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

¹ Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania
² Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
³ Department of Surgery, University of Missouri, Columbia, Missouri
⁴ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

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.

Key Words: antisense • oligonucleotides • oncogenes • peptides • radionuclides • scintigraphy

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