Abstract
Vascular research is largely performed in rodents with the goal of developing treatments for human disease. Micro-computed tomography (micro-CT) provides non-destructive three-dimensional imaging that can be used to study the vasculature of rodents. However, to distinguish vasculature from other soft tissues, long-circulating contrast agents are required. In this study, we demonstrated that poly(ethylene glycol) (PEG)-coated gadolinium nanoparticles can be used as a vascular contrast agent in micro-CT. The coated particles could be lyophilized and then redispersed in an aqueous solution to achieve 100 mg/mL of gadolinium. After an intravenous injection of the contrast agent into mice, micro-CT scans showed blood pool contrast enhancements of at least 200 HU for 30 min. Imaging and quantitative analysis of gadolinium in tissues showed the presence of contrast agent in clearance organs including the liver and spleen and very low amounts in other organs. In vitro cell culture experiments, subcutaneous injections, and analysis of mouse body weight suggested that the agents exhibited low toxicity. Histological analysis of tissues 5 days after injection of the contrast agent showed cytotoxicity in the spleen, but no abnormalities were observed in the liver, lungs, kidneys, and bladder.
Highlights
Vascular research is largely performed in rodents with the goal of developing treatments for human disease
While suspending high concentrations of lanthanides in an aqueous environments is challenging, we have recently reported the successful synthesis of block copolymer assembly encapsulations of erbium nanoparticles containing 100 mg/mL of erbium, and demonstrated its utility as a vascular contrast agent when operating at 90 k Vp40
The particle diameters measured by dynamic light scattering (DLS) were in good agreement with those observed in the transmission electron microscopy (TEM) images (Fig. 2B–D)
Summary
Vascular research is largely performed in rodents with the goal of developing treatments for human disease. X-ray attenuating contrast agents are injected intravenously to distinguish the vasculature from surrounding soft tissues during a micro-CT scan, enabling visualization and quantitative tracking of blood vessels, including during studies of novel therapies for re-vascularization[10,11,12]. Apart from gold, which has higher attenuation than iodine across the entire energy spectrum, metal-based agents such as alkaline earth m etals[21] and transition m etals[32], have been reported or commercialized Another class of metals that is ideally suited for micro-CT are the lanthanides (e.g. gadolinium, erbium)[33], which have k edges (38–64 keV)[34] that coincide with the peaks of the x-ray energy distributions typically used in high-resolution in vivo micro-CT scanners (typically operating at below 100 kVp). The ideal position of the k-edges offers potential to increase contrast attenuation for single-energy micro-CT scans[33] and, more importantly, offers the opportunity to match the available x-ray spectrum and contrast agent in dual-energy micro-CT, which is used to distinguish contrast-enhanced vessels from inherently high-attenuating tissues (e.g. bone, calcifications)[35]
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