Polymer-Stabilized Lanthanide Fluoride Nanoparticle Aggregates as Contrast Agents for Magnetic Resonance Imaging and Computed Tomography

Abstract

Poly(acrylic acid) consisting of 25 monomer units (PAA25) was used to stabilize nanoparticle aggregates (NPAs) consisting of either NaGdF4 or 50/50 mixtures of GdF3 and CeF3. The resulting polymer-stabilized nanoparticle aggregates (NPAs) were developed and tested for their application as contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT). The PAA25-stabilized NPAs exhibit low polydispersity and are colloidally stable at concentrations of 40 mg/mL, while their sizes can be be controlled by choosing a specific ratio of Gd3+ to Ce3+. Scanning transmission electron microscopy (STEM) reveals that NaGdF4 NPAs possess an average diameter of 400 nm. High-resolution STEM and powder X-ray diffraction (XRD) both show that these NPAs consist of a stable aggregate of smaller NPs, whose diameters are 20−22 nm. PAA25-stabilized NPAs consisting of a 50/50 mixture of GdF3 and CeF3 possess an average diameter of 70 nm, while the fundamental unit size is estimated to be 10−12 nm in diameter. The PAA25-stabilized GdF3/CeF3 NPAs possess mass relaxivities of 40 ± 2 and 30 ± 2 s−1 (mg/mL)−1 at 1.5 T and 3.0 T, respectively. Their effectiveness as contrast agents for CT X-ray imaging at various X-ray energies was also tested and compared to that of equivalent mass concentrations of Gd3+-diethylene triamine pentaacetic acid (Gd3+-DTPA) and iopromide. Gd-based NPAs exhibit superior CT contrast to equal-mass concentrations of either iopromide or Gd3+-DTPA below 30 keV and above 50 keV. Finally, PAA25 was functionalized by folic acid to explore targeted imaging. Confocal microscopy revealed that, by functionalizing the PAA25-stabilized NaGdF4:Tb3+ NPAs with ∼0.8 folates per polymer, binding and endocytosis occurred in SK-BR-3 human breast cancer cells. The utility of the PAA25-stabilized GdF3/CeF3 NPAs for MRI is demonstrated in rat perfusion MRI experiments, where T1-weighted MRI images of equivalent concentrations of either Gd3+-DTPA or the above NPAs are directly compared. The high relaxivities provide an opportunity to conduct perfusion MRI experiments with significantly lower concentrations than those needed for current commercial agents.