[alpha]v[latin sharp s]3-Integrin-Targeted Magnetic Resonance Imaging for the Assessment of Early Antiangiogenic Therapy Effects in Orthotopic Breast Cancer Xenografts.

Objectives: The aim of this study was to investigate magnetic resonance imaging (MRI) with [alpha]v[latin sharp s]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 [alpha]v[latin sharp s]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 ([DELTA]R2Therapy = -0.80 +/- 0.78 s-1; [DELTA]R2Control = +0.27 +/- 0.59 s-1; P = 0.002). Correspondingly, immunohistochemistry revealed a significantly lower [alpha]v[latin sharp s]3-integrin expression (91 +/- 30 vs 357 +/- 72; P 0.05). Conclusions: RGD-USPIO MRI allows for the noninvasive assessment of [alpha]v[latin sharp s]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. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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