title: Imaging integrin αvβ3 on blood vessels with 111In-RGD2 in head and neck tumor xenografts.
abstract: Arginine-glycine-aspartic acid (RGD)-based imaging tracers allow specific imaging of integrin αvβ3, a protein overexpressed during angiogenesis, leading to the possibility that it might serve as a tool to stratify patients for antiangiogenic treatment. However, these tracers have generally been characterized in xenograft models in which integrin αvβ3 was constitutively expressed by the tumor cells themselves. In the studies presented here, the use of (111)In-RGD2 as a tracer to image only integrin αvβ3 expression on blood vessels in the tumor was determined using tumor xenografts in which tumor cells were integrin αvβ3-negative.
  
  
  METHODS
  DOTA-E-[c(RGDfK)]2 was radiolabeled with (111)In ((111)In-RGD2), and biodistribution studies were performed in squamous cell carcinoma of the head and neck (HNSCC) xenograft mouse models to determine the optimal peptide dose to image angiogenesis. Next, biodistribution and imaging studies were performed at the optimal peptide dose in 3 HNSCC mouse models, FaDu, SCCNij3, and SCCNij202. Immunohistochemical analysis of tumor vascular and cell surface expression of integrin αvβ3 and correlation analysis of vascular integrin αvβ3 and autoradiography were completed.
  
  
  RESULTS
  All 3 HNSCC xenografts expressed integrin αvβ3 on the vessels only. The optimal peptide dose of (111)In-RGD2 was 1 μg or less for specific integrin αvβ3-mediated uptake of the tracer. SPECT/CT imaging showed clear uptake of the tracer in the periphery of the tumors, corresponding with well-vascularized areas of the tumor. Within the tumor, (111)In-RGD2 autoradiography coincided with vascular integrin αvβ3 expression, as determined immunohistochemically. Integrin αvβ3-mediated uptake was also detected in nontumor tissues, which, through immunohistochemical analysis, proved positive for integrin αvβ3.
  
  
  CONCLUSIONS
  (111)In-RGD2 allows the visualization of integrin αvβ3 in xenograft models in which integrin αvβ3 is expressed only on the neovasculature, such as in the HNSCC tumors. Thus, (111)In-RGD2 allows specific visualization of angiogenesis in tumor models lacking constitutive tumoral integrin αvβ3 expression but may be less useful for this purpose in many tumors in which tumor cells express integrin αvβ3.
authors.affiliation: Department of Nuclear Medicine, Radboud UMC, Nijmegen, The Netherlands.
authors.forename: Samantha Y A
authors.initials: SY
authors.lastname: Terry
authors.forename: Keelara
authors.initials: K
authors.lastname: Abiraj
authors.forename: Cathelijne
authors.initials: C
authors.lastname: Frielink
authors.forename: Laura K
authors.initials: LK
authors.lastname: van Dijk
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism; D007150:Immunohistochemistry; D007205:Indium Radioisotopes / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000737:chemistry; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; C047981:arginyl-glycyl-aspartic acid
keywords: SPECT imaging; angiogenesis; dimeric RGD; head and neck carcinoma; integrin αvβ3