Escherichia coli Nissle 1917 Facilitates Tumor Detection by Positron Emission Tomography and Optical Imaging

Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Clinical Cancer Research (Impact Factor: 8.72). 05/2008; 14(8):2295-302. DOI: 10.1158/1078-0432.CCR-07-4254
Source: PubMed


Bacteria-based tumor-targeted therapy is a modality of growing interest in anticancer strategies. Imaging bacteria specifically targeting and replicating within tumors using radiotracer techniques and optical imaging can provide confirmation of successful colonization of malignant tissue.
The uptake of radiolabeled pyrimidine nucleoside analogues and [18F]FDG by Escherichia coli Nissle 1917 (EcN) was assessed both in vitro and in vivo. The targeting of EcN to 4T1 breast tumors was monitored by positron emission tomography (PET) and optical imaging. The accumulation of radiotracer in the tumors was correlated with the number of bacteria. Optical imaging based on bioluminescence was done using EcN bacteria that encode luciferase genes under the control of an l-arabinose-inducible P(BAD) promoter system.
We showed that EcN can be detected using radiolabeled pyrimidine nucleoside analogues, [18F]FDG and PET. Importantly, this imaging paradigm does not require transformation of the bacterium with a reporter gene. Imaging with [18F]FDG provided lower contrast than [18F]FEAU due to high FDG accumulation in control (nontreated) tumors and surrounding tissues. A linear correlation was shown between the number of viable bacteria in tumors and the accumulation of [18F]FEAU, but not [18F]FDG. The presence of EcN was also confirmed by bioluminescence imaging.
EcN can be imaged by PET, based on the expression of endogenous E. coli thymidine kinase, and this imaging paradigm could be translated to patient studies for the detection of solid tumors. Bioluminescence imaging provides a low-cost alternative to PET imaging in small animals.

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    • "Radiopharmaceutical-based methods to image infection have been summarized in several recent reviews [15-17]. One promising new technique uses radiolabeled nucleoside analogs such as 2'-fluoro-2'-deoxy-1β-D-arabinofuranosyl-5- [ 124/5 I]iodouracil ([ 124/5 I]FIAU) [18] [19] [20] or 2'-[ 18 F] fluoro-2'-deoxy-1β-D-arabinofuranosyl-5- ethyluracil ([ 18 F]FEAU) [21], which are substrates of bacterial – but not human – thymidine kinase (TK). The feasibility of using "
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    ABSTRACT: 2'-Fluoro-2'-deoxy-1β-D-arabinofuranosyl-5-[(125)I]iodouracil ([(125)I]FIAU), a substrate for the thymidine kinase (TK) present in most bacteria, has been used as an imaging agent for single photon emission computed tomography (SPECT) in an experimental model of lung infection. Using SPECT-CT we show that [(125)I]FIAU is specific for bacterial infection rather than sterile inflammation. We report [(125)I]FIAU lung uptake values of 1.26 ± 0.20 percent injected dose per gram (%ID/g) in normal controls, 1.69 ± 0.32 %ID/g in lung inflammation and up to 7.14 ± 1.09 %ID/g in lung infection in ex vivo biodistribution studies at 24 h after intranasal administration of bacteria. Images of [(125)I]FIAU signal within lung can be used to estimate the number of bacteria present, with a limit of detection of 10(9) colony forming units per mL on the X-SPECT scanner. [(125)I]FIAU-Based bacterial imaging may be useful in preclinical models to facilitate the development of new antibiotics, particularly in cases where a corresponding human trial is planned.
    American Journal of Nuclear Medicine and Molecular Imaging 11/2012; 2(3):260-70. · 3.25 Impact Factor
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    • "To obtain the images of bacterial targeting to tumor sites in animal studies, Soghomonyan et al. (2005) produced a VNP20009 Salmonella-expressing HSV1-tk gene and could noninvasively detect bacterial tumor targeting by PET image with [ 124 I]FIAU. Brader et al. (2008) investigated that the endogenous thymidine kinase of E. coli Nissle 1917 (EcN) to phosphorylate [ 18 F]FEAU and [ 124 I]FIAU was applied for noninvasive PET imaging of EcN-colonized tumors. To monitor tuberculosis in preclinical animal studies, Davis et al. (2009) produced a Mycobacterium tuberculosis strain expressing bacterial tk due to the lack of tk in mycobacteria and could detect M. tuberculosis noninvasively in live animals with [ 125 I]FIAU. "
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    ABSTRACT: The importance of noninvasive imaging methods to bacterial infections is widely recognized. To obtain bacterial infection imaging with radioisotope-labeled nucleosides, bacterial thymidine kinase (tk) activities of Salmonella typhimurium with [(125)I]5-iodo-1-(2'-fluoro-2'-deoxy-β-d-arabinofuranosyl)uracil ([(125)I]FIAU) or 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) were measured. The infection model in BALB/c mice was imaged with [(125)I]FIAU or [(18)F]FLT using small-animal Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET), respectively. The accumulated radioactivity of [(125)I]FIAU or [(18)F]FLT in the two strains showed a linearly increased pattern with increasing incubation time or bacterial numbers. The image clearly demonstrated a high uptake of [(125)I]FIAU and [(18)F]FLT in the bacterial infection site. [(18)F]FLT uptake in the infection site of was 7.286±2.405, whereas that in the uninfected site was 0.519±0.561. The relative activity ratio of the infected region in relation to the uninfected region was 2.98 at 4h after an injection with [(125)I]FIAU determined by biodistribution data. In conclusion, the bacterial tk activity was confirmed by the cellular uptake and imaging with [(125)I]FIAU or [(18)F]FLT. Therefore, a localized bacterial infection in living mice can be monitored using radioisotope-labeled nucleosides with a nuclear medicine imaging modality.
    International journal of medical microbiology: IJMM 01/2012; 302(2):101-7. DOI:10.1016/j.ijmm.2011.11.002 · 3.61 Impact Factor
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    • "o monitor pathogen dynamics and host gene expression by optical imaging , and the resultant changes in host physiol - ogy and anatomy using other imaging modalities , will considerably enhance our understanding of the complexities of infection processes in vivo . Furthermore , the development of multiple probes is attracting increasing attention . Brader et al . ( 2008 ) recently reported the visualization in mice of a bioluminescent strain of E . coli by both optical imaging and PET ( based on the expression of endogenous bacterial thymidine kinase ) while two commercial optical - X - ray CT imaging systems are now available ( Table 2 ) ."
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    ABSTRACT: According to World Health Organization estimates, infectious organisms are responsible for approximately one in four deaths worldwide. Animal models play an essential role in the development of vaccines and therapeutic agents but large numbers of animals are required to obtain quantitative microbiological data by tissue sampling. Biophotonic imaging (BPI) is a highly sensitive, nontoxic technique based on the detection of visible light, produced by luciferase-catalysed reactions (bioluminescence) or by excitation of fluorescent molecules, using sensitive photon detectors. The development of bioluminescent/fluorescent microorganisms therefore allows the real-time noninvasive detection of microorganisms within intact living animals. Multiple imaging of the same animal throughout an experiment allows disease progression to be followed with extreme accuracy, reducing the number of animals required to yield statistically meaningful data. In the study of infectious disease, the use of BPI is becoming widespread due to the novel insights it can provide into established models, as well as the impact of the technique on two of the guiding principles of using animals in research, namely reduction and refinement. Here, we review the technology of BPI, from the instrumentation through to the generation of a photonic signal, and illustrate how the technique is shedding light on infection dynamics in vivo.
    FEMS microbiology reviews 09/2010; 35(2):360-94. DOI:10.1111/j.1574-6976.2010.00252.x · 13.24 Impact Factor
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