Several recent studies have demonstrated the use of intraoperative fluorescent imaging as a tool to overcome some limitations of conventional white light surgery, to enhance the visual contrast between tumor and normal tissue [6–10]. Oral administration of 5-ALA induces PpIX fluorescence in high grade glioblastoma tumors, which can be imaged during fluorescent-guided surgery (FGS). This has been adopted clinically in several countries, following success reported in both preclinical and clinical trials. However, the observed PpIX accumulation is thought to be partially due to the blood brain barrier breakdown, allowing the ALA to leak through, which can be less pronounced in the tumor edges [11, 12]. In comparison, exogenous protein targeting has allowed identification of several biomarkers which are overexpressed in many types of cancer such as the cell surface receptors EGFR and VEGFR [13–17] which have been studied as targets for therapeutic drug delivery [18–20] and diagnostic imaging [21–23]. Rosenthal and collaborators (2015) described the results of the first-in-human clinical trial using cetuximab conjugated to IRDye® 800CW to guide the surgery of head and neck squamous cell carcinoma and the fluorescence was correlated to EGFR expression of the tumor. The tumor-to-background contrast was dose-dependent, although there was evidence of receptor saturation at higher dose. However, because of the long biological half-life of antibodies, the tumor-to-normal contrast increases over time .