title: In vivo optical imaging of integrin alphaV-beta3 in mice using multivalent or monovalent cRGD targeting vectors.
abstract: BACKGROUND
  The cRGD peptide is a promising probe for early non-invasive detection of tumors. This study aimed to demonstrate how RAFT-c(-RGDfK-)4, a molecule allowing a tetrameric presentation of cRGD, improved cRGD-targeting potential using in vivo models of alphaVbeta3-positive or negative tumors.
  
  
  RESULTS
  We chose the human embryonic kidney cells HEK293(beta3) (high levels of alphaVbeta3) or HEK293(beta1) (alphaVbeta3-negative but expressing alphaV and beta1) engrafted subcutaneously (s.c.) in mice. Non-invasive in vivo optical imaging demonstrated that as compared to its monomeric cRGD analogue, Cy5-RAFT-c(-RGDfK-)4 injected intravenously had higher uptake, prolonged retention and markedly enhanced contrast in HEK293(beta3) than in the HEK293(beta1) tumors. Blocking studies further demonstrated the targeting specificity and competitive binding ability of the tetramer.
  
  
  CONCLUSIONS
  In conclusion, we demonstrated that Cy5-RAFT-c(-RGDfK-)4 was indeed binding to the alphaVbeta3 receptor and with an improved activity as compared to its monomeric analog, confirming the interest of using multivalent ligands. Intravenous injection of Cy5-RAFT-c(-RGDfK-)4 in this novel pair of HEK293(beta3) and HEK293(beta1) tumors, provided tumor/skin ratio above 15. Such an important contrast plus the opportunity to use the HEK293(beta1) negative control cell line are major assets for the community of researchers working on the design and amelioration of RGD-targeted vectors or on RGD-antagonists.
authors.affiliation: INSERM, U823, Cibles Diagnostiques ou Thérapeutiques et Vectorisation des Drogues dans le Cancer du Poumon, Institut Albert Bonniot, La Tronche Cedex, France. jinzhaohui67@yahoo.com
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Jin
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Foillard
authors.forename: Didier
authors.initials: D
authors.lastname: Boturyn
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Favrot
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C521994:Cy5-RAFT-c(-RGDfK-)4; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide