Amino Acids

, Volume 49, Issue 8, pp 1325–1335 | Cite as

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

  • Xiaoqin Yin
  • Mengzhe Wang
  • Hui Wang
  • Huaifu Deng
  • Tingting He
  • Yue Tan
  • Zehua Zhu
  • Zhanhong Wu
  • Shuo Hu
  • Zibo Li
Original Article

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.

Keywords

Neurotensin receptor Positron emission tomography Pancreatic ductal adenocarcinoma Fluorescence imaging Imaging guided surgery 

References

  1. Alshoukr F et al (2011) Novel DOTA-neurotensin analogues for 111In scintigraphy and 68Ga PET imaging of neurotensin receptor-positive tumors. Bioconjug Chem 22:1374–1385. doi:10.1021/bc200078p CrossRefPubMedGoogle Scholar
  2. Beer AJ, Kessler H, Wester H-J, Schwaiger M (2011) PET imaging of integrin αVβ3 expression. Theranostics 1:48–57CrossRefPubMedPubMedCentralGoogle Scholar
  3. Buchegger F et al (2003) Radiolabeled neurotensin analog, 99mTc-NT-XI, evaluated in ductal pancreatic adenocarcinoma patients. J Nucl Med 44:1649–1654PubMedGoogle Scholar
  4. Chakraborty S, Baine MJ, Sasson AR, Batra SK (2011) Current status of molecular markers for early detection of sporadic pancreatic cancer. Biochim Biophys Acta (BBA) Rev Cancer 1815:44–64CrossRefGoogle Scholar
  5. Chen K, Li Z-B, Wang H, Cai W, Chen X (2008) Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots. Eur J Nucl Med Mol Imaging 35:2235–2244CrossRefPubMedGoogle Scholar
  6. Deng H, Wang H, Wang M, Li Z, Wu Z (2015) Synthesis and evaluation of 64Cu-DOTA-NT-Cy5.5 as a dual-modality PET/fluorescence probe to image neurotensin receptor-positive tumor. Mol Pharm 12:3054–3061CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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
  8. Ehlers RA et al (2000) Gut peptide receptor expression in human pancreatic cancers. Ann Surg 231:838–848CrossRefPubMedPubMedCentralGoogle Scholar
  9. Evers BM, Ishizuka J, Chung DH, Townsend CM, Thompson JC (1992) Neurotensin expression and release in human colon cancers. Ann Surg 216:423–431CrossRefPubMedPubMedCentralGoogle Scholar
  10. Hamada S, Shimosegawa T (2011) Biomarkers of pancreatic cancer. Pancreatology 11:14–19CrossRefPubMedGoogle Scholar
  11. Herranz M, Ruibal A (2012) Optical imaging in breast cancer diagnosis: the next evolution. J Oncol 2012:10CrossRefGoogle Scholar
  12. Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617CrossRefPubMedGoogle Scholar
  13. Jennings LE, Long NJ (2009) ‘Two is better than one’—probes for dual-modality molecular imaging. Chem Commun, 3511–3524Google Scholar
  14. Kapuscinski M, Shulkes A, Read D, Hardy KJ (1990) Expression of neurotensin in endocrine tumors. J Clin Endocrinol Metab 70:100–106CrossRefPubMedGoogle Scholar
  15. Körner M, Waser B, Strobel O, Büchler M, Reubi JC (2015) Neurotensin receptors in pancreatic ductal carcinomas. EJNMMI Res 5:17CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kruttika B, Fengfei W, Qingyong M, Qinyu L, Sanku M, Tze-chen H, Erxi W (2012) Advances in biomarker research for pancreatic cancer. Curr Pharm Des 18:2439–2451CrossRefGoogle Scholar
  17. Kulinska-Niedziela I, Paluszak J (1997) Neurotensin—structure, origin and biological function. Postępy Higieny i Medycyny Doświadczalnej 51:329–342PubMedGoogle Scholar
  18. 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
  19. Lamerz R (1999) Role of tumour markers, cytogenetics. Ann Oncol 10:S145–S149CrossRefGoogle Scholar
  20. Liu S et al (2012) The efficient synthesis and biological evaluation of novel bi-functionalized sarcophagine for 64Cu radiopharmaceuticals. Theranostics 2:589–596CrossRefPubMedPubMedCentralGoogle Scholar
  21. Liu S et al (2013) Lewis acid-assisted isotopic 18F–19F exchange in BODIPY dyes: facile generation of positron emission tomography/fluorescence dual modality agents for tumor imaging. Theranostics 3:181–189CrossRefPubMedPubMedCentralGoogle Scholar
  22. Maschauer S, Einsiedel J, Hübner H, Gmeiner P, Prante O (2016) 18F- and 68Ga-labeled neurotensin peptides for PET imaging of neurotensin receptor 1. J Med Chem 59:6480–6492CrossRefPubMedGoogle Scholar
  23. Mijatovic T, Gailly P, Mathieu V, De Nève N, Yeaton P, Kiss R, Decaestecker C (2007) Neurotensin is a versatile modulator of in vitro human pancreatic ductal adenocarcinoma cell (PDAC) migration. Cell Oncol 29:315–326PubMedPubMedCentralGoogle Scholar
  24. Na Y et al (2015) Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model. J Control Release 220, Part B:766–782CrossRefGoogle Scholar
  25. Naghibalhossaini F, Yoder AD, Tobi M, Stanners CP (2007) Evolution of a tumorigenic property conferred by glycophosphatidyl-inositol membrane anchors of carcinoembryonic antigen gene family members during the primate radiation. Mol Biol Cell 18:1366–1374CrossRefPubMedPubMedCentralGoogle Scholar
  26. Olszewski U, Hamilton G (2009) Neurotensin signaling induces intracellular alkalinization and interleukin-8 expression in human pancreatic cancer cells. Mol Oncol 3:204–213CrossRefPubMedGoogle Scholar
  27. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921CrossRefPubMedGoogle Scholar
  28. Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R (2010) Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol 24:349–358CrossRefPubMedGoogle Scholar
  29. Reubi JC, Waser B, Friess H, Büchler M, Laissue J (1998) Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma. Gut 42:546–550. doi:10.1136/gut.42.4.546 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Reubi JC, Waser B, Schaer J-C, Laissue JA (1999) Neurotensin receptors in human neoplasms: high incidence in Ewing’s sarcomas. Int J Cancer 82:213–218CrossRefPubMedGoogle Scholar
  31. Schlyer D (2004) PET tracers and radiochemistry. Ann Acad Med Singapore 33:146–154PubMedGoogle Scholar
  32. Schulz J et al (2016) Comparative evaluation of the biodistribution profiles of a series of nonpeptidic neurotensin receptor-1 antagonists reveals a promising candidate for theranostic applications. J Nucl Med 57:1120–1123CrossRefPubMedGoogle Scholar
  33. Sehgal I, Powers S, Huntley B, Powis G, Pittelkow M, Maihle NJ (1994) Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer. Proc Natl Acad Sci USA 91:4673–4677CrossRefPubMedPubMedCentralGoogle Scholar
  34. Seibold U et al (2014) Bimodal imaging probes for combined PET and OI: recent developments and future directions for hybrid agent development. Biomed Res Int 2014:13CrossRefGoogle Scholar
  35. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29CrossRefPubMedGoogle Scholar
  36. Tsavaris N et al (2009) CEA and CA-19.9 serum tumor markers as prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis. J Chemother 21:673–680CrossRefPubMedGoogle Scholar
  37. Valerie NCK, Casarez EV, DaSilva JO, Dunlap-Brown ME, Parsons SJ, Amorino GP, Dziegielewski J (2011) Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation. Cancer Res 71:6817CrossRefPubMedGoogle Scholar
  38. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet (London, England) 378:607–620CrossRefGoogle Scholar
  39. Wang L et al (2000a) Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease. Clin Cancer Res 6:566–571PubMedGoogle Scholar
  40. Wang L et al (2000b) Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease. Clin Cancer Res 6:566PubMedGoogle Scholar
  41. Wang Q, Zhou Y, Evers BM (2006) Neurotensin phosphorylates GSK-3α/β through the activation of PKC in human colon cancer cells. Neoplasia (New York, NY) 8:781–787CrossRefGoogle Scholar
  42. Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH (2013) Recent progress in pancreatic cancer. CA Cancer J Clin 63:318–348CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wu Z et al (2014) Facile preparation of a thiol-reactive 18F-labeling agent and synthesis of 18F-DEG-VS-NT for PET imaging of a neurotensin receptor-positive tumor. J Nucl Med 55:1178–1184CrossRefPubMedGoogle Scholar
  44. Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA (2016) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30:355–385CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  • Xiaoqin Yin
    • 1
  • Mengzhe Wang
    • 2
  • Hui Wang
    • 2
  • Huaifu Deng
    • 2
  • Tingting He
    • 1
  • Yue Tan
    • 1
  • Zehua Zhu
    • 1
  • Zhanhong Wu
    • 2
  • Shuo Hu
    • 1
  • Zibo Li
    • 2
  1. 1.PET Center of Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Department of Radiology and Biomedical Research Imaging CenterUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations