Search

Magnetic resonance imaging (MRI) is a routine diagnostic modality in oncology that produces excellent imaging resolution and tumor contrast without the use of ionizing radiation. However, improved contrast agents are still needed to further increase detection sensitivity and avoid toxicity/allergic reactions associated with paramagnetic metal contrast agents, which may be seen in a small percentage of the human population. Fluorine‐19 (19F)‐MRI is at the forefront of the developing MRI methodologies due to near‐zero background signal, high natural abundance of 100%, and unambiguous signal specificity. In this study, we have developed a colloidal nanoemulsion (NE) formulation that can encapsulate high volumes of the fluorous MRI tracer, perfluoro‐[15‐crown‐5]‐ether (PFCE) (35% v/v). These nanoparticles exhibit long‐term (at least 100 days) stability and high PFCE loading capacity in formulation with our semifluorinated triblock copolymer, M2F8H18. With sizes of approximately 200 nm, these NEs enable in vivo delivery and passive targeting to tumors. Our diagnostic formulation, M2F8H18/PFCE NE, yielded in vivo19F‐MR images with a high signal‐to‐noise ratio up to 100 in a tumor‐bearing mouse model at clinically relevant scan times. M2F8H18/PFCE NE circulated stably in the vasculature, accumulated in high concentration of an estimated 4–9 × 1017 19F spins/voxel at the tumor site, and cleared from most organs over the span of 2 weeks. Uptake by the mononuclear phagocyte system to the liver and spleen was also observed, most likely due to particle size. These promising results suggest that M2F8H18/PFCE NE is a favorable 19F‐MR diagnostic tracer for further development in oncological studies and potential clinical translation. [ABSTRACT FROM AUTHOR]

MgF2-based formulations have unique physicochemical properties, making them attractive for diverse applications. Here, we show the ability to control the morphology of Sm3+-doped, paramagnetic MgF2 nanocrystals (Sm:MgF2 NCs) for use as nanosized imaging agents for 19F-magnetic resonance imaging (19F-MRI). By reducing the temperature of the reaction mixture from 160 to 110 °C and shortening the reaction time from 16 to 3 h, the morphology of the fabricated oleate-coated Sm:MgF2 NCs was transitioned from rod-shaped to spherical-shaped nanofluorides, both with a characteristic high-resolution liquid-state 19F-NMR resonance at −198 ppm. Further coating the surface of the spheric Sm:MgF2 NCs with a phospholipid layer resulted in a water-soluble formulation that was used to show its detectability with 19F-MRI. [ABSTRACT FROM AUTHOR]

"Hot spot" 19F magnetic resonance imaging (MRI) has garnered significant attention recently for its ability to image various disease markers quantitatively. Unlike conventional gadolinium-based MRI contrast agents, which rely on proton signal modulation, 19F-MRI's direct detection has a unique advantage in vivo, as the human body exhibits a negligible background 19F-signal. However, existing perfluorocarbon (PFC) or PFC-based contrast materials suffer from several limitations, including low longitudinal relaxation rates and relatively low imaging efficiency. Hence, we designed a macromolecular contrast agent featuring a high number of magnetically equivalent 19F-nuclei in a single macromolecule, adequate fluorine nucleus mobility, and excellent water solubility. This design utilizes superfluorinated polyphosphazene (PPz) polymers as the 19F-source; these are modified with sodium mercaptoethanesulfonate (MESNa) to achieve water solubility exceeding 360 mg/mL, which is a similar solubility to that of sodium chloride. We observed substantial signal enhancement in MRI with these novel macromolecular carriers compared to non-enhanced surroundings and aqueous trifluoroacetic acid (TFA) used as a positive control. In conclusion, these novel water-soluble macromolecular carriers represent a promising platform for future MRI contrast agents. [ABSTRACT FROM AUTHOR]

Abstract Background Non-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC. Methods We developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens. Results INC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens. Conclusions These results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose.

“Hot spot” 19F magnetic resonance imaging (MRI) has garnered significant attention recently for its ability to image various disease markers quantitatively. Unlike conventional gadolinium-based MRI contrast agents, which rely on proton signal modulation, 19F-MRI’s direct detection has a unique advantage in vivo, as the human body exhibits a negligible background 19F-signal. However, existing perfluorocarbon (PFC) or PFC-based contrast materials suffer from several limitations, including low longitudinal relaxation rates and relatively low imaging efficiency. Hence, we designed a macromolecular contrast agent featuring a high number of magnetically equivalent 19F-nuclei in a single macromolecule, adequate fluorine nucleus mobility, and excellent water solubility. This design utilizes superfluorinated polyphosphazene (PPz) polymers as the 19F-source; these are modified with sodium mercaptoethanesulfonate (MESNa) to achieve water solubility exceeding 360 mg/mL, which is a similar solubility to that of sodium chloride. We observed substantial signal enhancement in MRI with these novel macromolecular carriers compared to non-enhanced surroundings and aqueous trifluoroacetic acid (TFA) used as a positive control. In conclusion, these novel water-soluble macromolecular carriers represent a promising platform for future MRI contrast agents.

Background: Non-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC. Methods: We developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens. Results: INC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens. Conclusions: These results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Low SNR in fluorine‐19 (19F) MRI benefits from cryogenically‐cooled transceive surface RF probes (CRPs), but strong B1 inhomogeneities hinder quantification. Rapid acquisition with refocused echoes (RARE) is an SNR‐efficient method for MRI of neuroinflammation with perfluorinated compounds but lacks an analytical signal intensity equation to retrospectively correct B1 inhomogeneity. Here, a workflow was proposed and validated to correct and quantify 19F‐MR signals from the inflamed mouse brain using a 19F‐CRP. Methods: In vivo 19F‐MR images were acquired in a neuroinflammation mouse model with a quadrature 19F‐CRP using an imaging setup including 3D‐printed components to acquire co‐localized anatomical and 19F images. Model‐based corrections were validated on a uniform 19F phantom and in the neuroinflammatory model. Corrected 19F‐MR images were benchmarked against reference images and overlaid on in vivo 1H‐MR images. Computed concentration uncertainty maps using Monte Carlo simulations served as a measure of performance of the B1 corrections. Results: Our study reports on the first quantitative in vivo 19F‐MR images of an inflamed mouse brain using a 19F‐CRP, including in vivo T1 calculations for 19F‐nanoparticles during pathology and B1 corrections for 19F‐signal quantification. Model‐based corrections markedly improved 19F‐signal quantification from errors > 50% to < 10% in a uniform phantom (p < 0.001). Concentration uncertainty maps ex vivo and in vivo yielded uncertainties that were generally < 25%. Monte Carlo simulations prescribed SNR ≥ 10.1 to reduce uncertainties < 10%, and SNR ≥ 4.25 to achieve uncertainties < 25%. Conclusion: Our model‐based correction method facilitated 19F signal quantification in the inflamed mouse brain when using the SNR‐boosting 19F‐CRP technology, paving the way for future low‐SNR 19F‐MRI applications in vivo. [ABSTRACT FROM AUTHOR]

The rapid fluctuations of metal ion levels in biological systems are faster than the time needed to map fluorinated sensors designed for the 19 F-MRI of cations. An attractive modular solution might come from the activity-based sensing approach. Here, we propose a highly reactive but still ultimately specific synthetic fluorinated sensor for 19 F-MRI mapping of labile Zn 2+ . The sensor comprises a dipicolylamine scaffold for Zn 2+ recognition conjugated to a fluorophenyl acetate entity. Upon binding to Zn 2+ , the synthetic sensor is readily hydrolyzed, and the frequency of its 19 F-functional group in 19 F-NMR is shifted by 12 ppm, allowing the display of the Zn 2+ distribution as an artificial MRI-colored map highlighting its specificity compared to other metal ions. The irreversible Zn 2+ -induced hydrolysis results in a "turn-on" 19 F-MRI, potentially detecting the cation even upon a transient elevation of its levels. We envision that additional metal-ion sensors can be developed based on the principles demonstrated in this work, expanding the molecular toolbox currently used for 19 F-MRI.

Acute lung injury (ALI) is a severe complication in clinical settings. Alert diagnosis and severity assessment of ALI is pivotal to ensure curative treatment and increase survival rates. However, the development of a precise ALI diagnostic strategy remains a pending task. Here, leveraging neutrophil's inflammation-homing and physiological barrier-navigating capability, a facile strategy is proposed for achieving targeted 19 F-MRI detection of ALI based on the nanoengineered neutrophil internalized with perfluorocarbon nanoemulsion (Neu@PFC). The remodeling process poses a negligible impact on the neutrophil's inherent activation and transmigration functions. The migratory behavior of Neu@PFC toward pneumonia is confirmed in vivo using an LPS-induced ALI murine model. Direct intratracheal (i.t.) administration contributes to a vast deposition of Neu@PFC within the lung, allowing for real-time 19 F-MRI visualization and the potential to predict progressive pneumonia. Furthermore, intravenous (i.v.) administration of Neu@PFC enables quantitative assessment of the extent of ALI due to the chemokine-guided neutrophil migration. This study not only provides a pathway to diagnose ALI, but also sheds light on the neutrophil recruitment and activation cues in different tissues and inflammatory conditions, which is a prerequisite for developing potential therapeutic approaches., (© 2024 Wiley‐VCH GmbH.)

The weak thermal polarization of nuclear spins limits the sensitivity of MRI, even for MR‐sensitive nuclei as fluorine‐19. Therefore, despite being the source of inspiration for the development of background‐free MRI for various applications, including for multiplexed imaging, the inability to map very low concentrations of targets using 19F‐MRI raises the need to further enhance this platform's capabilities. Here, we employ the principles of CEST‐MRI in 19F‐MRI to obtain a 900‐fold signal amplification of a biocompatible fluorinated agent, which can be presented in a "multicolor" fashion. Capitalizing on the dynamic interactions in host–guest supramolecular assemblies in an approach termed GEST, we demonstrate that an inhalable fluorinated anesthetic can be used as a single 19F‐probe for the concurrent detection of micromolar levels of two targets, with potential in vivo translatability. Further extending GEST with new designs could expand the applicability of 19F‐MRI to the mapping of targets that have so‐far remained non‐detectable. [ABSTRACT FROM AUTHOR]

Purpose: To assess the reproducibility of percentage ventilated lung volume (%VV) measurements in healthy volunteers acquired by fluorine (19F)‐MRI of inhaled perfluoropropane, implemented at two research sites. Methods: In this prospective, ethically approved study, 40 healthy participants were recruited (May 2018‐June 2019) to one of two research sites. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% perfluoropropane/21% oxygen gas mixture. Each gas inhalation session lasted about 30 seconds, consisting of three deep breaths of gas followed by a breath‐hold. Four 19F‐MR ventilation images were acquired per participant, each separated by approximately 6 minutes. The value of %VV was determined by registering separately acquired 1H images to ventilation images before semi‐automated image segmentation, performed independently by two observers. Reproducibility of %VV measurements was assessed by components of variance, intraclass correlation coefficients, coefficients of variation (CoV), and the Dice similarity coefficient. Results: The MRI scans were well tolerated throughout, with no adverse events. There was a high degree of consistency in %VV measurements for each participant (CoVobserver1 = 0.43%; CoVobserver2 = 0.63%), with overall precision of %VV measurements determined to be within ± 1.7% (95% confidence interval). Interobserver agreement in %VV measurements revealed a high mean Dice similarity coefficient (SD) of 0.97 (0.02), with only minor discrepancies between observers. Conclusion: We demonstrate good reproducibility of %VV measurements in a group of healthy participants using 19F‐MRI of inhaled perfluoropropane. Our methods have been successfully implemented across two different study sites, supporting the feasibility of performing larger multicenter clinical studies. [ABSTRACT FROM AUTHOR]

Purpose: Inflammation is involved in many disease processes. However, accurate imaging tools permitting diagnosis and characterization of inflammation are still missing. As inflamed tissues exhibit a high rate of glycolysis, pyruvate metabolism may offer a unique approach to follow the inflammatory response and disease progression. Therefore, the aim of the study was to follow metabolic changes and recruitment of inflammatory cells after onset of inflammation in arthritic ankles using hyperpolarized 1-13C-pyruvate magnetic resonance spectroscopy (MRS) and 19F magnetic resonance imaging (MRI), respectively.Procedure: Experimental rheumatoid arthritis (RA) was induced by intraperitoneal injection of glucose-6-phosphate-isomerase-specific antibodies (GPI) containing serum. To monitor pyruvate metabolism, the transformation of hyperpolarized 1-13C-pyruvate into hyperpolarized 1-13C-lactate was followed using MRS. To track phagocytic immune cell homing, we intravenously injected a perfluorocarbon emulsion 48 h before imaging. The animals were scanned at days 1, 3, or 6 after GPI-serum injection to examine the different stages of arthritic inflammation. Finally, to confirm the pyruvate metabolic activity and the link to inflammatory cell recruitment, we conducted hematoxylin-eosin histopathology and monocarboxylase transporter (MCT-1) immune histochemistry (IHC) of inflamed ankles.Results: Hyperpolarized 1-13C-pyruvate MRS revealed a high rate of lactate production immediately at day 1 after GPI-serum transfer, which remained elevated during the progression of the disease, while 19F-MRI exhibited a gradual recruitment of phagocytic immune cells in arthritic ankles, which correlated well with the course of ankle swelling. Histopathology and IHC revealed that MCT-1 was expressed in regions with inflammatory cell recruitment, confirming the metabolic shift identified in arthritic ankles.Conclusions: Our study demonstrated the presence of a very early metabolic shift in arthritic joints independent of phagocytic immune cell recruitment. Thus, hyperpolarized 1-13C-pyruvate represents a promising tracer to monitor acute arthritic joint inflammation, even with minor ankle swelling. Furthermore, translated to the clinics, these methods add a detailed characterization of disease status and could substantially support patient stratification and therapy monitoring. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is a routine diagnostic modality in oncology that produces excellent imaging resolution and tumor contrast without the use of ionizing radiation. However, improved contrast agents are still needed to further increase detection sensitivity and avoid toxicity/allergic reactions associated with paramagnetic metal contrast agents, which may be seen in a small percentage of the human population. Fluorine-19 ( 19 F)-MRI is at the forefront of the developing MRI methodologies due to near-zero background signal, high natural abundance of 100%, and unambiguous signal specificity. In this study, we have developed a colloidal nanoemulsion (NE) formulation that can encapsulate high volumes of the fluorous MRI tracer, perfluoro-[15-crown-5]-ether (PFCE) (35% v/v). These nanoparticles exhibit long-term (at least 100 days) stability and high PFCE loading capacity in formulation with our semifluorinated triblock copolymer, M2F8H18. With sizes of approximately 200 nm, these NEs enable in vivo delivery and passive targeting to tumors. Our diagnostic formulation, M2F8H18/PFCE NE, yielded in vivo 19 F-MR images with a high signal-to-noise ratio up to 100 in a tumor-bearing mouse model at clinically relevant scan times. M2F8H18/PFCE NE circulated stably in the vasculature, accumulated in high concentration of an estimated 4-9 × 10 17 19 F spins/voxel at the tumor site, and cleared from most organs over the span of 2 weeks. Uptake by the mononuclear phagocyte system to the liver and spleen was also observed, most likely due to particle size. These promising results suggest that M2F8H18/PFCE NE is a favorable 19 F-MR diagnostic tracer for further development in oncological studies and potential clinical translation., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: To assess alveolar perfusion by applying dynamic susceptibility contrast MRI to 19F‐MRI of inhaled perfluoropropane (PFP). We hypothesized that passage of gadolinium‐based contrast agent (GBCA) through the pulmonary microvasculature would reduce magnetic susceptibility differences between water and gas components of the lung, elevating the T2∗ of PFP. Methods: Lung‐representative phantoms were constructed of aqueous PFP‐filled foams to characterize the impact of aqueous/gas phase magnetic susceptibility differences on PFP T2∗. Aqueous phase magnetic susceptibility was modulated by addition of different concentrations of GBCA. In vivo studies were performed to measure the impact of intravenously administered GBCA on the T2∗ of inhaled PFP in mice (7.0 Tesla) and in healthy volunteers (3.0 Tesla). Results: Perfluoropropane T2∗ was sensitive to modulation of magnetic susceptibility difference between gas and water components of the lung, both in phantom models and in vivo. Negation of aqueous/gas phase magnetic susceptibility difference was achieved in lung‐representative phantoms and in mice, resulting in a ~2 to 3× elevation in PFP T2∗ (3.7 to 8.5 ms and 0.7 to 2.6 ms, respectively). Human studies demonstrated a transient elevation of inhaled PFP T2∗ (1.50 to 1.64 ms) during passage of GBCA bolus through the lung circulation, demonstrating sensitivity to lung perfusion. Conclusion: We demonstrate indirect detection of a GBCA in the pulmonary microvasculature via changes to the T2∗ of gas phase PFP within directly adjacent alveoli. This approach holds potential for assessing alveolar perfusion by dynamic susceptibility contrast 19F‐MRI of inhaled PFP, with concurrent assessment of lung ventilation properties, relevant to lung physiology and disease. [ABSTRACT FROM AUTHOR]

Objectives: Peripheral artery disease (PAD) affects 12-14% of the world population, and many are not eligible for conventional treatment. For these patients, microencapsulated stem cells (SCs) offer a novel means to transplant mismatched therapeutic SCs to prevent graft immunorejection. Using c-arm CT and 19F-MRI for serial evaluation of dual X-ray/MR-visible SC microcapsules (XMRCaps) in a non-immunosuppressed rabbit PAD model, we explore quantitative evaluation of capsule integrity as a surrogate of transplanted cell fate.Materials and methods: XMRCaps were produced by impregnating 12% perfluorooctylbromine (PFOB) with rabbit or human SCs (AlloSC and XenoSC, respectively). Volume and 19F concentration measurements of XMRCaps were assessed both in phantoms and in vivo, at days 1, 8 and 15 after intramuscular administration in rabbits (n = 10), by 3D segmenting the injection sites and referencing to standards with known concentrations.Results: XMRCap volumes and concentrations showed good agreement between CT and MRI both in vitro and in vivo in XenoSC rabbits. Injected capsules showed small variations over time and were similar between AlloSC and XenoSC rabbits. Histological staining revealed high cell viability and intact capsules 2 weeks after administration.Conclusions: Quantitative and non-invasive tracking XMRCaps using CT and 19F-MRI may be useful to assess graft immunorejection after SC transplantation. [ABSTRACT FROM AUTHOR]

Introduction: We explored the use of a perfluoro-15-crown-5 ether nanoemulsion (PFC) for measuring tissue oxygenation using a mouse model of vascular cognitive impairment.Methods: Seventeen C57BL/6 mice underwent stereotactic injection of PFC coupled to a fluorophore into the striatum and corpus callosum. Combined 1H/19F magnetic resonance imaging (MRI) to localize the PFC and R1 mapping to assess pO2 were performed. The effect of gas challenges on measured R1 was investigated. All mice then underwent bilateral implantation of microcoils around the common carotid arteries to induce global cerebral hypoperfusion. 19F-MRI and R1 mapping were performed 1 day, 1 week, and 4 weeks after microcoil implantation. In vivo R1 values were converted to pO2 through in vitro calibration. Tissue reaction to the PFC was assessed through ex vivo immunohistochemistry of microglial infiltration.Results: R1 increased with increasing oxygen concentrations both in vitro and in vivo and the strength of the 19F signal remained largely stable over 4 weeks. In the two mice that received all four scans, tissue pO2 decreased after microcoil implantation and recovered 4 weeks later. We observed infiltration of the PFC deposits by microglia.Discussion: Despite remaining technical challenges, intracerebrally injected PFC is suitable for monitoring brain oxygenation in vivo. [ABSTRACT FROM AUTHOR]

Purpose Cellular MRI) was used to detect implanted human mesenchymal stem cells (hMSCs) and the resulting macrophage infiltration that occurs in response to xenotransplantation. Methods Human mesenchymal stem cells were prelabeled with a fluorine-19 (19F) agent prior to implantation, allowing for their visualization and quantification over time. Following implantation of 1 × 106 19F-labeled hMSCs into the mouse hind limb, longitudinal imaging was performed to monitor the stem cell graft. Macrophages were labeled in situ by the intravenous administration of an ultrasmall superparamagentic iron oxide (USPIO), allowing for tracking of the inflammatory response. Results Quantification of 19F MRI on day 0 agreed with the implanted number of cells, and 19F signal decreased over time. By day 14, only 22% ± 11% of the original 19F signal remained. In a second group, USPIO were administered intravenously after implantation of 19F-labeled hMSCs. When imaged on day 2, a significant decrease in 19F signal was observed compared to the first group alongside a large signal void region in the corresponding proton images. Immunohistochemistry confirmed the presence of iron-labeled macrophages in the stem cell tract. Conclusion A dual-labeling technique was used to noninvasively track two distinct cell populations simultaneously. This information could be used to provide additional insight into the cause of graft failure. Magn Reson Med 78:713-720, 2017. © 2016 International Society for Magnetic Resonance in Medicine [ABSTRACT FROM AUTHOR]

Recent advances in intratracheal delivery strategies have sparked considerable biomedical interest in developing this promising approach for lung cancer diagnosis and treatment. However, there are very few relevant studies on the behavior and mechanism of imaging nanoparticles (NPs) after intratracheal delivery. Here, we found that nanosized perfluoro-15-crown-5-ether (PFCE NPs, ∼200 nm) exhibite significant 19 F-MRI signal-to-noise ratio (SNR) enhancement than perfluorooctyl bromide (PFOB NPs) up to day 7 after intratracheal delivery. Alveolar macrophages (AMs) engulf PFCE NPs, become PFCE NPs-laden AMs, and then migrate into the tumor margin, resulting in increased tumor PFCE concentration and 19 F-MRI signals. AMs-mediated translocation of PFCE NPs to lung draning lymph nodes (dLNs) decreases the background PFCE concentration. Our results shed light on the dynamic AMs-mediated translocation of intratracheally delivered PFC NPs for effective lung tumor visualization and reveal a pathway to develop and promote the clinical translation of an intratracheal delivery-based imaging strategy.

Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is an emergent imaging technique for molecular imaging and cell tracking. Lack of intrinsic 19F signals in tissues allows unambiguous in vivo detection of exogenous fluorinated probes, complementary to the anatomical and multiparametric information obtained by standard 1H-MRI. However, the intrinsic low sensitivity of MRI technique requires the need of designing increasingly effective fluorinated tracers. PERFECTA, with its 36 magnetically equivalent 19F atoms and a designed branched molecular structure, represents an excellent superfluorinated tracer. In this paper, we report the development of PERFECTA loaded PLGA NPs stabilized by different coatings as promising 19F-MRI probes. The results clearly show the optimal cellular uptake of the produced colloidally stable PERFECTA loaded PLGA NPs without impact on cells viability. Importantly, NPs stabilization with the anionic surfactant sodium cholate (NaC) clearly enhances NPs internalization within cells with respect to PVA-coated NPs. Moreover, the optimized NPs are characterized by shorter T 1 relaxation times with respect to other PERFECTA formulations that would allow the increase of 19F-MRI sensitivity with fast imaging acquisitions. [Display omitted] • High encapsulation yield of PERFECTA in PLGA NPs guarantees improved 19F-MRI sensitivity. • PERFECTA loaded PLGA NPs shows reduced T 1 relaxation times enabling fast-imaging methods. • Using sodium cholate (NaC) as stabilizer on superfluorinated PLGA NPs facilitates NP cellular uptake. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) play a crucial role in cell-to-cell communication and have great potential as efficient delivery vectors. However, a better understanding of EV in vivo behavior is hampered by the limitations of current imaging tools. In addition, chemical labels present the risk of altering the EV membrane features and, thus, in vivo behavior. 19 F-MRI is a safe bioimaging technique providing selective images of exogenous probes. Here, we present the first example of fluorinated EVs containing PERFECTA, a branched molecule with 36 magnetically equivalent 19 F atoms. A PERFECTA emulsion is given to the cells, and PERFECTA-containing EVs are naturally produced. PERFECTA-EVs maintain the physicochemical features, morphology, and biological fingerprint as native EVs but exhibit an intense 19 F-NMR signal and excellent 19 F relaxation times. In vivo 19 F-MRI and tumor-targeting capabilities of stem cell-derived PERFECTA-EVs are also proved. We propose PERFECTA-EVs as promising biohybrids for imaging biodistribution and delivery of EVs throughout the body.

Abstract: Neural stem cell implantations have been extensively investigated for treatment of brain diseases such as stroke. In order to follow the localization and functional status of cells after implantation noninvasive imaging is essential. Therefore, we developed a comprehensive multi-modality platform for in vivo imaging of graft localization, density, and survival using 19F magnetic resonance imaging in combination with bioluminescence imaging. We quantitatively analyzed cell graft survival over the first 4 weeks after transplantation in both healthy and stroke-damaged mouse brain and correlated our findings of graft vitality with the host innate immune response. The multi-modality imaging platform will help to improve cell therapy also in context other than stroke and to gain indispensable information for clinical translation. [Copyright &y& Elsevier]

Abstract: The assessment of tumor oxygenation is a crucial factor in cancer therapy and may be carried out using fluorine MRI once fluorine probes have been distributed within the tumor. However, the deposit of those highly fluorinated compounds often jeopardizes anatomical image quality and requires emulsification of the probes. Due to the high density and the high lipophilicity of perfluorocarbons, nanoemulsion of these molecules usually requires high-energy processes. In the present work, we discuss the synthesis and the physico-chemical characterization of perfluorocarbon nanocapsules using a low-energy phase-inversion process. The nanocapsules were tested on a mouse tumor brain model to assess oxygenation. [Copyright &y& Elsevier]

Abstract: Perfluorocarbon (PFC) particles are currently on the rise as cell labeling agents for 19F-MRI tracking of dendritic cell (DC)-based vaccines. In this work, we design theranostic PFC particles for single-step loading of DCs with both antigenic protein and with a liquid PFC for 19F-MRI detection of the antigen-loaded cells. Upon addition to DCs in vitro, the antigen-loaded PFC particles are efficiently internalized, resulting in intracellular presence of up to 40pmol 19F atoms per cell. At the same time, the DCs become loaded with antigenic proteins, that can be efficiently processed, without important effects on cell viability or altering the DC's phenotype and the cell's capacity to respond to danger signals. In addition, antigen-loaded PFC particle containing DCs are capable of inducing extensive proliferation of antigen-specific CD8+ T cells in vitro. Importantly, the antigen-coated PFC particles allow in vitro 19F-MRI-based detection of the antigen-containing DCs with detection limits as low as 103 cellsμl−1. The dual-modality characteristics of the designed particles could assure that only those DCs that have taken up the antigen, and hence are responsible for an immune response, are traceable via 19F-MRI. Taken together, these novel dual-modality particles represent an interesting strategy in the development of a traceable DC vaccine. [Copyright &y& Elsevier]

A labeling strategy for in vivo 19 F-MRI (magnetic resonance imaging) based on highly fluorinated, short hydrophilic peptide probes, is developed. As dual-purpose probes, they are functionalized further by a fluorophore and an alkyne moiety for bioconjugation. High fluorination is achieved by three perfluoro-tert-butyl groups, introduced into asparagine analogues by chemically stable amide bond linkages. d-amino acids and β-alanine in the sequences endow the peptide probes with low cytotoxicity and high serum stability. This design also yielded unstructured peptides, rendering all 27 19 F substitutions chemically equivalent, giving rise to a single 19 F-NMR resonance with <10 Hz linewidth. The resulting performance in 19 F-MRI is demonstrated for six different peptide probes. Using fluorescence microscopy, these probes are found to exhibit high stability and long circulation times in living zebrafish embryos. Furthermore, the probes can be conjugated to bovine serum albumin with only amoderate increase in 19 F-NMR linewidth to ≈30 Hz. Overall, these peptide probes are hence suitable for in vivo 19 F-MRI applications., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)

Hexafluorobenzene (HFB) and perfluoro-15-crown-5-ether (15C5) were compared as fluorine reporter probes of tissue oxygenation using 19F MRI for dynamic assessment of muscle oxygenation, with special focus on muscle tissue toxicity of the probes, and consecutive alteration of animal behavior. The latter were also compared in terms of sensitivity to changes in oxygenation as well as of signal-to-noise ratio for accurate pO2 measurements. For that purpose, mouse muscles were imaged at 11.7 T, at 2- and 36-h after intramuscular injection of HFB or 15C5. Histological analysis of the muscle tissue revealed a lack of toxicity for 15C5 from 2 up to 36-h postinjection, whereas HFB induced tissue necrosis, blood clots and thrombosis as soon as 24-h postinjection. This muscle toxicity led to a limitation in mice mobility 24-h after injection of HFB as evidenced by behavioral testing (open-field, grip strength, and catwalk tests), which was not the case after 15C5 intramuscular injection. Finally, pO2 measurements assessed 2-h postinjection showed consistent values with both probes, evidencing cross-validation of the 19F MRI oximetry technique for acute measurements. However, the measurement at 36-h was hampered for HFB, which showed significant lower values of muscle pO2, whereas 15C5 was able to reliably assess muscle pO2 at 36-h postinjection. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Boron neutron capture therapy (BNCT) is a binary radiation therapy used to treat malignant brain tumours. It is based on the nuclear reaction (10B + n th → [11B*] → α + 7Li + 2.79 MeV) that occurs when 10B captures a thermal neutron to yield α particles and recoiling 7Li nuclei, both responsible of tumour cells destruction by short range and high ionization energy release. The clinical success of the therapy depends on the selective accumulation of the 10B carriers in the tumour and on the high thermal neutron capture cross-section of 10B. Magnetic resonance imaging (MRI) methods provide the possibility of monitoring, through 10B nuclei, the metabolic and physiological processes suitable to optimize the BNCT procedure. In this study, spatial distribution mapping of borocaptate (BSH) and 4-borono-phenylalanine (BPA), the two boron carriers used in clinical trials, has been obtained. The BSH map in excised rat brain and the 19F-BPA image in vivo rat brain, representative of BPA spatial distribution, were reported. The BSH image was obtained by means of double-resonance 10B-editing 1H-detection sequence, named M-Bend, exploiting the J-coupling interaction between 10B and 1H nuclei. Conversely, the BPA map was obtained by 19F-BPA using 19F-MRI. Both images were obtained at 7 T, in C6 glioma-bearing rat brain. Our results demonstrate the powerful of non conventional MRI techniques to optimize the BNCT procedure. [Copyright &y& Elsevier]

The objective was to present a method for the repeated noninvasive measurement of tumor oxygenation (Po2) over the whole period of tumor growth.A mixture of tumor homogenate (GH3 prolactinoma) and alginate capsules loaded with perfluoro-15-crown-5-ether (15C5) was injected into the flanks of Wistar Furth rats. The temporal behavior of tumor Po2 was monitored between Day 1 and 26 after injection using fluorine-19 (19F) magnetic resonance imaging (MRI). In addition, the response of tumor Po2 to modifiers of the tumor microenvironment (carbogen [95% O2/5% CO2], nicotinamide, and hydralazine) was investigated.An initial increase of tumor Po2, probably reflecting neovascularization, followed by a decrease after Week 2, probably indicating tumor hypoxia or necrosis, were observed. The minimum and maximum average Po2 ± SEM observed were 3.3 ± 2.0 mm Hg on Day 2 and 25.7 ± 3.8 mm Hg on Day 13, respectively. Carbogen increased the tumor Po2, whereas nicotinamide caused no significant change and hydralazine induced a significant decrease in tumor oxygenation.A preclinical method for the repeated noninvasive determination of tumor Po2 was presented. It might help to investigate tumor physiology and the mechanisms of modifiers of the tumor microenvironment and their role in different therapeutic approaches. [Copyright &y& Elsevier]

Purpose: Low SNR in fluorine-19 ( 19 F) MRI benefits from cryogenically-cooled transceive surface RF probes (CRPs), but strong B 1 inhomogeneities hinder quantification. Rapid acquisition with refocused echoes (RARE) is an SNR-efficient method for MRI of neuroinflammation with perfluorinated compounds but lacks an analytical signal intensity equation to retrospectively correct B 1 inhomogeneity. Here, a workflow was proposed and validated to correct and quantify 19 F-MR signals from the inflamed mouse brain using a 19 F-CRP., Methods: In vivo 19 F-MR images were acquired in a neuroinflammation mouse model with a quadrature 19 F-CRP using an imaging setup including 3D-printed components to acquire co-localized anatomical and 19 F images. Model-based corrections were validated on a uniform 19 F phantom and in the neuroinflammatory model. Corrected 19 F-MR images were benchmarked against reference images and overlaid on in vivo 1 H-MR images. Computed concentration uncertainty maps using Monte Carlo simulations served as a measure of performance of the B 1 corrections., Results: Our study reports on the first quantitative in vivo 19 F-MR images of an inflamed mouse brain using a 19 F-CRP, including in vivo T 1 calculations for 19 F-nanoparticles during pathology and B 1 corrections for 19 F-signal quantification. Model-based corrections markedly improved 19 F-signal quantification from errors > 50% to < 10% in a uniform phantom (p < 0.001). Concentration uncertainty maps ex vivo and in vivo yielded uncertainties that were generally < 25%. Monte Carlo simulations prescribed SNR ≥ 10.1 to reduce uncertainties < 10%, and SNR ≥ 4.25 to achieve uncertainties < 25%., Conclusion: Our model-based correction method facilitated 19 F signal quantification in the inflamed mouse brain when using the SNR-boosting 19 F-CRP technology, paving the way for future low-SNR 19 F-MRI applications in vivo., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

UiO-66-F/PPEG NPs were synthesized to strengthen the 19F MRI ability under a weak acidic tumor micro-environment. • Zr-based MOF nanoparticles (NPs) with ~21% of 19F content from organic ligand of tetrafluoro-terephthalic acid (F 4 PTA) was proposed as a pH-sensitive 19F MRI contrast agent. The NPs could turn on the 19F MRI signal in tumour under the weak acidic micro-environment. 19F MRI has been paid great attention because of its higher signal-to-noise ratio and larger chemical shift than 1H MRI. However, the low 19F content and sensitivity of environment limit its development in clinic. Herein, considering the large surface area and abundant metal active sites of metal organic framework (MOF) nanoparticles, we fabricated Zr-based MOF nanoparticles (UiO-66-F NPs) with an organic ligand of tetrafluoro-terephthalic acid (F 4 PTA) as a pH-sensitive 19F MRI contrast agent, which remained stable in a neutral condition, but could release free F 4 PTA in an acidic condition to enhance 19F MRI signal. As a proof of concept, UiO-66-F NPs-based contrast agent could turn on the 19F MRI signal in an acidic tumor micro-environment. The results provide an alternative strategy for the design of tumor micro-environment responsive 19F MRI contrast agents. [ABSTRACT FROM AUTHOR]

Purpose: To assess the reproducibility of percentage ventilated lung volume (%VV) measurements in healthy volunteers acquired by fluorine ( 19 F)-MRI of inhaled perfluoropropane, implemented at two research sites., Methods: In this prospective, ethically approved study, 40 healthy participants were recruited (May 2018-June 2019) to one of two research sites. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% perfluoropropane/21% oxygen gas mixture. Each gas inhalation session lasted about 30 seconds, consisting of three deep breaths of gas followed by a breath-hold. Four 19 F-MR ventilation images were acquired per participant, each separated by approximately 6 minutes. The value of %VV was determined by registering separately acquired 1 H images to ventilation images before semi-automated image segmentation, performed independently by two observers. Reproducibility of %VV measurements was assessed by components of variance, intraclass correlation coefficients, coefficients of variation (CoV), and the Dice similarity coefficient., Results: The MRI scans were well tolerated throughout, with no adverse events. There was a high degree of consistency in %VV measurements for each participant (CoV observer1 = 0.43%; CoV observer2 = 0.63%), with overall precision of %VV measurements determined to be within ± 1.7% (95% confidence interval). Interobserver agreement in %VV measurements revealed a high mean Dice similarity coefficient (SD) of 0.97 (0.02), with only minor discrepancies between observers., Conclusion: We demonstrate good reproducibility of %VV measurements in a group of healthy participants using 19 F-MRI of inhaled perfluoropropane. Our methods have been successfully implemented across two different study sites, supporting the feasibility of performing larger multicenter clinical studies., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Paramagnetic relaxation enhancement (PRE) is the current strategy of choice for enhancing magnetic resonance imaging (MRI) contrast and for accelerating MRI acquisition schemes. Yet, debates regarding lanthanides' biocompatibility and PRE-effect on MRI signal quantification have raised the need for alternative strategies for relaxation enhancement. Herein, we show an approach for shortening the spin-lattice relaxation time (T 1 ) of fluoride-based nanocrystals (NCs) that are used for in vivo 19 F-MRI, by inducing crystal defects in their solid-crystal core. By utilizing a phosphate-based rather than a carboxylate-based capping ligand for the synthesis of CaF 2 NCs, we were able to induce grain boundary defects in the NC lattice. The obtained defects led to a 10-fold shorter T 1 of the NCs' fluorides. Such paramagnetic-free relaxation enhancement of CaF 2 NCs, gained without affecting either their size or their colloidal characteristics, improved 4-fold the obtained 19 F-MRI signal-to-noise ratio, allowing their use, in vivo, with enhanced hotspot MRI sensitivity.

Purpose: To assess alveolar perfusion by applying dynamic susceptibility contrast MRI to 19 F-MRI of inhaled perfluoropropane (PFP). We hypothesized that passage of gadolinium-based contrast agent (GBCA) through the pulmonary microvasculature would reduce magnetic susceptibility differences between water and gas components of the lung, elevating the T 2 ∗ of PFP., Methods: Lung-representative phantoms were constructed of aqueous PFP-filled foams to characterize the impact of aqueous/gas phase magnetic susceptibility differences on PFP T 2 ∗ . Aqueous phase magnetic susceptibility was modulated by addition of different concentrations of GBCA. In vivo studies were performed to measure the impact of intravenously administered GBCA on the T 2 ∗ of inhaled PFP in mice (7.0 Tesla) and in healthy volunteers (3.0 Tesla)., Results: Perfluoropropane T 2 ∗ was sensitive to modulation of magnetic susceptibility difference between gas and water components of the lung, both in phantom models and in vivo. Negation of aqueous/gas phase magnetic susceptibility difference was achieved in lung-representative phantoms and in mice, resulting in a ~2 to 3× elevation in PFP T 2 ∗ (3.7 to 8.5 ms and 0.7 to 2.6 ms, respectively). Human studies demonstrated a transient elevation of inhaled PFP T 2 ∗ (1.50 to 1.64 ms) during passage of GBCA bolus through the lung circulation, demonstrating sensitivity to lung perfusion., Conclusion: We demonstrate indirect detection of a GBCA in the pulmonary microvasculature via changes to the T 2 ∗ of gas phase PFP within directly adjacent alveoli. This approach holds potential for assessing alveolar perfusion by dynamic susceptibility contrast 19 F-MRI of inhaled PFP, with concurrent assessment of lung ventilation properties, relevant to lung physiology and disease., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

19 F-magnetic resonance imaging (MRI) is of great significance for noninvasive imaging and detection of various diseases. However, the main obstacle in the application of 19 F-MRI agents stems from the unmet signal sensitivity due to the poor water solubility and restricted mobility of segments with high number of fluorine atoms. Herein, we report a kind of intracellular reducing microenvironment-induced amino-activatable 19 F-MRI nanoprobe, which can be used for specific imaging of biothiols. In principle, the nanoprobe has an initial architecture of hydrophobic core, where the trifluoromethyl-containing segments are compactly packed and 19 F NMR/MRI signals are quenched ("OFF" state). Upon encountering sulfydryl, the strong electron-withdrawing 2,4-dinitrobenzenesulfonyl groups are excised to recover secondary amino groups, whose p K a is proved to be 7.21. As a consequence, the molecular weight loss of the hydrophobic segment and the protonation of amino groups induce significant disturbance of hydrophilic/hydrophobic balance, leading to the disassembly of the nanoprobes and regain of spin-spin relaxation and 19 F NMR/MRI signals ("ON" state, T 2 up to 296 ± 5.3 ms). This nanoprobe shows high sensitivity and selectivity to biothiols, enabling intracellular and intratumoral imaging of glutathione. Our study not only provides a new nanoprobe candidate for biothiols imaging in vivo but also a promising strategy for the molecular design of real water-soluble and highly sensitive 19 F-MRI nanoprobes.