scholarly journals Development and preclinical evaluation of [68Ga]Ga-Alb-FAPtp-01, a novel tumour-associated fibroblast activation protein tracer for PET imaging of xenograft glioma

2021 ◽  
Author(s):  
Jia-Jia Lin ◽  
Chia-Pao Chuang ◽  
Jia-Yu Lin ◽  
Feng-Ting Huang ◽  
chiun-wei Huang
Keyword(s):  
Pet Imaging ◽  
Specific Binding ◽  
Fibroblast Activation Protein ◽  
Tracer Uptake ◽  
Cell Uptake ◽  
Response Monitoring ◽  
Tumour Uptake ◽  
Fibroblast Activation ◽  
Pet Tracer

Abstract Purpose Dynamic changes in tumour-associated fibroblast activation protein (FAP) expression in tumours of different stages may be helpful for prognostic evaluation and treatment response monitoring, making this protein a promising surveillance biomarker for timely diagnosis of malignant tumours and effective planning of patient care. Thus, novel FAP-PET imaging tracers were developed and evaluated for the diagnosis of xenograft glioma tumours. Methods To prospectively verify the prognostic value of the developed FAP tracers, [68Ga]Ga-FAPtp and [68Ga]Ga-Alb-FAPtp-01, measurements of FAP expression and cell uptake and specific binding assays were conducted in U87MG glioma cells. Dynamic/static PET/CT scans were acquired for tumour targeting studies in vivo and in comparison with the reference tracer [68Ga]Ga-FAPI-04 to evaluate diagnostic efficacy. Tumour autoradiography and immunohistochemistry images were acquired to confirm the tracer distribution within the tumour to determine whether it was in accordance with the pathologic data. Results Both [68Ga]Ga-FAPI-04 and [68Ga]Ga-FAPtp demonstrated marked tumour uptake and comparable pharmaceutical profiles in 1 h dynamic PET scans, and [68Ga]Ga-FAPtp had marginally favourable tumour uptake and less kidney and liver uptake. However, both tracers demonstrated rapid clearance from tumours. Thus, the optimized rationally designed FAP-targeting PET tracer [68Ga]Ga-Alb-FAPtp-01, with albumin binding capability, demonstrated prominent longitudinal tumour uptake in tumour xenografts and displayed significant tumour-to-background contrast over time. The tracer uptake values and T/M ratio were 1.775 ± 0.179 SUV and T/M = 5.9, 1.533 ± 0.222 SUV and T/M = 6.7, and 1.425 ± 0.204 SUV and T/M = 9.5, respectively, at 1 h, 2 h and 3 h. Major organs, such as the heart (0.504 ± 0.125% ID/g), muscle (0.156 ± 0.043% ID/g) and brain (0.119 ± 0.039% ID/g), all displayed comparatively low levels of tracer uptake. Conclusion Its improved tumour uptake and pharmacokinetics suggest that the [68Ga]Ga-Alb-FAPtp-01 tracer can noninvasively detect FAP activation in vivo, permitting a precise definition of its roles in tumours of different stages and yielding insights regarding novel FAP-targeted radiotherapeutic strategies at the molecular level.

scholarly journals Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [18F]Fluoro-PEG-Folate

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Durga M. S. H. Chandrupatla ◽  
Gerrit Jansen ◽  
Elise Mantel ◽  
Philip S. Low ◽  
Takami Matsuyama ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Folate Receptor ◽  
Tracer Uptake ◽  
Response Monitoring ◽  
Distribution Analysis ◽  
Pet Tracer ◽  
Systemic Inflammatory Disease ◽  
Before And After

Background. In rheumatoid arthritis, articular inflammation is a hallmark of disease, while the involvement of extra-articular tissues is less well defined. Here, we examined the feasibility of PET imaging with the macrophage tracer [18F]fluoro-PEG-folate, targeting folate receptorβ(FRβ), to monitor systemic inflammatory disease in liver and spleen of arthritic rats before and after methotrexate (MTX) treatment.Methods. [18F]Fluoro-PEG-folate PET scans (60 min) were acquired in saline- and MTX-treated (1 mg/kg, 4x) arthritic rats, followed by tissue resection and radiotracer distribution analysis. Liver and spleen tissues were stained for ED1/ED2-macrophage markers and FRβexpression.Results. [18F]Fluoro-PEG-folate PET and ex vivo tissue distribution studies revealed a significant (p<0.01) 2-fold lower tracer uptake in both liver and spleen of MTX-treated arthritic rats. Consistently, ED1- and ED2-positive macrophages were significantly (p<0.01) decreased in liver (4-fold) and spleen (3-fold) of MTX-treated compared with saline-treated rats. Additionally, FRβ-positive macrophages were also significantly reduced in liver (5-fold,p<0.005) and spleen (3-fold,p<0.01) of MTX- versus saline-treated rats.Conclusions. MTX treatment reduced activated macrophages in liver and spleen, as markers for systemic inflammation in these organs. Macrophage PET imaging with [18F]fluoro-PEG-folate holds promise for detection of systemic inflammation in RA as well as therapy (MTX) response monitoring.

scholarly journals PET imaging of P2X7R in the experimental autoimmune encephalomyelitis model of multiple sclerosis using [11C]SMW139

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wissam Beaino ◽  
Bieneke Janssen ◽  
Esther Kooijman ◽  
Ricardo Vos ◽  
Robert C. Schuit ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Pet Imaging ◽  
Specific Binding ◽  
Recovery Phase ◽  
Autoimmune Encephalomyelitis ◽  
Pet Tracer ◽  
The Brain ◽  
Experimental Autoimmune

Abstract Background Non-invasive imaging of the activation status of microglia and the ability to identify a pro- or anti-inflammatory environment can provide valuable insights not only into pathogenesis of neuro-inflammatory and neurodegenerative diseases but also the monitoring of the efficacy of immunomodulatory therapies. P2X7R is highly expressed on pro-inflammatory microglia and [11C]SMW139, a specific P2X7R tracer for positron emission tomography imaging, showed good pharmacokinetics, stability, and brain permeability in vivo. Our objective was to evaluate the potential of [11C]SMW139 for PET imaging of neuroinflammation in vivo in the experimental autoimmune encephalomyelitis (EAE) model. Methods We induced EAE in Lewis rats by immunization with MBP 69-88 in complete Freund’s adjuvant (CFA). We determined the affinity of [11C]SMW139 to human and rat P2X7R using saturation binding assay. Using this tracer, PET imaging was performed at the peak of disease and in the recovery phase. In vivo blocking experiments were conducted to validate the specific brain uptake of the tracer. Immunohistochemistry staining and autoradiography were performed to evaluate the level of neuroinflammation and validate the specific binding of [11C]SMW139. Results [11C]SMW139 showed good affinity for the rat P2X7R with a Kd of 20.6 ± 1.7 nM. The uptake of [11C]SMW139 was significantly higher in EAE animals at the peak of disease compared to the recovery phase but not in CFA control animals. The amplitude of increase of [11C]SMW139 uptake showed significant positive correlation with clinical scores mainly in the spinal cord (Pearson = 0.75, Spearman = 0.76; p < 0.0001). Treating EAE animals with P2X7R antagonist JNJ-47965567 blocked the uptake of [11C]SMW139 in the spinal cord, cerebellum, and brain stem, demonstrating specific accumulation of the tracer. P-glycoprotein blocking with tariquidar (30 mg/kg) did not affect tracer penetration in the brain showing that [11C]SMW139 is not a Pgp substrate. Conclusion Our data shows that [11C]SMW139 is a promising PET tracer for imaging neuroinflammation and evaluating the dynamics of pro-inflammatory microglia in the brain. This can provide crucial insights into the role of microglia in disease progression and enables the development of novel treatment strategies aimed at modulating the immune response in order to promote neuroprotection.

Human Fibronectin Extra-Domain B (EDB)-Specific Aptide (APTEDB) Radiolabelling with Technetium-99m as a Potent Targeted Tumour-Imaging Agent

2018 ◽  
Vol 18 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Mohsen Mohammadgholi ◽  
Nourollah Sadeghzadeh ◽  
Mostafa Erfani ◽  
Saeid Abediankenari ◽  
Seyed Mohammad Abedi ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Specific Binding ◽  
Specific Protein ◽  
Tumour Imaging ◽  
Specific Binding Ratio ◽  
Tumour Uptake ◽  
Technetium 99M ◽  
In Vivo Experiments ◽  
Human Fibronectin

Background: Human fibronectin extra-domain B (EDB) is particularly expressed during angiogenesis progression. It is, thus, a promising marker of tumour growth. Aptides are a novel class of peptides with high-affinity binding to specific protein targets. APTEDB is an antagonist-like ligand that especially interacts with human fibronectin EDB. Objective: This study was the first attempt in which the hydrazinonicotinamide (HYNIC)-conjugated APTEDB was labelled with technetium-99m (99mTc) as an appropriate radiotracer and tricine/EDDA exchange labeling. Methods: Radiochemical purity, normal saline, and serum stability were evaluated by HPLC and radio-isotope TLC scanner. Other examinations, such as protein-binding calculation, dissociation radioligand binding assay, and partition coefficient constant determination, were also carried out. The cellular-specific binding of 99mTc- HYNIC-conjugated APTEDB was assessed in two EDB-positive (U87MG) and EDB-negative (U373MG) cell lines. Bio-distribution was investigated in normal mice as well as in U87MG and U373MG tumour-bearing mice. Eventually, the radiolabelled APTEDB was used for tumour imaging using planar SPECT. Results: Radiolabelling was achieved with high purity (up to 97%) and accompanied by high solution (over 90% after overnight) and serum (80% after 2 hours) stability. The obtained cellular-specific binding ratio was greater than nine-fold. In-vivo experiments showed rapid blood clearance with mainly renal excretion and tumour uptake specificity (0.48±0.03% ID/g after 1h). The results of the imaging also confirmed considerable tumour uptake for EDB-positive cell line compared with the EDB-negative one. Conclusion: Aptides are considered to be a potent candidate for biopharmaceutical applications. They can be modified with imaging or therapeutic agents. This report shows the capability of 99mTc-HYNIC-APTEDB for human EDB-expressing tumours detection.

scholarly journals Fluorinated PET imaging probes targeting fibroblast activation protein: radiolabeling and preclinical evaluation

2021 ◽  
Vol 96-97 ◽  
pp. S40-S41
Author(s):  
Filipe Elvas ◽  
Muhammet Tanc ◽  
Yentl Van Rymenant ◽  
Lucas Beroske ◽  
Stef De Lombaerde ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Fibroblast Activation Protein ◽  
Preclinical Evaluation ◽  
Fibroblast Activation ◽  
Imaging Probes

scholarly journals Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryoichi Katsube ◽  
Kazuhiro Noma ◽  
Toshiaki Ohara ◽  
Noriyuki Nishiwaki ◽  
Teruki Kobayashi ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Therapeutic Resistance ◽  
Fibroblast Activation ◽  
Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

scholarly journals [18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

2020 ◽  
Vol 22 (5) ◽  
pp. 1226-1234
Author(s):  
Florian Guibbal ◽  
Samantha L. Hopkins ◽  
Anna Pacelli ◽  
Patrick G. Isenegger ◽  
Michael Mosley ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Cell Uptake ◽  
Pancreatic Cell ◽  
Anti Cancer ◽  
Damage Response ◽  
Automated Procedures

Abstract Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. Methods Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

scholarly journals Evaluation of [68Ga]Ga-NODAGA-RGD for PET Imaging of Rat Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Arghavan Jahandideh ◽  
Mia Ståhle ◽  
Jenni Virta ◽  
Xiang-Guo Li ◽  
Heidi Liljenbäck ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Cell Surface Receptor ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
Inflammatory Lesions ◽  
Pet Tracer ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant

The 68Gallium-labeled 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid conjugated radiolabelled arginine-glycine-aspartic acid peptide ([68Ga]Ga-NODAGA-RGD) is a positron emission tomography (PET) tracer binding to cell surface receptor αvβ3 integrin that is upregulated during angiogenesis and inflammation. We studied whether αvβ3 targeting PET imaging can detect myocardial inflammation in a rat model of autoimmune myocarditis. To induce myocarditis, rats (n = 8) were immunized with porcine cardiac myosin in complete Freund's adjuvant on days 0 and 7. Control rats (n = 8) received Freund's adjuvant alone. On day 21, in vivo PET/CT imaging with [68Ga]Ga-NODAGA-RGD followed by ex vivo autoradiography and immunohistochemistry were carried out. Inflammatory lesions were detected histologically in the myocardium of 7 out of 8 immunized rats. In vivo PET images showed higher [68Ga]Ga-NODAGA-RGD accumulation in the myocardium of rats with inflammation than the non-inflamed myocardium of control rats (SUVmean 0.4 ± 0.1 vs. 0.1 ± 0.02; P = 0.00006). Ex vivo autoradiography and histology confirmed that [68Ga]Ga-NODAGA-RGD uptake co-localized with inflammatory lesions containing αvβ3 integrin-positive capillary-like structures. A non-specific [68Ga]Ga-DOTA-(RGE)2 tracer showed 76% lower uptake than [68Ga]Ga-NODAGA-RGD in the inflamed myocardium. Our results indicate that αvβ3 integrin-targeting [68Ga]Ga-NODAGA-RGD is a potential PET tracer for the specific detection of active inflammatory lesions in autoimmune myocarditis.

The Role of Fibroblast Activation Protein Ligands in Oncologic PET Imaging

PET Clinics ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. 341-351
Author(s):  
Katharina Dendl ◽  
Joel Schlittenhardt ◽  
Fabian Staudinger ◽  
Clemens Kratochwil ◽  
Anette Altmann ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Fibroblast Activation Protein ◽  
Fibroblast Activation ◽  
Protein Ligands

Inhibitors of Fibroblast Activation Protein (FAP) Inhibit Primary Myeloma Growth and Osteoclastogenesis Ex Vivo and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 813-813
Author(s):  
Angela Pennisi ◽  
Xin Li ◽  
Dana Gaddy ◽  
Nisreen Akel ◽  
Nazneen Aziz ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Surface ◽  
Cell Survival ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Peptidase Activity ◽  
Dependent Manner ◽  
Pretreatment Level ◽  
Fibroblast Activation

Abstract Fibroblast activation protein (FAP), a cell surface serine protease with both dipeptidyl peptidase and collagenase activity, is selectively expressed by tumor stroma and involved in tumor metastasis. We have reported that FAP is upregulated in myelomatous bone and is overexpressed in osteoclasts after coculture with myeloma (MM) cells. FAP is not expressed by MM cells and FAP siRNA reduced MM cell survival in cocultures (Ge et al., BJH 2006). The aim of the study was to investigate the effect of FAP inhibitors, PT-100 and PT-630 on MM cell growth and osteoclastogenesis using coculture system and the SCID-hu model for primary MM. PT-630 inhibits cell surface dipeptidyl peptidase activity while PT-100 also inhibits intracellular activity of these enzymes. MM cells from 6 patients were cocultured with osteoclasts and treated twice a day with PT-100 and PT-630 (0.1–100 μM) for 5–7 days. Whereas PT-100 effectively inhibited MM cell growth in all tested doses by 38%–62% (p<0.002 vs. 100 μM), PT-630 inhibited MM cell growth in a dose dependent manner reaching 45% growth inhibition with 100 μM (p<0.02). These compounds had no direct effect on MM cell survival. Moreover, recombinant FAP had no impact on MM cells cultured alone, suggesting that FAP-induced MM cell survival depends on close contact between MM cells and osteoclasts. The anti-MM effect of PT-100 in cocultures was mediated through downregulation of phosphorylated p38 in MM cells as detected by Phospho MAPK array and confirmed by Western blot. MMP-2 and MMP-9 have been associated with FAP activity. The level of MMP-2 but not MMP-9 was reduced in coculture conditioned media by 44±7% (p<0.04) following treatment with PT-100 while PT-630 had no significant effect on production of these matrix metalloproteinases. To test effect on osteoclastogenesis, osteoclast precursors were incubated with RANKL and M-CSF in the absence and presence of PT-100 (1 μM) and PT-630 (10 μM) for 5–7 days. PT-100 and PT-630 inhibited formation of multinucleated osteoclasts by 78±6% (p<0.001) and 56±6% (p<0.003), respectively. Culture of osteoclasts on dentine slices in the presence of PT-100 and PT-630 reduced resorption pit area by 92% (p<0.01) and 69% (p<0.04), respectively. The anti-osteoclastogenic effects were mediated through inhibition of phosphorylated p38 MAPK in osteoclastic cultures in a dose related manner. In vivo, SCID-hu mice engrafted with MM cells from 4 patients were orally treated for 4–5 weeks with PT-100 (20 mg/day) and PT-630 (200 mg/day). These agents inhibited MM growth in 2 experiments, delayed growth in one experiment and had no effect on MM in an additional experiment. Overall, final hIg levels in hosts treated with vehicle, PT-100 and PT-630 were 355±170, 183±78 and 76±27 mg/ml, respectively. Bone mineral density (BMD) of the myelomatous bone was increased in responding hosts (3% vs. -32% change from pretreatment level in control) and had reduced severity of bone loss in myelomatous bone of nonresponding hosts (−15% vs. −28% change from pretreatment level in control), suggesting that, as shown in vitro, these agents directly affect bone cell function in vivo. We conclude that FAP is critically involved in MM osteolysis and tumor growth and thus approaches to inhibit FAP activity in myelomatous bone may help control MM and its associated bone disease.

The development of a Glypican-3-specific binding peptide using in vivo and in vitro two-step phage display screening for the PET imaging of hepatocellular carcinoma

2020 ◽  
Vol 8 (20) ◽  
pp. 5656-5665
Author(s):  
Yushuang Qin ◽  
Siyuan Cheng ◽  
Yesen Li ◽  
Sijuan Zou ◽  
Minglong Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phage Display ◽  
Pet Imaging ◽  
Specific Binding ◽  
Normal Liver ◽  
Liver Uptake ◽  
Binding Peptide ◽  
Screening Approach

An in vivo and in vitro two-step phage display screening approach to identify Glypican-3 targeting peptides for the detection of hepatocellular carcinoma with low normal liver uptake.

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