8 results on '"Müller, Cristina"'
Search Results
2. 18F-AzaFol for Detection of Folate Receptor-β Positive Macrophages in Experimental Interstitial Lung Disease-A Proof-of-Concept Study
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Schniering, Janine, Benešová, Martina, Brunner, Matthias, Haller, Stephanie, Cohrs, Susan, Frauenfelder, Thomas, Vrugt, Bart, Feghali-Bostwick, Carol, Schibli, Roger, Distler, Oliver, Müller, Cristina, Maurer, Britta, University of Zurich, and Maurer, Britta
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interstitial lung disease ,2403 Immunology ,positron emission tomography ,10042 Clinic for Diagnostic and Interventional Radiology ,Immunology ,10051 Rheumatology Clinic and Institute of Physical Medicine ,610 Medicine & health ,respiratory system ,folate-based 18F-PET tracer ,respiratory tract diseases ,macrophages ,folate receptor ,inflammation ,animal model of lung fibrosis ,10049 Institute of Pathology and Molecular Pathology ,2723 Immunology and Allergy ,imaging biomarkers ,Original Research - Abstract
Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of 18F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD. Methods: The pulmonary expression of folate receptor-β was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the 18F-based folate radiotracer 18F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies. Results: Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of 18F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01). Conclusion: Our preclinical proof-of-concept study demonstrated the potential of 18F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases.
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- 2019
3. F-18-AzaFol for Detection of Folate Receptor-beta Positive Macrophages in Experimental Interstitial Lung Disease-A Proof-of-Concept Study
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Schniering, Janine, Benešová, Martina, Brunner, Matthias, Haller, Stephanie, Cohrs, Susan, Frauenfelder, Thomas, Vrugt, Bart, Feghali-Bostwick, Carol, Schibli, Roger, Distler, Oliver, Müller, Cristina, and Maurer, Britta
- Subjects
interstitial lung disease ,folate receptor ,positron emission tomography ,inflammation ,animal model of lung fibrosis ,imaging biomarkers ,macrophages ,folate-based 18F-PET tracer ,respiratory system ,respiratory tract diseases - Abstract
Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of 18F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD. Methods: The pulmonary expression of folate receptor-β was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the 18F-based folate radiotracer 18F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies. Results: Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of 18F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01). Conclusion: Our preclinical proof-of-concept study demonstrated the potential of 18F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases., Frontiers in Immunology, 10, ISSN:1664-3224
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- 2019
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4. Radiation dosimetry of 18F-AzaFol: A first in-human use of a folate receptor PET tracer.
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Gnesin, Silvano, Müller, Joachim, Burger, Irene A., Meisel, Alexander, Siano, Marco, Früh, Martin, Choschzick, Matthias, Müller, Cristina, Schibli, Roger, Ametamey, Simon M., Kaufmann, Philipp A., Treyer, Valerie, Prior, John O., and Schaefer, Niklaus
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RADIATION dosimetry ,BLADDER ,INTRAVENOUS injections ,POSITRON emission tomography - Abstract
Background: The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the
18 F-AzaFol (3′-aza-2′-[18 F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Material and methods: Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of18 F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. Results: No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq). Conclusions:18 F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance. Trial registration: ClinicalTrial.gov, NCT03242993, posted on August 8, 2017 [ABSTRACT FROM AUTHOR]- Published
- 2020
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5. Improved PET Imaging of Tumors in Mice Using a Novel 18 F-Folate Conjugate with an Albumin-Binding Entity.
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Fischer, Cindy R., Groehn, Viola, Reber, Josefine, Schibli, Roger, Ametamey, Simon M., and Müller, Cristina
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POSITRON emission tomography ,CANCER tomography ,MEDICAL imaging systems ,CANCER cells ,LABORATORY mice ,IMAGE quality in imaging systems - Abstract
Purpose: The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a
18 F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio. Procedures: The novel18 F-folate was prepared by conjugation of a18 F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice. Results: The radiosynthesis of the albumin-binding [18 F]fluorodeoxyglucose–folate ([18 F]3) resulted in a radiochemical yield of 1–2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [18 F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [18 F]3 to KB tumor cells. In vivo we found an increasing uptake of [18 F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published18 F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging. Conclusions: [18 F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [18 F]3. [ABSTRACT FROM AUTHOR]- Published
- 2013
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6. Folate-Based Radiotracers for PET Imaging-Update and Perspectives.
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Müller, Cristina
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RADIOACTIVE tracers , *POSITRON emission tomography , *LUNG cancer , *OVARIAN cancer , *SINGLE photon emission computerized tomography centers , *RADIOISOTOPES - Abstract
The folate receptor (FR) is expressed in many tumor types, among those ovarian and lung cancer. Due to the high FR affinity of folic acid, it has been used for targeting of FR-positive tumors, allowing specific delivery of attached probes to the malignant tissue. Therefore, nuclear imaging of FR-positive cancer is of clinical interest for selecting patients who could benefit from innovative therapy concepts based on FR-targeting. Positron emission computed tomography (PET) has become an established technique in clinical routine because it provides an increased spatial resolution and higher sensitivity compared to single photon emission computed tomography (SPECT). Therefore, it is of critical importance to develop folate radiotracers suitable for PET imaging. This review article updates on the design, preparation and pre-clinical investigation of folate derivatives for radiolabeling with radioisotopes for PET. Among those the most relevant radionuclides so far are fluorine-18 (t½: 110 min, Eavβ+: 250 keV) and gallium-68 (t½: 68 min, Eav β+: 830 keV). Recent results obtained with new PET isotopes such as terbium-152 (t½: 17.5 h, Eβ+: 470 keV) or scandium-44 (t½: 3.97 h, Eav β+: 632 keV) are also presented and discussed. Current endeavors for clinical implementation of PET agents open new perspectives for identification of FR-positive malignancies in patients. [ABSTRACT FROM AUTHOR]
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- 2013
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7. Tumor targeting using 67Ga-DOTA-Bz-folate — investigations of methods to improve the tissue distribution of radiofolates
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Müller, Cristina, Vlahov, Iontcho R., Santhapuram, Hari Krishna R., Leamon, Christopher P., and Schibli, Roger
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FOLIC acid , *TISSUE analysis , *CANCER treatment , *INFLAMMATION , *POSITRON emission tomography , *BIOACCUMULATION , *PHOTON emission , *TOMOGRAPHY - Abstract
Abstract: Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [67Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl3 according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: 67Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%±0.75% ID/g, 1 h pi and 6.08%±0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of 67Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel 67Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [68Ga]-gallium radionuclide. [Copyright &y& Elsevier]
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- 2011
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8. Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute.
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Müller, Cristina, De Prado Leal, Maria, Dominietto, Marco D., Umbricht, Christoph A., Safai, Sairos, Perrin, Rosalind L., Egloff, Martina, Bernhardt, Peter, van der Meulen, Nicholas P., Weber, Damien C., Schibli, Roger, and Lomax, Antony J.
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PROTON therapy , *RADIOISOTOPES , *POSITRON emission tomography , *RADIOACTIVE tracers , *PILOT projects , *PROSTATE-specific membrane antigen - Abstract
Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy. [ABSTRACT FROM AUTHOR]
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- 2019
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