External Imaging of CCND1 Cancer Gene Activity in Experimental Human Breast Cancer Xenografts with 99mTc-Peptide-Peptide Nucleic Acid-Peptide Chimeras

Journal of Nuclear Medicine

Mohan R. Aruva¹  Wenyi Qin¹  Weizhu Zhu¹  Xiaobing Tian¹  Edward R. Sauter¹  Kevin T. Duffy¹  Mathew L. Thakur¹  Eric Wickstrom¹ 

关键词: antisense;    oligonucleotides;    oncogenes;    peptides;    radionuclides;    scintigraphy;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Detection of a new or recurrent breast cancer lesion relies on physical examination and imaging studies, primarily mammography, followed by histopathologic evaluation of biopsy tissue for morphologic confirmation. Approximately 66%–85% of detected lesions are not malignant. Therefore, biopsies are unnecessary for at least two thirds of patients. Human estrogen receptor-positive breast cancer cells typically display an elevated level of cyclin D1 protein because of the overexpression of CCND1 messenger RNA (mRNA) and an elevated level of insulin-like growth factor 1 (IGF1) receptor (IGF1R) because of the overexpression of IGF1R mRNA. We hypothesized that scintigraphic detection of CCND1 peptide nucleic acid (PNA) hybridization probes with a 99mTc-chelating peptide on the N terminus and an IGF1 peptide loop on the C terminus could detect CCND1 mRNA in human MCF7 breast cancer xenografts in nude mice from outside the body. Methods: We prepared the CCND1 probes as well as mismatched controls by solid-phase synthesis. We used fluorescence microscopy to detect the cellular uptake of fluoresceinyl probes and quantitative reverse transcription-polymerase chain reaction to detect the hybridization of probes to mRNA. We imaged 99mTc-probes in MCF7 xenografts scintigraphically and measured distribution by scintillation counting of dissected tissues. Results: IGF1R-overexpressing MCF7 cells internalized the fluorescein-chelator-CCND1 PNA-IGF1 peptide but not the mismatched control peptide. The chelator-CCND1 PNA-IGF1 peptide but not the control peptide lowered the level of cyclin D1 protein in IGF1R-overexpressing MCF7 xenografts in nude mice after intratumoral injection. IGF1R-overexpressing MCF7 xenografts in nude mice were visualized at 4, 12, and 24 h after tail vein administration of the 99mTc-CCND1 antisense probe but not the control probe. 99mTc-chimeras were distributed normally in the kidneys, liver, tumors, and other tissues. Conclusion: Cancer gene activity can be detected from outside the body by probing with radionuclide-chelator-PNA-peptide chimeras.

【 授权许可】

Unknown