title: Evaluation of a Fluorescent and Radiolabeled Hybrid Somatostatin Analog In Vitro and in Mice Bearing H69 Neuroendocrine Xenografts.
abstract: In the treatment of neuroendocrine tumors (NETs), complete surgical removal of malignancy is generally desirable, because it offers curative results. Preoperative guidance with radiolabeled somatostatin analogs, commonly used for NET diagnosis and preoperative planning, is limited by its low resolution, with the risk that tumor margins and small metastases will be incompletely resected with subsequent recurrence. A single hybrid probe combining radiotracer and optical dye would enable high-resolution optical guidance, also during surgery. In the current study, the hybrid labeled somatostatin analog Cy5-DTPA-Tyr(3)-octreotate (DTPA is diethylene triamine pentaacetic acid) was synthesized and evaluated for its ability to specifically trace NET cells in vitro and in an animal model. The performance of the hybrid tracer was compared with that of octreotate with only radiolabel or only optical label.
  
  
  
  The binding affinity and internalization capacity of Cy5-DTPA-Tyr(3)-octreotate were assessed in vitro. Biodistribution profiles and both nuclear and optical in vivo imaging of Cy5-(111)In -DTPA-Tyr(3)-octreotate were performed in NET-bearing mice and compared with the performance of (111)In-DTPA-Tyr(3)-octreotate.
  
  
  
  In vitro studies showed a low receptor affinity and internalization rate for Cy5-DTPA-Tyr(3)-octreotate. The dissociation constant value was 387.7 ± 97.9 nM for Cy5-DTPA-Tyr(3)-octreotate, whereas it was 120.5 ± 18.1 nM for DTPA-Tyr(3)-octreotate. Similarly, receptor-mediated internalization reduced from 33.76% ± 1.22% applied dose for DTPA-Tyr(3)-octreotate to 1.32% ± 0.02% applied dose for Cy5-DTPA-Tyr(3)-octreotate. In contrast, in vivo and ex vivo studies revealed similar tumor uptake values of Cy5-(111)In-DTPA-Tyr(3)-octreotate and (111)In -DTPA-Tyr(3)-octreotate (6.93 ± 2.08 and 5.16 ± 1.27, respectively). All organs except the kidneys showed low background radioactivity, with especially low activities in the liver, and high tumor-to-tissue ratios were achieved-both favorable for the tracer's toxicity profile. Hybrid imaging in mice confirmed that the nuclear and fluorescence signals colocalized.
  
  
  
  The correlation between findings with the optical and the nuclear probes underlines the potential of combining SPECT imaging with fluorescence guidance and shows the promise of this novel hybrid peptide for preoperative and intraoperative imaging of NET.
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands c.santini@erasmusmc.nl.
authors.forename: Costanza
authors.initials: C
authors.lastname: Santini
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, LUMC, Leiden, The Netherlands.
authors.forename: Joeri
authors.initials: J
authors.lastname: Kuil
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, LUMC, Leiden, The Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Bunschoten
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pool
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.affiliation: Department of Genetics, Erasmus MC, Rotterdam, The Netherlands; and.
authors.forename: Yanto
authors.initials: Y
authors.lastname: Ridwan
authors.affiliation: Department of Genetics, Erasmus MC, Rotterdam, The Netherlands; and Departments of Radiation Oncology and Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Monique R
authors.initials: MR
authors.lastname: Bernsen
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, LUMC, Leiden, The Netherlands.
authors.forename: Fijs W B
authors.initials: FW
authors.lastname: van Leeuwen
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence / Q000379:methods; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013004:Somatostatin / Q000031:analogs & derivatives*; D014018:Tissue Distribution
chemical_list: D005456:Fluorescent Dyes; D019275:Radiopharmaceuticals; D013004:Somatostatin
keywords: image-guided surgery; multimodal imaging; neuroendocrine tumors; octreotate