Chem., 2012, 22, 12802–12809 | 12807

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References

Fig. 11 Cytotoxitity test for hollow nanorice (Gd2O3:Eu).

nanoeyes, and hollow nanorice), an in vitro cytotoxicity test of hollow nanorice was performed on MCF-7 breast cancer cells (Fig. 11). The viability of the untreated cells was set as 100% in order to calculate the viability of the cells treated by different concentration of X-ray scintillators. Cell viability is not significantly affected by the Gd2O3:Eu nanoparticles up to concentration of at least 250 mg ml1 (24 h exposure).

Conclusion We successfully prepared magnetic luminescent nanoparticles using silica coated hematite as a template. The silica coating plays a critical role on the growth of scintillator shell on the surface of the nanocores. After synthesis, the cores were made magnetic via high temperature reduction in H2 and oxidization in air. The magnetic core size could be controlled while preserving the luminescent shell by dissolving the core in oxalic acid. Intermediate core sizes displayed both magnetic and luminescent properties. These novel magnetic luminescent nanoparticles are advantageous because they allow for magnetic separation and multimodal imaging with MRI, fluorescence and radioluminescence. We expect that such nanocomposites, combining the advantages of magnetism and luminescence, will find extensive applications in drug delivery and bioimaging. For example, the hollow structure in the partially dissolved iron oxide scintillator can be loaded with small dyes and drug molecules. Our synthesis technique is attractive because multifunctional particles can be made by coating the core templates with multiple layers of materials, each with a controlled thickness and composition. Different sizes, shapes (spherical and non-spherical), and structures (hollow and non-hollow) can be obtained by varying the shape and size of the hematite templates. Future work will study the effect of size and shape on magnetic, luminescent, and biodistribution properties.

Acknowledgements This research was supported in part by NASA through the SC Space Grants Palmetto Academy program under award no. NNG05GI68G. We thank the Clemson University Electron Microscope Facility for use of TEM imaging facilities. We also thank Professor Shiou-Jyh Hwu for use of his furnace. 12808 | J. Mater. Chem., 2012, 22, 12802–12809

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J. Mater. Chem., 2012, 22, 12802–12809 | 12809

Magnetic and optical properties of multifunctional core-shell radioluminescence nanoparticles.

When X-rays irradiate radioluminescence nanoparticles, they generate visible and near infrared light that can penetrate through centimeters of tissue...
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