Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma
Pancreatic cancer is one of the deadliest human malignancies and lack of effective diagnostic and therapeutic methods. Accumulating evidence suggests that the neurotensin (NT) and neurotensin receptors (NTRs) play key roles in pancreatic adenocarcinoma growth and survival. In this study, we not only evaluate the NTR1 expression in pancreatic cancer patient samples, but also explore the PET and fluorescence imaging of NTR1 expression in pancreatic cancer animal models. The NTR1 expression was evaluated by immunohistochemistry staining in clinical patient tissue samples with pancreatic ductal adenocarcinoma, insulinoma, and pancreatitis. The results showed 79.4% positive rate of NRT1 expression in pancreatic ductal adenocarcinoma, compared with 33.3 and 22.7% in insulinoma and pancreatitis samples, respectively. High NTR1 gene expression was also found in Panc-1 cells and confirmed by cell immunofluorescence. 64Cu-AmBaSar-NT and IRDye800-NT were synthesized as imaging probes and maintained the majority of NTR1-binding affinity. In vivo imaging demonstrated that 64Cu-AmBaSar-NT has prominent tumor uptake (3.76 ± 1.45 and 2.29 ± 0.10%ID/g at 1 and 4 h post-injection). NIR fluorescent imaging with IRDye800-NT demonstrated good tumor-to-background contrast (8.09 ± 0.38 × 108 and 6.67 ± 0.43 × 108 (p/s/cm2/sr)/(μW/cm2) at 30 and 60 min post-injection). Fluorescence guided surgery was also performed as a proof of principle experiment. In summary, our results indicated that NTR1 is a promising target for pancreatic ductal adenocarcinoma imaging and therapy. The imaging probes reported here may not only be considered for improved diagnosis of pancreatic ductal adenocarcinoma, but also has the potential to be fully integrated into patient screening and treatment monitoring of future NTR1 targeted therapies.
KeywordsNeurotensin receptor Positron emission tomography Pancreatic ductal adenocarcinoma Fluorescence imaging Imaging guided surgery
This work was supported by UNC Lineberger Comprehensive Cancer Center (pilot fund to Wu), Radiology Department and BRIC, P30-CA016086-35-37 from the National Cancer Institute, and the National Natural Science Foundation of China (NSFC) (Grant No. 81471689). We would also like to acknowledge Dr. Jen Jen Yeh at UNC for proof reading and editing the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that no conflicts of interest were disclosed.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Human subjects were recruited from the Pathology Department of Xiangya Hospital of Central South University from April 2010 to October 2015. All tissues were fully anonymized and de-identification before they were accessed for this study. Informed consent was obtained from all individual participants included in the study.
Informed consent was obtained from all individual participants included in the study.
- Deng H et al (2016) The synthesis and evaluation of 64Cu-DOTA-NT, 64Cu-NOTA-NT and 64Cu-AmBaSar-NT for PET imaging of neurotensin receptor in prostate cancer. J Nucl Med 57(suppl):1067Google Scholar
- Jennings LE, Long NJ (2009) ‘Two is better than one’—probes for dual-modality molecular imaging. Chem Commun, 3511–3524Google Scholar
- Kulkarni H, Schuchardt C, Wiessalla S, Smerling C, Reineke U, Osterkamp F, Baum R (2015) Radiopeptide therapy using Lu-177 3BP-227 in a patient with pancreatic adenocarcinoma. J Nucl Med 56(suppl):1235Google Scholar