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Melanoma Imaging with Pretargeted Bivalent Bacteriophage

¹ Department of Biochemistry, University of Missouri, Columbia, Missouri; ² College of Pharmacy, University of New Mexico, Albuquerque, New Mexico; and ³ Research Service, Harry S. Truman Veterans Memorial Hospital, Columbia, Missouri

View larger version (29K): [in this window] [in a new window]   FIGURE 1.  (A) Presence of displayed -MSH peptide analogs was probed by ability of antibody to C terminus of -MSH peptide to recognize and bind to phage-displayed peptide. Two 1-µL dots of phage solution containing 1011 virions per milliliter were immobilized on 0.2-µm nitrocellulose, and presence of phage particles was demonstrated with antiphage antibody (1:1,000 dilution). Presence of recognizable -MSH peptide was determined with antibody to C terminus of -MSH peptide (1:1,000). Complexes were detected with secondary antibody conjugated to horseradish peroxidase (1:1,500). (B) Ability of displayed peptide to be recognized and bound by MC1 receptor on cultured B16-F1 melanoma cells was determined by micropanning. Suspension of B16-F1 melanoma cells was incubated with bio-MSH2.0 phage or nonbiotinylated MSH2.0 phage at inputs of 108, 107, and 106 TU/mL for 1.5 h on rotator at 37°C. Cells were then extensively washed with PBS, and final wash containing 2.5% CHAPS was used for determination of phage titers with E. coli. Bio = biotinylated.

View larger version (24K): [in this window] [in a new window]   FIGURE 2.  (A) Biodistribution was determined through the use of C57BL/6 mice with syngeneic grafted B16-F1 melanoma tumors. These mice received tail vein injections of 5 x 1012 virions of bio-MSH2.0 phage. Four hours later, mice received tail vein injections of 1.85 MBq of 111In-SA. Mice were sacrificed at 0.5, 2, 4, 6, and 24 h after injection, and their organs were harvested for counting. (B) Tumor-to-muscle ratios and tumor-to-blood ratios for both bio-MSH2.0 phage and bio-WT phage were compared. C57BL/6 mice bearing B16-F1 tumors received tail injections of 5 x 1012 virions of bio-WT phage and, 4 h later, 1.85 MBq of 111In-SA. (C) At 24 h after injection of 111In-SA, levels of accumulation of radioactivity within tumor were compared for bio-MSH2.0 phage and bio-WT phage. (D) C57BL/6 mice with syngeneic grafted B16-F1 melanoma tumors received tail vein injections of either 5 x 1012 virions of bio-MSH2.0 phage or 5 x 1012 virions of bio-MSH2.0 phage mixed with 100 µg of NDP. Four hours later, mice received tail vein injections of 1.85 MBq of 111In-SA. Mice were sacrificed at 2 h after injection, and levels of accumulation of radiolabel within tumor were compared for both phage. *P = 0.001; **P = 0.002; ***P = 0.003.

View larger version (52K): [in this window] [in a new window]   FIGURE 3.  C57BL/6 mice with syngeneic grafted B16-F1 melanoma tumors received tail vein injections of 5 x 1012 virions of bio-MSH2.0 phage and, 4 h later, 7.40 MBq of 111In-SA. Mice were sacrificed at 4 h after injection, and image data were acquired with small-animal SPECT/CT system.