Assessment of candidate elements for development of spectral photon-counting CT specific contrast agents

Johoon Kim, Daniel Bar-Ness, Salim Si-Mohamed, Philippe Coulon, Ira Blevis, Philippe Douek, David P. Cormode
2018 Scientific Reports  
Spectral photon-counting computed tomography (SPCCT) is a rapidly emerging imaging modality that provides energy-dependent information on individual x-ray photons, leading to accurate material decomposition and simultaneous quantification of multiple contrast generating materials. Development of SPCCT-specific contrast agents is needed to overcome the issues with currently used iodinated contrast agents, such as difficulty in differentiation from calcified structures, and yield SPCCT's full
more » ... ise. In this study, the contrast generation of different elements is investigated using a prototype SPCCT scanner based on a modified clinical CT system and suitable elements for novel contrast agent development for SPCCT imaging are identified. Furthermore, nanoparticles were synthesized from tantalum as a proof of concept spectral photon-counting CT agent and tested for their in vitro cytotoxicity and contrast generation to provide insight into the feasibility of nanoparticle contrast agent development from these elements. We found that gadolinium, ytterbium and tantalum generate high contrast in spectral photon-counting CT imaging and may be suitable elements for contrast agent development for this modality. Our proof of concept results with tantalum-based nanoparticles underscore this conclusion due to their detectability with spectral photon-counting CT, as well as their biocompatibility. X-ray computed tomography (CT) is one of the most widely used imaging modalities in medicine due to its broad availability, low cost, high spatial resolution and fast image acquisition 1 . Spectral photon-counting CT (SPCCT) is a rapidly emerging form of CT that uses a standard polychromatic x-ray source and photon-counting detectors (PCDs) 2-9 . Prototypes of clinical-grade SPCCT scanners have been modified from clinical CT systems and are currently available for both pre-clinical and clinical research 4,6,7 . The energy integrating detectors (EIDs) used in conventional CT scanners discard the energy information of incident x-ray photons, since they sum all the energy deposited in each pixel, resulting in photons with higher energy being weighted more heavily than photons with lower energy 10,11 . PCDs, on the other hand, measure the energy of individual x-ray photons by converting x-rays into currents, inferring their energies via pulse height analysis, and separating them into several data bins with adjustable energy thresholds 12 . Since different materials have differing x-ray attenuation profiles, characterizing the energy distribution of the transmitted beam by SPCCT systems allows the specific detection of substances such as exogenous contrast agents 6,13 . SPCCT systems have multiple benefits, such as improved contrast-to-noise ratios (CNR), lower noise, higher spatial resolution and fewer image artifacts, such as blooming and beam hardening 3, 11, 14, 15 . These benefits can lead to the acquisition of higher quality images at lower radiation doses than with conventional CT systems. Preclinical and clinical studies have demonstrated the advantages of SPCCT imaging with several animal models, as well as for patients 2, 4, 7, 16, 17 . Besides the advantages of SPCCT in terms of image quality and patient dose, these systems can specifically distinguish multiple contrast generating materials in a single scan via material decomposition by assigning an appropriate number of energy bins and their thresholds 18-23 . This feature allows differentiation of exogenous contrast agents from soft tissues and calcified structures (e.g. bones and calcified atherosclerotic plaques), which can be especially beneficial in coronary CT angiography. Simultaneous material decomposition also eliminates the need for comparison of pre-and post-injection images, which can further reduce patient radiation exposure. As demonstrated by Si-Mohamed et al. 6 , SPCCT systems are also capable of providing absolute quantification of exogenous contrast agents in vivo to allow biodistribution determination without the need for ex vivo analysis. Iodine-based small molecules are the most commonly used intravenous contrast agents for CT imaging. While contrast generation of iodinated contrast agents in SPCCT systems is as effective as contrast generation in conventional and dual energy CT systems, they do not take full advantage of the capability of K-edge imaging in SPCCT since iodine's K-edge energy (33.2 keV) is too low for material decomposition for most clinical CT applications. This is because there are too few photons in CT x-ray beams below this K-edge for accurate data to be gathered. Iodine-based contrast agents are also known to cause allergic reactions, and there are concerns over kidney function reduction in patients with renal insufficiency through contrast-induced nephropathy (CIN) or contrast-induced acute kidney injury 14,24,25 . CIN does not develop into chronic renal failure in most cases; however, it may still result in complete renal failure in the patients with poor renal functions, increasing the risk of morbidity and mortality 14,26 . Thus, developing novel contrast agents specifically designed for SPCCT can be valuable to allow full utilization of its capabilities and broaden its applications. Substantial work has been done over the past decade using nanoparticles based on elements such as gold 27-31 , bismuth 32,33 , tantalum 34,35 and others 36-40 as contrast agents for EID-based CT. These nanoparticle-based CT contrast agents can be synthesized to have similar or different pharmacokinetics and biodistributions to iodine. They have been studied for various applications, such as vascular imaging 29,41 , theranostics in drug delivery 42 and radiotherapy 43 , as well as cell tracking 44, 45 . Contrast agents for SPCCT imaging need to be based on elements that have K-edge energies within a region where there are a reasonable number of photons above and below their K-edge (roughly 40-100 keV in a 120 kVp beam) for effective imaging (Fig. 1A) . There have been a number of reports focusing on the use of contrast agents for SPCCT that are based on elements such as gold, bismuth or gadolinium 2, 5, 13, 18, 21 . However, to the best of our knowledge, a systematic study of the contrast generation from different elements in SPCCT imaging has not been reported to date. We therefore decided to survey the elements for candidates for novel SPCCT contrast agents. From elements whose K-edge fell into the range of 40-100 keV, we first eliminated those that are highly toxic or radioactive, such as thulium and radium 14 . Then we considered economically viable elements that have been previously studied as experimental contrast agents or for nanoparticle syntheses. Taking those criteria into consideration, we selected gadolinium, ytterbium, tantalum, tungsten, gold and bismuth as the most suitable elements for contrast agent development (Fig. 1B) . Gold is the element that has been most commonly used as a contrast generating material for SPCCT 6,18,46 , therefore we included it in this panel despite its relatively high material cost. We herein report the
doi:10.1038/s41598-018-30570-y pmid:30108247 pmcid:PMC6092324 fatcat:lfuk5bllezcknihlrhm4wesqj4