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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

Correspondence: For correspondence or reprints contact: Susan L. Deutscher, PhD, Department of Biochemistry, M743 Medical Science Bldg., 1 Hospital Dr., Columbia, MO 65212. E-mail: deutschers{at}missouri.edu

Random bacteriophage (phage) display peptide libraries have traditionally been used for the selection of clones that bind specific tissues, tumors, and antigens. However, once the targeting peptide is synthetically produced, it often displays a lower affinity than the original phage because of a lack of avidity effects and removal from the virion surface. We hypothesized that multivalent bifunctional phage displaying peptides that target novel molecular biomarkers would facilitate the in vivo imaging of cancer. This study provides proof of principle for the use of phage displaying multiple melanocortin-1 receptor–homing peptides for the pretargeting and subsequent imaging of murine melanomas in vivo. Methods: A 2-step melanoma pretargeting–imaging system was developed by first generating and biotinylating phage that displayed up to 5 copies of -melanocyte–stimulating hormone (-MSH) peptide analogs. Second, streptavidin was conjugated to diethylenetriaminepentaacetic acid for the purpose of radiolabeling with ¹¹¹In. Results: The specificity of the MSH2.0 phage for the B16-F1 melanoma was demonstrated both in vitro and in vivo. In vitro micropanning assays with phage at inputs of 10⁷ and 10⁶ transducing units per milliliter resulted in 200- and 1,000-fold-greater recovery of the MSH2.0 phage over the background, respectively. In vivo distribution studies indicated that melanoma uptake values were 2.6 ± 1.1, 0.6 ± 0.2, and 1.0 ± 0.1 (mean ± SD) percentage injected dose per gram at 0.5, 6, and 24 h after the injection of ¹¹¹In-radiolabeled streptavidin (¹¹¹In-SA). The accumulation of radioactivity within the tumor was 1.8 times greater for the biotinylated MSH2.0 phage than for the biotinylated wild-type phage. These data, combined with reduction by 2.4-fold through competition with a nonradiolabeled -MSH peptide analog, indicated the specific targeting of melanoma tumors in vivo. SPECT/CT image analysis of B16-F1 melanoma–bearing mice showed that intravenously injected biotinylated -MSH phage were retained within melanoma tumors at 4 h after injection of ¹¹¹In-SA. Conclusion: This study demonstrated the use of multivalent bifunctional phage in a 2-step pretargeting–imaging system.

Key Words: bacteriophage • pretargeting • 2-step imaging • -melanocyte–stimulating hormone

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