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PET Imaging of CCND1 mRNA in Human MCF7 Estrogen Receptor–Positive Breast Cancer Xenografts with Oncogene-Specific [⁶⁴Cu]Chelator-Peptide Nucleic Acid-IGF1 Analog Radiohybridization Probes

¹ Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; ² Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ³ Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania; and ⁴ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

View larger version (16K): [in this window] [in a new window]   FIGURE 1.  Schematic of [64Cu]DO3A-PNA-IGF1 analog, designed to bind to the receptor for IGF1, internalize, and hybridize with CCND1 mRNA. PET of -particles created by electron annihilation of positrons from decaying 64Cu might identify sites of high CCND1 mRNA expression in breast cancer xenografts. (Adapted with permission of (10).)

View larger version (37K): [in this window] [in a new window]   Scheme 1

View larger version (40K): [in this window] [in a new window]   FIGURE 2.  Characterization of cyclized CCND1 hybridization probe WT4348. (A) Preparative HPLC on 10 x 250 mm Microsorb C18 column, eluted with a 35-min gradient from 0% to 60% CH3CN in aqueous 0.1% CF3CO2H, at 1 mL/min, = 260 nm, at 50°C. (B) ESI mass spectrum. Calculated exact mass: 4,344.32 Da; Experimental mass: 1,449.8 Da (M +3)/3; 1,087.8 Da (M +4)/4. (C) Analytic HPLC of [64Cu]WT4348 on 4.5 x 250 mm Dynamax C18 column eluted with a 28-min gradient from 10% to 90% CH3CN in aqueous 0.1% CF3CO2H at 1 mL/min, at 25°C. Percent CH3CN is shown on right y-axis, and radiometric -particle emission is shown on the y-axis. (D) Analytic HPLC of [64Cu]WT4348 recovered from urine of tumor-bearing mice 2 h after administration, chromatographed as in C.

View larger version (51K): [in this window] [in a new window]   FIGURE 3.  Transverse microPET and microCT images of immunocompromised NCr mice bearing human MCF7 ER+ xenografts on their right flanks recorded at 4 and 24 h after tail vein injection of 3.7–7.4 MBq (100–200 µCi) of CCND1 [64Cu]WT4348 hybridization probe, [64Cu]WT4273 peptide mismatch probe, [64Cu]WT4322 PNA mismatch probe, or free 64CuCl2 as an unchelated control. Yellow line on coronal CT image shows the level of transverse images. All images are displayed on the same scale. Color scale of the images was normalized to the maximum/minimum of frame to show dynamic range of tumor uptake. Ratios of maximum tumor PET image intensities to contralateral tissue average intensities were calculated for equal-sized ROI.

View larger version (47K): [in this window] [in a new window]   FIGURE 4.  Ratios of tumor PET pixel counts in each 1 x 1 x 1 mm3 voxel across a central 1-mm slice of human MCF7 ER+ xenograft, vs. contralateral tissue PET counts, 4 h after administration of [64Cu]DOTA-PNA-peptide radiohybridization probes. (A) PNA mismatch probe [64Cu]WT4322 or (B) CCND1 probe [64Cu]WT4348.