Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma

Abstract

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.

Upregulation of ASPM, BUB1B and SPDL1 in tumor tissues predicts poor survival in patients with pancreatic ductal adenocarcinoma

“…Commonly used tumor markers, such as CA19-9 and CEA, are ineffective for the early detection of PDAC (22). Furthermore, they fail to provide information on the exact location of the cancer lesions, thus making it difficult to determine a therapeutic strategy (23,24). Therefore, identifying prognostic factors for patients with PDAC remains critical, with the aim to develop novel therapeutic approaches and select adequate treatment strategies.…”

GPCRs in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets

“…Work on NTS 1 receptor as an imaging target by Yin et al (2017) used neurotensin analogues conjugated with Cu‐64 or IRDye800 to label pancreatic adenocarcinoma cell lines. Cu‐64 NT was able to detect AsPC‐1 orthotopic xenografts in mice by PET and of IRDye800‐labelled neurotensin for in vivo fluorescent imaging.…”

Application of Phage-Displayed Peptides in Tumor Imaging Diagnosis and Targeting Therapy

“…Larimer et al also reported an 111 In-DOTA labeled ERBB2-targeted SPECT imaging peptide 1-D03 (MEGPSKCCYSLALSH) may serve as a viable candidate for clinical imaging studies of breast carcinoma because of rapid clearance and tumor specificity (Larimer et al 2014 ). Furthermore, gastrin-releasing peptide (Ghosh et al 2019 ), cholecystokinin-2 (Kossatz et al 2013 ), melanocortin-1 (Li et al 2019a ), epidermal growth factor (Ulaner et al 2018 ), neurotensin (Yin et al 2017 ), somatostatin (Liu et al 2018 ) and glucagon-like peptide-1 (Stahle et al 2018 ) receptors have been successfully applied for early cancer imaging diagnosis.…”