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

Increased cellular proliferation is an integral part of the cancer phenotype. Hence, the sustained and continued demand on supply of DNA building blocks during the DNA replication presents a potential target for therapeutic intervention. For this propose, the α and Auger electron emitting nucleotides analogs are attractive for targeted endoradiotherapy, given that DNA of malignant cells is selectively addressed. This review summarizes development and preclinical and clinical studies of endoradiotherapeutic acting nucleoside analogs with a special focus on thymidine analogs.

Targeted endoradiotherapy using nucleotides.

Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue (125)I-labeled 5-iodo-4'-thio-2'-deoxyuridine ([(125)I]ITdU).

Auger electron emitter against multiple myeloma--targeted endo-radio-therapy with 125I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine.

In multiple myeloma, the presence of highly resistant cancer stem cells (CSC) that are responsible for tumor metastasis and relapse has been proven. Evidently, for achieving complete response, new therapeutic paradigms that effectively eradicate both, CSCs and bulk cancer populations, need to be developed. For achieving that goal, an innovative two-step treatment combining targeting of thymidine de novo synthesis pathway and a nanoirradiation by the Auger electron emitting thymidine analogue (123/125)I-5-iodo-4'-thio-2'-deoxyuridine ((123/125)I-ITdU) could be a promising approach. The pretreatment with thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FdUrd, 1 μmol/L for 1 hour) efficiently induced proliferation and terminal differentiation of isolated myeloma stem-like cells. Moreover, FdUrd stimulation led to a decreased activity of a functional CSC marker, aldehyde dehydrogenase (ALDH). The metabolic conditioning by FdUrd emerged to be essential for enhanced incorporation of (125)I-ITdU (incubation with 50 kBq/2 × 10(4) cells for 4 days) and, consequently, for the induction of irreparable DNA damage. (125)I-ITdU showed a pronounced antimyeloma effect on isolated tumor stem-like cells. More than 85% of the treated cells were apoptotic, despite activation of DNA repair mechanisms. Most important, exposure of metabolically conditioned cells to (125)I-ITdU resulted in a complete inhibition of clonogenic recovery. This is the first report showing that pretreatment with FdUrd sensitizes the stem-like cell compartment in multiple myeloma to apoptosis induced by (125)I-ITdU-mediated nanoirradiation of DNA.

Breaking the invulnerability of cancer stem cells: two-step strategy to kill the stem-like cell subpopulation of multiple myeloma.

Fatty acid synthase (FASN) is crucial to de novo long-chain fatty acid synthesis, needed to meet cancer cells' increased demands for membrane, energy, and protein production.

Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer.

The modification of biomaterials to comply with clinically employed monitoring techniques is a promising strategy to support clinical translation in regenerative medicine. Here, multimodal imaging of tissue-engineered vascular grafts (TEVG) was enabled by functionalizing the textile scaffold with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. The resulting MR-imageable grafts (iTEVG) were monitored non-invasively throughout their whole life-cycle, from initial quality control to longitudinal functional evaluation in an ovine model for up to 8 weeks. Crucial features such as the complete embedding of the textile mesh in the developing tissue and the grafts' structural stability were assessed in vitro using 1T-, 3T- and 7T-MRI scanners. In vivo, the grafts were imaged by 3T-MRI and PET-CT. Contrary to unlabeled constructs, iTEVG could be delineated from native arteries and precisely localized by MRI. USPIO labeling neither induced calcifications, nor negatively affected their remodeling with respect to tissue-specific extracellular matrix composition and endothelialization. Functionality was confirmed by MR-angiography. F-FDG uptake (assessed via PET-CT) indicated only transient post-surgical inflammation. In conclusion, USPIO-labeling enables accurate localization of TEVG and opens up opportunities for multimodal imaging approaches to assess transplant acceptance and function. Thereby, it can support clinical decision-making on the need for further pharmacological or surgical interventions.

MR and PET-CT monitoring of tissue-engineered vascular grafts in the ovine carotid artery.

Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as target for radio-ligand therapy (RLT).

Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer.

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.

Corrigendum to "MR and PET-CT monitoring of tissue-engineered vascular grafts in the ovine carotid artery" [Biomaterials 216 (2019) 119228].

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.

Endogenous targeted radiotherapy is emerging as an integral modality to treat a variety of cancer entities. Nevertheless, despite the positive clinical outcome of the treatment using radiolabeled peptides, small molecules, antibodies, and nanobodies, a high degree of hepatotoxicity and nephrotoxicity still persist. This limits the amount of dose that can be injected. In an attempt to mitigate these side effects, the use of nanocarriers such as nanoparticles (NPs), dendrimers, micelles, liposomes, and nanogels (NGs) is currently being explored. Nanocarriers can prolong circulation time and tumor retention, maximize radiation dosage, and offer multifunctionality for different targeting strategies. In this review, the authors first provide a summary of radiation therapy and imaging and discuss the new radiotracers that are used preclinically and clinically. They then highlight and identify the advantages of radio-nanomedicine and its potential in overcoming the limitations of endogenous radiotherapy. Finally, the review points to the ongoing efforts to maximize the use of radio-nanomedicine for efficient clinical translation.

Radiolabeled Nanocarriers as Theranostics-Advancement from Peptides to Nanocarriers.

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
Targeted endoradiotherapy using nucleotides. Methods (San Diego, Calif.)\| PubMed ID: 21782950	2011
Auger electron emitter against multiple myeloma--targeted endo-radio-therapy with 125I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine. Nuclear medicine and biology\| PubMed ID: 21982576	2011
Breaking the invulnerability of cancer stem cells: two-step strategy to kill the stem-like cell subpopulation of multiple myeloma. Molecular cancer therapeutics\| PubMed ID: 24174494	2014
Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer. Journal of translational medicine\| PubMed ID: 25947066	2015
MR and PET-CT monitoring of tissue-engineered vascular grafts in the ovine carotid artery. Biomaterials\| PubMed ID: 31195299	2019
Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer. Breast cancer research : BCR\| PubMed ID: 31640747	2019
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
Corrigendum to "MR and PET-CT monitoring of tissue-engineered vascular grafts in the ovine carotid artery" [Biomaterials 216 (2019) 119228]. Biomaterials\| PubMed ID: 33636550	2021
Tuning the Elasticity of Nanogels Improves Their Circulation Time by Evading Immune Cells. Angewandte Chemie (International ed. in English)\| PubMed ID: 35274425	2022
Radiolabeled Nanocarriers as Theranostics-Advancement from Peptides to Nanocarriers. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 35527333	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

Agnieszka Morgenroth

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