Dual-tracer background subtraction approach for fluorescent molecular tomography

Tichauer, Kenneth M.; Holt, Robert W.; El-Ghussein, Fadi; Davis, Scott C.; Samkoe, Kimberley S.; Gunn, Jason R.; Leblond, Frédéric; Pogue, Brian W.

doi:10.1117/1.jbo.18.1.016003

Cited by 28 publications

(23 citation statements)

References 40 publications

(64 reference statements)

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“…In Figure S2, it is shown that mouse skin has far less EGFR than the A431 and AsPC-1 tumors but could significantly contribute to the signal in U251 or 9L and as such appropriate receptor concentration thresholds need to be determined. However, non-invasive RCI has recently been demonstrated in mice for lymph node imaging of breast tumor metastases using fluorescence alone (38) and glioma tumors using MRI- and CT-guided fluorescence tomography (39, 40). Additionally, RCI has potential for imaging other primary cancers such as breast tumors (41–43) where multiple measurements could be taken over a course antibody therapy to monitor treatment progress.…”

Section: Discussionmentioning

confidence: 99%

Quantitative In Vivo Immunohistochemistry of Epidermal Growth Factor Receptor Using a Receptor Concentration Imaging Approach

et al. 2014

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As receptor-targeted therapeutics become increasingly used in clinical oncology, the ability to quantify protein expression and pharmacokinetics in vivo is imperative to ensure successful individualized treatment plans. Current standards for receptor analysis are performed on extracted tissues. These measurements are static and often physiologically irrelevant, therefore, only a partial picture of available receptors for drug targeting in vivo is provided. Until recently, in vivo measurements were limited by the inability to separate delivery, binding, and retention effects but this can be circumvented by a dual-tracer approach for referencing the detected signal. We hypothesized that in vivo receptor concentration imaging (RCI) would be superior to ex vivo immunohistochemistry. Using multiple xenograft tumor models with varying epidermal growth factor receptor (EGFR) expression, we determined the EGFR concentration in each model using a novel targeted agent (anti-EGFR affibody-IRDye800CW conjugate) along with a simultaneously delivered reference agent (control affibody-IRDye680RD conjugate). The RCI-calculated in vivo receptor concentration was strongly correlated with ex vivo pathologist-scored immunohistochemistry and computer-quantified ex vivo immunofluorescence. In contrast, no correlation was observed with ex vivo Western blot or in vitro flow cytometry assays. Overall, our results argue that in vivo RCI provides a robust measure of receptor expression equivalent to ex vivo immuno-staining, with implications for use in non-invasive monitoring of therapy or therapeutic guidance during surgery.

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Section: Discussionmentioning

confidence: 99%

Quantitative In Vivo Immunohistochemistry of Epidermal Growth Factor Receptor Using a Receptor Concentration Imaging Approach

et al. 2014

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“…Comparing the uptake of these dyes enables recovery of binding potential, BP, a quantitative parameter proportional to the concentration of receptors available for binding. 1,[4][5][6] With the rise of targeted therapeutic agents in the treatment of cancer, BP is a potentially clinically relevant parameter, which can either inform in regards to the binding affinity of a new targeted drug to a model cancer tumor or be used for receptor concentration estimation of a tumor using a targeted drug of known affinity.…”

Section: Introductionmentioning

confidence: 99%

Tomography of epidermal growth factor receptor binding to fluorescent Affibodyin vivostudied with magnetic resonance guided fluorescence recovery in varying orthotopic glioma sizes

et al. 2015

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Abstract. The ability to image targeted tracer binding to epidermal growth factor receptor (EGFR) was studied in vivo in orthotopically grown glioma tumors of different sizes. The binding potential was quantified using a dualtracer approach, which employs a fluorescently labeled peptide targeted to EGFR and a reference tracer with similar pharmacokinetic properties but no specific binding, to estimate the relative bound fraction from kinetic compartment modeling. The recovered values of binding potential did not vary significantly as a function of tumor size (1 to 33 mm 3 ), suggesting that binding potential may be consistent in the U251 tumors regardless of size or stage after implantation. However, the fluorescence yield of the targeted fluorescent tracers in the tumor was affected significantly by tumor size, suggesting that dual-tracer imaging helps account for variations in absolute uptake, which plague single-tracer imaging techniques. Ex vivo analysis showed relatively high spatial heterogeneity in each tumor that cannot be resolved by tomographic techniques. Nonetheless, the dual-tracer tomographic technique is a powerful tool for longitudinal bulk estimation of receptor binding. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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“…Similarly, such a concept was recently applied to FMT (Ref. 7) and showed the improved reconstruction of fluorescence localization. In order to move toward absolute quantification in contrast to relative quantification as presented herein, as well as improved localization, the adaptation of such internal control methods could further enhance multiparameter FMT methods, particularly in regard to longitudinal studies where the measurements at different time points should be quantitatively comparable.…”

Section: Discussionmentioning

confidence: 99%

“…One advantage of approaches like this is the creation of internal controls using, e.g., an active and an inactive form of an agent, each labeled with a different fluorochrome. 6,7 In this example, biodistribution and delivery of the agent can be separated by active targeting on the same animal by comparing the images at the two fluorescence channels. Alternatively, different contrast mechanisms can be concurrently studied, e.g., the relative expression of different receptors or the relative concentrations of different types of cells.…”

Section: Introductionmentioning

confidence: 99%

“…Dual-wavelength concepts based on the combination of one targeted and one untargeted probe have been introduced for 360-deg FMT systems. 7,26 Instead, we interrogated, herein, the performance of multispectral methods employing limitedprojection-angle FMT setups, which are more widely disseminated than 360-deg systems. Limited-projection-angle FMT offers implementation simplicity, as it does not require rotating gantries but offers a subset of the information available to 360-deg systems.…”

Section: Introductionmentioning

confidence: 99%

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Limited-projection-angle hybrid fluorescence molecular tomography of multiple molecules

et al. 2014

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Abstract. An advantage of fluorescence methods over other imaging modalities is the ability to concurrently resolve multiple moieties using fluorochromes emitting at different spectral regions. Simultaneous imaging of spectrally separated agents is helpful in interrogating multiple functions or establishing internal controls for accurate measurements. Herein, we investigated multimoiety imaging in the context of a limited-projection-angle hybrid fluorescence molecular tomography (FMT), and x-ray computed tomography implementation and the further registration with positron emission tomography (PET) data. Multichannel FMT systems may image fluorescent probes of varying distribution patterns. Therefore, it is possible that different channels may require different use of priors and regularization parameters. We examined the performance of automatically estimating regularization factors implementing priors, using data-driven regularization specific for limited-projectionangle schemes. We were particularly interested in identifying the implementation variations between hybrid-FMT channels due to probe distribution variation. For this reason, initial validation of the data-driven algorithm on a phantom was followed by imaging different agent distributions in animals, assuming superficial and deep seated activity. We further demonstrate the benefits of combining hybrid FMT with PET to gain multiple readings on the molecular composition of disease.

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Dual-tracer background subtraction approach for fluorescent molecular tomography

Cited by 28 publications

References 40 publications

Quantitative In Vivo Immunohistochemistry of Epidermal Growth Factor Receptor Using a Receptor Concentration Imaging Approach

Quantitative In Vivo Immunohistochemistry of Epidermal Growth Factor Receptor Using a Receptor Concentration Imaging Approach

Tomography of epidermal growth factor receptor binding to fluorescent Affibodyin vivostudied with magnetic resonance guided fluorescence recovery in varying orthotopic glioma sizes

Limited-projection-angle hybrid fluorescence molecular tomography of multiple molecules

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