Purpose: To improve the tumor detection accuracy using dual modality fluorescence molecular tomography and X-ray computed tomography (FMT/CT) on an image guided precision radiation platform, by developing active-targeting fluorescence nanoparticles and adaptive background fluorescence subtraction method.
Methods: To image triple negative breast tumors, near-infrared fluorescent poly lactic-co-glycolic acid (PLGA) nanoparticles (excitation/emission: 780/820 nm) were conjugated with anti- epidermal growth factor receptor (EGFR) for actively targeting EGFR-overexpressing cancer cells. During fluorescence imaging, the inevitable presence of nonspecific nanoparticle uptake induced considerable background, which compromised the detection sensitivity and specificity. Therefore, we further developed an adaptive strategy that can estimate the background fluorescence from the measured excitation distribution, and iteratively refine the background fluorescence subtraction. First, an in vivo experiment was performed on a mouse intratumorally injected with gold nanoparticles (GNP), to validate the reliability of the adaptive method in target identification and background subtraction. Then we performed experiments on 10 mice which were inoculated with orthotopic breast tumors and received intravenous injection of PLGA-anti-EGFR nanoparticles. One day after PLGA-anti-EGFR nanoparticle injection, X-ray projections were acquired every 1Â° for CT reconstruction. Fluorescence and excitation projections were collected at multiple angles (70Â°, 90Â°, 110Â°, 250Â°, 270Â°, 290Â°) for FMT reconstruction. Using rigorously geometrical registration, CT provided accurate 3D anatomical information for FMT reconstruction.
Results: Intratumoral GNP experiment successfully validated the reliability of the adaptive background subtraction strategy. The PLGA-anti-EGFR nanoparticles demonstrated 10 times higher tumor uptake than the passive-targeting nanoparticles. Combining active-targeting nanoparticles and adaptive background subtraction strategy, FMT/CT demonstrated improved tumor detection accuracy, even for 1.5 mm small tumor.
Conclusion: Active-targeting nanoparticles combined with the effective fluorescence background subtraction could reliably detect small tumors, and will be especially beneficial for early tumor detection. Capable of precise tumor localization, dual modality FMT/CT imaging will be able to accurately guide small animal radiation therapy.