Receptor-specific targeting with complementary peptide nucleic acids conjugated to peptide analogs and radionuclides |
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Authors: | Eric Wickstrom Mathew L. Thakur Edward R. Sauter |
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Affiliation: | (1) Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, 19107 Philadelphia, PA, USA;(2) Kimmel Cancer Center, Thomas Jefferson University, 19107 Philadelphia, PA, USA;(3) Department of Radiology, Thomas Jefferson University, 19107 Philadelphia, PA, USA;(4) Department of Radiation Oncology, Thomas Jefferson University, 19107 Philadelphia, PA, USA;(5) Cardeza Foundation for Hematologic Research, Thomas Jefferson University, 19107 Philadelphia, PA, USA;(6) Department of Surgery, University of Missouri, 65212 Columbia, MO, USA |
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Abstract: | Summary Genomic sequencing makes it possible to identify all the genes of an organism, now including Homo sapiens. Yet measurement of the expression of each gene of interest still presents a daunting prospect. Northern blots, RNase protection assays, as well as microarrays and related technologies permit measurement of gene expression in total RNA extracted from cultured cells or tissue samples. It would be most valuable, however, to quantitate gene expression noninvasively in living cells and tissues. Unfortunately, no reliable method has been available to measure levels of specific mRNAs in vivo. Peptide nucleic acids (PNAs) display superior ruggedness and hybridization properties as a diagnostic tool for gene expression, and could be used for this purpose. On the down side, they are negligibly internalized by normal or malignant cells in the absence of conjugated ligands. Nevertheless, we have observed that Tc-99m-peptides can delineate tumors, and PNA-peptides designed to bind to IGF-1 receptors on malignant cells are taken up specifically and concentrated in nuclei. We have postulated that antisense Tc-99m-PNA-peptides will be taken up by human cancer cells, will hybridize to complementary mRNA targets, and will permit scintigraphic imaging of oncogene mRNAs in human cancer xenografts in a mouse model. The oncogenes cyclin D1, ERBB2, c-MYC, K-RAS, and tumor suppressor p53 are being probed initially. These experiments provide a proof-of-principle for noninvasive detection of oncogene expression in living cells and tissues. This scintigraphic imaging technique should be applicable to any particular gene of interest in a cell or tissue type with characteristic receptors. |
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Keywords: | antisense breast cancer chelators conjugates gene expression hybridization imaging non-invasive oligonucleotides oncogenes peptides radionuclides scintigraphy tumors |
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