Synthesis, X-ray Opacity, and Biological Compatibility of Ultra-High Payload Elemental Bismuth Nanoparticle X-ray Contrast Agents

Inorganic nanoscale X-ray contrast agents (XCAs) offer many potential advantages over currently used intravascular molecular contrast agents, including longer circulation and retention times, lower administration volumes, and greater potential for site directed imaging. Elemental bismuth nanoparticles (BiNPs) are particularly attractive candidate XCAs due to the low cost, the high atomic number and high density of bismuth, and the likelihood that BiNPs will oxidatively decompose to biocompatible bismuth(III) ions at controlled rates for renal excretion. Herein we describe the synthesis of ultrahigh payload BiNPs in 1,2-propanediol using a borane reducing agent and glucose as a biocompatible surface stabilizer. Both synthetic solvent (1,2-propanediol) and surfactant (glucose) are evident on the BiNP surfaces when analyzed by ¹H NMR and FT-IR spectroscopies. These particles contain ∼6 million Bi atoms per NP and have large inorganic cores (74 nm by TEM) compared to their hydrodynamic size (86 nm by DLS). Thus, the dense BiNP core constitutes the majority (∼60%) of each particle's volume, a necessary property to realize the full potential of nanoscale XCAs. Using quantitative computed tomography in phantom and in vitro imaging studies, we demonstrate that these BiNPs have greater X-ray opacity than clinical small molecule iodinated contrast agents at the same concentrations. We furthermore demonstrate a favorable biocompatibility profile for these BiNPs in vitro. Altogether, these studies indicate that these ultrahigh payload BiNPs, synthesized from known biocompatible components, have promising physical and cytotoxicological properties for use as XCAs.