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Influence of Chelate Conjugation on a Newly Identified Tumor-Targeting Peptide

¹ Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany; ² Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany; ³ Research Laboratories, Bayer-Schering-Pharma AG, Berlin, Germany; ⁴ Department of Bimolecular Interactions, German Cancer Research Center, Heidelberg, Germany; and ⁵ Department of Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany

View larger version (19K): [in this window] [in a new window]   FIGURE 1.  Structural characteristics of peptides FROP-1 and FROPDOTA: CD spectra of 100 µg/mL FROP-1 (dashed line) and 100 µg/mL FROPDOTA (solid line) in aqueous solutions containing 10% TFE. Mol. Ellip. = molar ellipticity.

View larger version (10K): [in this window] [in a new window]   FIGURE 2.  (A and B) In vitro binding kinetics of 111In-FROPDOTA without 1% BSA (A) and with 1% BSA (B).

View larger version (9K): [in this window] [in a new window]   FIGURE 3.  In vitro competition assay with FROPDOTA using unlabeled FROP-1 as competitor. Unlabeled FROP-1 in concentrations ranging from 10–4 to 10–8 M was added to cells immediately before 111In-FROPDOTA and incubated for 3 h. All experiments were performed in triplicate; SDs are shown.

View larger version (10K): [in this window] [in a new window]   FIGURE 4.  (A and B) In vitro binding studies of FROPDOTA to various tumor cells lines: FRO82-2, SW1736, HCT116, MCF-7, HNO 97, HNO 223, HNO 210, and the nontumor cell line HPV-16-GM and the primary endothelial cells (HUVEC). Cells were incubated with 111In-FROPDOTA without competitor (–) or with 10–4 M unlabeled FROP-1 (+) for 3 h at 37°C. Experiments were performed in triplicate; SDs are shown.

View larger version (11K): [in this window] [in a new window]   FIGURE 5.  Internalization of 111In-FROPDOTA in MCF-7 cells. Cells were incubated with 3–5 x 105 cpm radioligand for 10 min, 1 h, and 3 h at 37°C. To remove outside-bound peptide, cells were washed with acidic glycine buffer (pH 2.8). Afterward, cells were lysed and internalized radioactivity was measured. 1W = first acidic wash; 2W = second acidic wash; L = lysate; C = control in presence of unlabeled peptide; 4°C = lysate fraction of same experiment conducted at 4°C. Experiments were performed in triplicate; SDs are shown.

View larger version (17K): [in this window] [in a new window]   FIGURE 6.  RP-HPLC analyses of degradation samples of 111In-FROPDOTA incubated in human serum. t0 = time 0.

View larger version (15K): [in this window] [in a new window]   FIGURE 7.  Biodistribution of FROPDOTA in female BALB/c nu/nu mice carrying FRO82-2 tumors (A) (n = 3 animals per time point) or MCF-7 tumors (B) (n = 3 animals per time point). Animals were injected intravenously with 111In-FROPDOTA, and the radioactivity was measured in tumor and control organs after 5, 15, 45, and 135 min; SDs are shown.

View larger version (6K): [in this window] [in a new window]   FIGURE 8.  Chemical structure of FROPDOTA (H-EDYELMDLLAYLK(DOTA)-NH2). Amino acids 1–7 comprise 4 carboxylic acids. The strong negative net charged part of molecule is linked to the chelator via a hydrophobic molecule part.