title: Triple targeting of Auger emitters using octreotate conjugated to a DNA-binding ligand and a nuclear localizing signal.
abstract: We investigated the effect of incorporation of a nuclear localization signal (NLS) into a conjugate comprising the DNA binding ligand para-iodoHoechst (PIH) and octreotate on its DNA binding and affinity to the somatostatin receptor (SSTR). Confirmation of these properties would support development of similar conjugates labelled with Auger emitters for their potential in Auger endoradiotherapy.
  
  
  
  We synthesized conjugates of PIH and octreotate (PO) or PIH and NLS (PN) and a conjugate comprising PIH, NLS and octreotate (PNO). DNA-binding characteristics of PIH and conjugates were assessed using synthetic DNA oligonucleotides employing spectrophotometric titration of ligand solutions with DNA. We used membranes from the type 2 SSTR (SSTR2) overexpressing human non-small cell lung cancer cell line A427-7 to investigate the binding affinity of PNO.
  
  
  
  We demonstrated PN and PNO retain specific high affinity DNA-binding properties observed for PIH, and acquire an additional non-specific binding capacity. No DNA binding was observed for PO. PNO retains its binding affinity for SSTR.
  
  
  
  The DNA-binding properties of PNO and its affinity for SSTR suggests that it could potentially be used for tumour-specific delivery of PIH labelled with an Auger emitter in SSTR expressing tumours.
authors.affiliation: a Division of Radiation Oncology and Cancer Imaging , Peter MacCallum Cancer Centre , East Melbourne , Victoria , Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Violet
authors.affiliation: b Molecular Radiation Biology Laboratory , Peter MacCallum Cancer Centre , East Melbourne , Victoria , Australia.|c The Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne , Victoria , Australia.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Farrugia
authors.affiliation: d School of Chemistry and Bio21 Institute , University of Melbourne , Melbourne , Victoria , Australia.
authors.forename: Colin
authors.initials: C
authors.lastname: Skene
authors.affiliation: d School of Chemistry and Bio21 Institute , University of Melbourne , Melbourne , Victoria , Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: White
authors.affiliation: b Molecular Radiation Biology Laboratory , Peter MacCallum Cancer Centre , East Melbourne , Victoria , Australia.|c The Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne , Victoria , Australia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Lobachevsky
authors.affiliation: b Molecular Radiation Biology Laboratory , Peter MacCallum Cancer Centre , East Melbourne , Victoria , Australia.|c The Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne , Victoria , Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Martin
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism*; D004583:Electrons / Q000627:therapeutic use; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007553:Isotope Labeling / Q000379:methods; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D007457:Iodine Radioisotopes; D019913:Nuclear Localization Signals; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-
keywords: Auger radionuclide therapy; DNA minor groove binder; neuroendocrine tumours; nuclear localizing signal; octreotate