TY  - JOUR
A1  - Weibel, Stephanie
A1  - Basse-Luesebrink, Thomas Christian
A1  - Hess, Michael
A1  - Hofmann, Elisabeth
A1  - Seubert, Carolin
A1  - Langbein-Laugwitz, Johanna
A1  - Gentschev, Ivaylo
A1  - Sturm, Volker Jörg Friedrich
A1  - Ye, Yuxiang
A1  - Kampf, Thomas
A1  - Jakob, Peter Michael
A1  - Szalay, Aladar A.
T1  - Imaging of Intratumoral Inflammation during Oncolytic Virotherapy of Tumors by \(^{19}\)F-Magnetic Resonance Imaging (MRI)
JF  - PLoS ONE
N2  - Background
Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate \(^{19}\)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy.

Methodology/Principal Findings
The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by \(^1H\)/\(^{19}\)F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the \(^{19}\)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the \(^{19}\)F signal hot spots and \(CD68^+\)-macrophages. Thereby, the \(CD68^+\)-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the \(^{19}\)F signal correlated with the extent of viral spreading within tumors.

Conclusions/Significance
These results suggest \(^{19}\)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, \(^{19}\)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response.
KW  - inflammation
KW  - fluorescence microscopy
KW  - oncolytic viruses
KW  - fluorescence imaging
KW  - macrophages
KW  - magnetic resonance imaging
KW  - histology
KW  - in vivo imaging
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130311
VL  - 8
IS  - 3
ER  - 
TY  - JOUR
A1  - Beitzinger, Christoph
A1  - Bronnhuber, Annika
A1  - Duscha, Kerstin
A1  - Riedl, Zsuzsanna
A1  - Huber-Lang, Markus
A1  - Benz, Roland
A1  - Hajos, György
A1  - Barth, Holger
T1  - Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin
JF  - PLoS ONE
N2  - Background
Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric \(PA_{63}\) binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the \(PA_{63}\)-channel in a dose dependent way.

Methodology/Principal Findings
Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the \(PA_{63}\)-channel in the µM range, when both, inhibitor and \(PA_{63}\) are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of \(PA_{63}\)-channel function also efficiently block intoxication of the cells by the combination lethal factor and \(PA_{63}\) in the same concentration range as they block the channels in vitro.

Conclusions/Significance
These results strongly argue in favor of a transport of lethal factor through the \(PA_{63}\)-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax.
KW  - intoxication
KW  - chloroquine
KW  - toxins
KW  - anthrax
KW  - cell membranes
KW  - lipid bilayer
KW  - macrophages
KW  - membrane potential
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130097
VL  - 8
IS  - 6
ER  -