Tc-99m and Cu-64 PNA-peptide hybridization probes for imaging of oncogene activation in pancreatic cancer Free

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Out of 30 thousand people who die from pancreatic cancer every year, 90% carry 12th codon activating mutations in their KRAS oncogenes. Physical examinations, X-rays, CT scans, blood analyses, and urinalyses, the only generally accepted screening tools available miss many early cancers. Current imaging modalities like CT or MRI provide precise structural details but nothing about function or molecular signature. Imaging gene expression non-invasively with high sensitivity and specificity could identify malignant foci at an early stage and provide a more powerful diagnostic tool than those currently used. Antisense PNA 12-mer probes were synthesized to target KRAS, MYC, and p53 mRNAs. PNA-peptide chimeras were prepared with a C-terminal IGF1 ligand designed to bind to IGF1 receptors on malignant cells, and N-terminal chelating moieties for radionuclide labeling. We have observed that PNA-peptides with IGF1 ligand were taken up specifically and that Tc-99m peptides can delineate tumors. The probes were purified by HPLC and characterized by electrospray and MALDI-TOF mass spectroscopy. Probes labeled with Tc-99m and Cu-64 accumulated in pancreatic cancer xenografts in immunocompromised mice. These experiments show that our concept for noninvasive detection of gene expression in tissues by gamma and positron imaging is plausible and could be applicable to image any particular mRNA of interest in a cell type with characteristic receptors. Supported by NCI CO-27175-01.