title: MicroPET imaging of breast cancer alphav-integrin expression with 64Cu-labeled dimeric RGD peptides.
abstract: OBJECTIVE
  Alphavbeta3 and alphavbeta5 integrins are cell adhesion molecules that play a vital role in tumor angiogenesis and metastasis. The ability to visualize and quantify integrin expression in vivo will foster our understanding of the role of integrins alphavbeta3 and alphavbeta5 in tumor angiogenesis and allow for direct assessment of anti-angiogenic treatment efficacy based on integrin antagonists. This study compared the tumor targeting characteristics of two dimeric 64Cu-labeled RGD peptide agonists of alphavbeta3 integrin.
  
  
  METHODS
  Dimeric RGD peptides E[c(RGDyK)]2 and E[c(RGDfK)]2 were conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with positron emitter 64Cu(t(1/2)=12.8 h, beta+=19%). Both 64Cu-DOTA-E[c(RGDyK)]2 and 64Cu-DOTA-E[c(RGDfK)]2 were used in biodistribution, microPET imaging and whole-body autoradiography studies in athymic female nude mice with orthotopically growing MDA-MB-435 breast carcinoma xenografts.
  
  
  RESULTS
  At all time points, activity accumulation of 64)Cu-DOTA-E[c(RGDyK)]2 in tumors was significantly higher compared to the D-Phe analog. Liver uptake of the D-Tyr derivative was lower than the D-Phe derivative at early time points but the difference became marginal with time. Overall, 64Cu-DOTA-E[c(RGDyK)]2 yielded better position emission tomography (PET) images in orthotopic MDA-MB-435 bearing mice than did 64Cu-DOTA-E[c(RGDfK)]2. Both radiotracers had alphav-integrin specific tumor activity accumulation, as demonstrated by significant reduction of uptake with a coinjected blocking dose of c(RGDyK).
  
  
  CONCLUSIONS
  The radiolabeled dimeric RGD peptides 64Cu-DOTA-E[c(RGDyK)]2 and 64Cu-DOTA-E[c(RGDfK)]2 have high and specific tumor uptake in a human breast cancer tumor xenograft, with the D-Tyr derivative showing better in vivo kinetics than the D-Phe derivative, most likely due to the increased hydrophilicity of the D-Tyr. Both dimeric peptides showed better tumor retention than the previously tested monomeric RGD counterparts, presumably because of bivalency and increase in apparent molecular size.
authors.affiliation: PET Imaging Science Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Yingping
authors.initials: Y
authors.lastname: Hou
authors.forename: Michel
authors.initials: M
authors.lastname: Tohme
authors.forename: Ryan
authors.initials: R
authors.lastname: Park
authors.forename: James R
authors.initials: JR
authors.lastname: Bading
authors.forename: Peter S
authors.initials: PS
authors.lastname: Conti
mesh_terms: D000818:Animals; D001345:Autoradiography; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D003301:Copper Radioisotopes; D019281:Dimerization; D005260:Female; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011859:Radiography
chemical_list: D003301:Copper Radioisotopes; D039564:Integrin alphaV; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid