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Evaluation of an ¹¹¹In-Radiolabeled Peptide as a Targeting and Imaging Agent for ErbB-2 Receptor–Expressing Breast Carcinomas

Authors' Affiliations: ¹ Department of Biochemistry, University of Missouri-Columbia and ² Harry S. Truman Veterans Hospital, Columbia, Missouri

Requests for reprints: Susan L. Deutscher, Department of Biochemistry, M743 Medical Sciences Building, University of Missouri-Columbia, Columbia, MO 65212. Phone: 573-882-2454; Fax: 573-884-4597; E-mail: deutschers{at}missouri.edu.

Purpose: The cellular targeting and tumor imaging properties of a novel ErbB-2-avid peptide, discovered from bacteriophage display, were evaluated in human breast carcinoma cells and in breast carcinoma–xenografted mice.

Experimental Design: The affinity of the ErbB-2 targeting peptide KCCYSL and its alanine substituted counterparts for the extracellular domain (ECD) of purified recombinant ErbB-2 (ErbB-2-ECD) was assessed by fluorescence titration. Binding of the KCCYSL peptide to breast and prostate carcinoma cells was analyzed by confocal microscopy. A DOTA(GSG)-KCCYSL peptide conjugate was radiolabeled with ¹¹¹In, and stability, target binding, and internalization were analyzed in vitro. In vivo biodistribution and single-photon emission computed tomography imaging studies were done with the radiolabeled peptide in MDA-MB-435 human breast tumor–bearing severe combined immunodeficient mice.

Results: KCCYSL peptide exhibited high affinity (295 ± 56 nmol/L) to ErbB-2-ECD. Substitution of alanine for lysine, tryptophan, and cysteine reduced the peptide affinity 1- to 2.4-fold, whereas replacing leucine completely abolished binding. Both biotin-KCCYSL and ¹¹¹In-DOTA(GSG)-KCCYSL were capable of binding ErbB-2–expressing human breast carcinoma cells in vitro. Approximately 11% of the total bound radioactivity was internalized in the carcinoma cells. Competitive binding studies indicated that the radiolabeled peptide exhibited an IC₅₀ value of 42.5 ± 2.76 nmol/L for the breast carcinoma cells. ¹¹¹In-DOTA(GSG)-KCCYSL was stable in serum and exhibited rapid tumor uptake (2.12 ± 0.32 %ID/g) at 15 min postinjection and extended retention coupled with rapid whole body disappearance, as observed by biodistribution and single-photon emission computed tomography imaging studies, respectively.

Conclusions: The DOTA(GSG)-KCCYSL peptide has the potential to be used as a tumor-imaging agent and a vehicle for specific delivery of radionuclide or cytotoxic agents for tumors overexpressing ErbB-2.

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