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Pharmaceutics Jun 2024EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic...
EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for Ga-labeling. The Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma.
PubMed: 38931935
DOI: 10.3390/pharmaceutics16060814 -
Pharmaceuticals (Basel, Switzerland) Jun 2024This study aimed to evaluate the feasibility of using [Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing...
PURPOSE
This study aimed to evaluate the feasibility of using [Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing pulmonary fibrosis in a mouse model. We also examined its value in monitoring treatment response and compared it with traditional [F]-fluorodeoxyglucose (FDG) PET and computed tomography (CT) imaging.
METHODS
A model of idiopathic pulmonary fibrosis was established using intratracheal injection of bleomycin (BLM, 2 mg/kg) into C57BL/6 male mice. For the treatment of IPF, a daily oral dose of 400 mg/kg/day of pirfenidone was administered from 9 to 28 days after the establishment of the model. Disease progression and treatment efficacy were assessed at different stages of the disease every week for four weeks using CT, [F]FDG PET, and [Ga]FAPI PET (baseline imaging performed at week 0). Mice were sacrificed and lung tissues were harvested for hematoxylin-eosin staining, picrosirius red staining, and immunohistochemical staining for glucose transporter 1 (GLUT1) and FAP. Expression levels of GLUT1 and FAP in pathological sections were quantified. Correlations between imaging parameters and pathological quantitative values were analyzed.
RESULTS
CT, [F]FDG PET and [Ga]FAPI PET revealed anatomical and functional changes in the lung that reflected progression of pulmonary fibrosis. In untreated mice with pulmonary fibrosis, lung uptake of [F]FDG peaked on day 14, while [Ga]FAPI uptake and mean lung density peaked on day 21. In mice treated with pirfenidone, mean lung density and lung uptake of both PET tracers decreased. Mean lung density, [F]FDG uptake, and [Ga]FAPI uptake correlated well with quantitative values of picrosirius red staining, GLUT1 expression, and FAP expression, respectively. Although traditional CT and [F]FDG PET reflect anatomical and metabolic status in fibrotic lung, [Ga]FAPI PET provides a means of evaluating fibrosis progression and monitoring treatment response.
PubMed: 38931393
DOI: 10.3390/ph17060726 -
Pharmaceuticals (Basel, Switzerland) May 2024The role of fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) is emerging for the assessment of non-oncological... (Review)
Review
The role of fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) is emerging for the assessment of non-oncological diseases, such as inflammatory and infectious diseases, even if the evidence in the literature is still in its initial phases. We conducted a systematic search of Scopus, PubMed/MEDLINE, Embase, and Cochrane library databases for studies published before 31 December 2023 reporting infectious and inflammatory disease imaging with FAPI PET/CT. We included twenty-one studies for a total of 1046 patients. The most frequent disease studied was lung interstitial disease, investigated in six studies for a total of 200 patients, followed by bone and joint diseases in two studies and 185 patients, IgG4-related disease in 53 patients, and Crohn's disease in 30 patients. Despite the heterogeneity of studies in terms of study design and technical features, FAPI PET/CT showed a high detection rate and diagnostic role. Moreover, when compared with 2-[F]FDG PET/CT ( = 7 studies), FAPI PET/CT seems to have better diagnostic performances. The presence of chronic inflammation and tissue remodeling, typical of immune-mediated inflammatory conditions, may be the underlying mechanism of FAPI uptake.
PubMed: 38931383
DOI: 10.3390/ph17060716 -
Pharmaceuticals (Basel, Switzerland) May 2024Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high...
Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[F]fluoroethyl)-L-tryptophan (L-[F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[F]FETrp had a comparable tumor uptake with [⁸F]fluorodeoxyglucose (FDG). However, L-[F]FETrp showed a significantly higher tumor-to-brain ratio than FDG ( = 4, < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan-kynurenine pathway as a therapeutic target for treating NF1.
PubMed: 38931352
DOI: 10.3390/ph17060685 -
Journal of Clinical Medicine Jun 2024Positron emission tomography (PET) plays a crucial role in breast cancer management. This review addresses the role of PET imaging in breast cancer care. We focus... (Review)
Review
Positron emission tomography (PET) plays a crucial role in breast cancer management. This review addresses the role of PET imaging in breast cancer care. We focus primarily on the utility of 18F-fluorodeoxyglucose (FDG) PET in staging, recurrence detection, and treatment response evaluation. Furthermore, we delve into the growing interest in precision therapy and the development of novel radiopharmaceuticals targeting tumor biology. This includes discussing the potential of PET/MRI and artificial intelligence in breast cancer imaging, offering insights into improved diagnostic accuracy and personalized treatment approaches.
PubMed: 38929989
DOI: 10.3390/jcm13123459 -
Journal of Clinical Medicine Jun 2024: To study the differences between malignant hypermetabolic axillary lymphadenopathy (MHL) and COVID-19 vaccine-associated axillary hypermetabolic lymphadenopathy (VAHL)...
: To study the differences between malignant hypermetabolic axillary lymphadenopathy (MHL) and COVID-19 vaccine-associated axillary hypermetabolic lymphadenopathy (VAHL) using clinical imaging. : A total of 1096 patients underwent Positron Emission Tomography-Computed Tomography (PET-CT) between 1 June 2021 and 30 April 2022 at Ehime University Hospital. In total, 188 patients with axillary lymphadenopathy after the COVID-19 vaccination were evaluated. The patients were classified into three groups such as VAHL ( = 27), MHL ( = 21), and equivocal hypermetabolic axillary lymphadenopathy (EqHL; = 140). Differences in lymph node (LN) swellings were statistically analyzed using clinical imaging (echography, CT, and F-FDG PET). : MHL included a higher female population (90.5%) owing to a higher frequency of breast cancer (80.9%). Axillary LNs of MHL did not show any LN fatty hilums (0%); however, those of VAHL and EqHL did (15.8 and 36%, respectively). After the logistic regression analysis of the patients who had axillary lymphadenopathy without any LN fatty hilums, the minor axis length and ellipticity (minor axis/major axis) in the largest axillary LN, SUVmax, and Tissue-to-Background Ratio (TBR) were useful in distinguishing malignant lymphadenopathies. A receiver-operating characteristic (ROC) analysis indicated that a cut-off value of ≥7.3 mm for the axillary LN minor axis (sensitivity: 0.714, specificity: 0.684) and of ≥0.671 for ellipticity (0.667 and 0.773, respectively) in the largest LN with the highest SUVmax and TBR were predictive of MHL. : Axillary lymphadenopathy of the minor axis and ellipticity in LN without fatty hilums may be useful to be suspicious for malignancy, even in patients who have received COVID-19 vaccination. Further examinations, such as F-FDG PET, are recommended for such patients.
PubMed: 38929916
DOI: 10.3390/jcm13123387 -
Brain Sciences Jun 2024As the population ages worldwide, Alzheimer's disease (AD), the most prevalent kind of neurodegenerative disorder among older people, has become a significant factor... (Review)
Review
As the population ages worldwide, Alzheimer's disease (AD), the most prevalent kind of neurodegenerative disorder among older people, has become a significant factor affecting quality of life, public health, and economies. However, the exact pathogenesis of Alzheimer's remains elusive, and existing highly recognized pathogenesis includes the amyloid cascade hypothesis, Tau neurofibrillary tangles hypothesis, and neuroinflammation hypothesis. The major diagnoses of Alzheimer's disease include neuroimaging positron emission computed tomography, magnetic resonance imaging, and cerebrospinal fluid molecular diagnosis. The therapy of Alzheimer's disease primarily relies on drugs, and the approved drugs on the market include acetylcholinesterase drugs, glutamate receptor antagonists, and amyloid-β monoclonal antibodies. Still, the existing drugs can only alleviate the symptoms of the disease and cannot completely reverse it. This review aims to summarize existing research results on Alzheimer's disease pathogenesis, diagnosis, and drug therapy, with the objective of facilitating future research in this area.
PubMed: 38928590
DOI: 10.3390/brainsci14060590 -
Tau Protein Accumulation Trajectory-Based Brain Age Prediction in the Alzheimer's Disease Continuum.Brain Sciences Jun 2024Clinical cognitive advancement within the Alzheimer's disease (AD) continuum is intimately connected with sustained accumulation of tau protein pathology. The biological...
Clinical cognitive advancement within the Alzheimer's disease (AD) continuum is intimately connected with sustained accumulation of tau protein pathology. The biological brain age and its gap show great potential for pathological risk and disease severity. In the present study, we applied multivariable linear support vector regression to train a normative brain age prediction model using tau brain images. We further assessed the predicted biological brain age and its gap for patients within the AD continuum. In the AD continuum, evaluated pathologic tau binding was found in the inferior temporal, parietal-temporal junction, precuneus/posterior cingulate, dorsal frontal, occipital, and inferior-medial temporal cortices. The biological brain age gaps of patients within the AD continuum were notably higher than those of the normal controls ( < 0.0001). Significant positive correlations were observed between the brain age gap and global tau protein accumulation levels for mild cognitive impairment ( = 0.726, < 0.001), AD ( = 0.845, < 0.001), and AD continuum ( = 0.797, < 0.001). The pathologic tau-based age gap was significantly linked to neuropsychological scores. The proposed pathologic tau-based biological brain age model could track the tau protein accumulation trajectory of cognitive impairment and further provide a comprehensive quantification index for the tau accumulation risk.
PubMed: 38928575
DOI: 10.3390/brainsci14060575 -
International Journal of Molecular... Jun 2024Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell...
Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase ( NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.
Topics: Nitroreductases; Nitroimidazoles; Metronidazole; Prodrugs; Escherichia coli Proteins; Positron-Emission Tomography; Escherichia coli; Catalytic Domain; Protein Engineering; Models, Molecular; Aziridines
PubMed: 38928299
DOI: 10.3390/ijms25126593 -
Cancers Jun 2024Orbital and ocular adnexal lymphoma (OAL) affects the orbit and the surrounding structures and can arise as several subtypes with variable prognoses. We performed an...
Orbital and ocular adnexal lymphoma (OAL) affects the orbit and the surrounding structures and can arise as several subtypes with variable prognoses. We performed an observational study on the relationship between OAL subtype, diagnostic features, and prognosis to offer valuable insights into imaging techniques, such as Positron Emission Tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with Computed Tomography (F-FDG PET-CT), in predicting outcomes. With this aim, we retrospectively reviewed 99 patients with OALs, recording demographics, cancer subtype, location and treatment, FDG avidity, and bone marrow positivity. We divided patients into Group 1 (those presenting with extranodal marginal zone lymphoma-EMZL) and Group 2, including all other subtypes. The primary outcome was long-term cancer-specific survival (CSS) based on key predictors, performed through Kaplan-Meier curves and the log-rank test, with a < 0.05 significance threshold. The mean patient age was 67 years (57-75.5). The most frequent histopathologic subtypes were EMZL lymphoma in 69 patients (69.7%), small lymphocytic lymphoma (11.1%) and diffuse-large B-cell lymphoma (10.1%). Patients of Group 1 showed a better prognosis (CSS = 80%) compared to those of Group 2 (CSS = 60%) ( = 0.01). In patients with high-grade lymphoma, the occurrence of FDG avidity ( = 0.003) and bone marrow positivity ( = 0.005) were related to a worse prognosis. In our group, EMZL was the most prominent subtype of OALs and exhibited the best prognosis, low 18FDG avidity, and bone marrow negativity. By observing specific patterns in radiological findings, it is possible to increase our understanding of disease progression, treatment response, and the overall prognosis in OAL patients.
PubMed: 38927956
DOI: 10.3390/cancers16122252