title: Preparation and preclinical evaluation of (66)Ga-DOTA-E(c(RGDfK))2 as a potential theranostic radiopharmaceutical.
abstract: BACKGROUND
  Integrin αvβ3 plays an important role in angiogenesis and is over-expressed in tumoral endothelial cells and some other tumor cells. RGD (Arg-Gly-Asn) peptides labeled with (68)Ga (t1/2=68min) have showed good characteristics for imaging of αvβ3 expression using positron emission tomography (PET). Gallium-66 has been proposed as a PET imaging alternative to (68)Ga and given the unique high energy of its emitted positrons (Emax 4.15MeV) it may also be useful for therapy. The aim of this research is to prepare [(66)Ga]DOTA-E-[c(RGDfK)]2 and evaluate in mice its potential as a new theranostic radiopharmaceutical.
  
  
  METHODS
  High specific activity (66)Ga was produced via the (66)Zn(p,n) reaction, and the labelling method of DOTA-E-[c(RGDfK)]2 with (66)Ga was optimized. Radiochemical purity was determined by TLC, and in vitro stability and protein binding were determined. Serial microPET imaging and biodistribution studies were carried out in nude mice bearing C6 xenografts. Radiation absorbed dose estimates were based on the biodistribution studies, where tumor and organs of interest were collected at 0.5, 1, 3, 5 and 24h post-injection of [(66)Ga]DOTA-E-[c(RGDfK)]2.
  
  
  RESULTS
  Our results have shown that [(66)Ga]DOTA-E-[c(RGDfK)]2 can be prepared with high radiochemical purity (>97%), specific activity (36-67GBq/μmol), in vitro stability, and moderate protein binding. MicroPET imaging up to 24 post-injection showed contrasting tumors reflecting αvβ3-targeted tracer accumulation. Biodistribution studies and dosimetry estimations showed a stable tumor uptake, rapid blood clearance, and favorable tumor-to-tissue ratios.
  
  
  CONCLUSIONS
  The peptide conjugated DOTA-E-[c(RGDfK)]2 labeled with (66)Ga may be attractive as a theranostic agent for tumors over-expressing αvβ3 integrins.
authors.affiliation: Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., Mexico.
authors.forename: V
authors.initials: V
authors.lastname: Lopez-Rodriguez
authors.affiliation: Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., Mexico.
authors.forename: R E
authors.initials: RE
authors.lastname: Gaspar-Carcamo
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Pedraza-Lopez
authors.affiliation: Instituto Nacional de Investigaciones Nucleares, Estado de México, Mexico.
authors.forename: E L
authors.initials: EL
authors.lastname: Rojas-Calderon
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., Mexico.
authors.forename: C
authors.initials: C
authors.lastname: Arteaga de Murphy
authors.affiliation: Instituto Nacional de Investigaciones Nucleares, Estado de México, Mexico.
authors.forename: G
authors.initials: G
authors.lastname: Ferro-Flores
authors.affiliation: Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., Mexico. Electronic address: avilarod@uwalumni.com.
authors.forename: M A
authors.initials: MA
authors.lastname: Avila-Rodriguez
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D005710:Gallium Radioisotopes / Q000627:therapeutic use; D005910:Glioma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
keywords: Angiogenesis; Gallium-66; Integrin α(v)β(3); PET imaging; RGD peptides; Theranostics