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Intraoperative imaging of positron emission tomographic radiotracers using Cerenkov luminescence emissions.

ABSTRACT: Imaging the location and extent of cancer provides invaluable information before, during, and after surgery. The majority of "image-guided" methods that use, for example, positron emission tomography (PET) involve preoperative imaging and do not provide real-time information during surgery. It is now well established that the inherent optical emissions (Cerenkov radiation) from various ?-emitting radionuclides can be visualized by Cerenkov luminescence imaging (CLI). Here we report the full characterization of CLI using the positron-emitting radiotracer 89Zr-DFO-trastuzumab for target-specific, quantitative imaging of HER2/neu-positive tumors in vivo. We also provide the first demonstration of the feasibility of using CLI for true image-guided, intraoperative surgical resection of tumors. Analysis of optical CLIs provided accurate, quantitative information on radiotracer biodistribution and tissue uptake that correlated well with the concordant PET images. CLI, PET, and biodistribution studies revealed target-specific uptake of 89Zr-DFO-trastuzumab in BT-474 (HER2/neu positive) versus MDA-MB-468 (HER2/neu negative) xenografts in the same mice. Competitive inhibition (blocking) studies followed by CLI also confirmed the in vivo immunoreactivity and specificity of 89Zr-DFO-trastuzumab for HER2/neu. Overall, these results strongly support the continued development of CLI as a preclinical and possible clinical tool for use in molecular imaging and surgical procedures for accurately defining tumor margins.

SUBMITTER: Holland JP

PROVIDER: S-EPMC3083828 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Intraoperative imaging of positron emission tomographic radiotracers using Cerenkov luminescence emissions.

Holland Jason P JP Normand Guillaume G Ruggiero Alessandro A Lewis Jason S JS Grimm Jan J

Molecular imaging 20110601 3

Imaging the location and extent of cancer provides invaluable information before, during, and after surgery. The majority of "image-guided" methods that use, for example, positron emission tomography (PET) involve preoperative imaging and do not provide real-time information during surgery. It is now well established that the inherent optical emissions (Cerenkov radiation) from various β-emitting radionuclides can be visualized by Cerenkov luminescence imaging (CLI). Here we report the full char ...[more]

PMID: 21496448

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Project description:Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers.MethodsThe anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI.Results64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy.ConclusionCLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.

Project description:ImportanceThe causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown.ObjectiveTo contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function.Design, setting, and participantsThis cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET).ExposuresImaging with fluorine 18-labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale.Main outcomes and measuresMain outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function.ResultsIn patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.Conclusions and relevancePatients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.

Project description:The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies.In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters (18)F, (64)Cu, (89)Zr, and (124)I; beta-emitter (131)I; and alpha-particle emitter (225)Ac for potential use in CLI. The novel radiolabeled monoclonal antibody (89)Zr-desferrioxamine B [DFO]-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies.Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-, beta-, and alpha-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of (89)Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities.These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear tomographic imaging and radiotherapy have the potential to be used in CLI. The value of CLI lies in its ability to image radionuclides that do not emit either positrons or gamma-rays and are, thus, unsuitable for use with current nuclear imaging modalities. Optical imaging of Cerenkov radiation emission shows excellent promise as a potential new imaging modality for the rapid, high-throughput screening of radiopharmaceuticals.

Project description:Hypoxia is an important microenvironmental factor influencing atherosclerosis progression by inducing foam-cell formation, metabolic adaptation of infiltrated macrophages, and plaque neovascularization. Therefore, imaging plaque hypoxia could serve as a marker of lesions at risk.Advanced aortic atherosclerosis was induced in 18 rabbits by atherogenic diet and double balloon endothelial denudation. Animals underwent (18)F-fluoromisonidazole positron emission tomographic and (18)F-fluorodeoxyglucose positron emission tomographic imaging after 6 to 8 months (atherosclerosis induction) and 12 to 16 months (progression) of diet initiation. Four rabbits fed standard chow served as controls. Radiotracer uptake of the abdominal aorta was measured using standardized uptake values. After imaging, plaque hypoxia (pimonidazole), macrophages (RAM-11), neovessels (CD31), and hypoxia-inducible factor-1? were assessed by immunohistochemistry.(18)F-fluoromisonidazole uptake increased with time on diet (standardized uptake value mean, 0.10±0.01 in nonatherosclerotic animals versus 0.20±0.03 [P=0.002] at induction and 0.25±0.03 [P<0.001] at progression). Ex vivo positron emission tomographic imaging corroborated the (18)F-fluoromisonidazole uptake by the aorta of atherosclerotic rabbits. (18)F-fluorodeoxyglucose uptake also augmented in atherosclerotic animals, with an standardized uptake value mean of 0.43±0.02 at induction versus 0.35±0.02 in nonatherosclerotic animals (P=0.031) and no further increase at progression. By immunohistochemistry, hypoxia was mainly located in the macrophage-rich areas within the atheromatous core, whereas the macrophages close to the lumen were hypoxia-negative. Intraplaque neovessels were found predominantly in macrophage-rich hypoxic regions (pimonidazole(+)/hypoxia-inducible factor-1?(+)/RAM-11(+)).Plaque hypoxia increases with disease progression and is present in macrophage-rich areas associated with neovascularization. (18)F-fluoromisonidazole positron emission tomographic imaging emerges as a new tool for the detection of atherosclerotic lesions.

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Intraoperative imaging of positron emission tomographic radiotracers using Cerenkov luminescence emissions.

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Intraoperative imaging of positron emission tomographic radiotracers using Cerenkov luminescence emissions.

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