Non-destructive High Atomic Number Elements Intratumoral Mapping Based On Quantitative X-ray Fluorescence Imaging System

High atomic number(Z)probes(e.g.iodine,gold,platinum,and gadolinium)have been intensively investigated and widely used in various biomedical applications,particularly in tumor imaging and tumor therapeutics.Quantifying high-Z elements that work as imaging biomarkers in tissues or animals is crucial for cancer staging and treatment assessment.High-Z elements are effective contrast agents for x-ray imaging because of their high x-ray attenuation.Therefore,computed tomography(CT)is heavily utilized to qualitatively image the distribution of high-Z contrast agents in tumors.However,CT imaging is not sensitive enough and unable to distinguish the material type and accurately quantify its concentration.So far,histology is the gold standard for examining the high-Z probes’ distribution but it is invasive and complicated.X-ray fluorescence computed tomography(XFCT)is an emerging imaging modality and has the potential of non-destructively and quantitatively mapping the distribution of high-Z elements by specifically detecting the characteristic x-ray fluorescence(XRF).XFCT experiments are commonly performed using synchrotron facilities which,however,are not amiably available.The development of benchtop XFCT systems,using ordinary polychromatic X-ray sources,accelerates the application of XFCT in molecular imaging field.In this study,an in-house dual-modality XFCT/CT imaging system was developed.By using a small pinhole collimator,the spatial resolution of the XFCT imaging system was 1mm,which was remarkable among pencil beam XFCT imaging systems based on ordinary polychromatic X-ray source.The XFCT image was reconstructed by the MLEM algorithm with attenuation correction using the prior information provided by CT images.The quantitative feature of XFCT was calibrated with high-Z elements solutions of various concentrations.A highly linear correlation between the XFCT signal intensity and high-Z elements concentrations indicated the feasibility of quantitative imaging.The minimum detection limit of XFCT imaging was estimated about one order more sensitive than CT imaging in phantom experiments.The system was employed in nondestructive XFCT imaging in quantitatively mapping the threedimensional distribution of high-Z probes(iodine contrast and gold nanoparticles)in the tumor.The tumor XFCT high-Z elements mapping was validated with histology.The results suggest the feasibility of non-destructive and quantitative high-Z elements three-dimensional mapping of XFCT imaging in tumor.Furthermore,the quantitative X-ray fluorescence projection imaging of a living tumor-bearing mouse with gold nanoparticles was conducted in our dual-modality imaging system.X-ray fluorescence projection revealed the quantitative distribution of gold nanoparticles in tumor region and the contour of the tumor provided by X-ray fluorescence projection was verified by a surface picture of mice captured by a CCD camera.The results suggest the X-ray fluorescence projection has the capabilities to simultaneously monitor the heterogeneous spatial distribution and the concentration of gold nanoparticles within tumors in vivo.In this study,we successfully demonstrated the feasibility of non-destructive and quantitative elemental mapping of ex vivo tumor and tumor-bearing mouse,by using an in-house benchtop dual-modality XFCT/CT system.This technique may open a new way of imaging-based nondestructive and quantitative 3D histology using targeted high-Z biomarkers and is essential for the in vivo evaluation of tumor-targeted high-Z biomarkers in preclinical studies.