Nanomaterials for boron and gadolinium neutron capture therapy for ...

Pure Appl. Chem. 2015; 87(2): 123–134

Conference paper Shanmin Gao, Rongrong Fu and Narayan S. Hosmane*

Nanomaterials for boron and gadolinium neutron capture therapy for cancer treatment Abstract: Cancer is one of the leading causes of death; with it may different types, it kills thousands of people every day. Various types of treatment have been developed to treat and cure cancer. Nanotechnology has emerged as one of the most fruitful areas of science in cancer treatment and the nanomaterials are considered as a medical boon for the diagnosis, treatment and prevention of cancer. The major approaches of nanotechnology in tumor treatment include the development of nanoparticles with less or no tissue-resistance, their biocompatibility, ability as nanocarriers for drug delivery, and enhanced energy deposition in tissue with or without the external influence of microwave, light, magnet, etc. This review presents some of the recent developments in the use of nanoparticles as adjuncts to boron and gadolinium containing compounds in boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT) along with the latest developments in the area of boron nanotubes (BNTs), gadolinium oxide, boron nitride nanotubes (BNNTs) and the boron agent itself. Keywords: boron; cancer treatment; carbon nanotubes; gadolinium; IMEBORON-XV; nanostructures; nanotechnology; neutron capture theory. DOI 10.1515/pac-2014-0801

Introduction Nanomaterials have made their presence in cancer treatment and they are considered as the miracle materials for the diagnosis, treatment and prevention of cancer [1]. Besides, paralleled by advances in chemistry, biology, pharmacy, nanotechnology, medicine and imaging, several different systems have been developed in the last decade in which disease diagnosis and therapy are combined [2]. The first generation of anticancer agents using novel nanomaterials has successfully entered widespread use. Newer nanomaterials are garnering increasing interest as potential multifunctional therapeutic agents; these drugs are conferred novel properties, by virtue of their size and shape [3]. Emerging inorganic nanomaterials, such as mesoporous silica, magnetic and gold nanoparticles, carbon nanotubes, quantum dots and polymeric nanoparticles have been widely used in biomedical research with great optimism for cancer diagnosis and therapy. Such nanoparticles possess unique optical, electrical, magnetic and/ or electrochemical properties. With such properties along with their impressive nano-size, these particles can be targeted to cancer cells, tissues, and ligands efficiently and monitored with extreme precision in real-time [4]. Article note: A collection of invited papers based on presentations at the 15th International Meeting on Boron Chemistry (IMEBORON-XV), Prague, Czech Republic, 24–28 August 2014.

*Corresponding author: Narayan S. Hosmane, Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA; and Visiting Professor of the Chinese Academy of Sciences for International Senior Scientists at Ningo Institute of Materials Technology and Engineering (NIMTE), Ningbo 315201, China, e-mail: [email protected] Shanmin Gao: Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA; and School of Chemistry and Materials Science, Ludong University, Yantai 264025, China Rongrong Fu: School of Chemistry and Materials Science, Ludong University, Yantai 264025, China © 2014 IUPAC & De Gruyter

124 S. Gao et al.: Neutron capture therapy for cancer treatment

Neutron capture therapy (NCT) has been considered as a new and innovative approach to the treatment of cancer that is still in its formative stage. However, the basic idea behind this approach has been around for more than 70 years, almost as long as the idea of the existence of the neutron. The basic approach in NCT was outlined in 1936 by Gordon L. Locher [5], when he formulated his binary concept of treating cancer. In particular, there exist the possibilities of introducing small quantities of strong neutron absorbers into the regions where it is desired to liberate ionization energy; a simple illustration would be the injection of a soluble, nontoxic compound of boron, lithium, gadolinium, or gold into a superficial cancer, followed by bombardment with slow neutrons. Three isotopes, 10B, 155Gd, and 157Gd, are the ones that are most studied in NCT [6]. At the present, nuclear reactors are the only source of nuclear beams with sufficient intensity for NCT use, and there are a limited number of nuclear reactors that produce high quality neutron beams that can be used in medical treatment [7]. Accelerator-based neutron sources produce neutrons when a charged particle, usually a proton, strikes a suitable target [8].

Boron neutron capture therapy Principles of boron neutron capture therapy It is generally accepted that boron neutron capture therapy (BNCT) is a useful binary cancer treatment, in which the delivery agents containing 10B are selectively transported into tumor cells and then irradiated with thermal neutrons of appropriate energy. As detailed in Equation 1, the 10B nucleus adsorbs a neutron to form an excited 11B nucleus that decays emitting α-particle (4He2+) and 7Li3+ ion with high kinetic energy. The linear energy transfer of these heavily charged particles has a range of approximately one cell diameter (5–9 µm) [9], which confines radiation damage to the cell from which they arise, hence minimizing cytotoxic effects on the surrounding tissue. 10

B + 1n → [ 11 B] → 4 He 2+ (α ) + 7 Li 3+ + 2.31 MeV.

(1)

Advantages of BNCT therapy include: (i) Boron-10 has a nuclear capture cross section of 3838 barns (1 barn = 1.0 × 10–24 cm2), which is more than three orders of magnitude higher than those of other nuclei commonly found in living tissue; (ii) unlike other natural radioactive elements used in radiotherapy [10], both the isotopes of boron and the one (10B) employed in BNCT treatment are nonradioactive; (iii) due to its high electrophilicity, boron can be easily incorporated into compounds containing a hydrolytically stable linkage [11]. In theory, BNCT treatment may cause only a minimal damage to the boron-free region, provided that 10 the B atoms are delivered to a targeted region with high selectivity and dosed with a sizeable neutron flux. However, under the neutron irradiation, damage caused by the reactions within normal tissue by nitrogen and hydrogen needs to be considered in order to define the dose limiting toxicity. For BNCT to be effective, the boron concentration is generally estimated to be 109 10B atoms (natural abundance 19.9 %) per cell, or approximately 35 µg 10B/g of tumor tissue [12]. To date, it remains a big challenge to selectively deliver the 10B agents into a tumor cell and reach the required high 10B concentration. Under these conditions, it has been estimated that approximately 85 % of the radiation damage arises from the neutron capture reaction. To avoid unnecessary damage to healthy tissue in the path of the neutron beam, the surrounding tissues should contain < 5 µg of 10B/g of tissue. Principally, BNCT is employed to treat brain tumors because the innovative technology maximizes the therapeutic effect in the tumor, while minimizing neurotoxicity in adjacent brain parenchyma [13]. Very recent reports demonstrate that BNCT may also be effective in treating other cancers, such as head and neck tumors [14]. To conduct a successful BNCT treatment, it is crucial to harvest both satisfied neutron flux and boron concentration in tumors. To meet the requirement of boron concentration, researchers have examined both small- and macro-molecular-based boron agents in the recent past and over a decade or two [15–18]. Unfortunately, none of these agents have been examined in clinical trials owing to their low selectivity and/or

S. Gao et al.: Neutron capture therapy for cancer treatment 125

high toxicity and, of course, due to restrictions imposed by federal food & drug administration (FDA). To date, the small molecules, Na2B12H11SH (BSH) and boronophenylalanine (BPA) remained the only two clinically used BNCT agents. Nevertheless, the clinical results from these two compounds are not universally attractive because of their low tumor-to-normal brain tissue and tumor-to-blood 10B ratios [19–23]. Nanotechnology has been highlighted to be of great interest in various research areas. Currently, advanced nanoscaled materials are well developed with many pharmaceutical applications, for example, to act as a drug carrier [24–26]. In BNCT, in comparison with the classical small agents containing less boron atoms, highly boron-enriched nanocomposites allow the selective delivery of the required amounts of boron to tumors. Therefore, various nanoscaled boron-enriched delivery agents have been synthesized and explored as boron carriers [27–31]. Research in this specific area is growing fast.

Carbon nanotubes Carbon nanotubes (CNTs), discovered by Sumio Ijima in 1991 [32], are currently attracting wide attention both in academia and industry because of their unique properties, such as nanoscaled size, cylindrical arrangement of carbon atoms, low mass density, high thermal stability, excellent conductivity, superb mechanical properties and their potential applications in electronics and medicine [33, 34]. It is well recognized that there are two major types of CNTs: single-walled CNTs (SWCNTs) and multi-walled CNTs, which differ according to the number of layers of graphene sheet that encapsulate the tubes [35]. The stability and flexibility of CNTs are likely to prolong the circulation time and the bioavailability of these macromolecules, thus enabling highly effective gene and drug therapies. We have reported the first BNCT application of the nido-carboranes-appended water-soluble SWCNTs (Fig. 1) [36]. The nanocomposites provided a favorable tumor-to-blood ratio of > 3:1 and a boron concentration of 21.5 µg/g of tumor within the 48-h period after administration. Furthermore, it was observed that retention in tumor tissue was higher than in the blood and other tissues [36]. Similar to other CNT-based drug carriers, it is crucial for CNT-based BNCT delivery agents to improve their water solubility and biocompatibility.

Boron and boron nitride nanotubes Another suggested nanomaterial for use as a BNCT agent is the boron nanotube (BNT). The first successful synthesis of a single-wall boron nanotube was achieved by the reaction of BCl3 and H2 over an Mg-MCM-41

Fig. 1 Synthesis of single-wall carbon nanotube-supported nido-carboranes. Reproduced from Ref. [36] with permission of American Chemical Society.


catalyst [37]. The nanotubes had diameters of ∼3 nm and lengths of ∼16 nm. Unfortunately, the materials were quite sensitive to high-energy electron beams and hence detailed structural characteristics could not be obtained. However, if the nanotubes could be functionalized to make them water soluble, then such nanostructured materials should prove to be powerful BNCT carriers. In contrast to boron nanotubes, boron-nitride nanotubes (BNNTs) have been demonstrated to be useful drug delivery agents. Boron-nitride is isoelectronic with carbon; thus, BNNTs are isosteres of CNTs. In comparison to CNTs, BNNTs have been shown to be nontoxic to HEK293 cells [38] and can be functionalized to promote water solubility. A number of methods for functionalizing BNNTs includes interacting them noncovalently with glycodendrimers [38], coating them with polyethyleneimine (PEI) [39] or poly-l-lysine (PLL), or reacting with substituted quinuclidine bases [40]. The PLL coated BNNTs could be further reacted with folic acid to give the foliate conjugated nanomaterial F-PLL-BBNT. In vitro studies showed that the F-PLLBNNT bioconjugant selectively localized in human glioblastoma multiforme (GBM) T98G cells [41]. Ciofani and co-workers reported that transferrin was successfully grafted with BNNTs as represented in Fig. 2. The nanocomposites demonstrated enhanced and targeted cellular uptake of BNNTs on primary human endothelia cells [42]. Considering the transferrin receptor is highly expressed by brain capillaries to mediate the delivery of iron to the brain, the transferrin–BNNT delivery agent is expected to access the brain via the blood–brain barrier (BBB). Although boron nanotubes have the potential to be the ideal BNCT agents, there remain many issues that need to be resolved before these materials can be applied to drug delivery. The major challenges are in the largescale fabrication of boron nanotubes and in developing strategies to make water-soluble boron nanotubes.

Liposome-based BNCT agents Liposomes are small, spherical vesicles composed of membranes of phospholipids. The phospholipids are molecules having a hydrophilic head and a hydrophobic tail. Cell membranes are composed of such molecules arranged in two layers. When these membranes are disrupted, they can reassemble as extremely small spheres, usually as bilayers (liposomes). Liposomes have the potential of delivering large amounts of boron to cancer cells [28]. In addition, modification of the liposome surface by PEGylation or attachment of antibodies or receptor groups can enhance the delivery of therapeutic molecules. Another, similar, vesicle is the low-density lipoprotein (LDL), which is a major carrier of cholesterol. Cancer cells avidly absorb LDL as a source of cholesterol for their rapidly dividing cells. The LDL can be isolated and their cholesterol core replaced by hydrophobic carboranes [43]. In vitro studies of hamster

Fig. 2 Transferrin-grafted boron nitride nanotube. Reproduced from Ref. [42] with permission of Elsevier B.V. All rights reserved.


V-79 cancer cells have shown that such boronated LDLs resulted in intercellular concentrations of ∼240 µg 10 B/cell, which is about 10 times the amount needed for effective BNCT [43]. The use of drug laden vesicles, such as liposomes or LDLs, also take advantage of a general phenomenon of the enhanced permeability and retention (EPR) effect [44]. Tumor cells have an increased vascular permeability and a decrease in their lymphatic drainage system, which leads to the passive accumulation of macromolecular drugs in these neoplastic cells. The macromolecules may also contain groups that are preferentially taken up by cancer cells. For example, the presence of folate ions on the surface of boron containing liposomes greatly enhances the boron uptake in human KB squamous epithelial cancer cells, which have overexpressed folate acceptors [45]. Other examples are the reconstituted LDLs, which still retain their ability to bond to LDL specific sites on the tumor cells. These liposomes and modified LDLs have the ability to deliver massive amounts of 10B to cancer cells and have been termed as “supertankers” for boron delivery [46].

Magnetic nanoparticles-based BNCT carriers One of the major problems in any type of cancer chemotherapy is that of directing the drug to the tumor and avoiding healthy tissue. Since all chemotherapeutic drugs are by their nature cytotoxic, the localization of these drugs in the vicinity of the tumor could result in the use of lower drug concentrations. This can be done by attaching the drug to a biomolecule that is overused in the malignant cell or to some receptor molecule that is overexpressed in the cancer cells. Another potential way to increase the efficacy of a cancer drug is to physically direct it to the tumor by some external means. This is the basic approach in magnetically targeted therapy. In this approach, the drug of choice is attached to a biocompatible magnetic nanoparticle carrier, usually in the form of a ferrofluid, and is injected into the patient via the circulatory system. When these particles enter the bloodstream, external, high-gradient magnetic fields can be used to concentrate the drug at a specific target site within the body. Once the drug/carrier is correctly concentrated, the drug can be released, either via enzymatic activity or changes in physiological conditions, and be taken up by the tumor cells [47]. The advantage of this methodology is that decreased amounts of cytotoxic drugs would be required, thereby decreasing unwanted side effects. Studies showed that particles as large as 1–2 µm could be concentrated at the site of intracerebral rat glioma-2 (RG-2) tumors; a later study demonstrated that 10–20 nm magnetic particles were even more effective in targeting these tumors in rats [48]. Studies of magnetic targeting in humans demonstrated that the infusion of ferrofluids was well tolerated in most patients, and the ferrofluid could be successfully directed to advanced sarcomas without associated organ toxicity. Therefore, application of this technique can be considered appropriate vectors for the use of BNCT treatment. Recently, we have successfully encapsulated magnetic nanocomposites with a high load of carborane cages as part of a preliminary study of their biodistrubutions [49]. In this work, commercially available MNPs of iron oxides, covered by starch, have been enriched with the carborane cages, 1-R-2-butyl-ortho-C2B10H10 (R = Me, 3; Ph, 4), by catalytic azide–alkyne cycloaddition reactions (Fig. 3) [49]. Boron concentrations in tissue have been examined and the results are shown in Fig. 4a and b [49]. It was found that boron concentrations at different time intervals in the tumor are < 14.7 µg/g of tumor, with a slow elimination after 30 h in the absence of an external magnetic field. However, as Fig. 4b demonstrates, in the presence of an external magnetic field, the boron concentration in the tumor reached to a high value of 51.4 µg/g of tumor with tumor/normal tissue ratios of approximately 10:1. According to the transmission electron microscopic (TEM) images (Fig. 5) [49], the entrapped magnetic nanocomposites aggregated inside the tumor. The exact mechanism of the accumulation of magnetic nanocomposite carriers in tumor cells has not yet been determined. Compared with the results, without the external magnetic field, it is apparent that introduction of an external magnetic field plays a key role in the enhanced accumulation of approximately a three-fold increase in nanoparticle concentrations within the tumor. In this regard, it should be pointed out that even the aggregated boron nanoparticles should be therapeutically effective for BNCT. These preliminary results provide new hopes for successful neutron capture therapy and the useful combination of the drugs with BNCT/MRI/thermotherapy characteristics.


Fig. 3 Synthesis of encapsulated magnetic nanocomposites. Reproduced from Ref. [49] with permission of Zhu et al.

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Fig. 4 Boron concentration distribution in tissues using compound 3. (a) Without external magnetic field and (b) with external magnetic field. Reproduced from Ref. [49] with permission of Zhu et al.

Fig. 5 Transmission electron microscopic image representing the magnetic cores of compound 3 inside tumor cells. Reproduced from Ref. [49] with permission of Zhu et al.

Other boron-enriched nanoparticles Other boron containing nanoparticles, derived from boron carbides [50, 51], block-copolymers [52, 53], boron powder [54] and borosilicates [55], have also been reported. Commercially available boron carbide has been


successfully functionalized with lissamine and the transacting transcriptional activator peptide, the resulting nanocomposites ( < 100 nm) can be translocated into B16 F10 malignant melanoma cells in a high amount of 1 wt% [50]. The particles have been reported to show significant proliferative inhibition both for particle-loaded and unloaded closely neighboring cells after neutron irradiation [50]. The functionalized boron carbide nanoparticles also show positive effects to the in vivo growth inhibition of an aggressive solid tumor, B16-OVA melanoma, by neutron capture [51]. However, no information is available regarding in vivo selectivity of this type of delivery agent. Polymer-based boron-containing nanoparticles were prepared by radical copolymerization of acetalpoly(ethyleneglycol)-block-poly(lactide)-methacrylate with 4-vinylbenzyl substituted closo-carborane (Fig. 6) [52, 53]. Compared with particles obtained from self-assembly (noncross-linked) rather than copolymerization, the particles from copolymerization of 1,2-bis(4-vinylbenzyl)-closo-carboranes demonstrated the following advantages [52]: improved stability in the presence of serum proteins without notable leakage in 50 h period; extended blood circulation time and increased tumor accumulation of up to 5.4 % injection dose/g. Similar results are reported from the same group for particles produced from self-assembly and copolymerization of mono-4-vinylbenzyl-substituted closo-carborane [53]. More straightforward methods of using commercially available elemental boron powder to prepare boron nanoparticles have been reported [54]. After milling and dopamine coating, the boron nanoparticles, with a size of approximately 40 nm, were prepared. The particles did not demonstrate toxicity to murine macrophage cells as claimed [54]. Borosilicate nanoparticles with a size range of between 100 and 200 nm were prepared by milling a xerogel of 2SiO2–B2O3 [55]. After functionalization with folic acid, the resulting particles demonstrated increased incorporation in the tumor cells and hemocompatibility [55].

Gadolinium neutron capture therapy (GdNCT) Background In contrast to boron, Gd3+-containing compounds, owing to their paramagnetic character, are widely used as contrast agents for magnetic resonance imaging (MRI), which is a powerful noninvasive imaging technique for clinical diagnosis [56–58]. The strongly paramagnetic Gd3+ ion has seven unpaired electrons (electron configuration [Xe]4f7), corresponding to a magnetic moment of 7.94 Bohr magnetons. Except for the noble gas nuclide 135Xe, gadolinium is the element with the highest cross-sectional value for thermal neutrons (2.55 × 105 and 6.10 × 104 barns for 157Gd and 155Gd, respectively) making it also the most interesting candidate for neutron capture therapy (NCT) [9, 31]. 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 (IC) electrons, γ-rays and X-rays after the capture of a single thermal neutron [31, 59–61]. The replacement of 10B by 155Gd or 157Gd isotope is expected to yield an improved effect since the latter exhibit a higher neutron capture cross-section (66 and 16 times higher for 157Gd and 155Gd, respectively). However, it is not really possible to compare the therapeutic efficiency of 10B and 155Gd or 157Gd based only on their neutron capture cross-sections because their mode of action resulting from neutron capture is

Fig. 6 Preparation of carborane-containing polymer nanoparticles. Reproduced from Ref. [52] with permission of Kluwer Academic Publishers.


different [9, 31, 62]. Neutron capture by 10B induces the fission of the boron nuclide yielding the 7Li isotope, an α-particle and γ-rays (photons), whereas no fission occurs in the case of 155Gd, 157Gd isotopes, whose interaction with a thermal neutron beam leads to the emission of γ-rays and Auger electrons. The Auger electrons and α-particles both exert a cytotoxic effect, but at long range for the latter and at short range for the former [9, 31, 62].

The problems and how to resolve it As the thermal neutron cross section of 157Gd is 66 times greater than that of 10B, a common NCT agent, and the γ photons produced have long flight ranges, there ought to be a greater chance of extensive tumor destruction with gadolinium compared to boron, especially if nanoparticles with high concentration of gadolinium, such as Gd2O3 can be used. The gadolinium cation is itself, to some extent, toxic. When used in a therapeutical context, it must be administered in non-toxic chemical form [63]. Non-toxicity, water-solubility, biocompatibility, and tissue-specific targeting are the requirements that must be met. This can be achieved by biomolecular functionalization of the particles. Different approaches have been suggested for such functionalizations (Fig. 7) [64, 65]. Being regarded as toxic to some extent, the in vivo use of gadolinium has to be limited to low doses. Systems where some of the Gd3+ ions have been substituted for the essentially non-toxic Fe3+ (with five unpaired electrons) are worth studying. A very important aspect is that if functionalized nanoparticles containing toxic elements are to be used as contrast agents in humans, the size of the particle–molecule complexes must not exceed a certain critical diameter in order to be safely excreted via the kidneys. Gd-doped iron oxide nanoparticles were developed for use in tumor therapy via magnetic fluid hyperthermia (MFH) [66]. GdFeO3 belongs to the perovskite rare-earth orthoferrites and can be used as magnetic and magneto-optical materials. These materials show promising relaxivity properties and a great potential to be a contrast agent for MRI [67–69].

Combinations of different types of functional nanomaterials Nanomaterials for cancer diagnosis and therapy consist of a number of components, including metal, inorganic nonmetal and biodegradable polymer nanocomposites. Clever combinations of different types of functional nanostructured materials will enable the development of multifunctional nanomedical platforms for multimodal imaging or simultaneous diagnosis and therapy [70]. The design of nanoparticles that combine several properties is an elaborate process that requires multi-steps of different kind [71], such as the depositing of metal layers onto a supporting nanoparticle core [72], modifying the biocompatible polymer to stabilize the nanoparticles, etc [73].

-Biocompatible polymeric backbone -Fluorescent tag -Reactive side-chain -Reactive end-group for attachment -Gadolinium metal-organic framework nanoparticle Magnetic resonance imaging -Therapeutic agent for treatment of disease -Targeting ligand for biomolecular recognition

Fig. 7 Polymer-modified Gd metal-organic framework nanoparticles as a nanomedicine construct for targeted imaging and treatment of cancer. Reproduced from Ref. [64] with permission of American Chemical Society.


Magnetic nanoparticles (MNPs) 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 [74, 75]. Fe3O4 has been considered to be an ideal candidate for biological applications due to its special magnetic properties, lack of toxicity, and good biocompatibility [76, 77]. 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-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 [78, 79]. The nanocomposites of these materials can carry an active agent and be guided to the target site inside the body, facilitating therapeutic efficiency and minimizing damage to normal tissue due to drug toxicity. We have developed a route consisting of encapsulating preformed Gd and Fe3O4 nanoparticles into silica. The aim was to obtain GdFeO3/Fe3O4/SiO2 core/shell nanoparticles, 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 [80]. The magnetization curve measured at room temperature for the GdFeO3/Fe3O4/SiO2 nanocomposites shows a small hysteresis loop suggesting that the nanocomposites have ferromagnetic behavior (Fig. 8). The magnetization saturation value for GdFeO3/Fe3O4/SiO2 is about 48.7 emug–1. The magnetic separation ability of the sample was tested in water by placing a magnet near the glass bottle containing a suspension of the nanocomposites. The black particles were attracted towards the magnet (Fig. 8, inset). This property will provide an easy and efficient way to separate the 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 [81].

Summary and outlook 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 cyto-

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Fig. 8 Measured magnetic hysteresis loops for GdFeO3/Fe3O4/SiO2 nanocomposites. Inset: photograph of magnetic targeting under an external magnet. Reproduced from Ref. [80] with permission of ChemPubSoc Europe (Wiley-VCH).


toxicity 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. In recent years, much efforts have been directed toward developing nanomaterials-based BNCT and GdNCT agents; to date, a majority of the studies has proved reasonably promising. Conversely, further in vivo studies and clinical trails are needed to establish them as appropriate boron and gadolinium carriers; this is especially so with the relatively novel boron nanotubes, gadolinium oxide nanoparticles and magnetic nanoparticles. More advanced forms of carbon nanostructures, boron nanotubes, boron nitride nanotubes, boron nanosheets and gadolinium compounds can be anticipated as the interest in their syntheses and future applications increases. Acknowledgments: This work was supported by the National Science Foundation (CHE-0906179), the Shandong Province Higher Educational Science and Technology Program (Grant No. J12LA01) and the Hundred Talents Program of the Chinese Academy of Sciences that supported the Visiting Professorship for Senior International Scientists.

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