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Magnetic resonance tumor targeting imaging using gadolinium labeled human telomerase reverse transcriptase antisense probes.

Abstract
To develop a molecular probe for MRI detection of human tumor telomerase reverse transcriptase (hTERT) mRNA expression. Uniformly phosphorothioate-modified hTERT antisense oligonucleotide (ASON) homing hTERT mRNA was labeled with gadolinium (Gd) through the bifunctional chelator 1,4,7, 10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) stirred within 45 minutes at 60 °C. The Gd labeled probes were characterized in vitro. The cellular uptake rate and biodistribution of (99m) Tc-DOTA-ASON was measured instead of that of Gd-DOTA-ASON. A549 lung adenocarcinoma model was established in BALB/c nude mice and Gd-DOTA-ASON was injected intraperitoneally and MR images were acquired using 7.0T Micro-MRI (Bruker Biospec, Ettlingen, Germany) at different time points. Immunohistochemical analysis of telomerase activity of each xenograft was operated two days after in vivo imaging. The binding efficiency of Gd-DOTA-ASON reached as high as 71.7 ± 4.5% (n = 6). Gd-DOTA-ASON displayed perfect stability in fresh human serum at 37 °C for 24 h. Compared with normal lung cells, A549 cells showed an obviously higher uptake of (99m) Tc-DOTA-ASON than that of lung cells (10.5 ± 2.7% vs. 4.8 ± 2.6%, P < 0.05). The signal intensity of A549 xenografts can be enhanced by Gd-DOTA-ASON and the signal to noise ratio (SNR) of tumor to muscle reached 2.37 and maintained a relatively high level within 6 h after injection. The activity of hTERT in A549 tumors can be suppressed by Gd-DOTA-ASON in pathological slices. The results of this study show that Gd-DOTA-ASON can be a promising intracellular MR contrast probe for targeting telomerase-positive carcinomas.
AuthorsBing Xiu Ren, Fan Yang, Gao Hong Zhu, Zi Xing Huang, Hua Ai, Rui Xia, Xi Jiao Liu, Man Lu, Bin Song
JournalCancer science (Cancer Sci) Vol. 103 Issue 8 Pg. 1434-9 (Aug 2012) ISSN: 1349-7006 [Electronic] England
PMID22534012 (Publication Type: Journal Article)
Copyright© 2012 Japanese Cancer Association.
Chemical References
  • Heterocyclic Compounds
  • Oligonucleotides, Antisense
  • Organometallic Compounds
  • RNA, Messenger
  • gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
  • TERT protein, human
  • Telomerase
Topics
  • Adenocarcinoma (diagnosis)
  • Animals
  • Cell Line, Tumor
  • Heterocyclic Compounds
  • Humans
  • Lung Neoplasms (diagnosis)
  • Magnetic Resonance Imaging (methods)
  • Mice
  • Mice, Nude
  • Oligonucleotides, Antisense
  • Organometallic Compounds
  • RNA, Messenger (metabolism)
  • Signal-To-Noise Ratio
  • Telomerase (genetics, metabolism)

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