uPAR-targeted optical near-infrared (NIR) fluorescence imaging and PET for image-guided surgery in head and neck cancer: proof-of-concept in orthotopic xenograft model

摘要

// Anders Christensen 1, 2 , Karina Juhl 2 , Morten Persson 2 , Birgitte Wittenborg Charabi 1 , Jann Mortensen 2 , Katalin Kiss 3 , Giedrius Lelkaitis 3 , Niclas Rubek 2 , Christian von Buchwald 1 , Andreas Kjær 2 1 Department of Otolaryngology, Head & Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital, Denmark 2 Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark 3 Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Denmark Correspondence to: Andreas Kjær, email: akjaer@sund.ku.dk Keywords: uPAR, image-guided surgery, tumor margin assessment, head and neck cancer, robotic surgery, PET Received: August 26, 2016      Accepted: November 30, 2016      Published: December 27, 2016 ABSTRACT Purpose: Urokinase-like Plasminogen Activator Receptor (uPAR) is overexpressed in a variety of carcinoma types, and therefore represents an attractive imaging target. The aim of this study was to assess the feasibility of two uPAR-targeted probes for PET and fluorescence tumor imaging in a human xenograft tongue cancer model. Experimental design and results: Tumor growth of tongue cancer was monitored by bioluminescence imaging (BLI) and MRI. Either ICG-Glu-Glu-AE105 (fluorescent agent) or 64 Cu-DOTA-AE105 (PET agent) was injected systemically, and fluorescence imaging or PET/CT imaging was performed. Tissue was collected for micro-fluorescence imaging and histology. A clear fluorescent signal was detected in the primary tumor with a mean in vivo tumor-to-background ratio of 2.5. Real-time fluorescence-guided tumor resection was possible, and sub-millimeter tumor deposits could be localized. Histological analysis showed co-localization of the fluorescent signal, uPAR expression and tumor deposits. In addition, the feasibility of uPAR-guided robotic cancer surgery was demonstrated. Also, uPAR-PET imaging showed a clear and localized signal in the tongue tumors. Conclusions: This study demonstrated the feasibility of combining two uPAR-targeted probes in a preclinical head and neck cancer model. The PET modality provided preoperative non-invasive tumor imaging and the optical modality allowed for real-time fluorescence-guided tumor detection and resection. Clinical translation of this platform seems promising.