Clinical management of anaplastic thyroid cancer (ATC) is very challenging due to its dedifferentiation and aggressiveness. We aim to develop HER2-targeted multimodal imaging approaches and assess the diagnostic efficacies of these molecular imaging probes in preclinical ATC models. Flow cytometry was used to detect HER2 expression status in thyroid cancer cell lines. We then developed a HER2-specific immunoPET imaging probe 89 Zr-Df-pertuzumab by radiolabeling a HER-2 specific monoclonal antibody (mAb) pertuzumab with 89 Zr (t 1/2 =78.4 h) and a fluorescent imaging probe IRDye 800CW-pertuzumab. The diagnostic efficacies of the probes were assessed in subcutaneous and orthotopic ATC models, followed by ex vivo biodistribution profile and immunofluorescence staining studies. HER2 was highly expressed on the surface of all the four primary thyroid cancer cell lines examined, which included two ATC cell lines (i.e., 8505C and THJ-16T). PET imaging with 89 Zr-Df-pertuzumab clearly visualized all the subcutaneous ATCs with a peak tumor uptake of 20.23±6.44 %ID/g (n=3), whereas the highest tumor uptake of the nonspecific probe 89 Zr-Df-IgG in subcutaneous ATC models was 6.30±0.95 %ID/g (n=3). More importantly, 89 Zr-Df-pertuzumab PET imaging strategy readily delineated all the orthotopic ATCs with a peak tumor uptake of 24.93±8.53 %ID/g (n=3). We also suggested that Cerenkov luminescence imaging (CLI) using 89 Zr-Df-pertuzumab and fluorescence imaging using IRDye 800CW-pertuzumab are useful tools for image-guided removal of ATCs. We demonstrate that HER2 is a promising biomarker for ATC, and multimodal imaging using 89 Zr-Df-pertuzumab and IRDye 800CW-pertuzumab is useful for identifying HER2-postive ATCs.
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