Preclinical Evaluation of a Novel In-111-Labeled Bombesin Homodimer for Improved Imaging of GRPR-Positive Prostate Cancer

Carlucci, G., Ananias, H. J. K., Yu, Z., Hoving, H. D., Helfrich, W., Dierckx, R. A. J. O., Liu, S., de Jong, I. J. & Elsinga, P. H., May-2013, In : Molecular pharmaceutics. 10, 5, p. 1716-1724 9 p.

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Rational-designed multimerization of targeting ligands can be used to improve kinetic and thermodynamic properties. Multimeric targeting ligands may be produced by tethering multiple identical or two or more monomeric ligands of different binding specificities. Consequently, multimeric ligands may simultaneously bind to multiple receptor molecules. Previously, multimerization has been successfully applied on radiolabeled RGD peptides, which resulted in an improved tumor targeting activity in animal models. Multimerization of peptide-based ligands may improve the binding characteristics by increasing local ligand concentration and by improving dissociation kinetics. Here, we present a preclinical study on a novel radiolabeled bombesin (BN) homodimer, designated In-111-DOTA-[(Aca-BN(7-14)](2), that was designed for enhanced targeting of gastrin-releasing peptide receptor (GRPR)-positive prostate cancer cells. A BN homodimer was conjugated with DOTA-NHS and labeled with In-111. After HPLC purification, the GRPR targeting ability of In-111-DOTA-[(Aca-BN(7-14)](2) was assessed by microSPECT imaging in SCUD mice xenografted with the human prostate cancer cell line PC-3. In-111 labeling of DOTA-[(Aca-BN(7-14)](2) was achieved within 30 min at 85 C with a labeling yield of >40%. High radiochemical purity (>95%) was achieved by HPLC purification. In-111-DOTA-[(Aca-BN(7-14)](2) specifically bound to GRPR-positive PC-3 prostate cancer cells with favorable binding characteristics because uptake of In-111-DOTA-[Aca-BN(7-14)](2) in GRPR-positive PC-3 cells increased over time. A maximum peak with 30% radioactivity was observed after 2 h of incubation. The log D value was -1.8 +/- 0.1. In-111-DOTA-[(Aca-BN(7-14)](2) was stable in vitro both in PBS and human serum for at least 4 days. In vivo biodistribution analysis and microSPECT/CT scans performed after 1, 4, and 24 h of injection showed favorable binding characteristics and tumor-to-normal tissue ratios. This study identifies In-111-DOTA-[(Aca-BN(7-14)](2) as a promising radiotracer for nuclear imaging of GRPR in prostate cancer.

Original languageEnglish
Pages (from-to)1716-1724
Number of pages9
JournalMolecular pharmaceutics
Issue number5
Publication statusPublished - May-2013


  • GRPR, bombesin homodimer, In-111-DOTA, prostate cancer imaging, PC-3 tumor model, RECEPTOR-EXPRESSING TUMORS, PEPTIDE-RECEPTOR, IN-VITRO, ANALOGS, RADIOPHARMACEUTICALS, THERAPY, DESIGN, LU-177, Y-90

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