Abstract
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Objectives Cerenkov luminescence imaging (CLI) is a novel optical molecular imaging that can image the distribution of radiopharmaceuticals and has many biomedical applications. However, CLI is two-dimensional (2D) imaging which only provides qualitative but not quantitative information. Three-dimensional (3D) Cerenkov luminescence tomography (CLT) provides semi-quantitative information, such as the specific location of the lesion, which is important for diagnosis and treatment of disease. However, the reconstruction results of CLT usually are not accurate. In this study, a novel 3D radiopharmaceutical-excited fluorescence tomography (REFT) has been developed to achieve more accurate spatial information of tumor using the Cerenkov radiation spectral characteristic-based (CRSC) source reconstruction method and dual excitation of europium oxide (EO) nanoparticles by both gamma rays and Cerenkov luminescence (CL) of radiopharmaceuticals.
Methods The up-conversion rare earth EO nanoparticles (excitable by CL and gamma rays, emission at 620 nm) were used for producing the REFT signal. REFT technique were presented as follows: REF images and biological structures were acquired by EMCCD and micro-CT system; REF images were mapped into the 3D surface mesh obtained through the grid subdivision of CT data; Based on the finite element method framework, a system equation and an optimization problem were established, which was solved by CRSC source reconstruction method to determine the 3D radioluminescence distribution. To compare the performance of REFT and CLT, the experiments of the phantom, artificial source-implanted mice models, and mice bearing hepatocellular carcinomas (HCCs) were performed. CL images, REF images, and CT images were acquired, and the distributions of radiopharmaceuticals were then reconstructed. The details were introduced as follows: Cubic phantoms with different source depths were used in ex vivo phantom study. The phantoms contained 68GaCl3 or mixture (68GaCl3; EO) were used for CLT and REFT experiments. To investigate the performance of REFT in the real biological scenario, anesthetized nude mice implanted with the mixture of 68GaCl3 and EO or only 68GaCl3 were used for REFT or CLT. For in vivo imaging study, athymic nude mice were injected with 5×106 HCC cells in the liver lobes and into the peritoneum. Two weeks later, the mice were injected with 18F-FDG (400 μCi, 0.1 mL) through tail vein and then imaged with a micro-PET scanner at 1h post-injection. Then the mice were further injected with EO nanoparticles (0.1 mL, 1 mg/mL) intravenously, and REF images were acquired using the IVIS Kinetic imaging system at 0.5h post-injection. After PET scans and optical imaging, the mice were undergone CT scan.
Results EO nanoparticles were excited by both gamma rays and Cerenkov luminescence (Figure1a). The framework of 3D REFT technique is depicted in Figure 1b. Both of the phantom and implanted experiment showed that the reconstructed distance errors of REFT were smaller than those of CLT in various source depths. Especially, when the implanted source was very deep in the mouse body (13 mm), the distance error of REFT was only 2.95 mm (Figure 1d) that was much smaller than that of CLT (6.03 mm, Figure 1c). Data demonstrated that reconstruction of REFT was more accurate than CLT. More interestingly, PET only detected one tumor in the orthotropic and ectopic HCC tumor-bearing mouse (red arrow; Figure 1e). In comparison, REFT detected three tumors (red arrows; Figure 1f), whose accuracy was further validated by the dissection of the mouse.
Conclusions The 3D REFT developed in this study demonstrates excellent performance to precisely localize tumor based on the REFT source reconstruction method and enhanced radioluminescence emitted from EO nanoparticles excited by the radiopharmaceuticals. It is a highly promising new technique for molecular imaging of cancer and other diseases.