A Quad-Modality X-ray Luminescence, X-ray Fluorescence, X-ray Rayleigh Scattering and X-ray Transmission Computed Tomography Imaging Platform for Monitoring and Stimulating the Therapeutic Delivery of Metal-Containing Nanoparticles

Objectives: X-ray-activated photodynamic therapy (X-PDT) techniques have gained traction for its potential to impart therapeutic effects at greater depths than possible with traditional photodynamic therapy [1], [2]. Interestingly, the underlying X-PDT process could also generate X-ray fluorescence (XF) with metal-based nanoparticles (NPs) and X-ray luminescence (XL), which could be used to monitor the delivery of PDT agents and the subsequent therapeutic process. This allows the possibility of using X-ray fluorescence (XFCT) and X-ray luminescence computed tomography (XLCT) to monitor the therapeutic delivery during radiation therapy. X-ray Raleigh scattering (XRS) produced by the scattered monochromatic incident X-ray can also be correlated with the data from XFCT/XLCT while X-ray transmission CT (XT CT) could show structure. This work explores a XF-XL-XRS-XT CT imaging platform that allows for quantitative monitoring of the X-ray PDT delivery process through complementary mechanisms, and demonstrates this platform’s ability to image X-PDT nanophosphors, such as Y₂O₃:Eu³⁺. The system geometry mimics the X-ray microbeam therapy environment, which provides the highly intense collimated X-rays needed to produce sufficient XF and XL for imaging. The irradiated NPs would produce therapeutic effects, either through indirect mechanisms such as photosensitization [2], or directly from secondary electrons killing the cells [3].

Methods: This imaging technique offers several unique features. First, these modalities are based on distinct but complementary imaging contrast mechanisms related to the delivery of X-PDT, and provides information that could be used to monitor the delivery process. Second, the physical measurements facilitating the technique could be performed with a simple integrated imaging system. X-ray Fluorescence CT: The XF signals emanating from the irradiated metal within the NPs could determine the NP distribution within the object. X-ray Luminescence CT: The XL signals allows for the quantification of the emitted scintillation light, which is related to the degree of photosensitizer activation and the actual therapeutic effect. X-ray Rayleigh Scattering CT: The XRS signal could contribute to an electron density map of the irradiated volume, which provides a measure of the incident X-ray attenuation, and can be correlated with the XLCT and XFCT data. X-ray Transmission CT: Lastly, an X-ray CT image would provide the structural information used to guide the delivery of the beam to the target region. In our setup (Fig. 1B), a gel sample (Fig. 1A) containing three 600 μm channels of Y2O3:Eu3+ NPs is scanned in both directions perpendicular to a 17.4 keV monochromatic beam with 200 μm step sizes over an 8 mm × 1 cm × 5 mm volume. A CCD collects both the XF and XRS signal with 20seconds per step for a total of 7 hours. An intensified EMCCD collects the XL signal with .5 seconds per step for a total imaging time of 8 minutes [5]. The XT CT images are collected in conventional cone-beam CT geometry using a Zyla CMOS camera.

Results: The system acquired quad-modal images with Fig. D-G co-registered with a CT image. The XF energy spectrum (Fig. 1C) shows a 14.96 keV Kα1 peak distinctly visible while the 16.74 keV Kβ1 peak and the Rayleigh scattering overlap. The images obtained include XF slice with the energy selected for the Kα1 peak of yttrium (Fig .1D), a XRS slice with the energy selected for the overlapping XRS signal and Kβ1 peak (Fig. 1E), and the XL slice of the NP (Fig. 1F). Lastly, Fig. 1G shows a 3D-rendered combined image of all four modalities.

Conclusion: The results show that a quad-modal image of a phantom containing X-PDT metal-containing NPs is achievable. Future work includes demonstrating the system’s ability to image other NPs such as LaF3:Tb3+ and CdSe quantum dots. Research Support: N/A