Boron nitride nanotubes decorated with magnetite nanoparticles for application as a multifunctional system in cancer treatment

Abstract

In this work, in addition to seeking to evaluate the potential of BNNT as a ceramic matrix for stabilizing magnetite nanoparticles, it was also investigated the performance of the nanocomposite BNNT-Fe₃ ${\mathrm{O}}_4$ as a multifunctional system to be applied both by magnetohyperthermia and for controlled drug release. The materials were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (MET), electron energy loss spectroscopy (EELS), Fourier transform infrared spectroscopy (FTIR), vibrant sample magnetometry (VSM) and Mössbauer spectroscopy. The results indicated an effective interaction of BNNT with the nanoparticles of magnetite and maghemite, showing a superparamagnetic behavior of the nanocomposite. Measurements of AC magnetic-field-induced heating properties of the obtained nanocomposite showed the potential of the BNNT-Fe₃O₄ sample to reach a temperature within the appropriate range for tumor cell death. The drug release test in the presence of an external magnetic field shows that the material can be activated by an alternating magnetic field provoking the vibration of the magnetic particles and the quick release of large quantities of drugs only in the region of interest. Therefore, the results confirm the system consisting of BNNT decorated with nanoparticles of magnetite (BNNT-Fe₃O₄) presented a multifunctional and promising character for applications related to cancer therapy, by magnetohyperthermia and chemotherapy

Introduction

Nanomaterials have enabled great scientific advances in several areas of knowledge, mainly in nanomedicine. These materials have contributed to the diagnosis and therapy of socially significant diseases, such as cancer, a disease that for decades has faced the challenge of seeking more effective therapy with fewer side effects. Among these nanomaterials, we highlight the boron nitride nanotubes (BNNT). An important historical reference about boron nitride nanotubes (BNNTs) synthesis is the work of Chopra and co-workers published in 1995 [1], and this discovery has opened new possibilities of applications in various areas of knowledge. Since then, different methods have been developed and improved in order to achieve BNNT with more quality, high-yield production and to greatly broadens the potential application of BNNTs [2], [3], [4]. BNNTs have excellent properties, such as high thermal stability, piezoelectricity, high mechanical resistance, and uniform band gap around 6.0 eV. In addition to these properties, BNNTs are characterized by high chemical stability [5]. However, since BNNTs have a hydrophobic surface due to typical sp² hybridized B–N bonds, they are incapable of forming stable hydrogen bonds with water molecules. Furthermore, the low dispersibility of BNNTs in most of the organic and inorganic solvents, combined with their chemical stability, has become a major issue to be explored, since it may impair their applicability [6].

Different materials have been combined with BNNT to find a wide range of potential applications such as magneto devices, microelectronic systems, chemical sensors, and bioapplication. Mirjam et al. [7] reported on the synthesis and characterization of nanocomposites based on semiconductor nanoparticles attached directly and noncovalently to boron nitride nanotubes. BNNTs have been decorated successfully with semiconducting nanoparticles such as PbSe, CdSe, and ZnO of various band gaps in a noncovalent fashion. Chunyi Zhi et al. [8] showed a study of SnO₂ coated on a BNNT surface which shows enhanced gas sensitivity and is worth using as effective gas sensors.

In nanomedicine, for example, the covalent and non-covalent modifications of the BNNT surface have opened interesting perspectives for the use of these nanomaterials in drug delivery and cell targeting [9]. Different approaches have been developed to render BNNT biocompatible and surface modifications were suggested to enhance their biological behavior and dispersibility using different materials. In recent studies of Mustafa et al. [10], BNNTs have been functionalized with DSPE-PEG-NH₂ to increase their colloidal stability and circulation time in the bloodstream, as well as to provide active sites on their surface for further functionalization with tumor-targeting agents. According to the authors, the materials are promising agents to evaluate them as drug carrying and targeting applications. Lisuzzo et al. [11] presented a review focused on the stabilization of nanotubular materials in solvent media, which is a key starting point for any application of nanotube-based formulations for pharmaceutical.

On the other hand, much attention has been also focused on magnetic nanoparticles, which can provide additional properties when associated with other materials [12]. The use of magnetic particles in biomedicine has expanded over the past decade due to its huge potential applications as contrast agents for magnetic resonance imaging (MRI), magnetic bio-separation, diagnosis, cell labeling, drug carriers, and magnetohyperthermia [13]. Among the magnetic nanomaterials, iron nanoparticles, such as magnetite, stand out due to their lower toxicity, low fabrication cost, high saturation magnetization and the possibility of the superparamagnetic behavior interesting for biomedical applications. The design of magnetic nanoparticles for applications in nanomedicine is not easily implemented since strategies for the protection of magnetic nanoparticles remain a challenge [14]. Non-surface-modified magnetic nanoparticles with a large surface-area-to-volume ratio tend to agglomerate and form large clusters, with the consequent loss of interesting characteristics. They can also rapidly biodegrade when directly exposed to biological systems [15].

Therefore, to overcome such limitations the physical andchemical stability is often obtained by a suitable combining magnetite nanoparticles with other materials, such as surface layers of polymers, silica, or BNNTs, which can be designed together preventing agglomeration, and consequently to obtain affinity to target molecules [16], [17], [18]. Thus, the association of the magnetite nanoparticles on the boron nitride nanotubes has the potential to widen the routes for biologicals applications. Magnetite presents an inverse spinel-type structure that enables it to provide characteristics such as low toxicity, biocompatibility, and high magnetization that besides conferring spontaneous magnetization provides important properties for bioapplications. However, these materials are very susceptible to environmental conditions and may oxidize from Fe${}^{+2}$ to Fe${}^{+3}$ [19]. Therefore, the combination of magnetite nanoparticles with boron nitride nanotubes, despite having been rarely reported, can be an interesting protection strategy. On the work of Huang et al. [20], an ethanol-thermal process was developed for in situ formation of dense and uniformly distributed Fe₃O₄ nanoparticles on the surfaces of multi-walled boron nitride nanotubes (BNNTs). According to them, these BNNT-based magnetic nanocomposites may find a wide range of potential in different technological applications including bioapplication.

In our previous work, Ferreira and co-works [13] incorporated magnetic particles into BNNTs to evaluate the behavior of HeLa tumor cells when subjected to a magnetic field, magnetohyperthermia. They observed good viability of cells treated with BNNT-Fe₃O₄ and confirmed the internalization capacity of these nanoparticles by the cells. The magnetohyperthemia assay demonstrated the potential of up-taken BNNT-Fe₃O₄ to trigger the cell death process in the tumorigenic lineage HeLa. This work was undertaken as a joint effort and was either particularly relevant to open future works with this innovative system. However, the iron content used in the final composition of the system was very high, which may limit its use in biological systems. Furthermore, studies involving the potential use of BNNT nanoparticles in the area of controlled release of drugs in synergism with the magnetohyperthermia are still incipient, and no works have actually addressed the use of BNNT/Fe₃O₄ nanocomposites as a multifunctional system on bioapplication focus. In this sense, the synthesis and bioapplications exploring the multifunctionality of BNNT-based materials still remain challenging, and studies to confirm their intrinsic properties to use as hyperthermia and drug delivery applications should continue to be researched.

In this context, this study was motivated by the promising potential of the BNNT-Fe₃O${}_4$ composite for different applications, because it is a relatively new material in the literature and the fact that BNNT is a material few yet been studied, especially when related to its possible applications. The work sought to evaluate the potential of BNNT as a ceramic matrix for the protection of magnetite nanoparticles, to avoid the problems related to its chemical instability, concomitantly, it sought to explore the potential of the nanocomposite in the controlled release of the drug methotrexate (MTX) and its use in treatment by magnetohyperthermia. The system has been shown to have a promising multifunctional character for applications related to cancer treatment. In this case, it was possible to think about the synergistic effects of magnetohyperthermia and controlled drug delivery for a nanocomposite system composed of the combination of Fe₃O₄ nanoparticles and BNNT. The nanocomposite indicated a slower drug release kinetics than that for pure BNNT-OH and, when in the presence of an external magnetic field, the targeted and local drug delivery controlled have shown promising to ensure that the drug can be released several times, beyond the capacity of reach temperatures satisfactory (42 °C to 45 °C) for the cancer cell death.