scholarly journals Performance of nanoScan PET/CT and PET/MR for quantitative imaging of 18F and 89Zr as compared with ex vivo biodistribution in tumor-bearing mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marion Chomet ◽  
Maxime Schreurs ◽  
Ricardo Vos ◽  
Mariska Verlaan ◽  
Esther J. Kooijman ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Tracer Uptake ◽  
Tumor Uptake ◽  
Preclinical Models ◽  
Recovery Coefficient ◽  
Tumor Bearing ◽  
Pet Ct ◽  
Ex Vivo Biodistribution

Abstract Introduction The assessment of ex vivo biodistribution is the preferred method for quantification of radiotracers biodistribution in preclinical models, but is not in line with current ethics on animal research. PET imaging allows for noninvasive longitudinal evaluation of tracer distribution in the same animals, but systemic comparison with ex vivo biodistribution is lacking. Our aim was to evaluate the potential of preclinical PET imaging for accurate tracer quantification, especially in tumor models. Methods NEMA NU 4-2008 phantoms were filled with 11C, 68Ga, 18F, or 89Zr solutions and scanned in Mediso nanoPET/CT and PET/MR scanners until decay. N87 tumor-bearing mice were i.v. injected with either [18F]FDG (~ 14 MBq), kept 50 min under anesthesia followed by imaging for 20 min, or with [89Zr]Zr-DFO-NCS-trastuzumab (~ 5 MBq) and imaged 3 days post-injection for 45 min. After PET acquisition, animals were killed and organs of interest were collected and measured in a γ-counter to determine tracer uptake levels. PET data were reconstructed using TeraTomo reconstruction algorithm with attenuation and scatter correction and regions of interest were drawn using Vivoquant software. PET imaging and ex vivo biodistribution were compared using Bland–Altman plots. Results In phantoms, the highest recovery coefficient, thus the smallest partial volume effect, was obtained with 18F for both PET/CT and PET/MR. Recovery was slightly lower for 11C and 89Zr, while the lowest recovery was obtained with 68Ga in both scanners. In vivo, tumor uptake of the 18F- or 89Zr-labeled tracer proved to be similar irrespective whether quantified by either PET/CT and PET/MR or ex vivo biodistribution with average PET/ex vivo ratios of 0.8–0.9 and a deviation of 10% or less. Both methods appeared less congruent in the quantification of tracer uptake in healthy organs such as brain, kidney, and liver, and depended on the organ evaluated and the radionuclide used. Conclusions Our study suggests that PET quantification of 18F- and 89Zr-labeled tracers is reliable for the evaluation of tumor uptake in preclinical models and a valuable alternative technique for ex vivo biodistribution. However, PET and ex vivo quantification require fully described experimental and analytical procedures for reliability and reproducibility.

scholarly journals Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1838 ◽  
Author(s):  
Jessica Bridoux ◽  
Sara Neyt ◽  
Pieterjan Debie ◽  
Benedicte Descamps ◽  
Nick Devoogdt ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
High Sensitivity ◽  
Radiochemical Yield ◽  
Control Group ◽  
Complexing Agent ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions ◽  
Pet Ct

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [18F]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [18F]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE−/− mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET/CT images and ex vivo data showed specific uptake of [18F]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the β-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology.

scholarly journals Elucidating the Influence of Tumor Presence on the Polymersome Circulation Time in Mice

Pharmaceutics ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 241 ◽  
Author(s):  
Robin M. de Kruijff ◽  
René Raavé ◽  
Annemarie Kip ◽  
Janneke Molkenboer-Kuenen ◽  
Stefan J. Roobol ◽  
...  
Keyword(s):  
Polyethylene Oxide ◽  
Tumor Targeting ◽  
Ex Vivo ◽  
Circulation Time ◽  
Tumor Bearing ◽  
Significant Difference ◽  
The Impact ◽  
Gamma Emitter ◽  
Ex Vivo Biodistribution

The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on nanocarrier circulation times. This paper reports on the influence of tumor presence on the in vivo circulation time and biodistribution of polybutadiene-polyethylene oxide (PBd-PEO) polymersomes. For this purpose, polymersomes were loaded with the gamma-emitter 111In and administered intravenously, followed by timed ex vivo biodistribution. A large reduction in circulation time was observed for tumor-bearing mice, with a circulation half-life of merely 5 min (R2 = 0.98) vs 117 min (R2 = 0.95) in healthy mice. To determine whether the rapid polymersome clearance observed in tumor-bearing mice was mediated by macrophages, chlodronate liposomes were administered to both healthy and tumor-bearing mice prior to the intravenous injection of radiolabeled polymersomes to deplete their macrophages. Pretreatment with chlodronate liposomes depleted macrophages in the spleen and liver and restored the circulation time of the polymersomes with no significant difference in circulation time between healthy mice and tumor-bearing mice pretreated with clodronate liposomes (15.2 ± 1.2% ID/g and 13.6 ± 2.7% ID/g, respectively, at 4 h p.i. with p = 0.3). This indicates that activation of macrophages due to tumor presence indeed affected polymersome clearance rate. Thus, next to particle design, the presence of a tumor can also greatly impact circulation times and should be taken into account when designing studies to evaluate the distribution of polymersomes.

scholarly journals In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

2020 ◽  
Author(s):  
Marco F. Taddio ◽  
Claudia A. Castro Jaramillo ◽  
Peter Runge ◽  
Alain Blanc ◽  
Claudia Keller ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Tracer Uptake ◽  
Local Inflammation ◽  
Inoculation Site ◽  
Positron Emission ◽  
Pet Ct ◽  
Antigen Presenting

Abstract Purpose The co-stimulatory molecules CD80 and CD86 are upregulated on activated antigen-presenting cells (APC). We investigated whether local APC activation, induced by subcutaneous (s.c.) inoculation of lipopolysaccharides (LPS), can be imaged by positron emission tomography (PET) with CD80/CD86-targeting 64Cu-labelled abatacept. Procedures Mice were inoculated s.c. with extracellular-matrix gel containing either LPS or vehicle (PBS). Immune cell populations were analysed by flow cytometry and marker expression by RT-qPCR. 64Cu-NODAGA-abatacept distribution was analysed using PET/CT and ex vivo biodistribution. Results The number of CD80+ and CD86+ immune cells at the LPS inoculation site significantly increased a few days after inoculation. CD68 and CD86 expression were higher at the LPS than the PBS inoculation site, and CD80 was only increased at the LPS inoculation site. CTLA-4 was highest 10 days after LPS inoculation, when CD80/CD86 decreased again. A few days after inoculation, 64Cu-NODAGA-abatacept distribution to the inoculation site was significantly higher for LPS than PBS (4.2-fold). Co-administration of unlabelled abatacept or human immunoglobulin reduced tracer uptake. The latter reduced the number of CD86+ immune cells at the LPS inoculation site. Conclusions CD80 and CD86 are upregulated in an LPS-induced local inflammation, indicating invasion of activated APCs. 64Cu-NODAGA-abatacept PET allowed following APC activation over time.

scholarly journals Preclinical Assessment Addressing Intravenous Administration of a [68Ga]Ga-PSMA-617 Microemulsion: Acute In Vivo Toxicity, Tolerability, PET Imaging, and Biodistribution

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2650
Author(s):  
Vusani Mandiwana ◽  
Lonji Kalombo ◽  
Rose Hayeshi ◽  
Jan Rijn Zeevaart ◽  
Thomas Ebenhan
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Intravenous Administration ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Post Injection ◽  
In Vivo Toxicity ◽  
Ex Vivo Biodistribution

It has been herein presented that a microemulsion, known to be an effective and safe drug delivery system following intravenous administration, can be loaded with traces of [68Ga]Ga-PSMA-617 without losing its properties or causing toxicity. Following tolerated IV injections the capability of the microemulsion in altering [68Ga]Ga-PSMA-617 distribution was presented at 120 min post injection based on its ex vivo biodistribution results.

scholarly journals Preclinical and Exploratory Clinical Studies of Novel 68Ga-labeled ᴅ-Peptide Antagonist for PET Imaging of TIGIT Expression in Cancers

2021 ◽  
Author(s):  
Xiaobo Wang ◽  
Ming Zhou ◽  
Bei Chen ◽  
Huanhuan Liu ◽  
Jianyang Fang ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Ct Imaging ◽  
Whole Body ◽  
Binding Assays ◽  
Pet Ct ◽  
Peptide Antagonist

Abstract Purpose While TIGIT has been propelled under the spotlight as a next-generation target in cancer immunotherapy, anti-TIGIT therapy seems to be promising for a fraction of patients in clinical trials. Therefore, patient stratification is critical for this therapy, which could benefit from a whole-body, non-invasive and quantitative evaluation of TIGIT expression in cancers. In this study, a 68Ga-labeled ᴅ-peptide antagonist, 68Ga-GP12, was developed and validated for PET imaging of TIGIT expression in vitro, in vivo, and first-in-human pilot study. Methods The ᴅ-enantiomer peptide antagonists were modified and radiolabeled with 68Ga. In vitro binding assays were performed in human peripheral blood mononuclear cells (PBMCs) to assess their affinity and specificity. The imaging capacity, biodistribution, pharmacokinetics, and radiation dosimetry were investigated in vivo. Flow cytometry, autoradiography, and immunohistochemical staining were used to confirm the expression of TIGIT ex vivo. The safety and potential of 68Ga-GP12 for PET/CT imaging of TIGIT expression were further evaluated in a first-in-human pilot study with advanced NSCLC. Results 68Ga-labeled ᴅ-peptides were conveniently produced with high radiochemical yields,radiochemical purity and molar activities. In vitro binding assays demonstrated 68Ga-GP12 has favorable affinity and specificity for TIGIT with a KD of 37.28 nM. In vivo and ex vivo studies demonstrated the favorable pharmacokinetics of 68Ga-GP12 for PET imaging of TIGIT expression with high tumor uptake of 4.22 ± 0.68 %ID/g and the tumor-to-muscle ratio of 12.94 ± 2.64 at 60 min post-injection. The primary and metastatic lesions found in the first-in-human studies of 68Ga-GP12 PET/CT imaging were comparable to that in 18F-FDG PET/CT imaging. Moreover, the inhomogenous intra-and-inter-tumoral uptake of 68Ga-GP12 was presented, reflecting the heterogeneity of TIGIT expression levels. Conclusion 68Ga-GP12 is a promising radiotracer for PET imaging of TIGIT expression in cancers, indicating its potential as a potential companion diagnostic for anti-TIGIT therapies.

scholarly journals Development of [18F]FPy-WL12 as a PD-L1 Specific PET Imaging Peptide

2019 ◽  
Vol 18 ◽  
pp. 153601211985218 ◽  
Author(s):  
Wojciech G. Lesniak ◽  
Ronnie C. Mease ◽  
Samit Chatterjee ◽  
Dhiraj Kumar ◽  
Ala Lisok ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Whole Body ◽  
In Vivo Evaluation ◽  
Positron Emission ◽  
Comprehensive Picture ◽  
Specific Uptake ◽  
Ex Vivo Biodistribution

Expression of programmed cell death ligand 1 (PD-L1) within tumors is an important biomarker for guiding immune checkpoint therapies; however, immunohistochemistry-based methods of detection fail to provide a comprehensive picture of PD-L1 levels in an entire patient. To facilitate quantification of PD-L1 in the whole body, we developed a peptide-based, high-affinity PD-L1 imaging agent labeled with [18F]fluoride for positron emission tomography (PET) imaging. The parent peptide, WL12, and the nonradioactive analog of the radiotracer, 19FPy-WL12, inhibit PD-1/PD-L1 interaction at low nanomolar concentrations (half maximal inhibitory concentration [IC50], 26-32 nM). The radiotracer, [18F]FPy-WL12, was prepared by conjugating 2,3,5,6-tetrafluorophenyl 6-[18F]fluoronicotinate ([18F]FPy-TFP) to WL12 and assessed for specificity in vitro in 6 cancer cell lines with varying PD-L1 expression. The uptake of the radiotracer reflected the PD-L1 expression assessed by flow cytometry. Next, we performed the in vivo evaluation of [18F]FPy-WL12 in mice bearing cancer xenografts by PET imaging, ex vivo biodistribution, and blocking studies. In vivo data demonstrated a PD-L1-specific uptake of [18F]FPy-WL12 in tumors that is reduced in mice receiving a blocking dose. The majority of [18F]FPy-WL12 radioactivity was localized in the tumors, liver, and kidneys indicating the need for optimization of the labeling strategy to improve the in vivo pharmacokinetics of the radiotracer.

Dose Formulation, Biodistribution and PET Imaging Studies of a First-In-Class Fluorine-18 Organophosphorus Cholinesterase Inhibitor Tracer in Rat

2020 ◽  
Vol 14 ◽  
Author(s):  
Kiel D. Neumann ◽  
Joseph E. Blecha ◽  
Chih-Kai Chao ◽  
Tony Huynh ◽  
Kurt R. Zinn ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Male Rats ◽  
Imaging Data ◽  
Live Tissue ◽  
Dose Formulation ◽  
Pet Tracer ◽  
Ex Vivo Biodistribution

Background:: To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 (18F) radiolabeled positron emission tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. Objective.: We sought to evaluate the PET tracer in vivo using a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivo tracer performance to previous data collected using a CH3CN:PBS formulation. Methods:: A high molar activity [18F] tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. Results and Discussion:: An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included tracer and a single metabolite. The ex vivo biodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Conclusions:: Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we find that the i.v. dose formulation changed the in vivo profile of an organophosphorus PET tracer is considered an important finding for future organophosporus PET tracer studies.

scholarly journals Head-to-head intra-individual comparison of biodistribution and tumor uptake of 68Ga-FAPI and 18F-FDG PET/CT in cancer patients

2021 ◽  
Author(s):  
Frederik L. Giesel ◽  
Clemens Kratochwil ◽  
Joel Schlittenhardt ◽  
Katharina Dendl ◽  
Matthias Eiber ◽  
...  
Keyword(s):  
Fdg Pet ◽  
Standard Of Care ◽  
Blood Pool ◽  
Tracer Uptake ◽  
Time Interval ◽  
Tumor Uptake ◽  
Primary Tumors ◽  
Individual Comparison ◽  
Pet Ct ◽  
Fdg Pet Ct

Abstract Purpose FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of 68Ga-FAPI versus standard-of-care 18F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers. Material and Methods This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both 68Ga-FAPI and 18F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ). Results A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. 68Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for 68Ga-FAPI than 18F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, 68Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases. Conclusion Quantitative tumor uptake is comparable between 68Ga-FAPI and 18F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for 68Ga-FAPI. Thus, 68Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological 18F-FDG uptake.

scholarly journals Increased [18F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoichi Shimizu ◽  
Yukihiro Nakai ◽  
Hiroyuki Watanabe ◽  
Shimpei Iikuni ◽  
Masahiro Ono ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Pet Imaging ◽  
Multidrug Resistant ◽  
Ct Images ◽  
Pet Scan ◽  
Reduced Form ◽  
Pet Ct ◽  
Fadu Cells ◽  
Hypoxic State

Abstract Background [18F]Fluoromisonidazole ([18F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [18F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [18F]FMISO uptake level varied depending on the cellular glutathione conjugation and excretion ability such as enzyme activity of glutathione-S-transferase and expression levels of multidrug resistance-associated protein 1 (MRP1, an efflux transporter), in addition to the cellular hypoxic state. In this study, we evaluated whether MRP1 activity affected [18F]FMISO PET imaging. Methods FaDu human pharyngeal squamous cell carcinoma cells were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, incubated with [18F]FMISO for 4 h under hypoxia, and their radioactivity was then measured. FaDu tumor-bearing mice were intravenously injected with [18F]FMISO, and PET/CT images were acquired at 4 h post-injection (1st PET scan). Two days later, the same mice were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, and PET/CT images were acquired (2nd PET scan). Results FaDu cells pretreated with MRP1 inhibitors exhibited significantly higher radioactivity than those without inhibitor treatment (cyclosporine A: 6.91 ± 0.27, lapatinib: 10.03 ± 0.47, MK-571: 10.15 ± 0.44%dose/mg protein, p < 0.01). In the in vivo PET study, the SUVmean ratio in tumors [calculated as after treatment (2nd PET scan)/before treatment of MRP1 inhibitors (1st PET scan)] of the mice treated with MRP1 inhibitors was significantly higher than those of control mice (cyclosporine A: 2.6 ± 0.7, lapatinib: 2.2 ± 0.7, MK-571: 2.2 ± 0.7, control: 1.2 ± 0.2, p < 0.05). Conclusion In this study, we revealed that MRP1 inhibitors increase [18F]FMISO accumulation in hypoxic cells. This suggests that [18F]FMISO-PET imaging is affected by MRP1 inhibitors independent of the hypoxic state.

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