19F MRI contrast agents and drug nanocarriers based on fluorinated hyperbranched polyether copolymers.
RI provides unique insights into disease pathogenesis. For molecular and cellular MRI, several contrast agents, each with different ability to enhance water proton relaxivity, have been exploited, including gadolinium chelates, iron oxide particles, and a family of chemical shift saturation transfer contrast agents (1-3). More recently, interest in fluorine 19 ( 19 F) emulsions has grown because fluorine MR signal from soft tissues is absent, and emulsions of fluorocarbon are biocompatible agents (4). Therefore, 19 F MRI is being explored for several applications, including cell tracking (4-8), molecular sensing (9,10) and for imaging inflammation in various diseased models (11)(12)(13)(14)(15)(16). Furthermore, since the 19 F MRI signal is directly related to the number of fluorine atoms, labeled cells can be quantified and monitored for a long time. Importantly, 19 F signal from fluorocarbons does not disturb standard proton ( 1 H) MRI and does not need precontrast data acquisition.Multicolor 19 F MRI has been previously attempted (8,17,18) with the use of fluorocarbons with multiresonance frequencies from nonequivalent fluorine nuclei that induce image artifacts and considerably limit the sensitivity and specificity of fluorine signal (19).We propose the use of two fluorocarbons with two clearly distinct resonance frequencies and a high number of chemically equivalent fluorine nuclei suitable for multispectral 19 F MRI. In particular, both 19 F nanoparticles were used to differentiate the normal and enhanced activity of phagocytosis after temporary inhibition of the colony stimulating factor 1 receptor (CSF1R), a key regulator of mononuclear cell production, differentiation, migration, and activation (20). CSF1R inhibition has been reported to be effective for depleting macrophages and microglial cells, which are rapidly regenerated within a few days after treatment interruption (21) and with an increase of phagocytic activity (20). In our study, we aimed to follow this
Molecular imaging techniques are essential tools for better investigating biological processes and detecting disease biomarkers with improvement of both diagnosis and therapy monitoring. Often, a single imaging technique is not sufficient to obtain comprehensive information at different levels. Multimodal diagnostic probes are key tools to enable imaging across multiple scales. The direct registration of in vivo imaging markers with ex vivo imaging at the cellular level with a single probe is still challenging. Fluorinated ( 19 F) probes have been increasingly showing promising potentialities for in vivo cell tracking by 19 F-MRI. Here we present the unique features of a bioorthogonal 19 F-probe that enables direct signal correlation of MRI with Raman imaging. In particular, we reveal the ability of PERFECTA, a superfluorinated molecule, to exhibit a remarkable intense Raman signal distinct from cell and tissue fingerprints. Therefore, PERFECTA combines in a single molecule excellent characteristics for both macroscopic in vivo 19 F-MRI, across the whole body, and microscopic imaging at tissue and cellular levels by Raman imaging.
Experimental autoimmune encephalomyelitis (EAE) is the primary disease model of multiple sclerosis (MS), one of the most diffused neurological diseases characterized by fatigue, muscle weakness, vision loss, anxiety and depression. EAE can be induced through injection of myelin peptides to susceptible mouse or rat strains. In particular, EAE elicited by the autoimmune reaction against myelin oligodendrocyte glycoprotein (MOG) presents the common features of human MS: inflammation, demyelination and axonal loss. Optic neuritis affects visual pathways in both MS and in several EAE models. Neurophysiological evaluation through visual evoked potential (VEP) recording is useful to check visual pathway dysfunctions and to test the efficacy of innovative treatments against optic neuritis. For this purpose, we investigate the extent of VEP abnormalities in the dark agouti (DA) rat immunized with MOG, which develops a relapsing-remitting disease course. Together with the detection of motor signs, we acquired VEPs during both early and late stages of EAE, taking advantage of a non-invasive recording procedure that allows long follow-up studies. The validation of VEP outcomes was determined by comparison with ON histopathology, aimed at revealing inflammation, demyelination and nerve fiber loss. Our results indicate that the first VEP latency delay in MOG-EAE DA rats appeared before motor deficits and were mainly related to an inflammatory state. Subsequent VEP delays, detected during relapsing EAE phases, were associated with a combination of inflammation, demyelination and axonal loss. Moreover, DA rats with atypical EAE clinical course tested at extremely late time points, manifested abnormal VEPs although motor signs were mild. Overall, our data demonstrated that non-invasive VEPs are a powerful tool to detect visual involvement at different stages of EAE, prompting their validation as biomarkers to test novel treatments against MS optic neuritis.Castoldi et al VEPs in preclinical models of multiple sclerosis Brain Pathology 30 (2020) 137-150
In recent years, fluorine‐magnetic resonance imaging (19F‐MRI) has emerged as a promising diagnostic technique, complementary to traditional proton magnetic resonance imaging (1H‐MRI) and easily translatable for clinical use, providing in‐depth in vivo quantification without the use of radioactive agents. This creates a need for the development of appropriate delivery systems for highly omniphobic fluorinated probes. The use of the film‐forming protein hydrophobin (HFBII) represents a sustainable and simple method to invert the philicity of fluorinated surfaces. Here, the ability of HFBII to form a rigid protein monolayer on superfluorinated coatings rendering them hydrophilic is shown, a property that is also retained in biological environment. This approach is then translated to directly disperse a solid superfluorinated 19F‐MRI probe, PERFECTA, in aqueous solution through the formation of core‐shell hydrophobin stabilized PERFECTA nanoparticles (NPs). The obtained NPs are fully characterized in terms of morphology, magnetic properties, colloidal stability, protein corona formation, cellular viability, and imaging performance.
A protocol to load perfluoro-crown-ether (PFCE) nanoemulsion directly into yeast-derived glucan particles (GPs) was developed. It was observed that the PFCE encapsulation did not affect the 19 F-MRI properties of the nanoemulsion that is currently in clinical trials. GPs loaded with PFCE nanoemulsion were taken up avidly by murine macrophages in vitro, resulting in a cellular uptake 150 % higher than the not GPs-entrapped nanoemulsion. Accordingly, a corresponding improvement in the 19 F-MRI detection of the labelled cells can be obtained. The high biotolerability and versatility of GPs, makes these microcarriers a promising option for designing of improved in vivo cellular imaging protocols.
Conspectus Future medicine is primarily aiming at the development of novel approaches for an early diagnosis of diseases and a personalized therapy for patients. For achieving these objectives, a key role is played by medical imaging. Among available noninvasive imaging techniques, Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is emerging as a powerful quantitative detection modality for clinical use both for molecular imaging and for cell tracking. The strength of using 19F-MRI is mainly related to the lack of endogenous organic fluorine in tissues, with no background, enabling the visualization of fluorinated tracers as hot-spot images, adding secondary independent information to the anatomical features provided by the grayscale 1H-MRI. The main challenge for 19F-MRI clinical application is the intrinsic reduced sensitivity of MRI. To improve sensitivity, undoubtedly the use of a high field MRI scanner and cryogenic radiofrequency probes is advantageous, but there is a clear need of developing increasingly effective fluorinated tracers. The ideal tracer should bear as many as possible magnetically equivalent fluorine atoms and show optimal magnetic resonance relaxivity properties (i.e., T 1 and T 2), which enable reduced acquisition time with the possibility to apply fast imaging methods. Moreover, it should be biocompatible with reduced tendency to bioaccumulate in tissues, which is one of the main drawbacks in using perfluorocarbons (PFCs), together with their difficulty to be chemically modified with functional groups. In fact, PFCs such as perfluorooctyl bromide (PFOB), perfluoro-15-crown-5-ether (PFCE), and linear perfluoropolyethers (PFPE) are currently the most used tracers in 19F-MRI preclinical and clinical studies, with the above-mentioned limitations. In this regard, molecules bearing short branched fluorinated chains gained a lot of attention for their high number of equivalent fluorines and expected capability of reducing bioaccumulation concerns. A valuable building block for branched fluorinated tracers is perfluoro-tert-butanol (PFTB), with nine magnetically equivalent fluorines and easy availability and modification. In this Account we will discuss the main challenges that 19F-MRI has to overcome for increasing its clinical use, highlighting on one hand the need of developing customized fluorinated materials for increasing sensitivity and enabling multimodal properties, and on the other hand, the importance of the ultrastructure of the final formulation for the final biological response (i.e., clearance). In this context, our group has been focusing on the synthesis and development of branched fluorinated tracers, for which the originator is a molecule called PERFECTA (from suPERFluorinatEdContrasT Agent), bearing 36 equiv 19F atoms, which showed not only optimal relaxometry properties but also a very specific and intense Raman signal. Thus, PERFECTA and its derivatives represent a new family of multimodal tracers enabling multiscale analysis, from whole body imaging (19F-MRI) to microsco...
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