radiosynthesis-quality-control-small-animal-positron-emission

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of <sup>68</sup>Ga-Labelled Nano Molecules

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical ...

University Hospital RWTH Aachen

Maastricht University Medical Center

Maastricht University

Rupture of a vulnerable carotid plaque is one of the leading causes of stroke. Carotid magnetic resonance imaging (MRI) is able to visualize all the main hallmarks of plaque vulnerability. Various MRI sequences have been developed in the last two decades to quantify carotid plaque burden and composition. Often, a combination of multiple sequences is used. These MRI techniques have been extensively validated with histological analysis of carotid endarterectomy specimens. High agreement between the MRI and histological measures of plaque burden, intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), fibrous cap (FC) status, inflammation and neovascularization has been demonstrated. Novel MRI sequences allow to generate three-dimensional isotropic images with a large longitudinal coverage. Other new sequences can acquire multiple contrasts using a single sequence leading to a tremendous reduction in scan time. IPH can be easily identified as a hyperintense signal in the bulk of the plaque on strongly T-weighted images, such as magnetization-prepared rapid acquisition gradient echo images, acquired within a few minutes with a standard neurovascular coil. Carotid MRI can also be used to evaluate treatment effects. Several meta-analyses have demonstrated a strong predictive value of IPH, LRNC, thinning or rupture of the FC for ischemic cerebrovascular events. Recently, in a large meta-analysis based on individual patient data of asymptomatic and symptomatic individuals with carotid artery stenosis, it was shown that IPH on MRI is an independent risk predictor for stroke, stronger than any known clinical risk parameter. Expert recommendations on carotid plaque MRI protocols have recently been described in a white paper. The present review provides an overview of the current status and applications of carotid plaque MR imaging and its future potential in daily clinical practice.

Magnetic resonance imaging of carotid plaques: current status and clinical perspectives.

Given the high sensitivity and specificity of sodium [F]Fluoride (Na[F]F) for vascular calcifications and positive emerging data of vitamin K on vascular health, the aim of this study is to assess the ability of Na[F]F to monitor therapy and disease progression in a unitary atherosclerotic mouse model. ApoE mice were placed on a Western-type diet for 12-weeks and then split into four groups. The early stage atherosclerosis group received a chow diet for an additional 12-weeks, while the advanced atherosclerosis group continued the Western-type diet. The Menaquinone-7 (MK-7) and Warfarin groups received MK-7 or Warfarin supplementation during the additional 12-weeks, respectively. Control wild type mice were fed a chow diet for 24-weeks. All of the mice were scanned with Na[F]F using a small animal positron emission tomography (PET)/computed tomography (CT). The Warfarin group presented spotty calcifications on the CT in the proximal aorta. All of the spots corresponded to dense mineralisations on the von Kossa staining. After the control, the MK-7 group had the lowest Na[F]F uptake. The advanced and Warfarin groups presented the highest uptake in the aortic arch and left ventricle. The advanced stage group did not develop spotty calcifications, however Na[F]F uptake was still observed, suggesting the presence of micro-calcifications. In a newly applied mouse model, developing spotty calcifications on CT exclusively in the proximal aorta, Na[F]F seems to efficiently monitor plaque progression and the beneficial effects of vitamin K on cardiovascular disease.

Sodium [F]Fluoride PET Can Efficiently Monitor In Vivo Atherosclerotic Plaque Calcification Progression and Treatment.

Despite recent medical advances, cardiovascular disease remains the leading cause of death worldwide. As (micro)-calcification is a hallmark of atherosclerosis, this review will elaborately discuss advantages of sodium fluoride positron emission tomography (PET) as a reliable cardiovascular imaging technique for identifying the early onset of vascular calcification (i.e. locking onto the target). We assess state-of-the-art meta-analysis and clinical studies of possible treatment options and evaluate the concept of vitamin K supplementation to preserve vascular health (i.e. loading the bullet).

Locking and loading the bullet against micro-calcification.

INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin K2 and vitamin D3 supplementation on micro-calcification in carotid artery disease as imaged by hybrid Sodium [F]Fluoride (Na[F]F) positron emission tomography (PET)/ magnetic resonance imaging (MRI). Arterial calcification is an actively regulated process and results from the imbalance between calcification promoting and inhibiting factors. Considering the recent advancements in medical imaging, ultrasound (US), PET/MRI, and computed tomography (CT) can be used for the selection and stratification of patients with atherosclerosis. Fifty-two subjects with asymptomatic carotid artery disease on at least one side of the neck will be included in the study. At baseline, an Na[F]F PET/MRI and CT examination will be performed. Afterwards, subjects will be randomized (1:1) to a vitamin K (400 µg MK-7/day) and vitamin D3 (80 µg/day) or to placebo. At the 3-month follow-up, subjects will undergo a second Na[F]F PET/MRI and CT scan. The primary endpoint is the change in Na[F]F PET/MRI (baseline vs. after 3 months) in the treatment group as compared to the placebo arm. Secondary endpoints are changes in plaque composition and in blood-biomarkers. The INTRICATE trial bears the potential to open novel avenues for future large scale randomized controlled trials to intervene in the plaque development and micro-calcification progression.

Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design.

Angiogenesis is an active process, regulating new vessel growth, and is crucial for the survival and growth of tumours next to other complex factors in the tumour microenvironment. We present possible molecular imaging approaches for tumour vascularisation and vitality, focusing on radiopharmaceuticals (tracers). Molecular imaging in general has become an integrated part of cancer therapy, by bringing relevant insights on tumour angiogenic status. After a structured PubMed search, the resulting publication list was screened for oncology related publications in animals and humans, disregarding any cardiovascular findings. The tracers identified can be subdivided into direct targeting of angiogenesis (i.e., vascular endothelial growth factor, laminin, and fibronectin) and indirect targeting (i.e., glucose metabolism, hypoxia, and matrix metallo-proteases, PSMA). Presenting pre-clinical and clinical data of most tracers proposed in the literature, the indirect targeting agents are not 1:1 correlated with angiogenesis factors but do have a strong prognostic power in a clinical setting, while direct targeting agents show most potential and specificity for assessing tumour vascularisation and vitality. Within the direct agents, the combination of multiple targeting tracers into one agent (multimers) seems most promising. This review demonstrates the present clinical applicability of indirect agents, but also the need for more extensive research in the field of direct targeting of angiogenesis in oncology. Although there is currently no direct tracer that can be singled out, the RGD tracer family seems to show the highest potential therefore we expect one of them to enter the clinical routine.

Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status.

Peptide receptor radionuclide therapy is used to treat solid tumors by locally delivering radiation. However, due to nephro- and hepato-toxicity, it is limited by its dosage. To amplify radiation damage to tumor cells, radiolabeled nanogels can be used. We show that by tuning the mechanical properties of nanogels significant enhancement in circulation half-life of the gel could be achieved. We demonstrate why and how small changes in the mechanical properties of the nanogels influence its cellular fate. Nanogels with a storage modulus of 37 kPa were minimally phagocytosed by monocytes and macrophages compared to nanogels with 93 kPa modulus. Using PET/CT a significant difference in the blood circulation time of the nanogels was shown. Computer simulations affirmed the results and predicted the mechanism of cellular uptake of the nanogels. Altogether, this work emphasizes the important role of elasticity even for particles that are inherently soft such as nano- or microgels.

Tuning the Elasticity of Nanogels Improves Their Circulation Time by Evading Immune Cells.

The cellular and molecular mechanisms of orthodontic tooth movement (OTM) are not yet fully understood, partly due to the lack of dynamical datasets within the same subject. Inflammation and calcification are two main processes during OTM. Given the high sensitivity and specificity of [Ga]Ga-Pentixafor and Sodium [F]Fluoride (Na[F]F) for inflammation and calcification, respectively, the aim of this study is to assess their ability to identify and monitor the dynamics of OTM in an established mouse model. To monitor the processes during OTM in real time, animals were scanned using a small animal PET/CT during week 1, 3, and 5 post-implantation, with [Ga]Ga-Pentixafor and Na[F]F. Both tracers showed an increased uptake in the region of interest compared to the control. For [Ga]Ga-Pentixafor, an increased uptake was observed within the 5-week trial, suggesting the continuous presence of inflammatory markers. Na[F]F showed an increased uptake during the trial, indicating an intensification of bone remodelling. Interim and end-of-experiment histological assessments visualised increased amounts of chemokine receptor CXCR4 and TRAP-positive cells in the periodontal ligament on the compression side. This approach establishes the first in vivo model for periodontal remodelling during OTM, which efficiently detects and monitors the intricate dynamics of periodontal ligament.

[Ga]Ga-Pentixafor and Sodium [F]Fluoride PET Can Non-Invasively Identify and Monitor the Dynamics of Orthodontic Tooth Movement in Mouse Model.

The structural process of bone and periodontal ligament (PDL) remodeling during long-term orthodontic tooth movement (OTM) has not been satisfactorily described yet. Although the mechanism of bone changes in the directly affected alveolar bone has been deeply investigated, detailed knowledge about specific mechanism of PDL remodeling and its interaction with alveolar bone during OTM is missing. This work aims to provide an accurate and user-independent analysis of the alveolar bone and PDL remodeling following a prolonged OTM treatment in mice. Orthodontic forces were applied using a Ni-Ti coil-spring in a split-mouth mice model. After 5 weeks both sides of maxillae were scanned by high-resolution micro-CT. Following a precise tooth movement estimation, an extensive 3D analysis of the alveolar bone adjacent to the first molar were performed to estimate the morphological and compositional parameters. Additionally, changes of PDL were characterized by using a novel 3D model approach. Bone loss and thinning, higher connectivity as well as lower bone mineral density were found in both studied regions. Also, a non-uniformly widened PDL with increased thickness was observed. The extended and novel methodology in this study provides a comprehensive insight about the alveolar bone and PDL remodeling process after a long-duration OTM.

Periodontal ligament and alveolar bone remodeling during long orthodontic tooth movement analyzed by a novel user-independent 3D-methodology.

Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [Lu]Lu-PSMA-I&T. This study aimed to assess and compare the therapeutic efficacy of a single dose with a fractionated dose of [Lu]Lu-PSMA-I&T in an orthotopic model of TNBC.

The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [Lu]Lu-PSMA-I&T for triple-negative breast cancer.

Article	Year
Magnetic resonance imaging of carotid plaques: current status and clinical perspectives. Annals of translational medicine\| PubMed ID: 33178798	2020
Sodium [F]Fluoride PET Can Efficiently Monitor In Vivo Atherosclerotic Plaque Calcification Progression and Treatment. Cells\| PubMed ID: 33573188	2021
Locking and loading the bullet against micro-calcification. European journal of preventive cardiology\| PubMed ID: 33611501	2020
Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design. Nutrients\| PubMed ID: 33808652	2021
Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status. International journal of molecular sciences\| PubMed ID: 34073992	2021
Tuning the Elasticity of Nanogels Improves Their Circulation Time by Evading Immune Cells. Angewandte Chemie (International ed. in English)\| PubMed ID: 35274425	2022
[Ga]Ga-Pentixafor and Sodium [F]Fluoride PET Can Non-Invasively Identify and Monitor the Dynamics of Orthodontic Tooth Movement in Mouse Model. Cells\| PubMed ID: 36230911	2022
Periodontal ligament and alveolar bone remodeling during long orthodontic tooth movement analyzed by a novel user-independent 3D-methodology. Scientific reports\| PubMed ID: 37964111	2023
The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [Lu]Lu-PSMA-I&T for triple-negative breast cancer. Breast cancer research : BCR\| PubMed ID: 38378689	2024

Alexandru Florea

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