title: Novel (188)Re multi-functional bone-seeking compounds: Synthesis, biological and radiotoxic effects in metastatic breast cancer cells.
abstract: BACKGROUND
  Radiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β(-) emitting radionuclides for bone pain palliation. As a β(-) emitter, (188)Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)], (L=BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line.
  
  
  METHODS
  After synthesis and characterization of the novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively.
  
  
  RESULTS
  Among all complexes, (188)Re3 was obtained with high radiochemical purity (>95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of (188)Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1 ± 3.3% IA/g organ, 1h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by (188)Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [(188)ReO4](-). Additionally, (188)Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed.
  
  
  CONCLUSIONS
  Altogether, our results demonstrate that (188)Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce radiation damage.
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal. Electronic address: celiaf@ctn.ist.utl.pt.
authors.forename: Célia
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Monteiro
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Belchior
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal.
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal.
authors.forename: João D G
authors.initials: JD
authors.lastname: Correia
authors.affiliation: Centro de Ciências e Tecnologias Nucleares (C(2)TN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), LRS, 2695-066 Bobadela, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
mesh_terms: D000818:Animals; D001692:Biological Transport; D001859:Bone Neoplasms / Q000532:radiotherapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D017886:Durapatite / Q000378:metabolism; D005260:Female; D051379:Mice; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D011868:Radioisotopes / Q000009:adverse effects / Q000627:therapeutic use*; D012211:Rhenium / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D009942:Organometallic Compounds; D011868:Radioisotopes; D012211:Rhenium; D017886:Durapatite
keywords: Bisphosphonates; Bone pain palliation; Radiocytotoxic effects; Radiopharmaceuticals; Rhenium-188; Systemic radiotherapy