Ytterbium Nanoparticle Contrast Agents for Conventional and Spectral Photon-Counting CT and Their Applications for Hydrogel Imaging

Abstract

Significant work has been done to develop nanoparticle contrast agents for computed tomography (CT), with a focus on identifying safer and more effective formulations. Contrast agents for spectral photon-counting computed tomography (SPCCT), a fast-growing imaging modality derived from conventional CT, have also recently gained considerable attention. In this study, we explored the synthesis of ultrasmall ytterbium nanoparticles (YbNP) and demonstrated that, potentially, they can be used as conventional CT and SPCCT contrast agents. These nanoparticles were tested in vitro for their cytotoxicity and contrast-generating properties with a variety of imaging systems. When scanned with conventional CT and SPCCT at clinically relevant energies, YbNP are significantly more attenuating than gold nanoparticles (AuNP), the contrast agents that have been most well studied. Furthermore, YbNP were studied for their potential application for labeling and monitoring hydrogels. The presence of the YbNP payload in hydrogels allowed for hydrogel localization and tracking in vivo. Additionally, the in vivo imaging results revealed that YbNP generate higher contrast when compared to AuNP used as a label. In summary, this is the first research study to examine ultrasmall YbNP as conventional CT and SPCCT contrast agents, as well as using them in a hydrogel system to make it radiopaque. These findings underscore YbNP's utility as CT and SPCCT contrast agents, as well as their potential for tracking hydrogels in vivo.

Keywords: computed tomography; contrast agents; hydrogel; spectral photon-counting CT; ytterbium nanoparticles.

Figure 1.

YbNP synthesis and characterizations. (A) Schematic depiction of YbNP synthesis. (B) Schematic depiction of surface modification of water-soluble YbNP. (C) Transmission electron micrograph of YbNP. (D) Table summarizing the core diameter, hydrodynamic diameter, and surface potential values of YbNP. (E) Photograph of the Se–PCPP hydrogel loaded with 8 mg of YbNP.

Figure 2.

EDX spectra of (A) YbNP and (B) YbNP-loaded hydrogels. XRD spectra of (C) YbNP and (D) YbNP-loaded hydrogels.

Figure 3.

Effect of (A) YbNP and (B) YbNP-loaded hydrogels on cell viability after 8 h of incubation (mean ± SEM; n = 6).

Figure 4.

In vitro phantom imaging with CT. (A) Representative images acquired with a MILabs micro-CT at an energy of 55 kV. (B) X-ray attenuation changes versus concentration for YbNP and AuNP. (C) Comparison of attenuation rates of YbNP and AuNP when using the MILabs micro-CT. Error bars are standard deviations in all cases (mean ± SD; n = 9; **P < 0.01).

Figure 5.

In vitro phantom imaging with SPCCT. (A) Conventional equivalent CT image and ytterbium-specific K-edge image of YbNP acquired using an SPCCT scanner. (B) X-ray attenuation changes versus concentration for YbNP. (C) CNR of ytterbium at a range of concentrations from 0 to 10 mg mL⁻¹ (mean ± SD; n = 4).

Figure 6.

In vivo evaluation of contrast generation of YbNP and AuNP-loaded hydrogels. (A) Representative 2D CT images of the full body of a mouse in a coronal view. Insets represent enlarged images of injected YbNP-loaded hydrogels (blue) and AuNP-loaded hydrogels (yellow) on the left and right flanks, respectively. (B) Quantification of total CT attenuation arising from hydrogels. (C) Representative 3D volume-rendered CT images of a mouse injected with YbNP and AuNP-loaded hydrogels at different time points: preinjection, 5 min p.i., and 1-week p.i. YbNP-loaded hydrogels on the left flank are highlighted in blue, and AuNP-loaded hydrogels on the right flank are highlighted in yellow. (D) 3D reconstruction of the YbNP-loaded hydrogel based on CT images. The hydrogel was artificially colored based on intensity thresholding using the same window level and width as in (A). (E) Biodistribution of YbNP and AuNP in major tissues and organs, and carcass of injected mice 2 weeks after injections. Data is presented as percent injected dose (%ID) (mean ± SEM; n = 5; *P < 0.05; ****P < 0.001).