title: Necrosis avid near infrared fluorescent cyanines for imaging cell death and their use to monitor therapeutic efficacy in mouse tumor models.
abstract: 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.
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Bangwen
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Percuros BV, Enschede, The Netherlands.|In-vivo-NMR Laboratory, Max Planck Institute for Neurological Research, Cologne, Germany.
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Stammes
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Percuros BV, Enschede, The Netherlands.
authors.forename: Pieter B A A
authors.initials: PB
authors.lastname: van Driel
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Cruz
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Percuros BV, Enschede, The Netherlands.
authors.forename: Vicky T
authors.initials: VT
authors.lastname: Knol-Blankevoort
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Martijn A M
authors.initials: MA
authors.lastname: Löwik
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Mezzanotte
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Que
authors.affiliation: Percuros BV, Enschede, The Netherlands.
authors.forename: Alan
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jeroen P H M
authors.initials: JP
authors.lastname: van den Wijngaard
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Siebes
authors.affiliation: Faculty of Medicine, Technical University of Munich, Munich, Germany.|Institute for Biological and Medical Imaging, Helmholtz Center Munich, Munich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Gottschalk
authors.affiliation: Faculty of Medicine, Technical University of Munich, Munich, Germany.|Institute for Biological and Medical Imaging, Helmholtz Center Munich, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Razansky
authors.affiliation: Faculty of Medicine, Technical University of Munich, Munich, Germany.|Institute for Biological and Medical Imaging, Helmholtz Center Munich, Munich, Germany.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Ntziachristos
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stijn
authors.initials: S
authors.lastname: Keereweer
authors.affiliation: School of Life Sciences, College of Medical, Veterinary and Life Sciences, The University of Glasgow, Glasgow, Scotland, UK.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Horobin
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Percuros BV, Enschede, The Netherlands.|In-vivo-NMR Laboratory, Max Planck Institute for Neurological Research, Cologne, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hoehn
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Kaijzel
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Medres, Cologne, Germany.
authors.forename: Ermond R
authors.initials: ER
authors.lastname: van Beek
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Thomas J A
authors.initials: TJ
authors.lastname: Snoeks
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Clemens W G M
authors.initials: CW
authors.lastname: Löwik
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002232:Carbocyanines / Q000737:chemistry*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D008223:Lymphoma / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal / Q000379:methods; D009336:Necrosis / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D011897:Random Allocation
chemical_list: D002232:Carbocyanines; D005456:Fluorescent Dyes
keywords: cancer; cell death; cyanines; imaging; necrosis avid contrast agents