Oncotarget

Research Papers:

Targeting the extradomain A of fibronectin allows identification of vascular resistance to antiangiogenic therapy in experimental glioma

Güliz Acker, Sophie Käthe Piper, Anna Lena Datwyler, Thomas Broggini, Irina Kremenetskaia, Melina Nieminen-Kelhä, Janet Lips, Ulrike Harms, Susanne Mueller, Gilla Lättig-Tünnemann, Eveline Trachsel, Alessandro Palumbo, Dario Neri, Jan Klohs, Matthias Endres, Peter Vajkoczy, Christoph Harms and Marcus Czabanka _

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Oncotarget. 2018; 9:27760-27772. https://doi.org/10.18632/oncotarget.25570

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Abstract

Güliz Acker1,*, Sophie Käthe Piper2,3,*, Anna Lena Datwyler2,4, Thomas Broggini1, Irina Kremenetskaia1, Melina Nieminen-Kelhä1, Janet Lips2,4, Ulrike Harms2,4, Susanne Mueller2,4, Gilla Lättig-Tünnemann2,4, Eveline Trachsel5, Alessandro Palumbo5, Dario Neri5, Jan Klohs4,6, Matthias Endres2,4, Peter Vajkoczy1,2, Christoph Harms2,4,* and Marcus Czabanka1,*

1Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurosurgery, Berlin, Germany

2Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Stroke Research, Berlin, Germany

3Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany

4Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology and Experimental Neurology, Berlin, Germany

5Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland

6Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland

*These authors contributed equally to this work

Correspondence to:

Marcus Czabanka, email: marcus.czabanka@charite.de

Christoph Harms, email: christoph.harms@charite.de

Keywords: NIRF imaging; antiangiogenic resistance; F8; glioma; SF126

Received: March 15, 2018     Accepted: May 19, 2018     Published: June 12, 2018

ABSTRACT

Introduction: Clinical application of antiangiogenic therapy lacks direct visualization of therapy efficacy and vascular resistance. We aimed to establish molecular imaging during treatment with sunitinib using the fibronectin extradomain A specific small immunoprotein(SIP)-F8 in glioma.

Methods: Biodistribution analysis of F8-SIP-Alexa-555 was performed in SF126-glioma bearing or control mice (n = 23 and 7, respectively). Intravital microscopy(IVM) was performed on a microvascular level after 7 days (n = 5 per group) and subsequently after 6 days of sunitinib treatment (n = 4) or without (n = 2).

Additionally, near infrared fluorescence(NIRF) imaging was established with F8-SIP-Alexa-750 allowing non-invasive imaging with and without antiangiogenic treatment in orthotopic tumors (n = 38 divided in 4 groups). MRI was used to determine tumor size and served as a reference for NIRF imaging.

Results: F8-SIP demonstrated a time and hemodynamic dependent tumor specific accumulation. A significantly higher vascular accumulation occurred with antiangiogenic treatment compared to untreated tumors enabling visualization of resistant tumor vessels by F8-SIP-mediated NIRF imaging. In orthotopic tumors, sunitinib reduced F8-SIP-Alexa-750 enrichment volume but not fluorescence intensity indicative of F8-SIP accumulation in fewer vessels.

Conclusion: F8-SIP is highly tumor specific with time and hemodynamic dependent biodistribution. The higher vascular accumulation to remaining vessels enables molecular imaging and targeting of therapy resistant tumor vessels.


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