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首页> 中文期刊> 《中国癌症研究：英文版》 >Preclinical characterization and validation of a dual-labeled trastuzumab-based imaging agent for diagnosing breast cancer

Preclinical characterization and validation of a dual-labeled trastuzumab-based imaging agent for diagnosing breast cancer

         
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Objective: The combination of both nuclear and fluorescent reporters provides unique opportunities for noninvasive nuclear imaging with subsequent fluorescence image-guided resection and pathology. Our objective was to synthesize and optimize a dual-labeled trastuzumab-based imaging agent that can be used to validate an optical imaging agent with potential use in identifying tumor metastases in human epidermal growth factor receptor 2(HER2) positive breast cancer patients.Methods: [111In]-DTPA-trastuzumab-IRDye 800 was synthesized by a three-step procedure. Purity, stability, immunoreactivity, internalization and biodistribution were explored in HER2+ SKBR-3 cells. Biodistribution of [111In]-DTPA-trastuzumab-IRDye 800 was performed in a SKBR-3 xenograft model.Results: [111In]-DTPA-trastuzumab-IRDye 800 demonstrated high purity by both chemical and fluorometric determinations. Both flow cytometry and the Lindmo assay demonstrated a high binding affinity of [111In]-DTPA-trastuzumab-IRDye 800 to HER2-overexpressing cells. The dual-labeled conjugate was stable in PBS, but not in serum after 24 h at 37 ℃. Larger molecules(>150 k D) were seen after a 24 h-incubation in human serum. Biodistribution studies revealed tumor-specific accumulation of [111In]-DTPAtrastuzumab-IRDye 800 in SKBR-3 tumors, and tumor uptakes at 24 and 48 h were(12.42±1.72)% and(9.96±1.05)%, respectively, following intravenous administration. The tumor-to-muscle ratio was 9.13±1.68 at 24 h, and increased to 12.79±2.13 at 48 h. Liver and kidney showed marked uptake of the dual-labeled imaging agent.Conclusions: [111In]-DTPA-trastuzumab-IRDye 800 is an effective diagnostic biomarker that can be used to validate dual-labeled, molecularly targeted imaging agents and can allow these agents to be translated into clinical practice for identifying HER2+ lesions.

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