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

Poly(acrylic acid) consisting of 25 monomer units (PAA 25 ) was used to stabilize nanoparticle aggregates (NPAs) consisting of either NaGdF 4 or 50/50 mixtures of GdF 3 and CeF 3 . 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 PAA 25 -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 Gd 3+ to Ce 3+ . Scanning transmission electron microscopy (STEM) reveals that NaGdF 4 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. PAA 25 -stabilized NPAs consisting of a 50/50 mixture of GdF 3 and CeF 3 possess an average diameter of 70 nm, while the fundamental unit size is estimated to be 10−12 nm in diameter. The PAA 25 -stabilized GdF 3 /CeF 3 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 Gd 3+ -diethylene triamine pentaacetic acid (Gd 3+ -DTPA) and iopromide. Gd-based NPAs exhibit superior CT contrast to equal-mass concentrations of either iopromide or Gd 3+ -DTPA below 30 keV and above 50 keV. Finally, PAA 25 was functionalized by folic acid to explore targeted imaging. Confocal microscopy revealed that, by functionalizing the PAA 25 -stabilized NaGdF 4:Tb 3+ NPAs with ∼0.8 folates per polymer, binding and endocytosis occurred in SK-BR-3 human breast cancer cells. The utility of the PAA 25 -stabilized GdF 3 /CeF 3 NPAs for MRI is demonstrated in rat perfusion MRI experiments, where T 1 -weighted MRI images of equivalent concentrations of either Gd 3+ -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.