title: αvß3-Integrin-Targeted Magnetic Resonance Imaging for the Assessment of Early Antiangiogenic Therapy Effects in Orthotopic Breast Cancer Xenografts.
abstract: The aim of this study was to investigate magnetic resonance imaging (MRI) with αvß3-integrin-targeted ultrasmall superparamagnetic iron oxide nanoparticles (RGD-USPIO) for the in vivo monitoring of early antiangiogenic therapy effects in experimental breast cancer.
  
  
  
  Orthotopic human breast cancer (MDA-MB-231) xenograft-bearing severe combined immunodeficiency mice were imaged before and after a 1-week therapy with the vascular endothelial growth factor receptor-antibody bevacizumab or placebo (n = 10 per group, daily intraperitoneal injections of bevacizumab or a volume-equivalent placebo solution, respectively) on a clinical 3 T scanner (Magnetom Skyra; Siemens Healthcare, Erlangen, Germany) before and 60 minutes after the intravenous injection of RGD-USPIO (P04000; Guerbet, Villepinte, France). R2 relaxometry employing a T2-weighted spin-echo sequence with 4 echo times (echo time, 20/40/60/80 milliseconds; repetition time, 3800 milliseconds; matrix, 128 × 128; field of view, 50 × 50; slice thickness, 1.2 mm; time to acquisition, 25 minutes) was used as semiquantitative measure to determine RGD-USPIO endothelial binding. In addition, the T2-weighted images were used to perform volumetric tumor response assessments. Imaging results were validated by ex vivo multiparametric immunohistochemistry with regard to αvß3-integrin expression, microvascular density (CD31), proliferation (Ki-67), and apoptosis (TUNEL).
  
  
  
  RGD-USPIO endothelial binding was significantly reduced after vascular endothelial growth factor inhibition, compared with the control group in which an increased endothelial binding was detected ([INCREMENT]R2Therapy = -0.80 ± 0.78 s; [INCREMENT]R2Control = +0.27 ± 0.59 s; P = 0.002). Correspondingly, immunohistochemistry revealed a significantly lower αvß3-integrin expression (91 ± 30 vs 357 ± 72; P < 0.001), microvascular density (CD31, 109 ± 46 vs 440 ± 208; P < 0.001), tumor cell proliferation (Ki-67, 4040 ± 1373 vs 6530 ± 1217; P < 0.001), as well as significantly higher apoptosis (TUNEL, 11186 ± 4387 vs 4017 ± 1191; P = 0.004) in the therapy compared with the control group. Contrary to the changes in αvß3-integrin expression detected by RGD-USPIO MRI, morphology-based tumor response assessments did not show a significant intergroup difference in tumor volume development over the course of the experiment (ΔVolTherapy +71 ± 40 μL vs ΔVolControl +125 ± 81 μL; P > 0.05).
  
  
  
  RGD-USPIO MRI allows for the noninvasive assessment of αvß3-integrin expression in the investigated breast cancer model. RGD-USPIO MRI may be applicable for the in vivo monitoring of early antiangiogenic therapy effects in experimental breast cancer, generating possible complementary molecular imaging biomarkers to morphology-based tumor response assessments.
authors.affiliation: From the *Institute for Clinical Radiology, Laboratory for Experimental Radiology, †Institute for Clinical Radiology, Josef-Lissner-Laboratory for Biomedical Imaging, and ‡Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Hospital Munich, Munich; and §Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Philipp Maximilian
authors.initials: PM
authors.lastname: Kazmierczak
authors.forename: Moritz
authors.initials: M
authors.lastname: Schneider
authors.forename: Thomas
authors.initials: T
authors.lastname: Habereder
authors.forename: Heidrun
authors.initials: H
authors.lastname: Hirner-Eppeneder
authors.forename: Ralf S
authors.initials: RS
authors.lastname: Eschbach
authors.forename: Matthias
authors.initials: M
authors.lastname: Moser
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000068258:Bevacizumab / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003287:Contrast Media; D003911:Dextrans; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D039302:Integrin alphaVbeta3; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D003911:Dextrans; D039302:Integrin alphaVbeta3; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10; D000068258:Bevacizumab