Hybrid X-ray Fluorescence, Luminescence and Transmission Computed Tomography for Image-Guided Nanoparticle Mediated X-ray Micro-Beam Therapy

1953 Objectives In this study, we develop a hybrid imaging modality that relies on X-ray fluorescence (XF), X-ray luminescence (XL), and X-ray transmission (XCT) measurements to produce 3-D multicolor images for guiding and monitoring nanoparticle-mediated microbeam therapy. XF refers to the emission of characteristic X-rays by an atom, while XL refers to emission of optical photons by a substance upon X-ray irradiation. During the microbeam therapeutic delivery process, a highly collimated X-ray beam irradiates the object. The pre-administrated metal-containing nanoparticles (NPs) preferably absorb the X-rays to produce therapeutic effects, either indirectly through mechanisms such as photosensitization [1, 2] and thermal ablation [3], or directly from radiation effects induced by low-energy secondary electrons (including Auger electrons) [4]. Resultant XF signals could determine the distribution of the NPs in the object and the absorption of X-ray energy through photoelectron interactions. The XL signals could provide quantitative information and indirect spatial mapping of the scintillation process induced by the X-ray irradiation of nanophosphors conjugated with photosensitizers. Finally, the micro-CT images provide structural details of the object for confirmation of the delivery of the beam to the target area. Combining these three imaging techniques would provide a unique tool for guiding therapeutic delivery with highly detailed spatial and functional information. Methods The XFCT/XLCT/XCT imaging setup used in this study is shown in Fig. 1.A. It consists of (1) a benchtop monochromatic source that delivers a pencil beam of 17.4 keV X-rays and with diameter tunable from 30 to 100 μm diameter, (2) a conventional micro-focus (25 μm) polychromatic X-ray source equipped with multiple filter configurations, (3) a direct-detection deep-depleted X-ray CCD camera coupled to user-adjustable (slit or multiple-pinhole) apertures, (4) an iXon Andor EMCCD camera with various optical filters, and (5) a Zyla 5.5 CMOS X-ray camera with a pixel size of 6.5um. For the imaging study, we use phantoms filled with the following four different X-ray activable therapeutic and imaging agents: LaF3:Tb, Y2O3:Eu, and HfO2 NPs as well as CdSe:Eu quantum dots. These samples were prepared in solutions of various concentrations and loaded into an agarose-based composite mixture to produce an optically tissue-equivalent imaging phantom [5]. For XFCT imaging, a pencil beam irradiated the object and the CCD camera coupled to a multiple-slit aperture collected the XF photons. For XLCT imaging, the Andor iXon EMCCD camera (with band-pass filter) collected the XL photons. The micro-X-ray CT images are collected with a traditional transmission geometry. Results Fig. 1.B is a combined XFCT/XCT image of a mouse phantom loaded with solutions of Y2O3:Eu NPs and bromide. Figs. 1.C and D show single-slice XF and XL images of a phantom consisting of three tubes of 0.5 mm diameter loaded with yttrium and lanthanum and pure water. The XL and XF images are overlaid onto an X-ray CT image. In this work, we will: (a) generate 3D XLCT, XFCT and micro X-ray CT images of an optically tissue-equivalent gel-based phantom loaded with the four imaging/therapeutic agents, (b) experimentally determine the sensitivity of XL and XF imaging for these NPs in a mouse-like object geometry, and (c) study the correlation between XF and XL images and explore how these two imaging modalities could reveal the distribution of the NPs and the activation of the therapeutic agents in the object. Conclusions The results from the study will demonstrate the feasibility of using XFET and XLCT to image NPs in volumetric objects. We will assess the combined modality’s potential for imaging deeper/larger objects, and determine the strengths and weaknesses of each of the modalities to explore how best to combine the complementary information provided by XFCT/XLCT/XCT.