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Keywords:

  • biofunctional materials;
  • gel combustion techniques;
  • nanocomposites;
  • neutron capture therapy

Cancer is one of the leading causes of death worldwide; with many different types, it kills thousands of people every day. Various types of treatments have been developed to treat cancer, and new approaches that are currently under investigation include boron neutron capture therapy (BNCT)1 and gadolinium neutron capture therapy (GdNCT).2 Neutron capture therapy is primarily used to treat brain tumors, such as glioblastoma, a particularly aggressive type of brain tumor that is difficult to treat by conventional means such as radiation therapy. BNCT and GdNCT involve a bimodal approach to treatment, utilizing a cancer-specific drug and a neutron source (neutron beam). The approach is based on the ability of a boron isotope (10B) to absorb neutrons and emit localized cell-killing particles. The main mechanism that takes place in BNCT is the absorption of a neutron to convert 10B to 11B, with the release of 4He2+, 7Li3+, and energy.3 The energy that is released can then destroy the tumor cell. Gadolinium also attracted interest for its potential use in neutron capture therapy because it is the element with the highest cross-sectional value for thermal neutrons—2.55×105 b and 6.10×104 b for 157Gd and 155Gd, respectively.4 In fact, the thermal neutron value of 157Gd (2.55×105 b) is 65 times that of 10B, and it releases Auger electrons, internal conversion electrons, γ-ray and X-ray after the capture of a single thermal neutron.[1, 5–7]

Targeted delivery of an anticancer drug is very desirable, as most of the commonly used agents have serious side effects associated with their use due to undesirable interactions with healthy cells. Moreover, targeted delivery can potentially enhance the therapeutic efficacy.8 Research on nanomaterials has grown explosively in the last few years, including an increased emphasis on developing nanomaterials as drug delivery vehicles.9, 10 The size of such delivery vehicles (<1000 nm) has attracted wide interest in the field of drug targeting. Nanomaterial-based drug systems provide the advantage of being able to penetrate cell membranes through minuscule capillaries in the cell wall of rapidly dividing tumor cells, while at the same time having low cytotoxicity toward normal cells. Nanomaterials have been found to have favorable interaction with the brain blood vessel endothelial cells of mice, and thus they might have the possibility of being transported to other brain tissues, making them potential neutron capture therapy agents.11, 12 In theory, in BNCT and GdNCT nanomaterials, a large number of boron and gadolinium atoms could be incorporated, thereby lowering the dose requirement for delivering critical amounts of 10B and Gd to tumor cells. Accordingly, improvement of the drug storage capacity is very important.7

Magnetic nanoparticles are being studied in terms of their highly promising applications in biology and medicine, including magnetic cell separation, magnetic resonance imaging (MRI) contrast enhancement, and magnetic targeted drug delivery for cancer magnetic hyperthermia.10 MRI is a noninvasive technique for obtaining real-time three-dimensional images of the interior of solids (particularly cells), tissues, and organs. But magnetic nanoparticles tend to aggregate due to strong magnetic dipole–dipole attraction between particles brought together by van der Waals interparticle attractions and their inherently large surface energy. Therefore, coating agents, such as surfactants or capping ligands with some specific functional groups, have been used to modify these particles in order to prevent the sedimentation and to obtain better surface properties.13

Silicates have attracted significant interest because of their rich structural chemistry, which makes the development of new structures and functionalities possible. Amorphous silica with a nontoxic nature, tunable diameter, and very high specific surface area with abundant Si[BOND]OH bonds on the surface are promising candidates for use as carriers in drug delivery systems. Thus, nanocomposites of SiO2 and magnetic particles have attracted considerable attention in targeted drug delivery because of the high surface area and magnetic separability.14

Crystalline FeBO3 material is known for its unique magnetic and acoustic resonance properties.15 In contrast, GdFeO3 shows promising relaxivity properties and has potential as an MRI contrast agent.16 Fe3O4 has been considered to be an ideal candidate for biological applications due to its special magnetic properties, lack of toxicity, and good biocompatibility.17 The nanocomposites of these materials can carry an active agent (drug) and be guided to the target site inside the body, facilitating therapeutic efficiency and minimizing damage to normal tissue due to drug toxicity.

In recent years, several different routes have been used to synthesize biofunctional magnetic nanocomposites.18 The gel combustion method has been developed and widely used to prepare phase-pure nanopowders.19 The method has the advantages of using inexpensive precursors, requiring a simple experimental process, and resulting in an ultrafine, homogenous powder. Chavan and Tyagi used a combustion method to produce GdFeO3 nanoparticles with sizes in the range of 40–65 nm.20 However, there have been only a few reports on combinations of magnetic Fe3O4 with FeBO3 and GdFeO3 nanoparticles. For this reason, we developed a route consisting of encapsulating preformed 10B, Gd and Fe3O4 nanoparticles into silica. The aim was to obtain core shell nanoparticles, denoted Fe10BO3/Fe3O4/SiO2, and GdBO3/Fe3O4/SiO2, which will 1) improve the drug storage capacity, 2) have sufficiently powerful magnetic properties, 3) form a stable dispersion at physiological pH, and 4) have facile surface chemistry to allow the use of coupling agents, such as commercially available alkoxysilane derivatives.

The reactions described herein were generally performed under air or argon, and Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 nanocomposites were prepared via the route shown in Scheme 1. Powder X-ray diffraction (XRD) was used to investigate the variations in structure of the samples produced by the gel combustion method under different conditions (Figures 1). Fe10BO3 and GdFeO3 crystallized as a phase-pure material at calcination temperatures as low as 680 °C in 2 h (Figure 1 a,c). The diffraction peaks of the product can be readily indexed to the pure Fe10BO3 and GdFeO3 (Joint Committee on Powder Diffraction Standard (JCPDS) card no. 76-0701 and 78-0451, respectively). No additional peaks for other phases or impurities were found. These results demonstrate that well-crystallized Fe10BO3 and GdFeO3 can be obtained using the gel combustion technique. After coating with Fe3O4, the product is a nanocomposite of Fe10BO3 or GdFeO3 and Fe3O4 (Figure 1 b,d), suggesting that a hybrid material, composed of Fe10BO3 or GdFeO3 and Fe3O4, had formed. No peaks of other phases were detected, indicating that no other reaction occurred between the core and the shell during the synthesis.

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Scheme 1. Schematic representation of the fabrication of Fe10BO3/Fe3O4/SiO2 nanocomposites. TEOS=tetraethoxysilane.

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Figure 1. Powder X-ray diffraction (XRD) patterns of the Fe10BO3 (top) and GdFeO3 (bottom) sample before (a and c) and after (b and d) Fe3O4 and SiO2 coating. * Characteristic diffraction peaks of Fe3O4.

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The typical microstructure of the sample was examined by transmission electron microscopy (TEM) analysis. Figure 2 shows the TEM images of the samples before and after coated with Fe3O4 and SiO2. For pure Fe10BO3 and GdFeO3, the TEM images indicate that the nanoparticles are spherical and the particle diameter is about 60 nm (Figure 2 a,d). When coated with Fe3O4, the particles tend to aggregate due to strong magnetic dipole–dipole attractions between them (Figure 2 b,e). After the particles were coated with SiO2, there was a thin layer of amorphous silica covering the surface (Figure 2 c,f).

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Figure 2. Transmission electron microscopy (TEM) images of the samples after each coating step. a) Fe10BO3, b) Fe10BO3/Fe3O4, c) Fe10BO3/Fe3O4/SiO2, d) GdFeO3, e) GdFeO3/Fe3O4, f) GdFeO3/Fe3O4/SiO2.

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In order to deduce the composition of the nanocomposites, energy-dispersive X-ray spectroscopy (EDS) analysis was carried out (Figure 3). Before coating with Fe3O4 and SiO2, the EDS specta of the samples depict no other peaks except those for Fe10BO3 (Fe and O, Figure 3 a) and GdFeO3 (Gd, Fe and O, Figure 3 c), indicating the high purity of the composites obtained by the method described above. After coating with Fe3O4 and SiO2, the EDS spectra indicate that Fe, Si and O composited for Fe10BO3/Fe3O4/SiO2 and Gd, Fe, Si and O for GdFeO3/Fe3O4/SiO2 nanocomposites. Because boron is a light element, EDS cannot detect its presence, but the pattern seen in the XRD spectrum indicates that the compound is a composite of Fe10BO3 and Fe3O4.

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Figure 3. Energy-dispersive X-ray spectroscopy (EDS) of samples before and after Fe3O4 and SiO2 coatings. a) Fe10BO3, b) GdFeO3, c) Fe10BO3/Fe3O4/SiO2, d) GdFeO3/Fe3O4/SiO2.

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Fourier-transformed infrared (FT-IR) spectroscopy was used to identify the surface functional groups of the samples. Figure 4 shows the FT-IR spectra of Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 nanocomposites in the region of 500 cm−1 to 4000 cm−1. A broad band with a maximum at 3437.8 cm−1 is attributed to the O[BOND]H stretching vibrations in both the Si[BOND]OH groups and some physisorbed water, which is confirmed by the presence of an H2O deformation band (bending vibration of H[BOND]O[BOND]H) at 1633.6 cm−1. For the Fe10BO3/Fe3O4/SiO2 sample, bands at 1254.8 and 1965.6 cm−1 are due to vibrations of the B[BOND]O bond and other bonds attached to the B or the O of the B[BOND]O bond.2123 The band at ∼1050 cm−1 corresponds to υ(Si[BOND]OH); the bands at ∼1100 and ∼860 cm−1 correspond to υasym(Si[BOND]O[BOND]Si) and υsym(Si[BOND]O[BOND]Si) modes, respectively. The absorption at 767.7 cm−1 could be attributed to the O[BOND]H stretching vibration on the surface of Fe3O4. An additional absorption at 667 cm−1 could be attributed to the Fe[BOND]O[BOND]B bending vibration analogous to Si[BOND]O[BOND]B.23,24 A very small band shoulder at ∼560–580 cm−1, observed in the IR spectra, can be assigned to υ(Fe[BOND]O) and υ(Gd[BOND]O) in Fe[BOND]O[BOND]Fe and Gd[BOND]O[BOND]Fe systems, respectively.2527 These results indicate that Fe3O4 and SiO2 are immobilized on the surfaces of the Fe10BO3 and GdFeO3 nanoparticles.

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Figure 4. Fourier-transformed infrared (FT-IR) spectra of nanocomposites a) Fe10BO3/Fe3O4/SiO2 and b) GdFeO3/Fe3O4/SiO2.

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The magnetization curve measured at room temperature for the Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 nanocomposites shows a small hysteresis loop suggesting that the nanocomposites have ferromagnetic behavior (Figure 5). It has been reported that magnetic Fe3O4 particles exhibit super-paramagnetic behavior when the particle size decreases to below a critical value, generally around 20 nm.28 The Fe3O4 particles are aggregated and connected to form larger particles, resulting from the ferromagnetic behavior. The magnetization saturation values for Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 are about 22.6 and 48.7 emu g−1, respectively. These values are lower than that of pure Fe3O4 (87 emu g−1), probably because of the small percentage of Fe3O4 in the nanocomposites. The magnetic separation ability of the sample was tested in water by placing a magnet near the glass bottle containing a suspension of the nanocomposite. The deep brown and black particles were attracted towards the magnet (Figure 5, inset). This property will provide an easy and efficient way to separate the Fe10BO3/Fe3O4/SiO2 and GdFeO3/Fe3O4/SiO2 nanocomposites from a suspension system and to carry drugs to targeted locations under an external magnetic field. These results indicate that the nanocomposites possess excellent magnetic responsiveness. The magnetic property permits the use of the biofunctional nanoparticles in biomedical applications because they have sufficiently strong magnetization for efficient magnetic separation in the presence of an externally applied magnetic field.29

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Figure 5. Measured magnetic hysteresis loops for nanocomposites a) Fe10BO3/Fe3O4/SiO2 and b) GdFeO3/Fe3O4/SiO2. Inset: photograph of magnetic targeting under an external magnet.

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A novel kind of magnetic sphere with 10B or Gd and Fe3O4 nanoparticles encapsulated in the cores of silica shells has been fabricated. The nanocomposite spheres, which combine the advantages of silica and magnetic carrier technology, are likely to be applied in targeted drug delivery. The main focus of this research was to synthesize novel neutron capture therapy materials that are both effective and relatively harmless to the patient. The next stage of this research involves the biological evaluation of the two nanocomposites reported here and is currently underway in our laboratories.

Experimental Section

  1. Top of page
  2. Experimental Section
  3. Acknowledgements

The chemicals used in this study, such as Gd(NO3)3⋅6H2O, Fe(NO3)3⋅9H2O, FeCl2⋅4H2O, FeCl3, H310BO3, citric acid, tetraethoxysilane (TEOS), were all of analytical reagent grade, purchased from Aldrich, and used as received without any further purification. Water used was deionized and doubly distilled.

The combustion synthesis utilized Fe(NO3)3⋅9H2O (1.92 g, 0.0048 mol) and H310BO3 (0.92 g, 0.015 mol) as the starting materials. Citric acid was used as the fuel, and chelation was in the ratio 1:1.25. The precursors and fuel were mixed in water (50 mL) to obtain a transparent aqueous solution, which on thermal dehydration resulted in a highly viscous liquid. On further heating to high temperature (190 °C), the viscous liquid swelled and dried. The residue was then ground to obtain a powder, which was then subjected to further heat treatment at 680 °C for 2 h under an argon atmosphere to isolate Fe10BO3 nanoparticles. In the synthesis of GdFeO3 nanoparticles, the H310BO3 was replaced by Gd(NO3)3⋅6H2O.

The obtained Fe10BO3 or GdFeO3 nanoparticles (0.20 g) were ultrasonically dispersed in water (50 mL), then FeCl3 (0.81 g, 0.005 mol) and FeCl2 (0.5 g, 0.0025 mol) were added, followed by the dropwise addition of aq NaOH (0.37 g in 30 mL H2O) with vigorous stirring. The resulting black suspension was further stirred for 30 min at RT to form black magnetite nanocomposites, which were first separated magnetically, washed several times with deionized water and EtOH, and then vacuum dried at 60 °C for 5 h. All main synthetic steps using Fe3O4 were carried out by passing argon through the solution to avoid possible oxygen contamination during the operations.

Silica-coated Fe10BO3/Fe3O4 and GdFeO3/Fe3O4 nanocomposites were produced by hydrolysis of TEOS on the surfaces of these magnetic nanocomposites. The freshly prepared Fe10BO3/Fe3O4 or GdFeO3/Fe3O4 nanocomposite powder (0.40 g) was ultrasonically redispersed in a solution containing EtOH (120 mL) and water (14 mL). The solution was then loaded into a three-necked bottle, and the pH of the solution was adjusted to 9 with NH4OH (3.0 mL, 14.8 M), and TEOS (2 mL, 0.009 mol) was added to the mixture under vigorous stirring. After 24 h, the particles were separated magnetically, washed with deoxygenated distilled water and anhydrous EtOH, and then vacuum dried at 50 °C overnight to collect the silica-coated nanocomposites Fe10BO3/Fe3O4/SiO2 or GdFeO3/Fe3O4/SiO2.

The phases of the final products were identified using an X-ray diffractometer (Rigaku D/max-2500 VPC) with Ni-filtered Cu Kα radiation at a scanning rate of 0.02° s−1 from 20° to 80°. A Hitachi model H800 transmission electron microscope was used for determining the size and shape of the powder particles. Fourier-transform infrared (FT-IR) spectra were recorded using a MAGNA 550 FT-IR spectrometer on samples embedded in KBr pellets. Magnetization measurements were performed using an ACBH-100K B-H hysteresis loops measuring instrument. All measurements were performed at room temperature.

Acknowledgements

  1. Top of page
  2. Experimental Section
  3. Acknowledgements

This work was supported by the US National Science Foundation (CHE-0906179 to NSH and CBET-1150617 to TX), the Shandong Province Higher Educational Science and Technology Program (grant no. J12LA01), and the Hundred Talents Program of the Chinese Academy of Sciences. NSH thanks the Chinese Academy of Sciences for the visiting professorship for senior international scientists and Northern Illinois University (USA) for granting a leave of absence. YZ thanks the Institute of Chemical and Engineering Sciences (ICES, Singapore) for financial support.