Necrosis avid near infrared fluorescent cyanines for imaging cell death and their use to monitor therapeutic efficacy in mouse tumor models
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Bangwen Xie1, Marieke A. Stammes1,2,3, Pieter B.A.A. van Driel1,2, Luis J. Cruz1, Vicky T. Knol-Blankevoort1,2, Martijn A.M. Löwik1, Laura Mezzanotte1, Ivo Que1, Alan Chan2, Jeroen P.H.M. van den Wijngaard4, Maria Siebes4, Sven Gottschalk5,6, Daniel Razansky5,6, Vasilis Ntziachristos5,6, Stijn Keereweer1, Richard W. Horobin7, Mathias Hoehn1,2,3, Eric L. Kaijzel1, Ermond R. van Beek1,8, Thomas J.A. Snoeks1, Clemens W.G.M. Löwik1
1Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
2Percuros BV, Enschede, The Netherlands
3In-vivo-NMR Laboratory, Max Planck Institute for Neurological Research, Cologne, Germany
4Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
5Faculty of Medicine, Technical University of Munich, Munich, Germany
6Institute for Biological and Medical Imaging, Helmholtz Center Munich, Munich, Germany
7School of Life Sciences, College of Medical, Veterinary and Life Sciences, The University of Glasgow, University Avenue, Glasgow, Scotland, UK
8Medres, Cologne, Germany
Clemens W.G.M. Löwik, e-mail: firstname.lastname@example.org
Keywords: cell death, imaging, cyanines, necrosis avid contrast agents, cancer
Received: June 29, 2015 Accepted: September 30, 2015 Published: October 12, 2015
Quantification of tumor necrosis in cancer patients is of diagnostic value as the amount of necrosis is correlated with disease prognosis and it could also be used to predict early efficacy of anti-cancer treatments. In the present study, we identified two near infrared fluorescent (NIRF) carboxylated cyanines, HQ5 and IRDye 800CW (800CW), which possess strong necrosis avidity. In vitro studies showed that both dyes selectively bind to cytoplasmic proteins of dead cells that have lost membrane integrity. Affinity for cytoplasmic proteins was confirmed using quantitative structure activity relations modeling. In vivo results, using NIRF and optoacoustic imaging, confirmed the necrosis avid properties of HQ5 and 800CW in a mouse 4T1 breast cancer tumor model of spontaneous necrosis. Finally, in a mouse EL4 lymphoma tumor model, already 24 h post chemotherapy, a significant increase in 800CW fluorescence intensity was observed in treated compared to untreated tumors. In conclusion, we show, for the first time, that the NIRF carboxylated cyanines HQ5 and 800CW possess strong necrosis avid properties in vitro and in vivo. When translated to the clinic, these dyes may be used for diagnostic or prognostic purposes and for monitoring in vivo tumor response early after the start of treatment.
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