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.

• Authors: Bing Xiu Ren, Fan Yang, Gao Hong Zhu, Zi Xing Huang, Hua Ai, Rui Xia, Xi Jiao Liu, Man Lu, Bin Song
• Journal: Cancer science (Cancer Sci) Vol. 103 Issue 8 Pg. 1434-9 (Aug 2012) ISSN: 1349-7006 [Electronic] England
• PMID: 22534012 (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)
• Adenocarcinoma of Lung
• 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)