Evaluation of a technetium-99m labeled bombesin homodimer for GRPR imaging in prostate cancer

Zilin Yu*, Giuseppe Carlucci, Hildo J. K. Ananias, Rudi A. J. O. Dierckx, Shuang Liu, Wijnand Helfrich, Fan Wang, Igle J. de Jong, Philip H. Elsinga

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)

Abstract

Multimerization of peptides can improve the binding characteristics of the tracer by increasing local ligand concentration and decreasing dissociation kinetics. In this study, a new bombesin homodimer was developed based on an epsilon-aminocaproic acid-bombesin(7-14) (Aca-bombesin(7-14)) fragment, which has been studied for targeting the gastrin-releasing peptide receptor (GRPR) in prostate cancer. The bombesin homodimer was conjugated to 6-hydrazinopyridine-3-carboxylic acid (HYNIC) and labeled with Tc-99m for SPECT imaging. The in vitro binding affinity to GRPR, cell uptake, internalization and efflux kinetics of the radiolabeled bombesin dimer were investigated in the GRPR-expressing human prostate cancer cell line PC-3. Biodistribution and the GRPR-targeting potential were evaluated in PC-3 tumor-bearing athymic nude mice. When compared with the bombesin monomer, the binding affinity of the bombesin dimer is about ten times lower. However, the Tc-99m labeled bombesin dimer showed a three times higher cellular uptake at 4 h after incubation, but similar internalization and efflux characters in vitro. Tumor uptake and in vivo pharmacokinetics in PC-3 tumor-bearing mice were comparable. The tumor was visible on the dynamic images in the first hour and could be clearly distinguished from non-targeted tissues on the static images after 4 h. The GRPR-targeting ability of the Tc-99m labeled bombesin dimer was proven in vitro and in vivo. This bombesin homodimer provides a good starting point for further studies on enhancing the tumor targeting activity of bombesin multimers.

Original languageEnglish
Pages (from-to)543-553
Number of pages11
JournalAmino Acids
Volume44
Issue number2
DOIs
Publication statusPublished - Feb-2013

Keywords

  • GRPR
  • Bombesin homodimer
  • Radiolabeled
  • Imaging
  • Prostate cancer
  • PC-3
  • Tc-99m
  • HYNIC
  • SPECT
  • GASTRIN-RELEASING-PEPTIDE
  • ALPHA(V)BETA(3) INTEGRIN
  • RGD PEPTIDES
  • HETERODIMER
  • TUMORS
  • PET
  • IMMUNOREACTIVITY
  • EXPRESSION
  • ANALOGS
  • DIMERS

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