Fluorine polymer probes for magnetic resonance imaging: quo vadis?
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Over the last few years, the development and relevance of 19F magnetic resonance imaging (MRI) for use in clinical practice has emerged. MRI using fluorinated probes enables the achievement of a specific signal with high contrast in MRI images. However, to ensure sufficient sensitivity of 19F MRI, fluorine probes with a high content of chemically equivalent fluorine atoms are required. The majority of 19F MRI agents are perfluorocarbon emulsions, which have a broad range of applications in molecular imaging, although the content of fluorine atoms in these molecules is limited. In this review, we focus mainly on polymer probes that allow higher fluorine content and represent versatile platforms with properties tailorable to a plethora of biomedical in vivo applications. We discuss the chemical development, up to the first imaging applications, of these promising fluorine probes, including injectable polymers that form depots that are intended for possible use in cancer therapy.
KeywordsFluorine Magnetic resonance imaging (MRI) Polymer 19F MRI probe Molecular imaging
Atom transfer polymerization
Cloud point temperature
Transmission electron cryomicroscopy
Dynamic light scattering
Enhanced permeability and retention effect
Lower critical solution temperature
Magnetic resonance imaging
PEO monomethylether methacrylate
Oligo(ethylene glycol) methyl ether acrylate
Reversible addition fragmentation chain transfer
Reactive oxygen species
Ultrashort echo time
Zero echo time
Magnetic resonance imaging (MRI) using fluorinated probes (19F MRI) enables high contrast in images due to the negligible fluorine background of living tissues. For this reason, fluorine isotopes are visualized with high specificity, allowing for so-called “hot spot” imaging where the 19F MR signal is overlaid on a proton reference MR image. Moreover, the fluorine isotope 19F resonates at a Larmor frequency close to that of the proton 1H (94% of 1H); therefore, the hardware used for 1H MR imaging, with minor modifications, can also be used for 19F MRI. Currently, many clinical and experimental scanners have become available for hardware modifications and the use of appropriate radiofrequency (RF) coils. Usually, the RF coils intended for 19F MR are constructed to be dual-tuned for both 1H/19F MRI. The 19F MR signal is proportional to the number of 19F nuclei, which allows absolute quantification of the 19F content.
For 19F MRI, fluorine-containing probes need to be synthesized and then administered into the organism by either injection (intravenously or locally to the site of interest) or exogenous labeling of cells. Currently, there is a wide range of available fluorine probes for experimental and even clinical applications summarized in many excellent reviews [1, 2, 3, 4]. The implementation of 19F MR probes ranges from cell targeting [5, 6, 7, 8] and in vivo tracking of labeled cells [9, 10, 11, 12, 13, 14, 15, 16, 17, 18], cancer diagnosis [19, 20, 21, 22], inflammation monitoring [23, 24, 25, 26], amyloid plaque detection or suppression [27, 28, 29], in situ partial oxygen pressure (pO2) determination [30, 31], drug metabolism (e.g., of 5-fluorouracil) investigation , intra/extracellular pH measurement [33, 34] or cation concentration estimation in cells and tissues . In humans, the 19F probes have been tested in the immunotherapy of colorectal cancer with labeled dendritic cells, and a number of other clinical trials are ongoing [3, 12]. Currently, several theranostic 19F MR probes combining both diagnosis and therapy  have been implemented; however, testing of the probes on biological models of diseases is far behind their constantly evolving chemical development.
The main drawback of 19F MR imaging is its low sensitivity due to the low amount of 19F nuclei per molecule of the synthesized fluorine-based probes. Usually, the concentration of 19F atoms in fluorine-based probes is in the millimolar range (for comparison, water has a proton concentration of approximately 110 M under ambient conditions); therefore, agents containing a large number of 19F atoms are necessary for a sufficiently high signal-to-noise ratio (SNR). For a well-resolved single spectral peak, the key property needed for fluorine probes is an as-high-as-possible fraction of chemically equivalent 19F atoms in the molecule. A single peak allows us to detect a higher 19F MR signal compared to multiple spectral peaks, which can cause chemical shift artifacts in the MR images.
These demands can be accomplished, e.g., by probes based on polymer structures. Polymer probes enable the incorporation of a large amount of chemically equivalent fluorine atoms into a single molecule and thus could overcome the sensitivity issue of 19F MRI. Moreover, polymer probes can be easily modified to increase their biological response and improve their behavior in living systems (pH, thermoresponsive parts or bonds, which might be enzymatically degraded) or to add the imaging labels to drug moieties. In this review, we summarize the current state of the art for polymer-based 19F MRI probes that have great potential in human medicine.
Types of fluorine-containing probes
Overview of the most commonly used fluorine-containing probes
The most frequently used 19F MR agents are liquid PFCs, e.g., perfluoro-15-crown-5-ether (PFCE) (containing 20 fluorine atoms), perfluorooctyl bromide (PFOB) (17 fluorine atoms), a superfluorinated probe called PERFECTA (bearing 36 chemically equivalent fluorine atoms per molecule) , or perfluoropolyethers (PFPE) (with more than 40 fluorine atoms per molecule). These probes possess convenient features for in vivo applications such as nontoxicity, biological and chemical inertness and the ability to be internalized into cells, enabling their labeling. In this way, e.g., macrophages, stem cells, immune cells [8, 11, 13], or even clusters of cells such as pancreatic islets [17, 43] may be visualized and tracked. PFCs are both hydrophobic and lipophobic, and thus, liquid PFC emulsions must be stabilized with surfactants (lipids or phospholipids) or entrapped in polymer nanoparticles [44, 45] for stabilization and biocompatibility [15, 44]. There are many preclinical applications using PFC-based agents covering the imaging of cardiac progenitor stem cells and bone-derived bone marrow macrophages , detection of dendritic cells , visualization of the immune response [47, 48], tracking of cells or pancreatic islets , etc. PFCs with a single 19F MR peak in their spectra have been implemented in various studies, including a clinical trial with labeled dendritic cells (DCs) intended for adenocarcinoma treatment . Although widely implemented, PFCs also have limitations, such as nonspecific accumulation in tissues or at the site of inflammation , possible macrophage activation after high dosage , altered cellular responses due to the incorporation of PFCs into the cellular membranes  and long retention times in the body.
In addition to cell labeling and tracking, fluorine-containing probes can also be implemented for other purposes. Recently, polymer agents consisting of molecular hydrophobic and hydrophilic blocks (copolymers) have shown promising properties for biomedical applications, especially for tumor diagnosis based upon their responsiveness to the chemical environment or as possible drug carriers due to their nanoscale size. These probes can carry large amounts of fluorine atoms, resulting in a high sensitivity of visualization, although their short relaxation times resulting from polymerization need to be adjusted. In the majority of these amphiphilic agents, the fluorinated block is based on acrylic acid, specifically on 2,2,2-trifluorethylacrylate (TFEA), 2,2,2-trifluorethyl methacrylate (TFEMA), poly[N-(2,2-difluorethyl)acrylamide] (PDFEA) [39, 40] or octafluoropentyl methacrylate (OFPMA). There are also polymers based on functionalized styrenes (e.g., 2,3,4,5,6-pentafluorostyrene (PFS))  or polydimethylsiloxanes (PDMS) . These probes are described in more detail in the section “Polymer agents for drug delivery”
Fluorine-containing agents can also be targeted to specific structures (e.g., the cell surface); accumulated in specific cells such as macrophages, stem cells and immune cells [1, 53]; and responsive to specific stimuli in the environment (physiological processes, enzymatic activity, concentrations of metal ions, pH or pO2) [3, 35, 54, 55, 56].
Preparation of fluorinated probes
The most commonly employed probes are PFCs, which are typically used as stabilized aqueous (nano)emulsions prepared under high pressure; emulsification is usually performed by probe sonication. An emerging class of 19F probes are fluorinated polymers. These polymers can be used either alone or as colloidal stabilizers for PFCs. Fluorinated copolymers are typically synthesized analogously to their nonfluorinated counterparts, i.e., by (controlled pseudo living) radical, cationic, anionic or coordination polymerization. The most commonly used controlled radical polymerization techniques involve nitroxide-mediated polymerization [66, 67], atom transfer polymerization (ATRP) [68, 69] and reversible addition fragmentation chain transfer (RAFT) polymerization [70, 71]. It is worth mentioning that if multiple fluorine atoms are in close proximity to the polymerizable moiety, then they may dramatically reduce the electron density of the moiety, greatly influencing its reactivity to polymerization. Other procedures to introduce fluorine atoms into polymer structures involve fluoroalkanoyl peroxide initiation [72, 73], telomerizations with fluorinated mercaptan and fluorinated iodides  and esterification with perfluoroacyl chloride . The fluorine block can also be introduced within the termination process . The various copolymer structures include linear copolymers, hyperbranched copolymers, dendrimers [77, 78, 79], micelles  and star- and knedel-like structures [51, 65].
Properties of fluorinated polymers
A high density of equivalent fluorine atoms is required in the probes suitable for 19F MRI. However, (per)fluorinated—fluorophilic parts of the molecules/polymer blocks are naturally insoluble in water and aggregation of 19F probes with high fluorine content is often observed in aqueous solution. This causes attenuation of MR signal and decreasing the 19F MR sensitivity. Therefore, it is necessary to solubilize them in aqueous milieus for their use as contrast agents. This may be done by adding covalently bound sufficiently hydrophilic moieties or polymer block(s) or by noncovalent incorporation of fluorophilic molecules into supramolecular assemblies containing amphiphiles solubilizing the whole system in aqueous milieu.
The specific advantage of polymer systems, especially from a diagnostic and therapeutic point of view, is the possibility to construct delivery systems for drugs, nucleic acids, imaging labels or radionuclides to target cancerous tissue, macrophages or other cells and their subcellular compartments. The polymer systems can easily build “molecular toolboxes”, which can be targeted and used as efficient theranostic tools . Self-assembled (supramolecular) polymer systems are very promising. Supramolecular polymer systems are assembled from many molecules that can be bound together by various noncovalent interactions, such as hydrophobic, ion–ion, and coordination interactions [82, 83]. The degradability of such systems may be controlled not only chemically but also physically. According to the type of bonds and molecules, different polymer systems can be created, such as polymer micelles, polymersomes, polyplexes, and polymer nanoparticles [76, 84]. Many fluorinated polymers exhibit self-assembly properties, which are based on the ability of fluorinated molecules to phase separate and assemble into a fluorous phase that is both hydrophobic and lipophobic. The advantage of the self-assembly feature is its dependency on environmental conditions; therefore, these agents can act primary as environmentally responsive probes. These systems are responsive to external stimuli, such as changes in pH, temperature, redox potential, enzymes, and ion concentrations. Their features can be used for custom-built self-assembling scaffolds and depots.
From an imaging point of view, the challenge in synthesizing multiblock copolymers is ensuring high fluorine contents and suitable relaxation times for 19F MRI. Under optimal conditions, the T1 relaxation time should not be too long for recovery of the longitudinal magnetization; T1 relaxation times of many fluorinated molecules are in the range of 1–4 s, which results in long acquisition times for in vivo experiments [85, 86]. Fluorine T2 relaxation times are based on the mobility of the fluorine segments and need to be adjusted to permit imaging by standard spin, gradient and ultrashort echo time (UTE) sequences , which means the T2 relaxation times should not be too short (> 10 ms). Adjustment of the relaxation times is crucial and challenging, and various chemical approaches have been tested [53, 87, 88, 89]. For instance, control over the molecular mobility can be achieved by preventing the very strong fluorine–fluorine interactions by hydration of the fluorosegments . Moreover, the association of the fluorine segments needs to be taken into account due to strong dipole–dipole interactions and shortening of the relaxation times . The proximity of paramagnetic atoms, such as lanthanides, also highly influences fluorine relaxation.
From a diagnostic point of view, fluorine-containing contrast agents possess the added value of specificity and responsiveness. The specificity can be achieved by modification with a targeting moiety; therefore, it is crucial to prepare easily modifiable chemical structures for the probes.
a high content of equivalent fluorine atoms so that all of them fit into the chemical shift window of interest,
efficient mobility and limited association resulting in suitable relaxation times,
adequate solubility in water,
an easily modifiable structure for targeting, and
reliable pharmacokinetic and pharmacodynamic properties, including biodegradability and elimination after the probe fulfills its task
The commercially available PFC-based probes include the PFPE-based agents Cell Sense and V-Sense (CS-1000-DM-Red and VS-1000H, Celsense, Inc., Pittsburgh, USA). These types of probes were introduced in the 1980s for tumor detection [60, 61], and their use as a cell label was shown for the first time in 2005 . Although PFPE-based agents have been implemented in various preclinical and clinical studies, they are difficult to further functionalize, and the possible extra covalent bond would break the symmetry of the probe, which could lead to multiple 19F peaks . Therefore, there is a need for the synthesis of novel probes with higher fluorine content and the potential for easy modification. In 2017, Zhang et al.  synthesized a polymer agent based on PFPE with a high fluorine content between 10 and 29% wt. The polymer consists of PFPE end-functionalized homopolymers of oligo(ethylene glycol) methyl ether acrylate (poly(OEGA)m-PFPE). These polymers are water-soluble and possess outstanding imaging sensitivity as was shown with in vitro and in vivo experiments. The long T2 relaxation times (> 80 ms) of these PFPE-based probes are suitable for imaging using common MR sequences, such as a spin-echo-based sequence. The polymers accumulated in the liver, kidneys and spleen of mice after intravenous administration of the probe. The difference in the ratio of hydrophobic (PFPE) and hydrophilic [oligo(ethylene oxide) methyl ether acrylate] segments played an important role in the accumulation of the probe in biological tissue. The polymer showed resistance to rapid uptake by macrophages and thus longer circulation times in the blood. This effect is also seen in other studies [90, 91]. The polymer with exposed PFPE segments showed enhanced recognition and filtration by macrophages, resulting in faster clearance from the body.
Fluorine molecular blocks
Development of fluorine copolymers for 19F MRI: from chemical concept to first in vivo 19F MR images
Since the first reports on the synthesis of copolymers consisting of fluorinated molecular blocks, these probes have been extensively studied. In 2007, Cheng et al.  introduced a hyperbranched fluorinated copolymer consisting of a fluorinated backbone and PDMS. The proposed cross-linking of the hyperbranched fluoropolymers with PDMS or poly(ethylene oxide) (PEO) showed unique properties, such as an anti-biofouling ability, release behavior for various molecules and mechanical performance . This approach inspired the further synthesis of 19F copolymers intended for 19F MRI. In 2008, the Wooley group synthesized polymers of trifluorethyl methacrylates and acrylic acid grafted onto a hydrophobic hyperbranched core. The fluoropolymers possessed good imaging properties (T1/T2 = 500/50 ms) and achieved a high SNR in a phantom study, although with an extensive scanning time (13 h) . Later, this group studied the imaging performance of styrene-based polymers and observed that the packaging of fluorine-rich segments into the core restricts the mobility of the chains and limits 19F detectability . The polymers had to be dissolved in dimethyl sulfoxide (DMSO) to increase their mobility, which increased the sensitivity of 19F MR signal detection in MR spectra; therefore, this approach is not suitable for biological applications due to the toxicity of DMSO.
The first report of 19F MRI of fluorinated copolymers was published in 2009 by Peng et al. . This group synthesized diblock copolymers of acrylic acid with partially fluorinated acrylate or methacrylate monomers, which undergo spontaneous assembly in mixed or aqueous solvents resulting in the formation of micelles (diameter 20-45 nm). The micelles exhibited a strong signal in 19F MR images, with a higher signal obtained from the methacrylate polymers compared to the acrylate polymers due to the short T2 relaxation times of the acrylate. The 19F T1 relaxation times were approximately 500 – 600 ms, and the 19F T2 relaxation times were 331 ms and 249 ms for TFEA and TFEMA, respectively. These ranges for the T1 and T2 relaxation times are suitable for visualization with routinely used MR imaging sequences without the need to use UTE or zero echo time (ZTE) sequences. The 19F MR images of phantoms containing the copolymers were acquired within 1 h 20 min using a 3D spin-echo sequence at 7 T (2.5 mm slice thickness). The low 19F MR signal detection attributed to the restricted mobility of the fluorinated segments; however, the group later introduced various approaches to increase the mobility of the fluorinated segments while maintaining the high amount of 19F atoms in a molecule. In 2010, the group reported an approach to enhance the hydration of the fluorinated blocks by preventing their aggregation in water by exploiting the electrostatic repulsion between monomeric units, which contributed to higher detectability .
Then, in 2010, highly flexible hyperbranched polymers that maintained the molecular mobility of the fluorinated chains were introduced by Thurecht et al. . Moreover, this cytocompatible hyperbranched polymer can be easily functionalized for tracking or targeting. The polymer possesses “shape-resistance”, which is important for cell targeting and ensures the proper orientation for biological recognition. To eliminate the toxic effect of the cationic hyperbranched core, PEO monomethylether methacrylate (PEOMA) was incorporated into the molecule. Importantly, the polymer had been modified with mannose for biological targeting, e.g., the immune responses mediated by macrophages, which possess DC-SIGN surface receptors for mannosylated species. Fluorine T2 relaxation times of the polymers were in the detectable range (68–122 ms).
The same group reported a study focused on testing the solvent influence on an assembly of TFEA/TFEMA-based polymers . Diffuse aggregates were formed in dichloromethane and micelles were formed in acetone. After the addition of water to these systems, both systems formed cylindrical structures. The highest 19F MR signal was observed from polymers dissolved in acetone, which highlights the dependence of imaging properties on the solvent used due to the rigidity of the structure. Association of the fluorine segments leads to strong dipole–dipole interactions between the 19F spins, causing shortening of the 19F spin–spin relaxation times and therefore lowering the 19F MR detectability. To overcome the effect of dipole–dipole interactions, several approaches for improving MRI detectability were proposed, such as distributing the monomers along the polymer chain, incorporating branches and limiting the content of the fluorinated monomers . Although this study was performed in biologically irrelevant organic solvents, it reveals rules of general applicability.
Fluorine copolymers responsive to environmental changes: from optimization of the chemical structure to biological applications
In addition to the use of fluorine copolymers for contrast modulation in 19F MR images, various probes also respond to environmental stimuli and can act as responsive probes for, e.g., controlled in situ supramolecular nanostructure formation due to external environment change or even responsive 19F MRI. The rationale for such a responsive agent would be, e.g., the evaluation of treatment response by changes in pH, controlled release of drugs upon changes in pH, and accumulation of the system at the target site according to pH (acidity in tumors).
The agents mostly respond to changes in pH or temperature by triggering self-assembly. For the synthesis and application of these types of polymers, it is crucial to achieve a lower critical solution temperature (LCST) within an adequate range. The LCST refers to the temperature below which the components of the polymer are miscible. At temperatures above the LCST, polymers lose their hydration layer, start to precipitate and change into a solid phase. As a macroscopic measure, the value most often used is the cloud point temperature (CPT), which is where the polymer visibly phase-separates at the given concentration, where LCST is the temperature minimum in the function CPT = f(concentration). As the components become less mobile, the relaxation times are shortened. These aggregation properties can be implemented in the creation of solid implants without the need for surgical intervention [40, 95].
In 2007, the group of Mao et al.  presented amphiphilic hyperbranched star-block copolymers containing poly[2-(N,N-dimethylamino)ethyl methacrylate] (PDMAEMA) and OFPMA, which self-assemble into micelles in either an acidic aqueous solution or in a dimethylformamide/water mixture (both at pH 3). The size (expressed as hydrodynamic diameter, DH) of the micelles depends on the length of the DMAEMA segment and varies with pH. The authors reported various sizes (50–200 nm) and structures for the synthesized probes ranging from micelles to fibers depending on the length of the protonated PDMAEMA chains. Fluorine MR spectra showed multiple 19F peaks for the polymer.
Similar thermo- and pH-responsive fluoroalkyl end-capped amphiphilic diblock copolymers containing PDMAEMA and poly[2-(N,N-diethylamino)ethyl methacrylate] (PDEA) were synthesized by the Zhang . These polymers can form flower-like micelles in aqueous solution upon pH changes or by changing the linking order of the PDMA and PDEA blocks. The LCST of these polymers decreases with increasing concentration or pH. At a low pH of approximately 3, there is no aggregation, and the copolymers exist in the aqueous solution as unimers. At a higher pH (7- 9), the copolymer forms micelles, and at a pH of approximately 9, the immiscible components aggregate into a core. By changing the linking order of the PDMA and PDEA blocks and changing the pH, different morphologies were obtained such as sphere-on-sphere, flower-like micelles and anomalous vesicles. Fluorine MR spectroscopy showed three 19F peaks in the spectra of the polymers.
In another study, PEO-coated nanogels constructed from PEO chains and a polyamine gel core compound with 19F showed suitable properties for targeting solid tumors via their responsiveness to the low pH (6.5) present in the tumor environment . The polymer prepared from 2-(N,N-diethylamino)ethyl methacrylate (DEAMA) and TFEMA at various molar ratios with PEO chains showed volume phase transition points in the pH range of 6.8–7.3. This effect is caused by the hydrophobicity of the gel core and deprotonization of the amino groups, leading to a broadening of the 19F MR signals due to the limited molecular motion, suggesting that the PEO-coated nanogels will swell only in the acidic environment of, e.g., tumors (pH 6.5–7.0). This effect was confirmed by 19F MR spectroscopy; the polymers were only detected at acidic pH, and there was almost no 19F MR signal in the physiological pH range (7.4). A stable on–off behavior was observed even in the presence of 90% fetal bovine serum, which is promising for future biological applications. The probe showed high sensitivity (the detection threshold as measured by 19F MR spectroscopy was 55 µM at 12 T), although 19F MR imaging was not performed in this study.
Polymer agents for drug delivery
In theranostics (therapy + diagnosis), nanoparticles and micelles (with DH, below 200 nm) can be used for passive targeting of solid tumors due to the enhanced permeability and retention effect (EPR) [97, 98, 99], which is caused by the leaky vasculature and limited lymphatic drainage of solid tumor tissue. Moreover, the probes can be further functionalized to prolong their circulation times [e.g., with PEO or poly(2-methyl-2-oxazolines)] and thus increase their probability of accumulation in tumor tissue [100, 101, 102, 103].
The first example of 19F MR imaging of the accumulation of fluoropolymers in tumors was reported in 2014 by Rolfe et al. 2014 . In this study, a tunable polymer probe, which targeted melanoma cells and enabled multimodal imaging due to the addition of a fluorescent dye, was introduced. The probe was further functionalized for tumor targeting via modification with folate. The probe was found to be taken up by B16 melanoma cells, which overexpress folate receptors. The probe was detected in the tumors of mice after intravenous administration. Fluorescence and 19F MR images revealed the accumulation of the probe in the major organs (the liver, kidneys and bladder) 4 h following injection. 19F MR images of the mice were acquired within 18 min at 16.4 T.
In 2017, the nanoparticles of block copolymers containing a PEO hydrophilic block and a fluorine-containing polymethacrylate block were synthesized by Fu et al. . These polymer nanoparticles exhibit a higher 19F MR signal in the presence of H2O2 (i.e., after micelle disassembly due to hydrophilization after oxidation of the thioethers to sulfoxide), suggesting a promising direction for future biological applications. The sensitivity of the imaging agents was further enhanced by adding a pH switch, resulting in a reactive oxygen species (ROS)/pH dual-responsive 19F MRI agent. The most pronounced change in the intensity of the 19F MR signal was achieved in response to the presence of ROS in a mildly acidic environment.
Conclusion and future perspectives
19F MRI using fluorine-containing agents represents a specific imaging method with applications in both experimental and clinical medicine due to the negligible 19F MR signals from the body. To achieve sufficient sensitivity of 19F MRI, novel fluorine-containing probes are needed. Polymer-based probes are a very promising and versatile platform with properties tailorable to a plethora of in vivo biomedical applications. In particular, stimuli-responsive supramolecular polymer nanostructures allowing for functional imaging in response to changes in temperature, pH, reactive oxygen species and other physiological stimuli hold promise for noninvasive functional diagnostics of pathological tissues in the future. Targeted cell labeling for long-term tracking of transplanted cells by 19F MRI is another highly promising direction for such 19F agents.
To employ the 19F MRI polymer probes in practice, especially in clinics, several properties of these probes must be fulfilled. Among them are a high content of fluorine atoms that are chemically equivalent so that all of them fit into the chemical shift window of interest, an efficient mobility and limited association of the fluorine segments resulting in suitable relaxation times, an adequate solubility in water, an easily modifiable structure for targeting, reliable pharmacokinetic/pharmacodynamic properties including biodegradability, clearance of the probe after the system fulfills its task, and the capability of functional imaging if needed in the particular application. Another important challenge that must be solved is the biodegradability of the imaging agents so that the system may be fully eliminated from the organism after fulfilling its task.
The authors thank the Czech Science Foundation for financial support (D.J., A.G., M.H.: Grant # 16-03156S and K.K., D.B.: Grant # 18-07983S) and by the Ministry of Health of the Czech Republic (D.J., A.G.: CZ-DRO, IN 00023001).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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