Molecular Imaging And Biology[JOURNAL]
Sun
200 papers
Imaging of Chromophobe Renal Cell Carcinoma with Tc-Sestamibi SPECT/CT: Considerations Regarding Risk Stratification and Histologic Reclassification.
Rowe SP, Murtazaliev S, Oldan JD … +9 more , Kaufmann B, Khan A, Allaf ME, Singla N, Pavlovich CP, De Marzo AM, Baraban E, Gorin MA, Solnes LB
Mol Imaging Biol · 2024 Oct · PMID 39078524 · Publisher ↗
PURPOSE: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. Tc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify onc...
PURPOSE: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. Tc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify oncocytomas and oncocytic renal neoplasms, including a subset of chromophobe renal cell carcinomas (chRCCs), which are viewed as false-positive. PROCEDURE: Patients imaged with renal sestamibi scans between 2014 and 2023 were reviewed. Those patients with solitary tumors that were originally classified as chRCC were included in the analysis. Imaging with SPECT/CT from the liver dome down had been carried out 75 min after the administration of 925 MBq of Tc-sestamibi. All available H&E and immunostained slides were re-reviewed and classified according to WHO 2022 criteria. Confirmatory immunohistochemical stains were performed in tumors considered morphologically suspicious for non-chRCC entities. RESULT: A total of 18 patients with solitary tumors were included in the final analysis. 13/18 (72.2%) tumors in this cohort remained classified as chRCC, with 4/18 (22.2%) being eosinophilic-variant chRCC. The reclassified tumors (5/18 [27.8%]) included 2/18 (11.1%) low-grade oncocytic tumor (LOT), 1/18 (5.5%) eosinophilic vacuolated tumor (EVT), and 2/18 (11.1%) unclassified low-grade oncocytic neoplasms. As such, only 2/9 (22.2%) qualitatively "hot" tumors were chRCC other than eosinophilic-variant and only 1/9 (11.1%) "cold" tumors was a histology other than chRCC. CONCLUSION: Based on current histopathologic classification methods, it is likely that the "false-positive" rate of uptake on renal sestamibi scans with chRCC has been over-stated. Further study is warranted to better refine the optimal utility of renal sestamibi scans for non-invasive risk stratification of indeterminate renal masses.
A Feasibility Study of [F]F-AraG Positron Emission Tomography (PET) for Cardiac Imaging-Myocardial Viability in Ischemia-Reperfusion Injury Model.
Shrestha UM, Chae HD, Fang Q … +8 more , Lee RJ, Packiasamy J, Huynh L, Blecha J, Huynh TL, VanBrocklin HF, Levi J, Seo Y
Mol Imaging Biol · 2024 Oct · PMID 39060882 · Full text
PURPOSE: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help d...
PURPOSE: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, F-labeled 2'-deoxy-2'-F-fluoro-9-β-d-arabinofuranosylguanine ([F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI. PROCEDURE: To test whether the myocardial [F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [F]F-AraG uptake in normal heart by comparing [F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [F]F-AraG and 2-deoxy-2[F]fluoro-D-glucose ([F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis. RESULTS: The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [F]FDG signals showed wider variability at different time points. Noticeable [F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates. CONCLUSIONS: Our preliminary preclinical data show that [F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI.
Cryo-Fluorescence Tomography as a Tool for Visualizing Whole-Body Inflammation Using Perfluorocarbon Nanoemulsion Tracers.
Leach BI, Lister D, Adams SR … +5 more , Bykowski J, Schwartz AB, McConville P, Dimant H, Ahrens ET
Mol Imaging Biol · 2024 Oct · PMID 39023693 · Full text
PURPOSE: We explore the use of intravenously delivered fluorescent perfluorocarbon (PFC) nanoemulsion tracers and multi-spectral cryo-fluorescence tomography (CFT) for whole-body tracer imaging in murine inflammation mod...
PURPOSE: We explore the use of intravenously delivered fluorescent perfluorocarbon (PFC) nanoemulsion tracers and multi-spectral cryo-fluorescence tomography (CFT) for whole-body tracer imaging in murine inflammation models. CFT is an emerging technique that provides high-resolution, three-dimensional mapping of probe localization in intact animals and tissue samples, enabling unbiased validation of probe biodistribution and minimizes reliance on laborious histological methods employing discrete tissue panels, where disseminated populations of PFC-labeled cells may be overlooked. This methodology can be used to streamline the development of new generations of non-invasive, cellular-molecular imaging probes for in vivo imaging. PROCEDURES: Mixtures of nanoemulsions with different fluorescent emission wavelengths were administered intravenously to naïve mice and models of acute inflammation, colitis, and solid tumor. Mice were euthanized 24 h post-injection, frozen en bloc, and imaged at high resolution (~ 50 µm voxels) using CFT at multiple wavelengths. RESULTS: PFC nanoemulsions were visualized using CFT within tissues of the reticuloendothelial system and inflammatory lesions, consistent with immune cell (macrophage) labeling, as previously reported in in vivo magnetic resonance and nuclear imaging studies. The CFT signals show pronounced differences among fluorescence wavelengths and tissues, presumably due to autofluorescence, differential fluorescence quenching, and scattering of incident and emitted light. CONCLUSIONS: CFT is an effective and complementary methodology to in vivo imaging for validating PFC nanoemulsion biodistribution at high spatial localization, bridging the resolution gap between in vivo imaging and histology.
MHC-I and PD-L1 Expression is Associated with Decreased Tumor Outgrowth and is Radiotherapy-inducible in the Murine Head and Neck Squamous Cell Carcinoma Model MOC1.
Boreel DF, Sandker GGW, Ansems M … +6 more , van den Bijgaart RJE, Peters JPW, Span PN, Adema GJ, Heskamp S, Bussink J
Mol Imaging Biol · 2024 Oct · PMID 39009951 · Full text
INTRODUCTION: Combined radiotherapy and immune checkpoint inhibition is a potential treatment option for head and neck squamous cell carcinoma (HNSCC). Immunocompetent mouse models can help to successfully develop radio-...
INTRODUCTION: Combined radiotherapy and immune checkpoint inhibition is a potential treatment option for head and neck squamous cell carcinoma (HNSCC). Immunocompetent mouse models can help to successfully develop radio- immunotherapy combinations and to increase our understanding of the effects of radiotherapy on the tumor microenvironment for future clinical translation. Therefore, the aim of this study was to develop a homogeneous, reproducible HNSCC model originating from the Mouse Oral Cancer 1 (MOC1) HNSCC cell line, and to explore the radiotherapy-induced changes in its tumor microenvironment, using flow cytometry and PD-L1 microSPECT/CT imaging. MATERIALS AND METHODS: In vivo growing tumors originating from the parental MOC1 line were used to generate single cell derived clones. These clones were screened in vitro for their ability to induce programmed cell death ligand 1 (PD-L1) and major histocompatibility complex class I (MHC-I) following IFNγ exposure. Clones with different IFNγ sensitivity were inoculated in C57BL/6 mice and assessed for tumor outgrowth. The composition of the tumor microenvironment of a stably growing (non)irradiated MOC1-derived clone was assessed by immunohistochemistry, flow cytometry and PD-L1 microSPECT/CT. RESULTS: Low in vitro inducibility of MHC-I and PD-L1 by IFNγ was associated with increased tumor outgrowth of MOC1 clones in vivo. Flow cytometry analysis of cells derived from a stable in vivo growing MOC1 clone MOC1.3D5 showed expression of MHC-I and PD-L1 on several cell populations within the tumor. Upon irradiation, MHC-I and PD-L1 increased on leukocytes (CD45.2) and cancer associated fibroblasts (CD45.2/EpCAM/CD90.1). Furthermore, PD-L1 microSPECT/CT showed increased tumor uptake of radiolabeled PD-L1 antibodies with a heterogeneous spatial distribution of the radio signal, which co-localized with PD-L1 and CD45.2 areas. DISCUSSION: PD-L1 and MHC-I inducibility by IFNγ in vitro is associated with tumor outgrowth of MOC1 clones in vivo. In tumors originating from a stably growing MOC1-derived clone, expression of these immune-related markers was induced by irradiation shown by flow cytometry on several cell populations within the tumor microenvironment such as immune cells and cancer associated fibroblasts. PD-L1 microSPECT/CT showed increased tumor uptake following radiotherapy, and autoradiography showed correlation of uptake with areas that are heavily infiltrated by immune cells. Knowledge of radiotherapy-induced effects on the tumor microenvironment in this model can help optimize timing and dosage for radio- immunotherapy combination strategies in future research.
Correction: Monitoring Immune Cell Function Through Optical Imaging: a Review Highlighting Transgenic Mouse Models.
Chawda C, McMorrow R, Gaspar N … +2 more , Zambito G, Mezzanotte L
Mol Imaging Biol · 2024 Oct · PMID 38995479 · Full text
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In vivo Hyperpolarized Metabolic Imaging to Monitor the Progression of Hepatitis B Virus (HBV)-Related Hepatitis to Liver Fibrosis.
Moon CM, Heo SH, Jeong YY … +3 more , Lee YY, Kim SK, Shin SS
Mol Imaging Biol · 2024 Aug · PMID 38992246 · Publisher ↗
PURPOSE: This study aimed to assess metabolic changes to monitor the progression from normal liver to hepatitis B virus (HBV)-related hepatitis and liver fibrosis using hyperpolarized C magnetic resonance imaging (MRI)....
PURPOSE: This study aimed to assess metabolic changes to monitor the progression from normal liver to hepatitis B virus (HBV)-related hepatitis and liver fibrosis using hyperpolarized C magnetic resonance imaging (MRI). PROCEDURES: Hepatitis was induced in mice (n = 16) via hydrodynamic injection of HBV 1.2 plasmid (25 μg). Among them, liver fibrosis was induced in the mice (n = 8) through weight-adapted administration of thioacetamide with ethanol. Normal control mice (n = 8) were injected with a phosphate buffer solution. Subsequently, a hyperpolarized C MRI was performed on the mouse liver in vivo. The level of hepatitis B surface antigen (HBsAg) in blood serum was measured. Statistical analysis involved comparing the differential metabolite ratios, blood biochemistry values, and body weight among the three groups using the Kruskal-Wallis one-way analysis of variance. RESULTS: HBsAg was absent in the normal and fibrosis groups, while it was detected in the hepatitis group. The ratios of [1-C] lactate/pyruvate, [1-C] alanine/pyruvate, [1-C] lactate/total carbon, and [1-C] alanine/total carbon were significantly lower in the normal control group than in the hepatitis and fibrosis groups (p < 0.05). Moreover, these ratios were significantly higher in the fibrosis group than in the hepatitis group (p < 0.05). However, no significant differences were observed in either [1-C] pyruvate-hydrate/pyruvate or [1-C] pyruvate-hydrate/total carbon among the three groups. CONCLUSIONS: The levels of [1-C] lactate and [1-C] alanine in vivo may serve as valuable indicators for differentiating between HBV-related hepatitis, liver fibrosis, and normal liver.
A Phase 2 Multicenter Clinical Trial of Intraoperative Molecular Imaging of Lung Cancer with a pH-Activatable Nanoprobe.
Kennedy GT, Azari FS, Chang A … +7 more , Bou-Samra P, Desphande C, Predina J, Delikatny EJ, Olson M, Rice DC, Singhal S
Mol Imaging Biol · 2024 Aug · PMID 38992245 · Full text
PURPOSE: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer. Recently, a probe has been developed that only fluoresces when activated in a...
PURPOSE: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer. Recently, a probe has been developed that only fluoresces when activated in an acidic pH, which is common to many malignancies. We report the first multicenter Phase 2 trial of a pH-activatable nanoprobe (pegsitacianine, ONM-100) for IMI of lung cancer. METHODS: Patients with suspected or biopsy-confirmed lung cancer scheduled for sublobar resection were administered a single intravenous infusion of pegsitacianine (1 mg/kg) one to three days prior to surgery. Intraoperatively, the patients underwent a white light thoracoscopic evaluation, and then were imaged with an NIR thoracoscope to detect tumor fluorescence. The primary study endpoint was the proportion of patients with a clinically significant event (CSE) which was defined as an intraoperative discovery during IMI that led to a change in the surgical procedure. Possible CSEs included (i) localizing the index lung nodule that could not be located by white light, (ii) identifying a synchronous malignant lesion, or (iii) recognizing a close surgical margin (< = 10 mm). Secondary endpoints were sensitivity, specificity, NPV, and PPV of pegsitacianine in detecting tumor-containing tissue. The safety evaluation was based on adverse event reporting, clinical laboratory parameters, and physical examinations. RESULTS: Twenty patients were confirmed as eligible and administered pegsitacianine. Most of the patients were female (n = 12 [60%]), middle-aged (mean age 63.4 years), and former smokers (n = 13 [65%], 28.6 mean pack years). Mean lesion size was 1.9 cm, and most lesions (n = 17 [85%]) were malignant. The most common histologic subtype was adenocarcinoma (n = 9). By utilizing IMI with pegsitacianine, one patient had a CSE in the detection of a close margin and another had localization of a tumor not detectable by traditional surgical means. Six of 19 (31.6%) malignant lesions fluoresced with mean tumor-to-background ratio (TBR) of 3.00, as compared to TBR of 1.20 for benign lesions (n = 3). Sensitivity and specificity of pegsitacianine-based IMI for detecting malignant tissue was 31.6% and 33.3%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of pegsitacianine-based IMI was 75% and 7.1%, respectively. Pegsitacianine-based imaging was not effective in differentiating benign and malignant lymph nodes. From a safety perspective, no drug-related serious adverse events occurred. Four patients experienced mild pegsitacianine-related infusion reactions which required discontinuing the study drug with complete resolution of symptoms. CONCLUSIONS: Pegsitacianine-based IMI, though well tolerated from a safety perspective, does not consistently label lung tumors during resection and does not provide significant clinical benefit over existing standards of surgical care. The biology of lung tumors may not be as acidic as other solid tumors in the body thereby not activating the probe as predicted.
[Ga]Ga-labeled FAPI Conjugated with Gly-Pro Sequence for PET Imaging of Malignant Tumors.
Shang Y, Zhang G, Yao X … +7 more , Lai C, Wang F, Zeng B, Liu E, Yuan H, Cheng Z, Jiang L
Mol Imaging Biol · 2024 Aug · PMID 38987449 · Publisher ↗
PURPOSE: To improve tumor uptake and prolong tumor retention, a novel fibroblast activation protein (FAP) ligand based on a quinoline-based FAP inhibitor (FAPI) conjugated with the Gly-Pro sequence and 1,4,7,10-tetraazac...
PURPOSE: To improve tumor uptake and prolong tumor retention, a novel fibroblast activation protein (FAP) ligand based on a quinoline-based FAP inhibitor (FAPI) conjugated with the Gly-Pro sequence and 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) was radiolabeled with [Ga]GaCl ([Ga]Ga-DOTA-GPFAPI-04). Due to the tumor heterogeneity, this study aimed to further validate the preclinical value of [Ga]Ga-DOTA-GPFAPI-04 PET imaging in tumor mice models with different FAP expression levels. METHODS: [Ga]Ga-DOTA-GPFAPI-04 was synthesized and its partition coefficient was measured. The stability of [Ga]Ga-DOTA-GPFAPI-04 was tested in phosphate-buffered saline (PBS, pH 7.4) and fetal bovine serum (FBS). Small animal PET and semi-quantitative studies were conducted in Panc-1 and A549 xenograft tumor mice models compared with [Ga]Ga-DOTA-FAPI-04. Immunofluorescent and immunohistochemical staining and western blot assay were performed to confirm FAP expression in xenograft tumors. RESULTS: [Ga]Ga-DOTA-GPFAPI-04 exhibited a radiochemical purity of > 99% and high stability in PBS and FBS. [Ga]Ga-DOTA-GPFAPI-04 had higher hydrophilic property than [Ga]Ga-DOTA-FAPI-04 (-4.09 ± 0.05 vs -3.45 ± 0.05). Small animal PET and semi-quantitative analysis revealed Panc-1 xenograft tumor displayed higher tumor uptake of [Ga]Ga-DOTA-GPFAPI-04 and tumor-to-background ratios compared to A549 xenograft tumor, consistent with the results of immunofluorescence, immunohistochemistry, and western blot. Moreover, [Ga]Ga-DOTA-GPFAPI-04 demonstrated higher tumor accumulation and longer tumor retention than [Ga]Ga-DOTA-FAPI-04 in both Panc-1 and A549 xenograft tumors. Furthermore, the FAP-binding specificity of [Ga]Ga-DOTA-GPFAPI-04 was confirmed in vivo by co-injection of unlabeled GPFAPI-04. CONCLUSION: [Ga]Ga-DOTA-GPFAPI-04 showed more favorable in vivo tumor imaging and longer tumor retention compared to [Ga]Ga-DOTA-FAPI-04, which has high potential to be a promising PET probe for detecting FAP-positive tumors.
Nuclear-Based Labeling of Cellular Immunotherapies: A Simple Protocol for Preclinical Use.
Volpe A, Lyashchenko SK, Ponomarev V
Mol Imaging Biol · 2024 Aug · PMID 38958882 · Full text
Labeling and tracking existing and emerging cell-based immunotherapies using nuclear imaging is widely used to guide the preclinical phases of development and testing of existing and new emerging off-the-shelf cell-based...
Labeling and tracking existing and emerging cell-based immunotherapies using nuclear imaging is widely used to guide the preclinical phases of development and testing of existing and new emerging off-the-shelf cell-based immunotherapies. In fact, advancing our knowledge about their mechanism of action and limitations could provide preclinical support and justification for moving towards clinical experimentation of newly generated products and expedite their approval by the Food and Drug Administration (FDA).Here we provide the reader with a ready to use protocol describing the labeling methodologies and practical procedures to render different candidate cell therapies in vivo traceable by nuclear-based imaging. The protocol includes sufficient practical details to aid researchers at all career stages and from different fields in familiarizing with the described concepts and incorporating them into their work.
Pilot Evaluation of S-(3-[F]Fluoropropyl)-D-Homocysteine and O-(2-[F]Fluoroethyl)-D-Tyrosine as Bacteria-Specific Radiotracers for PET Imaging of Infection.
Betts HM, Luckett JC, Hill PJ
Mol Imaging Biol · 2024 Aug · PMID 38942967 · Full text
PURPOSE: There is currently no ideal radiotracer for imaging bacterial infections. Radiolabelled D-amino acids are promising candidates because they are actively incorporated into the peptidoglycan of the bacterial cell...
PURPOSE: There is currently no ideal radiotracer for imaging bacterial infections. Radiolabelled D-amino acids are promising candidates because they are actively incorporated into the peptidoglycan of the bacterial cell wall, a structural feature which is absent in human cells. This work describes fluorine-18 labelled analogues of D-tyrosine and D-methionine, O-(2-[F]fluoroethyl)-D-tyrosine (D-[F]FET) and S-(3-[F]fluoropropyl)-D-homocysteine (D-[F]FPHCys), and their pilot evaluation studies as potential radiotracers for imaging bacterial infection. PROCEDURES: D-[F]FET and D-[F]FPHCys were prepared in classical fluorination-deprotection reactions, and their uptake in Staphylococcus aureus and Pseudomonas aeruginosa was evaluated over 2 h. Heat killed bacteria were used as controls. A clinically-relevant foreign body model of S. aureus infection was established in Balb/c mice, as well as a sterile foreign body to mimic inflammation. The ex vivo biodistribution of D-[F]FPHCys in the infected and inflamed mice was evaluated after 1 h, by dissection and gamma counting. The uptake was compared to that of [F]FDG. RESULTS: In vitro uptake of both D-[F]FET and D-[F]FPHCys was specific to live bacteria. Uptake was higher in S. aureus than in P. aeruginosa for both radiotracers, and of the two, higher for D-[F]FPHCys than D-[F]FET. Blocking experiments with non-radioactive D-[F]FPHCys confirmed specificity of uptake. In vivo, D-[F]FPHCys had greater accumulation in S. aureus infection compared with sterile inflammation, which was statistically significant. As anticipated, [F]FDG showed no significant difference in uptake between infection and inflammation. CONCLUSIONS: D-[F]FPHCys uptake was higher in infected tissues than inflammation, and represents a fluorine-18 labelled D-AA with potential to detect a S. aureus reference strain (Xen29) in vivo. Additional studies are needed to evaluate uptake of this radiotracer in clinical isolates.
Optimizing SUV Analysis: A Multicenter Study on Preclinical FDG-PET/CT Highlights the Impact of Standardization.
Kuntner C, Alcaide C, Anestis D … +11 more , Bankstahl JP, Boutin H, Brasse D, Elvas F, Forster D, Rouchota MG, Tavares A, Teuter M, Wanek T, Zachhuber L, Mannheim JG
Mol Imaging Biol · 2024 Aug · PMID 38907124 · Full text
PURPOSE: Preclinical imaging, with translational potential, lacks a standardized method for defining volumes of interest (VOIs), impacting data reproducibility. The aim of this study was to determine the interobserver va...
PURPOSE: Preclinical imaging, with translational potential, lacks a standardized method for defining volumes of interest (VOIs), impacting data reproducibility. The aim of this study was to determine the interobserver variability of VOI sizes and standard uptake values (SUV and SUV) of different organs using the same [F]FDG-PET and PET/CT datasets analyzed by multiple observers. In addition, the effect of a standardized analysis approach was evaluated. PROCEDURES: In total, 12 observers (4 beginners and 8 experts) analyzed identical preclinical [F]FDG-PET-only and PET/CT datasets according to their local default image analysis protocols for multiple organs. Furthermore, a standardized protocol was defined, including detailed information on the respective VOI size and position for multiple organs, and all observers reanalyzed the PET/CT datasets following this protocol. RESULTS: Without standardization, significant differences in the SUV and SUV were found among the observers. Coregistering CT images with PET images improved the comparability to a limited extent. The introduction of a standardized protocol that details the VOI size and position for multiple organs reduced interobserver variability and enhanced comparability. CONCLUSIONS: The protocol offered clear guidelines and was particularly beneficial for beginners, resulting in improved comparability of SUV and SUV values for various organs. The study suggested that incorporating an additional VOI template could further enhance the comparability of the findings in preclinical imaging analyses.
Rapid Assessment of Bio-distribution and Antitumor Activity of the Photosensitizer Bremachlorin in a Murine PDAC Model: Detection of PDT-induced Tumor Necrosis by IRDye® 800CW Carboxylate, Using Whole-Body Fluorescent Imaging.
McMorrow R, de Bruijn HS, Que I … +6 more , Stuurman DC, de Ridder CMA, Doukas M, Robinson DJ, Mezzanotte L, Lowik CWGM
Mol Imaging Biol · 2024 Aug · PMID 38890241 · Full text
Photodynamic therapy (PDT) is a light-based anticancer therapy that can induce tumor necrosis and/or apoptosis. Two important factors contributing to the efficacy of PDT are the concentration of the photosensitizer in th...
Photodynamic therapy (PDT) is a light-based anticancer therapy that can induce tumor necrosis and/or apoptosis. Two important factors contributing to the efficacy of PDT are the concentration of the photosensitizer in the tumor tissue and its preferential accumulation in the tumor tissue compared to that in normal tissues. In this study, we investigated the use of optical imaging for monitoring whole-body bio-distribution of the fluorescent (660 nm) photosensitizer Bremachlorin in vivo, in a murine pancreatic ductal adenocarcinoma (PDAC) model. Moreover, we non-invasively, examined the induction of tumor necrosis after PDT treatment using near-infrared fluorescent imaging of the necrosis avid cyanine dye IRDye®-800CW Carboxylate. Using whole-body fluorescence imaging, we observed that Bremachlorin preferentially accumulated in pancreatic tumors. Furthermore, in a longitudinal study we showed that 3 hours after Bremachlorin administration, the fluorescent tumor signal reached its maximum. In addition, the tumor-to-background ratio at all-time points was approximately 1.4. Ex vivo, at 6 hours after Bremachlorin administration, the tumor-to-muscle or -normal pancreas ratio exhibited a greater difference than it did at 24 hours, suggesting that, in terms of efficacy, 6 hours after Bremachlorin administration was an effective time point for PDT treatment of PDAC. In vivo administration of the near infrared fluorescence agent IRDye®-800CW Carboxylate showed that PDT, 6 hours after administration of Bremachlorin, selectively induced necrosis in the tumor tissues, which was subsequently confirmed histologically. In conclusion, by using in vivo fluorescence imaging, we could non-invasively and longitudinally monitor, the whole-body distribution of Bremachlorin. Furthermore, we successfully used IRDye®-800CW Carboxylate, a near-infrared fluorescent necrosis avid agent, to image PDT-induced necrotic cell death as a measure of therapeutic efficacy. This study showed how fluorescence can be applied for optimizing, and assessing the efficacy of, PDT.
Evaluations of an Early Change in Tumor Pathophysiology in Response to Radiotherapy with Oxygen Enhanced Electron Paramagnetic Resonance Imaging (OE EPRI).
Li T, Murley GA, Liang X … +4 more , Chin RL, de la Cerda J, Schuler FW, Pagel MD
Mol Imaging Biol · 2024 Jun · PMID 38869818 · Full text
PURPOSE: Electron Paramagnetic Resonance Imaging (EPRI) can image the partial pressure of oxygen (pO) within in vivo tumor models. We sought to develop Oxygen Enhanced (OE) EPRI that measures tumor pO with breathing gase...
PURPOSE: Electron Paramagnetic Resonance Imaging (EPRI) can image the partial pressure of oxygen (pO) within in vivo tumor models. We sought to develop Oxygen Enhanced (OE) EPRI that measures tumor pO with breathing gases of 21% O (pO) and 100% O (pO), and the differences in pO between breathing gases (ΔpO). We applied OE EPRI to study the early change in tumor pathophysiology in response to radiotherapy in two tumor models of pancreatic cancer. PROCEDURES: We developed a protocol that intraperitoneally administered OX071, a trityl radical contrast agent, and then acquired anatomical MR images to localize the tumor. Subsequently, we acquired two pO and two pO maps using the T1 relaxation time of OX071 measured with EPRI and a R-pO calibration of OX071. We studied 4T1 flank tumor model to evaluate the repeatability of OE EPRI. We then applied OE EPRI to study COLO 357 and Su.86.86 flank tumor models treated with 10 Gy radiotherapy. RESULTS: The repeatability of mean pO for individual tumors was ± 2.6 Torr between successive scans when breathing 21% O or 100% O, representing a precision of 9.6%. Tumor pO and pO decreased after radiotherapy for both models, although the decreases were not significant or only moderately significant, and the effect sizes were modest. For comparison, ΔpO showed a large, highly significant decrease after radiotherapy, and the effect size was large. MANOVA and analyses of the HF10 hypoxia fraction provided similar results. CONCLUSIONS: EPRI can evaluate tumor pO with outstanding precision relative to other imaging modalities. The change in ΔpO before vs. after treatment was the best parameter for measuring the early change in tumor pathophysiology in response to radiotherapy. Our studies have established ΔpO from OE EPRI as a new parameter, and have established that OE EPRI is a valuable new methodology for molecular imaging.
Tumor Pre-Targeting System Using Streptavidin-Expressing Bacteria.
Kwon SY, You SH, Im JH … +7 more , Nguyen DH, Kim DY, Pyo A, Kim GJ, Bom HS, Hong Y, Min JJ
Mol Imaging Biol · 2024 Aug · PMID 38814379 · Publisher ↗
PURPOSE: A major obstacle to targeted cancer therapy is identifying suitable targets that are specifically and abundantly expressed by solid tumors. Certain bacterial strains selectively colonize solid tumors and can del...
PURPOSE: A major obstacle to targeted cancer therapy is identifying suitable targets that are specifically and abundantly expressed by solid tumors. Certain bacterial strains selectively colonize solid tumors and can deliver genetically encoded cargo molecules to the tumor cells. Here, we engineered bacteria to express monomeric streptavidin (mSA) in tumors, and developed a novel tumor pre-targeting system by visualizing the presence of tumor-associated mSA using a biotinylated imaging probe. PROCEDURES: We constructed a plasmid expressing mSA fused to maltose-binding protein and optimized the ribosome binding site sequence to increase solubility and expression levels. E. coli MG1655 was transformed with the recombinant plasmid, expression of which is driven by the pBAD promotor. Expression of mSA was induced by L-arabinose 4 days after injection of bacteria into mice bearing CT26 mouse colon carcinoma cells. Selective accumulation of mSA in tumor tissues was visualized by optical imaging after administration of a biotinylated fluorescent dye. Counting of viable bacterial cells was also performed. RESULTS: Compared with a conventional system, the novel expression system resulted in significantly higher expression of mSA and sustained binding to biotin. Imaging signals in tumor tissues were significantly stronger in the mSA-expressing group than in non-expressing group (P = 0.0005). Furthermore, the fluorescent signal in tumor tissues became detectable again after multiple inductions with L-arabinose. The bacterial counts in tumor tissues showed no significant differences between conditions with and without L-arabinose (P = 0.45). Western blot analysis of tumor tissues confirmed expression and binding of mSA to biotin. CONCLUSIONS: We successfully engineered tumor-targeting bacteria carrying a recombinant plasmid expressing mSA, which was targeted to, and expressed in, tumor tissues. These data demonstrate the potential of this novel tumor pre-targeting system when combined with biotinylated imaging probes or therapeutic agents.
Partial Acquisition of Spectral Projections Accelerates Four-dimensional Spectral-spatial EPR Imaging for Mouse Tumor Models: A Feasibility Study.
Oba M, Taguchi M, Kudo Y … +6 more , Yamashita K, Yasui H, Matsumoto S, Kirilyuk IA, Inanami O, Hirata H
Mol Imaging Biol · 2024 Jun · PMID 38811467 · Publisher ↗
PURPOSE: Our study aimed to accelerate the acquisition of four-dimensional (4D) spectral-spatial electron paramagnetic resonance (EPR) imaging for mouse tumor models. This advancement in EPR imaging should reduce the acq...
PURPOSE: Our study aimed to accelerate the acquisition of four-dimensional (4D) spectral-spatial electron paramagnetic resonance (EPR) imaging for mouse tumor models. This advancement in EPR imaging should reduce the acquisition time of spectroscopic mapping while reducing quality degradation for mouse tumor models. PROCEDURES: EPR spectra under magnetic field gradients, called spectral projections, were partially measured. Additional spectral projections were later computationally synthesized from the measured spectral projections. Four-dimensional spectral-spatial images were reconstructed from the post-processed spectral projections using the algebraic reconstruction technique (ART) and assessed in terms of their image qualities. We applied this approach to a sample solution and a mouse Hs766T xenograft model of human-derived pancreatic ductal adenocarcinoma cells to demonstrate the feasibility of our concept. The nitroxyl radical imaging agent H,N-DCP was exogenously infused into the mouse xenograft model. RESULTS: The computation code of 4D spectral-spatial imaging was tested with numerically generated spectral projections. In the linewidth mapping of the sample solution, we achieved a relative standard uncertainty (standard deviation/| mean |) of 0.76 μT/45.38 μT = 0.017 on the peak-to-peak first-derivative EPR linewidth. The qualities of the linewidth maps and the effect of computational synthesis of spectral projections were examined. Finally, we obtained the three-dimensional linewidth map of H,N-DCP in a Hs766T tumor-bearing leg in vivo. CONCLUSION: We achieved a 46.7% reduction in the acquisition time of 4D spectral-spatial EPR imaging without significantly degrading the image quality. A combination of ART and partial acquisition in three-dimensional raster magnetic field gradient settings in orthogonal coordinates is a novel approach. Our approach to 4D spectral-spatial EPR imaging can be applied to any subject, especially for samples with less variation in one direction.
Challenges in Pharmacokinetic Modelling of [F]fluoro-PEG-folate PET/CT Imaging in Epithelial Ovarian Cancer Patients.
Ruytenberg T, Ciggaar IA, Peters ITA … +13 more , Noortman WA, Dibbets-Schneider P, de Muynck LDAN, Kuil J, de Kroon CD, Molenaar TJM, Helmerhorst HJF, Pereira Arias-Bouda LM, Vahrmeijer AL, Windhorst AD, van Velden FHP, Gaarenstroom KN, de Geus-Oei LF
Mol Imaging Biol · 2024 Aug · PMID 38775919 · Full text
PURPOSE: To describe the pharmacokinetic properties of the [F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC). PROCEDURES: In five pati...
PURPOSE: To describe the pharmacokinetic properties of the [F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC). PROCEDURES: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v. administration of 185 MBq [F]fluoro-PEG-folate. Arterial blood samples collected at nineteen timepoints were used to determine the plasma input function. A static volume of interest (VOI) for included tumor lesions was drawn manually on the PET images. Modelling was performed using PMOD software. Three different models (a 1-tissue compartment model (1T2k) and two 2-tissue compartment models, irreversible (2T3k) and reversible (2T4k)) were compared in goodness of fit with the time activity curves by means of the Akaike information criterion. RESULTS: The pharmacokinetic analysis in the pelvic area has proven to be much more challenging than expected. Only four out of 22 tumor lesions in five patients were considered suitable to perform modelling on. The remaining tumor lesions were inapt due to either low tracer uptake, small size, proximity to other [F]fluoro-PEG-folate -avid structures and/or displacement by abdominal organ motion in the dynamic scan. Data from the four analyzed tumor lesions suggest that the irreversible 2T3k may best describe the pharmacokinetics. All 22 lesions were immunohistochemically stained positive for the folate receptor alpha (FRα) after resection. CONCLUSION: Performing pharmacokinetic analysis in the abdominal pelvic region is very challenging. This brief article describes the challenges and pitfalls in pharmacokinetic analysis of a tracer with high physiological accumulation in the intestines, in case of lesions of limited size in the abdominal pelvic area.
Prostate Specific Membrane Antigen Expression in a Syngeneic Breast Cancer Mouse Model.
Shirke AA, Wang J, Ramamurthy G … +6 more , Mahanty A, Walker E, Zhang L, Panigrahi A, Wang X, Basilion JP
Mol Imaging Biol · 2024 Aug · PMID 38760621 · Full text
PURPOSE: Prostate specific membrane antigen (PSMA) has been studied in human breast cancer (BCa) biopsies, however, lack of data on PSMA expression in mouse models impedes development of PSMA-targeted therapies, particul...
PURPOSE: Prostate specific membrane antigen (PSMA) has been studied in human breast cancer (BCa) biopsies, however, lack of data on PSMA expression in mouse models impedes development of PSMA-targeted therapies, particularly in improving breast conserving surgery (BCS) margins. This study aimed to validate and characterize the expression of PSMA in murine BCa models, demonstrating that PSMA can be utilized to improve therapies and imaging techniques. METHODS: Murine triple negative breast cancer 4T1 cells, and human cell lines, MDA-MB-231, MDA-MB-468, implanted into the mammary fat pads of BALB/c mice, were imaged by our PSMA targeted theranostic agent, PSMA-1-Pc413, and tumor to background ratios (TBR) were calculated to validate selective uptake. Immunohistochemistry was used to correlate PSMA expression in relation to CD31, an endothelial cell biomarker highlighting neovasculature. PSMA expression was also quantified by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). RESULTS: Accumulation of PSMA-1-Pc413 was observed in 4T1 primary tumors and associated metastases. Average TBR of 4T1 tumors were calculated to be greater than 1.5-ratio at which tumor tissues can be distinguished from normal structures-at peak accumulation with the signal intensity in 4T1 tumors comparable to that in high PSMA expressing PC3-pip tumors. Extraction of 4T1 tumors and lung metastases followed by RT-PCR analysis and PSMA-CD31 co-staining shows that PSMA is consistently localized on tumor neovasculature with no expression in tumor cells and surrounding normal tissues. CONCLUSION: The selective uptake of PSMA-1-Pc413 in these cancer tissues as well as the characterization and validation of PSMA expression on neovasculature in this syngeneic 4T1 model emphasizes their potential for advancements in targeted therapies and imaging techniques for BCa. PSMA holds great promise as an oncogenic target for BCa and its associated metastases.
Comparison of the Pharmacokinetics of Gadolinium-Based and Iron Oxide-Based Contrast Agents inside the Lymphatic Structure using Magnetic Resonance Lymphangiography.
Chae YJ, Kim KW, Kim MH … +8 more , Woo CW, Kim ST, Kim JW, Shin TH, Lee DW, Kim JK, Choi Y, Woo DC
Mol Imaging Biol · 2024 Aug · PMID 38684581 · Publisher ↗
PURPOSE: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to a...
PURPOSE: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels. PROCEDURES: All animals utilized in this study were male Sprague-Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine. RESULTS: Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 μmol (15 mM, 30 μL) and 0.75 μmol (15 mM, 50 μL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement. CONCLUSION: In MRL, INV-001, a novel T contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination.
Molecular Imaging of Fibroblast Activation in Rabbit Atherosclerotic Plaques: a Preclinical PET/CT Study.
Ji T, Zan C, Li L … +7 more , Cao J, Su Y, Wang H, Wu Z, Yang MF, Dou K, Li S
Mol Imaging Biol · 2024 Aug · PMID 38664355 · Publisher ↗
AIM: Atherosclerosis remains the pathological basis of myocardial infarction and ischemic stroke. Early and accurate identification of plauqes is crucial to improve clinical outcomes of atherosclerosis patients. Our stud...
AIM: Atherosclerosis remains the pathological basis of myocardial infarction and ischemic stroke. Early and accurate identification of plauqes is crucial to improve clinical outcomes of atherosclerosis patients. Our study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-04 PET/CT in identifying plaques via a preclinical rabbit model of atherosclerosis. METHODS: New Zealand white rabbits were fed high-fat diet (HFD), and randomly divided into the model group injured by the balloon, and the sham group only with incisions. Ultrasound was performed to detect plaques, and FAPI-avid was determined through AlF-NOTA-FAPI-04 PET/CT. Mean standardized uptake values (SUVmean) in lesions were compared, and biodistribution of AlF-NOTA-FAPI-04 and target-to-background ratios (TBRs) were calculated. Histological staining was performed to display arterial plaques, and autoradiography (ARG) was employed to measure the in vitro intensity of AlF-NOTA-FAPI-04. At last, the correlation among FAP levels, plaque area, SUVmean values and fibrous cap thickness was assessed. RESULTS: The rabbit carotid and abdominal atherosclerosis model was established. AlF-NOTA-FAPI-04 showed a higher uptake in carotid plaques (SUVmean 1.32 ± 0.11) and abdominal plaques (SUVmean 0.73 ± 0.13) compared to corresponding controls (SUVmean 1.07 ± 0.06; 0.46 ± 0.03) (P < 0.05). Biodistribution analysis of AlF-NOTA-FAPI-04 revealed that the bigger plaques were delineated with higher TBRs. Pathological staining showed the formation of arterial plaques, and ARG staining exhibited a higher intensity of AlF-NOTA-FAPI-04 in the bigger plaques. Lastly, plaque area was found to be positively correlated to FAP expression and SUVmean, while FAP expression was negatively correlated to fibrous cap thickness of plaques. CONCLUSIONS: We successfully achieve molecular imaging of fibroblast activation in atherosclerotic lesions of rabbits, suggesting AlF-NOTA-FAPI-04 PET/CT may be a potentially valuable tool to identify plaques.
PDX Models in Theranostic Applications: Generation and Screening for B Cell Lymphoma of Human Origin.
Shmuel S, Monette S, Ibrahim D … +1 more , Pereira PMR
Mol Imaging Biol · 2024 Aug · PMID 38649626 · Full text
This MIB guide briefly summarizes the generation of patient-derived xenografts (PDXs) and highlights the importance of validating PDX models for the presence of B cell lymphoma of human origin before their use in radioth...
This MIB guide briefly summarizes the generation of patient-derived xenografts (PDXs) and highlights the importance of validating PDX models for the presence of B cell lymphoma of human origin before their use in radiotheranostic applications. The use of this protocol will allow researchers to learn different methods for screening PDX models for Epstein-Barr virus (EBV)-infected B cell lymphoma.
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