Molecular Imaging: a Novel Tool To Visualize Pathogenesis of Infections
            <i>In Situ</i>

Gordon, Oren; Ruiz-Bedoya, Camilo A.; Ordoñez, Alvaro A.; Tucker, Elizabeth W.; Jain, Sanjay

doi:10.1128/mbio.00317-19

Cited by 39 publications

(31 citation statements)

References 81 publications

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“…To achieve bacterial specific accumulation with a radiotracer, an active transport mechanism, conceptually similar to [ 18 F]fluorodeoxyglucose, resulting in sufficiently high accumulation of radionuclides in the infection, seems to be highly desirable for successful in vivo targeting. Recently, several small molecule pathogen-specific radiotracers have been reported, for review see [ 29 ], targeting differences in carbohydrate uptake and metabolism (e.g. [ 18 F]fluorodeoxysorbitol, [ 18 F]fluoromaltose and [ 18 F]fluoromaltotriose), folate biosynthesis (e.g.…”

Section: Discussionmentioning

confidence: 99%

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68Ga-labelled desferrioxamine-B for bacterial infection imaging

Petřík

Umlaufova

Raclavsky

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose With the increase of especially hospital-acquired infections, timely and accurate diagnosis of bacterial infections is crucial for effective patient care. Molecular imaging has the potential for specific and sensitive detection of infections. Siderophores are iron-specific chelators recognized by specific bacterial transporters, representing one of few fundamental differences between bacterial and mammalian cells. Replacing iron by gallium-68 without loss of bioactivity is possible allowing molecular imaging by positron emission tomography (PET). Here, we report on the preclinical evaluation of the clinically used siderophore, desferrioxamine-B (Desferal®, DFO-B), radiolabelled with 68 Ga for imaging of bacterial infections. Methods In vitro characterization of [ 68 Ga]Ga-DFO-B included partition coefficient, protein binding and stability determination. Specific uptake of [ 68 Ga]Ga-DFO-B was tested in vitro in different microbial cultures. In vivo biodistribution was studied in healthy mice and dosimetric estimation for human setting performed. PET/CT imaging was carried out in animal infection models, representing the most common pathogens. Results DFO-B was labelled with 68 Ga with high radiochemical purity and displayed hydrophilic properties, low protein binding and high stability in human serum and PBS. The high in vitro uptake of [ 68 Ga]Ga-DFO-B in selected strains of Pseudomonas aeruginosa , Staphylococcus aureus and Streptococcus agalactiae could be blocked with an excess of iron-DFO-B. [ 68 Ga]Ga-DFO-B showed rapid renal excretion and minimal retention in blood and other organs in healthy mice. Estimated human absorbed dose was 0.02 mSv/MBq. PET/CT images of animal infection models displayed high and specific accumulation of [ 68 Ga]Ga-DFO-B in both P. aeruginosa and S. aureus infections with excellent image contrast. No uptake was found in sterile inflammation, heat-inactivated P. aeruginosa or S. aureus and Escherichia coli lacking DFO-B transporters. Conclusion DFO-B can be easily radiolabelled with 68 Ga and displayed suitable in vitro characteristics and excellent pharmacokinetics in mice. The high and specific uptake of [ 68 Ga]Ga-DFO-B by P. aeruginosa and S. aureus was confirmed both in vitro and in vivo, proving the potential of [ 68 Ga]Ga-DFO-B for specific imaging of bacterial infections. As DFO-B is used in clinic for many years and the estimated rad...

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Section: Discussionmentioning

confidence: 99%

“…were the kidneys and urinary bladder. One of the major goals of bacteria-specific radiotracers is to distinguish microbial growth from the non-bacterial inflammation [ 29 ]. A murine model of myositis was used to determine the specificity of [ 68 Ga]Ga-DFO-B for living bacteria in vivo.…”

Section: Discussionmentioning

confidence: 99%

68Ga-labelled desferrioxamine-B for bacterial infection imaging

Petřík

Umlaufova

Raclavsky

et al. 2020

Eur J Nucl Med Mol Imaging

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“…It shall not be underestimated, that the type and placement of the chelator can influence the tumor-targeting properties, the blood clearance rate and uptake into healthy tissue of the antibody [54]. By enabling early detection, realtime therapeutic monitoring and the ability to streamline drug development, molecular imaging is preferable to invasive tissue sampling, which is usually limited to a single time point and cannot capture tumor heterogeneity [55]. Up to date, numerous investigations with radiolabeled monoclonal antibodies that address HER2 have been conducted.…”

Section: Radiolabeled Her2 Targeting Monoclonal Antibodiesmentioning

confidence: 99%

HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging

Altunay

Morgenroth

Beheshti

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose The aim of the present paper is to review the role of HER2 antibodies, affibodies and nanobodies as vehicles for imaging and therapy approaches in breast cancer, including a detailed look at recent clinical data from antibody drug conjugates and nanobodies as well as affibodies that are currently under development. Results Clinical and preclinical studies have shown that the use of monoclonal antibodies in molecular imaging is impaired by slow blood clearance, associated with slow and low tumor uptake and with limited tumor penetration potential. Antibody fragments, such as nanobodies, on the other hand, can be radiolabelled with short-lived radioisotopes and provide high-contrast images within a few hours after injection, allowing early diagnosis and reduced radiation exposure of patients. Even in therapy, the small radioactively labeled nanobodies prove to be superior to radioactively labeled monoclonal antibodies due to their higher specificity and their ability to penetrate the tumor. Conclusion While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach.

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“…However, since 18 F-FDG is a marker for glucose uptake, any metabolically active tissue is detected and this tracer is therefore non-specific and cannot accurately distinguish between inflammation due to infection versus that caused by non-infectious processes. In the future, novel PET-based imaging tracers specific to the pathogen or components of the inflammatory response may serve as precision medicine tools to facilitate acquisition of temporal and spatial information on infection progression, unachievable by current modalities ( Censullo and Vijayan, 2017 ; Gordon et al, 2019 ; Hammoud, 2016 ). The extent and location of infection and inflammatory response could facilitate risk stratification of patients with post-surgical IASI.…”

Section: Discussionmentioning

confidence: 99%

Rabbit model of Staphylococcus aureus implant-associated spinal infection

Gordon

Miller

Thompson

et al. 2020

Disease Models &Amp; Mechanisms

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Post-surgical implant-associated spinal infection is a devastating complication commonly caused by Staphylococcus aureus. Biofilm formation is thought to reduce penetration of antibiotics and immune cells, contributing to chronic and difficult-to-treat infections. A rabbit model of a posterior-approach spinal surgery was created, in which bilateral titanium pedicle screws were interconnected by a plate at the level of lumbar vertebra L6 and inoculated with a methicillin-resistant S.aureus (MRSA) bioluminescent strain. In vivo whole-animal bioluminescence imaging (BLI) and ex vivo bacterial cultures demonstrated a peak in bacterial burden by day 14, when wound dehiscence occurred. Structures suggestive of biofilm, visualized by scanning electron microscopy, were evident up to 56 days following infection. Infection-induced inflammation and bone remodeling were also monitored using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and computed tomography (CT). PET imaging signals were noted in the soft tissue and bone surrounding the implanted materials. CT imaging demonstrated marked bone remodeling and a decrease in dense bone at the infection sites. This rabbit model of implant-associated spinal infection provides a valuable preclinical in vivo approach to investigate the pathogenesis of implant-associated spinal infections and to evaluate novel therapeutics.

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Molecular Imaging: a Novel Tool To Visualize Pathogenesis of Infections In Situ

Cited by 39 publications

References 81 publications

68Ga-labelled desferrioxamine-B for bacterial infection imaging

68Ga-labelled desferrioxamine-B for bacterial infection imaging

HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging

Rabbit model of Staphylococcus aureus implant-associated spinal infection

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