Targeting the extradomain A of fibronectin allows identification of vascular resistance to antiangiogenic therapy in experimental glioma
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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
Marcus Czabanka, email: firstname.lastname@example.org
Christoph Harms, email: email@example.com
Keywords: NIRF imaging; antiangiogenic resistance; F8; glioma; SF126
Received: March 15, 2018 Accepted: May 19, 2018 Published: June 12, 2018
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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