Escherichia coli Nissle 1917 facilitates tumor detection by positron emission tomography and optical imaging
ABSTRACT 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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ABSTRACT: Background Identification of cancer or inflammatory bowel disease in the intestinal tract by PET/computed tomography (CT) imaging can be hampered by physiological uptake of F-18-fluorodeoxyglucose (F-18-FDG) in the normal colon. Previous work has localized this F-18-FDG uptake to the intestinal lumen, predominantly occupied by bacteria. We sought to determine whether pretreatment with an antibiotic could reduce F-18-FDG uptake in the healthy colon.Patients and methodsThirty patients undergoing restaging PET/CT for nongastrointestinal lymphoma were randomly selected to receive rifaximin 550mg twice daily for 2 days before their scan (post-rifaximin). Their PET/CT images were compared with those from their prior study (pre-rifaximin). Cecal maximum standard uptake value (SUVmax) and overall colonic F-18-FDG uptake were compared between scans. All PET/CT images were blindly scored by a radiologist. The same comparison of sequential scans was also undertaken in 30 patients who did not receive antibiotics.ResultsThirty post-rifaximin scans were compared with 30 pre-rifaximin scans in the same patients. SUVmax in the cecum was significantly lower in the patient's post-rifaximin scans than in their pre-rifaximin scans (P=0.002). The percentage of scans with greater than grade 1 colonic F-18-FDG uptake was significantly lower in the post-rifaximin scans than in the pre-rifaximin scans (P<0.05). In contrast, there was no significant difference in the paired sequential scans from control patients, nor a reduction in the percentage of scans with greater than grade 1 colonic F-18-FDG uptake.Conclusion This pilot study shows that treatment with rifaximin for 2 days before PET/CT scanning can significantly reduce physiological F-18-FDG uptake in the normal colonic lumen.Nuclear Medicine Communications 07/2014; 35(10). DOI:10.1097/MNM.0000000000000170 · 1.37 Impact Factor
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ABSTRACT: By delivering payloads in response to specific exogenous stimuli, smart bacterial therapeutics have the potential to overcome many limitations of conventional therapies, including poor targeting specificity and dosage control in current cancer treatments. Although not yet explored as a trigger for bacterial drug delivery, light is an ideal induction mechanism because it offers fine spatiotemporal control and is easily and safely administered. Using recent advances in optogenetics, we have engineered two strains of Escherichia coli to secrete a potent mammalian cytotoxin in response to blue or red light. The tools in this study demonstrate the initial feasibility of light-activated bacterial therapeutics for applications such as tumor cytolysis, and their modular nature should enable simple substitution of other payloads of interest.ACS Synthetic Biology 01/2014; 3(12). DOI:10.1021/sb400174s · 3.95 Impact Factor
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ABSTRACT: Current conventional treatments for cancer lack tumour selectivity resulting in the destruction of healthy tissue and severe adverse effects to the patient in addition to limiting the administration dose and efficacy. Hence, it is imperative that we seek alternative approaches to treat cancer that localise therapeutic agents to the site of the tumour and spare normal tissue. The use of bacteria in cancer therapy represents one such approach. Bacteria were first used as anti-cancer agents over a century ago. Today, this field has re-emerged from the past and is progressing at a rapid rate. Bacteria are used as anticancer agents either alone or in combination with conventional treatments and have been armed with an arsenal of therapeutic genes, which enhance their efficacy. Bacterial directed enzyme prodrug therapy (BDEPT) is one of the most promising approaches, which harnesses the tumour-specific location of bacteria to locally activate systemically administered 'prodrugs' within the tumour in order to induce selective tumour destruction. BDEPT is a relatively new concept. It was originally conceived more than 10 years ago but it is only until recently that we witness a surge in activity in this field. In this review, we provide a full account of developments in the field of BDEPT since its inception. We share technical knowhow and discuss optimization strategies for vector and enzyme combinations, provide a clear view of the research landscape and suggest possible directions for the field.Journal of Controlled Release 08/2013; DOI:10.1016/j.jconrel.2013.05.005 · 7.63 Impact Factor