Imaging of human pancreatic cancer xenografts by single-photon emission computed tomography with 99mTc-Hynic-PEG-AE105

Zhang,Xin; Tian,Ye; Sun,Fangfang; Feng,Hongbo; Yang,Chun; Gong,Xiaoyan; Tan,Guang

doi:10.3892/ol.2015.3504

Imaging of human pancreatic cancer xenografts by single-photon emission computed tomography with 99mTc-Hynic-PEG-AE105

Authors:
- Xin Zhang
- Ye Tian
- Fangfang Sun
- Hongbo Feng
- Chun Yang
- Xiaoyan Gong
- Guang Tan
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Affiliations: Department of Nuclear Medicine, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Emergency Medicine, Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China, Department of General Surgery, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: July 17, 2015 https://doi.org/10.3892/ol.2015.3504
Pages: 2253-2258

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Abstract

The elevated expression of urokinase-type plasminogen activator receptor (uPAR) is associated with the poor prognosis of pancreatic cancer patients. Thus, uPAR is a promising candidate as a molecular target for the non‑invasive imaging of pancreatic cancer. The present study aimed to develop a technetium-99m (99mTc)‑labeled uPAR‑binding peptide for non‑invasive single-photon emission computed tomography (SPECT) assessment of uPAR expression in pancreatic cancer xenograft models. A linear high‑affinity uPAR peptide antagonist, Hynic‑PEG‑AE105, was labeled with 99mTc. Human uPAR‑positive pancreatic cancer BxPC‑3 cells were inoculated into nude mice. SPECT was performed in the pancreatic cancer xenograft mice models. The results showed that the rate of the 99mTc labeling of Hynic‑PEG‑AE105 was 97.72±1.73%. The tumor uptake of 99mTc‑Hynic‑PEG‑AE105 was higher than the control inactive peptide 99mTc‑Hynic‑PEG‑AE105mut at 4 h (3.37±0.11 vs. 1.36±0.18; P<0.001) and 6 h (3.64±0.25 vs. 1.28±0.20; P<0.001) (n=10). Moreover, a significant correlation was observed between the tumor uptake of 99mTc‑Hynic‑PEG‑AE105 and uPAR expression (r=0.791, P=0.006). In conclusion, in the present study, a peptide‑based SPECT tracer, 99mTc‑Hynic‑PEG‑AE105, with a high purity and specific radioactivity was synthesized. 99mTc‑Hynic‑PEG‑AE105 is a promising agent for the non-invasive determination of uPAR expression in pancreatic cancer.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, LortetTieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ryan DP, Hong TS and Bardeesy N: Pancreatic adenocarcinoma. N Engl J Med. 371:2140–2141. 2014. View Article : Google Scholar : PubMed/NCBI
3	Parikh PY and Lillemoe KD: Surgical management of pancreatic cancer - distal pancreatectomy. Semin Oncol. 42:110–122. 2015. View Article : Google Scholar : PubMed/NCBI
4	Rombouts SJ, Vogel JA, van Santvoort HC, van Lienden KP, van Hillegersberg R, Busch OR, Besselink MG and Molenaar IQ: Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br J Surg. 102:182–193. 2015. View Article : Google Scholar : PubMed/NCBI
5	Gorantla B, Asuthkar S, Rao JS, Patel J and Gondi CS: Suppression of the uPAR-uPA system retards angiogenesis, invasion and in vivo tumor development in pancreatic cancer cells. Mol Cancer Res. 9:377–389. 2011. View Article : Google Scholar : PubMed/NCBI
6	Sorio C, Mafficini A, Furlan F, Barbi S, Bonora A, Brocco G, Blasi F, Talamini G, Bassi C and Scarpa A: Elevated urinary levels of urokinase-type plasminogen activator receptor (uPAR) in pancreatic ductal adenocarcinoma identify a clinically high-risk group. BMC Cancer. 11:4482011. View Article : Google Scholar : PubMed/NCBI
7	Khoi PN, Xia Y, Lian S, Kim HD, Kim do H, Joo YE, Chay KO, Kim KK and Jung YD: Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-κB and AP-1 signaling pathways. Int J Oncol. 45:1760–1768. 2014.PubMed/NCBI
8	Kotipatruni RR, Nalla AK, Asuthkar S, Gondi CS, Dinh DH and Rao JS: Apoptosis induced by knockdown of uPAR and MMP-9 is mediated by inactivation of EGFR/STAT3 signaling in medulloblastoma. PLoS One. 7:e447982012. View Article : Google Scholar : PubMed/NCBI
9	Zhuo J, Tan EH, Yan B, Tochhawng L, Jayapal M, Koh S, Tay HK, Maciver SK, Hooi SC, SaltoTellez M, et al: Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade. PLoS One. 7:e435942012. View Article : Google Scholar : PubMed/NCBI
10	Knör S, Sato S, Huber T, Morgenstern A, Bruchertseifer F, Schmitt M, Kessler H, Senekowitsch-Schmidtke R, Magdolen V and Seidl C: Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in alpha-emitter therapy for disseminated ovarian cancer. Eur J Nucl Med Mol Imaging. 35:53–64. 2008. View Article : Google Scholar : PubMed/NCBI
11	Liu D, Overbey D, Watkinson L and Giblin MF: Synthesis and characterization of an (111) In-labeled peptide for the in vivo localization of human cancers expressing the urokinase-type plasminogen activator receptor (uPAR). Bioconjug Chem. 20:888–894. 2009. View Article : Google Scholar : PubMed/NCBI
12	Daozhen C, Lu L, Min Y, Xinyu J and Ying H.: Synthesis of (131) I-labeled-[(131)I]iodo-17-allylamino-17-demethoxy geldanamycin ([(131)I]iodo-17-AAG) and its biodistribution in mice. Cancer Biother Radiopharm. 22:607–612. 2007. View Article : Google Scholar : PubMed/NCBI
13	McPherson DW and Knapp FF Jr: A rapid and simple Sep Pak method for purification of radioiodinated IQNP, a high affinity ligand for the muscarinic receptor. Nucl Med Biol. 26:859–863. 1999. View Article : Google Scholar : PubMed/NCBI
14	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
15	Michl P and Gress TM: Current concepts and novel targets in advanced pancreatic cancer. Gut. 62:317–326. 2013. View Article : Google Scholar : PubMed/NCBI
16	Persson M, Madsen J, Østergaard S, Jensen MM, Jørgensen JT, Juhl K, Lehmann C, Ploug M and Kjaer A: Quantitative PET of human urokinase-type plasminogen activator receptor with 64Cu-DOTA-AE105: Implications for visualizing cancer invasion. J Nucl Med. 53:138–145. 2012. View Article : Google Scholar : PubMed/NCBI
17	Li ZB, Niu G, Wang H, He L, Yang L, Ploug M and Chen X: Imaging of urokinase-type plasminogen activator receptor expression using a 64Cu-labeled linear peptide antagonist by microPET. Clin Cancer Res. 14:4758–4766. 2008. View Article : Google Scholar : PubMed/NCBI
18	Persson M, Madsen J, Østergaard S, Ploug M and Kjaer A: 68Ga-labeling and in vivo evaluation of a uPAR binding DOTA- and NODAGA-conjugated peptide for PET imaging of invasive cancers. Nucl Med Biol. 39:560–569. 2012. View Article : Google Scholar : PubMed/NCBI
19	Younes CK, Boisgard R and Tavitian B: Labelled oligonucleotides as radiopharmaceuticals: Pitfalls, problems and perspectives. Curr Pharm Des. 8:1451–1466. 2002. View Article : Google Scholar : PubMed/NCBI
20	Lindberg H, Hofström C, Altai M, Honorvar H, Wållberg H, Orlova A, Ståhl S, Gräslund T and Tolmachev V: Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for 99mTc-labelling at the C terminus. Tumour Biol. 33:641–651. 2012. View Article : Google Scholar : PubMed/NCBI
21	Nock B and Maina T: Tetraamine-coupled peptides and resulting (99m)Tc-radioligands: An effective route for receptor-targeted diagnostic imaging of human tumors. Curr Top Med Chem. 12:2655–2667. 2012. View Article : Google Scholar : PubMed/NCBI
22	Spanu A, Farris A, Chessa F, Sanna D, Pittalis M, Manca A and Madeddu G: Planar scintimammography and SPECT in neoadjuvant chemo or hormonotherapy response evaluation in locally advanced primary breast cancer. Int J Oncol. 32:1275–1283. 2008.PubMed/NCBI
23	Cyran CC, Paprottka PM, Eisenblätter M, Clevert DA, Rist C, Nikolaou K, Lauber K, Wenz F, Hausmann D, Reiser MF, et al: Visualization, imaging and new preclinical diagnostics in radiation oncology. Radiation Oncology. 9:32014. View Article : Google Scholar : PubMed/NCBI
24	Gorantla B, Asuthkar S, Rao JS, Patel J and Gondi CS: Suppression of the uPAR-uPA system retards angiogenesis, invasion and in vivo tumor development in pancreatic cancer cells. Mol Cancer Res. 9:377–389. 2011. View Article : Google Scholar : PubMed/NCBI