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Quantitative imaging of gold nanoparticle distribution in a tumor-bearing mouse using benchtop x-ray fluorescence computed tomography.

ABSTRACT: X-ray fluorescence computed tomography (XFCT) is a technique that can identify, quantify, and locate elements within objects by detecting x-ray fluorescence (characteristic x-rays) stimulated by an excitation source, typically derived from a synchrotron. However, the use of a synchrotron limits practicality and accessibility of XFCT for routine biomedical imaging applications. Therefore, we have developed the ability to perform XFCT on a benchtop setting with ordinary polychromatic x-ray sources. Here, we report our postmortem study that demonstrates the use of benchtop XFCT to accurately image the distribution of gold nanoparticles (GNPs) injected into a tumor-bearing mouse. The distribution of GNPs as determined by benchtop XFCT was validated using inductively coupled plasma mass spectrometry. This investigation shows drastically enhanced sensitivity and specificity of GNP detection and quantification with benchtop XFCT, up to two orders of magnitude better than conventional x-ray CT. The results also reaffirm the unique capabilities of benchtop XFCT for simultaneous determination of the spatial distribution and concentration of nonradioactive metallic probes, such as GNPs, within the context of small animal imaging. Overall, this investigation identifies a clear path toward in vivo molecular imaging using benchtop XFCT techniques in conjunction with GNPs and other metallic probes.

SUBMITTER: Manohar N

PROVIDER: S-EPMC4766520 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Project description:PURPOSE:This report describes upgrades and performance characterization of an experimental benchtop cone-beam x-ray fluorescence computed tomography (XFCT) system capable of determining the spatial distribution and concentration of metal probes such as gold nanoparticles (GNPs). Specifically, a high-power (~3 kW) industrial x-ray source and transmission CT capability were deployed in the same platform under the cone-beam geometry. METHODS:All components of the system are described in detail, including the x-ray source, imaging stage, cadmium-telluride detector for XFCT, and flat-panel detector for transmission CT imaging. The general data acquisition scheme for XFCT and transmission CT is also explicated. The detection limit of the system was determined using calibration samples containing water and GNPs at various concentrations. Samples were then embedded in a small-animal-sized phantom and imaged with XFCT and CT. The reconstructed XFCT and CT images were compared and analyzed using the contrast-to-noise ratio for each GNP-containing region of interest. Also, measurements of the incident beam spectra used for XFCT and CT imaging were made and the corresponding x-ray dose rates were estimated, along with the imaging dose. RESULTS:The present configuration produced a GNP detection limit of 0.03 wt. % with the delivery of an effective dose of 1.87 cGy per projection. XFCT scan of an animal-sized phantom containing low concentrations (down to 0.03 wt. %) of GNP-loaded inserts can be performed within an hour. CONCLUSIONS:The high performance of the system combined with the ability to perform transmission CT in tandem with XFCT suggests that the currently developed benchtop cone-beam XFCT/CT system, in conjunction with GNPs, can be used for routine multimodal preclinical imaging tasks with less stringent dose constraints such as ex vivo imaging. With further effort to minimize XFCT imaging dose as discussed in this report, it may also be used for in vivo imaging.

Project description:To develop a proof-of-principle L-shell x-ray fluorescence (XRF) imaging system that locates and quantifies sparse concentrations of gold nanoparticles (GNPs) using a benchtop polychromatic x-ray source and a silicon (Si)-PIN diode x-ray detector system.12-mm-diameter water-filled cylindrical tubes with GNP concentrations of 20, 10, 5, 0.5, 0.05, 0.005, and 0 mg∕cm3 served as calibration phantoms. An imaging phantom was created using the same cylindrical tube but filled with tissue-equivalent gel containing structures mimicking a GNP-loaded blood vessel and approximately 1 cm3 tumor. Phantoms were irradiated by a 3-mm-diameter pencil-beam of 62 kVp x-rays filtered by 1 mm aluminum. Fluorescence∕scatter photons from phantoms were detected at 90° with respect to the beam direction using a Si-PIN detector placed behind a 2.5-mm-diameter lead collimator. The imaging phantom was translated horizontally and vertically in 0.3-mm steps to image a 6 mm×15 mm region of interest (ROI). For each phantom, the net L-shell XRF signal from GNPs was extracted from background, and then corrected for detection efficiency and in-phantom attenuation using a fluorescence-to-scatter normalization algorithm.XRF measurements with calibration phantoms provided a calibration curve showing a linear relationship between corrected XRF signal and GNP mass per imaged voxel. Using the calibration curve, the detection limit (at the 95% confidence level) of the current experimental setup was estimated to be a GNP mass of 0.35 μg per imaged voxel (1.73×10(-2) cm3). A 2D XRF map of the ROI was also successfully generated, reasonably matching the known spatial distribution as well as showing the local variation of GNP concentrations.L-shell XRF imaging can be a highly sensitive tool that has the capability of simultaneously imaging the spatial distribution and determining the local concentration of GNPs presented on the order of parts-per-million level within subcentimeter-sized ex vivo samples and superficial tumors during preclinical animal studies.