Preparation of stable dispersion of barium titanate nanoparticles: Potential applications in biomedicine

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Abstract

Nanoscale structures and materials have been explored in many biological applications because of their extraordinary novel properties. Here we propose a study of cellular interactions with barium titanate nanoparticles, an interesting ceramic material that has received a lot of interest in the nanotechnology research, but without any attention about its biological potential. We introduced for the first time an efficient method for the preparation of stable aqueous dispersions of barium titanate nanoparticles, characterized with FIB, TEM and AFM imaging, light scattering, Z-potential and UV/vis analysis. Finally, we presented a systematic study of short-term cytotoxicity of the prepared dispersion based both on quantitative (metabolism, proliferation) and qualitative (apoptosis, viability, differentiation) assays.

Introduction

Ceramic materials based on perovskite-like oxides are of intense interest because of their applications in electrical and electronic devices. Due to its high dielectric constant, barium titanate (BaTiO3, BT) is probably one of the most studied compounds of this family and still represents the basis for the preparation of multilayer ceramic capacitors and thermistors with positive temperature coefficient of resistivity [1], [2]. No evidence of bio-applications of this nanomaterial has been found in the literature, so we first proposed a preliminary investigation of cytocompatibility and cell interactions with BT nanoparticles (NPs).

Nanoscale structures and materials (e.g., NPs, nanowires, nanofibers, and nanotubes) have been explored in many biological applications (e.g., biosensing, biological separation, molecular imaging, and/or anticancer therapy) because of their novel properties [3]. In particular, their high volume/surface ratio, surface tailorability, improved solubility, and multifunctionality show a high potential for nanomedicine. Moreover, the intrinsic optical, magnetic, and biological properties owned by nanomaterials can offer remarkable opportunities of interaction with complex biological processes for biomedical applications. It is thus necessary not only to understand the impacts of the presence of nanomaterials inside the cells, but also to extend biological investigations to many different cell types, eventually in vivo, in order to highlight different biological responses following the treatment with nanoparticulate systems. In fact, distinct cell types treated in vitro with nanomaterials may respond with different dose sensitivity. Nanovector platforms are particularly complex systems that can arise opposite phenomena up to the analyzed in vitro model [4]. The first step towards the application of a new nanomaterial in the medical field is its stabilization in an environment suitable for biological testing, and therefore the dispersion of the NPs in appropriate aqueous solutions.

The dispersion of BaTiO3 ceramic powders in either an aqueous or a non-aqueous medium has received great attention being an important subject of many publications [5], [6], [7], [8]. Recent attention [9], [10], [11], [12] was focused on the development of aqueous-based casting systems, because of their low cost and reduced environmental impact. Unfortunately, it has been reported [13], [14], [15] that BT is not thermodynamically stable in acidic aqueous solutions. Ba2+ ions are leached out from the powder, resulting in a titanium-enriched surface layer. It is also found that the amount of Ba2+ leached increases with decreasing pH [16], [17]. This phenomenon has been shown to increase the pH of the resulting suspension with changes in the surface chemistry of BaTiO3. The reported iso-electric points (IEP) of commercial BaTiO3 in aqueous suspension vary considerably from pH 4 to 10 [18], [19], depending upon the Ba/Ti ratio, processing history and measurement equipment. This renders the effects of pH on the dissolution and dispersion behavior of BaTiO3 powders in aqueous solution still unclear.

It is thereafter fundamental to find an appropriate solution that (i) stabilizes the NPs leading to the obtainment of homogeneous dispersions, and (ii) allows the protection of the NP surface against ions leaching, thanks to both a physical protection (e.g., a wrapping of the NPs) and a stable not acidic pH (that is also amenable for biological applications).

BaTiO3 water systems have been extensively investigated [20], [21], [22]. Aqueous BT suspensions can be stabilized by electrostatic and/or steric mechanisms. Polyelectrolyte species, which ionize in the solution adsorbing onto the surface of BT particles, have been found to combine these mechanisms and promote dispersion [23]. In the last decade, many studies focusing on the dispersion and stabilization of aqueous BT suspensions have been reported, and various polymers and polyelectrolytes as dispersant have been tested [24], [25]. Colloidal stabilization of BT suspensions by the ammonium salt of polyacrylic acid (PAANH4) [26] and of polymethacrylic acid (PMAANH4) [27] has been for example investigated by Jean and Wang, while Hu et al. reported on BaTiO3 aqueous suspensions based on PVA-b-COOH [28]; the colloidal stability of nanosized BT aqueous suspensions based on ammonium polyacrylate (PAANH4) has been investigated by Shen et al. [29] and an analogue study using polyaspartic acid (PApA-Na) has been carried out by Wang et al. [30].

Basing on our positive results on other NPs [31], we have prepared BT NP dispersion following a non-covalent wrapping with poly-l-lysine. In this paper we describe the preparation and the characterization of the obtained dispersion, and we propose for the first time a biological investigation of BT NPs. We found that poly-l-lysine coated BT NPs were well tolerated by rat cardiomyocytes up to a concentration of 5 μg/ml. Interestingly, after labeling the BT NPs with a fluorescent protein, we noticed that not only the BT NPs were strongly internalized by the cells, but they also acted as effective nanocarriers, dramatically improving the cellular up-take of the protein.

Section snippets

Preparation and characterization of BT NPs dispersion

BT NPs were purchased by Nanostructured & Amorphous Materials, Inc. (Houston, TX). Details of sample purity and composition, as provided by the supplier, include: yield 99%; BaO/TiO2: 0.999–1.001; purity: 99.9%; APS: 100 nm; SSA: 10–11 m2/g; color: white; morphology: spherical; true density: 5.85 g/cm3. After purchasing, BT NP samples were further analyzed in order to show additional characterization.

Energy-dispersive X-ray (EDS) microanalysis was performed on BT NP samples using a scanning

Results and discussion

Fig. 1b shows a SEM image of the BT NPs as purchased form the supplier: strong aggregation in macro-clusters is evident even at high magnification. EDS analysis (Fig. 1a) performed on the samples confirmed the data provided by the supplier: no significant impurities were detected by the microanalysis, with a quantitative composition as following: Ba ∼60%, Ti ∼18% and O ∼22%.

From XRD analysis, BT NPs resulted to have a perovskite-like crystallographic structure. Cubic (and not tetragonal) phase

Conclusion

Despite the great interest that ceramic materials based on perovskite-like oxides have attracted in the nanotechnology research, no evidence of biological applications and investigations can be found in the literature. Here we proposed an efficient method to obtain stable BT NP dispersion, based on a non-covalent wrapping with poly-l-lysine, that allowed the BT NPs to be stabilized in an aqueous environment.

After a characterization of BT NP dispersions in terms of TEM, FIB and AFM imaging,

Acknowledgments

Authors gratefully acknowledge Mr. Carlo Filippeschi (Scuola Superiore Sant’Anna, Pisa, Italy) for his assistance for the FIB and AFM imaging, Ms. Cristina Riggio (Scuola Superiore Sant’Anna, Pisa, Italy) for her kind assistance for the spectrophometric analysis, Dr. Matilde Masini (Dept. of Experimental Pathology BMIE, University of Pisa, Pisa, Italy) for TEM technical support, and, finally, Mr. Piero Narducci (Dept. of Chemical Engineering, University of Pisa, Pisa, Italy) for his valuable

References (38)

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