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Kazmierczak, Philipp Maximilian; Schneider, Moritz; Habereder, Thomas; Hirner-Eppeneder, Heidrun; Eschbach, Ralf S.; Moser, Matthias; Reiser, Maximilian F.; Lauber, Kirsten; Nikolaou, Konstantin; Cyran, Clemens C. (2016): ανβ3-Integrin-Targeted Magnetic Resonance Imaging for the Assessment of Early Antiangiogenic Therapy Effects in Orthotopic Breast Cancer Xenografts. In: Investigative Radiology, Vol. 51, No. 11: pp. 746-755
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Abstract

Objectives The aim of this study was to investigate magnetic resonance imaging (MRI) with (v)ss(3)-integrin-targeted ultrasmall superparamagnetic iron oxide nanoparticles (RGD-USPIO) for the in vivo monitoring of early antiangiogenic therapy effects in experimental breast cancer. Materials and Methods 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 x 128;field of view, 50 x 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 (v)ss(3)-integrin expression, microvascular density (CD31), proliferation (Ki-67), and apoptosis (TUNEL). Results 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 (R2(Therapy) = -0.80 0.78 s(-1);R2(Control) = +0.27 +/- 0.59 s(-1);P = 0.002). Correspondingly, immunohistochemistry revealed a significantly lower (v)ss(3)-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 (v)ss(3)-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 (Vol(Therapy) +71 +/- 40 L vs Vol(Control) +125 +/- 81 L;P > 0.05). Conclusions RGD-USPIO MRI allows for the noninvasive assessment of (v)ss(3)-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.