Background Combining modalities using dual-labeled antibodies may allow preoperative and intraoperative tumor localization and could be used in image-guided surgery to improve complete tumor... Show moreBackground Combining modalities using dual-labeled antibodies may allow preoperative and intraoperative tumor localization and could be used in image-guided surgery to improve complete tumor resection. Trastuzumab is a monoclonal antibody against the human epidermal growth factor-2 (HER2) receptor and dual-labeled trastuzumab with both a fluorophore (IRDye800CW) and a radioactive label (In-111) can be used for multimodal imaging of HER2-positive breast cancer. The aim of this study was to demonstrate the feasibility of HER2-targeted multimodal imaging using [In-111]In-DTPA-trastuzumab-IRDye800CW in an orthotopic breast cancer model. Methods Trastuzumab was conjugated with p-isothiocyanatobenzyl (ITC)-diethylenetriaminepentaacetic acid (DTPA) and IRDye800CW-NHS ester and subsequently labeled with In-111. In a dose escalation study, the biodistribution of 10, 30, and 100 mu g [In-111]In-DTPA-trastuzumab-IRDye800CW was determined 48 h after injection in BALB/c nude mice with orthotopic high HER2-expressing tumors. Also, a biodistribution study was performed in a low HER2-expressing breast cancer model. In addition, multimodal image-guided surgery was performed in each group. Autoradiography, fluorescence microscopy, and immunohistochemically stained slices of the tumors were compared for co-localization of tumor tissue, HER2 expression, fluorescence, and radiosignal. Results Based on the biodistribution data, a 30 mu g dose of dual-labeled trastuzumab (tumor-to-blood ratio 13 +/- 2) was chosen for all subsequent studies. [In-111]In-DTPA-trastuzumab-IRDye800CW specifically accumulated in orthotopic HER2-positive BT474 tumors (101 +/- 7 %IA/g), whereas uptake in orthotopic low HER2-expressing MCF7 tumor was significantly lower (1.2 +/- 0.2 %IA/g, p = 0.007). BT474 tumors could clearly be visualized with both micro-SPECT/CT, fluorescence imaging and subsequently, image-guided resection was performed. Immunohistochemical analyses of BT474 tumors demonstrated correspondence in fluorescence, radiosignal, and high HER2 expression. Conclusions Dual-labeled trastuzumab showed specific accumulation in orthotopic HER2-positive BT474 breast tumors with micro-SPECT/CT and fluorescence imaging and enabled image-guided tumor resection. In the clinical setting, [In-111]In-DTPA-trastuzumab-IRDye800CW could be valuable for preoperative detection of (metastatic) tumors by SPECT/CT imaging, and intraoperative localization by using a gamma probe and fluorescence image-guided surgery to improve radical resection of tumor tissue in patients with HER2-positive tumors. Show less
For years, pancreatic cancer had a dismal prognosis with a long term survival of around 5%. Since the centralization of pancreatic cancer surgery and the introduction of systemic chemotherapy... Show moreFor years, pancreatic cancer had a dismal prognosis with a long term survival of around 5%. Since the centralization of pancreatic cancer surgery and the introduction of systemic chemotherapy with FOLFIRINOX, the median overall survival increased to around 20%. Radical tumor-margin free resection provides the patient with the best potential chance for cure. However, due to late onset of symptoms, the majority of patients present with inoperable disease. These patients can benefit from neoadjuvant therapy, or palliative chemotherapy. During clinical practice, this means that decision-making before and during surgery is critical to select the most optimal primary treatment modality. Currently, conventional imaging modalities lack sensitivity to detect small metastatic lesions, and are unable to visualize treatment response on neoadjuvant therapy. Tumor-specific molecular imaging in the form of fluorescence and photoacoustic imaging aids the surgeon to accurately recognize and resect malignant tissues in real-time during surgery. This thesis focuses on the challenges a surgeon faces during pancreatic cancer treatment, and the potential improvements that could be achieved by the use of tumor-specific imaging. In addition, the regulatory aspects of clinical translation of tumor-specific optical imaging agents are addressed. Show less
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