Comparison of Methods for Surface Modification of Barium Titanate Nanoparticles for Aqueous Dispersibility: Toward Biomedical Utilization of Perovskite Oxides

Colloidal perovskite barium titanate (BaTiO₃, or BT) nanoparticles (NPs), conventionally used for applications in electronics, can also be considered for their potential as biocompatible computed tomography (CT) contrast agents. NPs of BT produced by traditional solid-state methods tend to have broad size distributions and poor dispersibility in aqueous media. Furthermore, uncoated BT NPs can be cytotoxic because of leaching of the heavy metal ion, Ba²⁺. Here, we present and compare three approaches for surface modification of BT NPs (8 nm) synthesized by the gel collection method to improve their aqueous stability and dispersibility. The first approach produced citrate-capped BT NPs that exhibited extremely high aqueous dispersibility (up to 50 mg/mL) and a small hydrodynamic size (11 nm). Although the high dispersibility was found to be pH-dependent, such aqueous stability sufficiently enabled a feasibility analysis of BT NPs as CT contrast agents. The second approach, a core/shell design, aimed to encapsulate BT nanoaggregates with a silica layer using a modified Stöber method. A cluster of 7–20 NPs coated with a thick layer (20–100 nm) of SiO₂ was routinely observed, producing larger NPs in the 100–200 nm range. A third approach was developed using a reverse-microemulsion method to encapsulate a single BT core within a thin (10 nm) silica layer, with an overall particle size of 29 nm. The −OH groups on the silica layer readily enabled surface PEGylation, allowing the NPs to remain highly stable in saline solutions. We report that the silica-coated BT NPs in both methods exhibited a low level of Ba²⁺ leaching (≤3% of total barium in NPs) in phosphate-buffered saline for 48 h compared to the unmodified BT NPs (14.4%).