4 results on '"Siwowska, Klaudia"'
Search Results
2. In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs
- Author
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Schniering, Janine, Borgna, Francesca, Siwowska, Klaudia, Benešová, Martina, Cohrs, Susan, Hasler, Roger, van der Meulen, Nicholas P., Maurer, Britta, Schibli, Roger, and Müller, Cristina
- Abstract
Increased vascular permeability is an important hallmark of many diseases, including cancer, cerebral ischemia, and severe inflammatory disorders. In this regard, the noninvasive assessment of pathologically increased vascular permeability in vivo is of great interest. In this study, the potential of albumin- and transthyretin-binding radioligands was evaluated for imaging of vascular hyperpermeability. For this purpose, the bleomycin-induced lung injury model was used as a model of inflammation-associated vascular leakage. The plasma protein-binding ligands, which bind to albumin (DOTA-PPB-01) and transthyretin (DOTA-PPB-03), were radiolabeled and used for nuclear imaging and biodistribution studies. In this regard, 177Lu was employed as a surrogate nuclide for detailed preclinical investigations, including single-photon emission computed tomography (SPECT) studies, whereas 44Sc was proposed as a radionuclide for positron emission tomography (PET), which may be relevant for future clinical translation. Mice were administered with these radioligands 6–9 days after intratracheal instillation of bleomycin or saline. Bleomycin-treated mice developed pronounced lung inflammation with enhanced vascular permeability that was reflected in significantly increased lung size and weight due to edema and infiltration with inflammatory cells. Biodistribution studies revealed significantly higher accumulation of 177Lu-DOTA-PPB-01 in injured lungs as compared to lungs of control animals at all investigated time points (4–48 h p.i.). The best contrast was achieved at late time points (16.1 ± 2.91% IA/g vs 2.03 ± 1.22% IA/g, 48 h p.i.) when the blood activity levels were ∼7.5% IA/g. Injection of 177Lu-DOTA-PPB-03 also resulted in increased lung accumulation in bleomycin-treated mice at all investigated time points (2–8 h p.i.). The pharmacokinetics was significantly faster, however, resulting in good contrast already at 8 h p.i. (4.32 ± 0.85% IA/g vs 1.06 ± 0.10% IA/g) when blood activity levels were ∼2% IA/g. The absolute lung accumulation of 177Lu-DOTA-PPB-03 was significantly lower than that of 177Lu-DOTA-PPB-01. PET/CT scans performed with 44Sc-DOTA-PPB-01 distinguished injured from healthy lungs only at late time points (20 h p.i.), whereas 44Sc-DOTA-PPB-03 already allowed the differentiation at 4 h p.i. due to its faster clearance. The investigated radioligands, 44Sc/177Lu-DOTA-PPB-01 and 44Sc/177Lu-DOTA-PPB-03, hold promise for the visualization of vascular leakage in a variety of pathological conditions. 44Sc would be the radionuclide of choice for clinical application as it can be stably coordinated with a DOTA chelator and enables PET imaging over extended periods.
- Published
- 2018
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3. Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties
- Author
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Siwowska, Klaudia, Haller, Stephanie, Bortoli, Francesca, Benešová, Martina, Groehn, Viola, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina
- Abstract
Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor α (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with 177Lu (t1/2= 6.65 days, Eβ–,average= 134 keV; Eγ= 113 keV, 208 keV), a clinically established radionuclide for therapeutic purposes. The evaluation revealed that all of the albumin-binding radiofolates exhibited increased in vitro stability compared with the reference compound (177Lu-cm14) without albumin binder. Serum protein binding, determined with an ultrafiltration assay, was high (>88%) for the derivatives with albumin-binding entities. The FR-binding affinity was in the same range (KD= 4.0–7.5 nM) for all of the radiofolates, independent of the albumin-binding entity and spacer length. FR-specific uptake was proven in vitro using FR-positive KB tumor cells. In vivo studies with KB-tumor-bearing mice were performed in order to assess the tissue distribution profile of the novel radiofolates. 177Lu-cm13 showed high tumor uptake at late time points (13.3 ± 2.94% IA/g, 48 h p.i.) and tumor-to-kidney ratios (0.59 ± 0.03, 48 h p.i.) in the same range as 177Lu-cm10 (0.55 ± 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of 177Lu-cm12 (0.28 ± 0.07, 48 h p.i.) was reduced compared with 177Lu-cm10 and 177Lu-cm13. The results of this study indicate that the spacer entity between folic acid and the albumin binder is of critical importance with regard to the tissue distribution profile of the radiofolate. The PEG spacer compromised the beneficial effects of the lead compound, but the design with a short alkane spacer appeared to be promising. Future studies will focus on the design of radiofolates with lipophilic and more rigid spacer entities, which may allow a further improvement of their tissue distribution profiles.
- Published
- 2017
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4. 64Cu- and 68Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA–Folate
- Author
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Farkas, Renáta, Siwowska, Klaudia, Ametamey, Simon M., Schibli, Roger, van der Meulen, Nicholas P., and Müller, Cristina
- Abstract
A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with 64Cu and 68Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with 64Cu and 68Ga was carried out at room temperature within 10 min resulting in 64Cu-rf42 and 68Ga-rf42 with >95% radiochemical purity. 64Cu-rf42 and 68Ga-rf42 were stable (>95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of 64Cu-rf42 and 68Ga-rf42 was determined to be >96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to <1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of 64Cu-rf42 and 68Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43–0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of 64Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of 64Cu-rf42 and 68Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with 64Cu-rf42 and a 64Cu-labeled DOTA–folate conjugate (cm10) clearly proved the superiority of NODAGA for stable coordination of 64Cu. 64Cu-cm10 showed high liver uptake, most probably as a consequence of released 64Cu2+. The data reported in this study clearly proved the promising features of 64Cu-rf42, particularly in terms of favorable tumor-to-kidney ratios. The relatively long half-life of 64Cu (T1/2= 12.7 h) matches well with the enhanced circulation time of the albumin-binding NODAGA–folate, allowing PET imaging at longer time points after injection than is possible when using 68Ga (T1/2= 68 min).
- Published
- 2016
- Full Text
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