19F Magnetic Resonance Imaging Research Articles

Fluorinated POSS‐Star Polymers for 19F MRI

Star polymers with a polyhedral oligomeric silsesquioxanes (POSS) core and eight partly fluorinated arms have been synthesized by reversible addition–fragmentation chain transfer polymerization. A macroCTA having eight chain transfer agent (CTA) molecules attached to a POSS core is prepared and used for the synthesis of star polymers by the R‐group approach. The arms are composed of statistical copolymers of 2,2,2‐trifluoroethyl acrylate and poly(ethylene glycol) methyl ether acrylate. The polymerization kinetics are studied, and yield of star polymer is optimized. Star polymers having different arm lengths are prepared and characterized. The star polymers exhibit a single 19F resonance in 19F nuclear magnetic resonance spectra in aqueous solution, and the T2 relaxation time increases with arm length. The relaxation properties and the fluorine content are consistent with these polymers being effective 19F magnetic resonance imaging (MRI) agents. This work indicates that these POSS‐star polymers have potential as theranostic agents for 19F MRI and drug delivery. image

Theranostic tumor targeted nanoparticles combining drug delivery with dual near infrared and 19F magnetic resonance imaging modalities

Combining imaging and drug delivery of “theranostic” nanoparticles has enabled concurrent diagnosis and therapy of diseases. Here, we describe a novel theranostic system that combines two imaging tracers, perfluorooctyl bromide (PFOB) for 19F magnetic resonance imaging (MRI) and indocyanine green (ICG) for near infrared (NIR) imaging, with the chemotherapeutic agent doxorubicin (Dox) into poly (lactic-co-glycolic acid)- poly (ethylene-glycol)-folate (PLGA-PEG-folate) nanoparticles. Cell culture studies using flow cytometry, confocal laser scanning microscope imaging, and 19F MRI showed enhanced uptake of nanoparticles via folate receptors expressed on human nasopharyngeal epidermal carcinoma (KB) cells. In vivo, higher MRI and fluorescence signals were obtained from tumors with 19F MRI and NIR, respectively, using folate-receptor-targeted nanoparticles compared with non-targeted equivalents. An in vitro cytotoxicity assay showed that folate-targeted nanoparticles were able to kill cancer cells more efficiently than non-folate conjugated particles. Our results suggest a potential use of PLGA-PEG-folate PFOB/ICG/Dox nanoparticles as a targeted chemotherapy agent traceable by either 19F MRI or NIR imaging.

Superfluorinated copper sulfide nanoprobes for simultaneous 19F magnetic resonance imaging and photothermal ablation

Copper sulfide (Cu7S4) nanoparticles coated with an ultra-high payload (~5.0 × 107 fluorine atoms per particle) of fluorinated ligands (oleylamine functionalized 3,5-bis(trifluoromethyl)benzaldehyde, 19FOAm) exhibited a single intense 19F magnetic resonance (MR) signal and efficient near infrared photothermal performance in water medium. In vivo assessment revealed strong 19F MR signals at cancerous lesions and effective inhibition of tumor growth after photothermal treatment, indicating the great potential of these fabricated nanoprobes for simultaneous 19F MR imaging and photothermal therapy.

Epicardium-Derived Cells Formed After Myocardial Injury Display Phagocytic Activity Permitting In Vivo Labeling and Tracking.

Epicardium-derived cells (EPDCs) cover the heart surface and can function as a source of both progenitor cells and trophic factors for cardiac repair. Currently, EPDCs cannot be conveniently labeled in vivo to permit imaging and cell tracking. EPDCs formed after myocardial infarction (MI) preferentially take up a perfluorocarbon-containing nanoemulsion (PFC-NE; 130 ± 32 nm) injected 3 days after injury, as measured by (19)F-magnetic resonance imaging ((19)F-MRI). Flow cytometry, immune electron microscopy, and green fluorescent protein (GFP)-transgenic rats (only immune cells, but not epicardial cells, are GFP(+)) demonstrated that PFC-containing EPDCs are nonhematopoietic (CD45(-)/CD11b(-)) but stain positive for markers of mesenchymal stem cells such as platelet-derived growth factor receptor α (PDGFR-α) CD73, CD105, and CD90. When rhodamine-coupled PFC-NE was used, we found that ρ(+) vessel-like structures formed within the infarcted myocardium, comprising approximately 10% of all large vessels positive for smooth muscle actin (SM-actin). The epicardial cell layer, positive for Wilms' tumor 1 (WT-1), PDGFR-α, or KI-67, was shown to be well capillarized (293 ± 78 capillaries per mm(2)), including fenestrated endothelium. Freshly isolated EPDCs were positive for WT-1, GATA-4, KI-67, and FLK-1 (75%), PDGFR-α (50%), and SM-actin (28%) and also exhibited a high capacity for nanoparticle and cell debris uptake. This study demonstrates that EPDCs formed after MI display strong endocytic activity to take up i.v.-injected labeled nanoemulsions. This feature permitted in vivo labeling and tracking of EPDCs, demonstrating their role in myo- and vasculogenesis. The newly discovered endocytic activity permits in vivo imaging of EPDCs with (19)F-MRI and may be used for the liposomal delivery of substances to further study their reparative potential. The present study reports that epicardium-derived cells (EPDCs) formed after myocardial infarction can specifically endocytose nanoparticles in vivo and in vitro. This novel feature permitted in vivo targeting of EPDCs with either a perfluorocarbon-containing or rhodamine-conjugated nanoemulsion to track migration and fate decision of EPDC with (19)F-magnetic resonance imaging and fluorescence microscopy. The liposomal nanoemulsions used in the present study may be useful in the future as a nanomedical device for the delivery of substances to direct cell fate of EPDCs.

A bisphosphonate for 19F-magnetic resonance imaging.

19F-magnetic resonance imaging (MRI) is a promising technique that may allow us to measure the concentration of exogenous fluorinated imaging probes quantitatively in vivo. Here, we describe the synthesis and characterisation of a novel geminal bisphosphonate (19F-BP) that contains chemically-equivalent fluorine atoms that show a single and narrow 19F resonance and a bisphosphonate group that may be used for labelling inorganic materials based in calcium phosphates and metal oxides. The potential of 19F-BP to provide contrast was analysed in vitro and in vivo using 19F-MRI. In vitro studies demonstrated the potential of 19F-BP as an MRI contrast agent in the millimolar concentration range with signal-to-noise ratios (SNR) comparable to previously reported fluorinated probes. The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of 19F-BP, showing uptake in the liver and in the bladder/urinary system areas. However, bone uptake was not observed. In addition, 19F-BP showed undesirable toxicity effects in mice that prevent further studies with this compound at the required concentrations for MRI contrast. This study highlights the importance of developing 19F MRI probes with the highest signal intensity achievable.

A CoII complex for 19F MRI-based detection of reactive oxygen species.

A fluorinated, air-stable cobalt(ii) complex serves as a turn-on 19F magnetic resonance imaging (MRI) tracer for reactive oxygen species including H2O2. Upon oxidation with H2O2, the complex converts from paramagnetic high spin CoII to diamagnetic low spin CoIII resulting in a chemical shift change and enhancement in 19F NMR signal. Further, the oxidation can be reversed in the presence of reductant Na2S2O4. The turn-on response is demonstrated by 19F MRI, characterized by a ∼2-3 fold enhancement in signal.

In Vivo (19)F-Magnetic Resonance Imaging of Adoptively Transferred NK Cells.

In order to assess the biodistribution, homing, and persistence of adoptively transferred natural killer (NK) cell immunotherapies, there is a need for imaging methodology suitable for use in preclinical studies with relevance to clinical translation. Amongst the available approaches, (19)F-MRI is very appealing for in vivo imaging due to the absence of background signal, enabling clear detection of (19)F labeled cells in vivo. Here we describe a methodology for in vivo imaging of adoptively transferred NK cells labeled with (19)F nano-emulsion, using clinically translatable technology of (19)F/(1)H magnetic resonance imaging.

Quantitative "Hot Spot" Imaging of Transplanted Stem Cells using Superparamagnetic Tracers and Magnetic Particle Imaging (MPI).

Magnetic labeling of stem cells enables their noninvasive detection by magnetic resonance imaging (MRI). In practical terms, most MRI studies have been limited to the visualization of local engraftment because other sources of endogenous hypointense contrast complicate the interpretation of systemic (whole-body) cell distribution. In addition, MRI cell tracking is inherently nonquantitative in nature. We report herein on the potential of magnetic particle imaging (MPI) as a novel tomographic technique for noninvasive “hot-spot” imaging and quantification of stem cells using superparamagnetic iron oxide (SPIO) tracers. Neural and mesenchymal stem cells, representing small and larger cell bodies, were labeled with 3 different SPIO tracer formulations, including 2 preparations (Feridex and Resovist) that have previously been used in clinical MRI cell-tracking studies. Magnetic particle spectroscopy measurements demonstrated a linear correlation between MPI signal and iron content for both free particles in homogeneous solution and for internalized and aggregated particles in labeled cells over a wide range of concentrations. The overall MPI signal ranged from 1 × 10−3 to 3 × 10−4 Am2/g Fe, which was equivalent to 2 × 10−14 to 1 × 10−15 Am2 per cell, indicating that cell numbers can be quantified with MPI analogous to the use of radiotracers in nuclear medicine or fluorine tracers in 19F MRI. When SPIO-labeled cells were transplanted in the mouse brain, they could be readily detected by MPI at a detection threshold of about 5 × 104 cells, with MPI/MRI overlays showing an excellent agreement between the hypointense MRI areas and MPI hot spots. The calculated tissue MPI signal ratio for 100 000 vs 50 000 implanted cells was 2.08. Hence, MPI can potentially be further developed for quantitative and easy-to-interpret, tracer-based noninvasive cell imaging, preferably with MRI as an adjunct anatomical imaging modality.

Recent Advances in 19Fluorine Magnetic Resonance Imaging with Perfluorocarbon Emulsions.

The research roots of 19fluorine (19F) magnetic resonance imaging (MRI) date back over 35 years. Over that time span, 1H imaging flourished and was adopted worldwide with an endless array of applications and imaging approaches, making magnetic resonance an indispensable pillar of biomedical diagnostic imaging. For many years during this timeframe, 19F imaging research continued at a slow pace as the various attributes of the technique were explored. However, over the last decade and particularly the last several years, the pace and clinical relevance of 19F imaging has exploded. In part, this is due to advances in MRI instrumentation, 19F/1H coil designs, and ultrafast pulse sequence development for both preclinical and clinical scanners. These achievements, coupled with interest in the molecular imaging of anatomy and physiology, and combined with a cadre of innovative agents, have brought the concept of 19F into early clinical evaluation. In this review, we attempt to provide a slice of this rich history of research and development, with a particular focus on liquid perfluorocarbon compound-based agents.

Control of the radiofrequency field in fluorine (19F) magnetic resonance imaging

Ways of recording 19F NMR signals using different configurations of transmitting and receiving coils, including the version with a nonresonant transmitting coil and one of the receiving coils serving as an RF amplifier, are considered.

Design of protein homocystamides with enhanced tumor uptake properties for 19F magnetic resonance imaging

Straightforward and reliable tools for in vivo imaging of tumors can benefit the studies of cancer development, as well as contribute to successful diagnosis and treatment of cancer. 19F NMR offers an exceptional quantitative way of in vivo imaging of the infused agents because of the lack of 19F signals from the endogenous molecules in the body. The purpose of this study is to develop molecular probes with appropriate NMR characteristics and the biocompatibility for in vivo applications using 19F MRI. We have studied the reaction between perfluorotoluene and homocysteine thiolactone resulting in the formation of N-substituted homocysteine thiolactone derivative. It has been shown that the reaction occurs selectively at the para position. This fluorine-labeled homocysteine thiolactone has been employed for the introduction of a perfluorotoluene group as a 19F-containing tag into human serum albumin. The modified protein has been studied in terms of its ability to aggregate and promote the formation of free radicals. By comparing the properties of N-perfluorotoluene-homocystamide of albumin with N-homocysteinylated albumin, it has been revealed that blocking of the alpha-amino group of the homocysteine residue in the fluorinated albumin conjugate inhibits the dangerous aggregation process, as well as free radical formation. A dual-labeled albumin-based molecular probe for 19F MRI and fluorescence microscopy has been obtained by functionalizing the protein with both maleimide of a fluorescent dye and a fluorinated thiolactone derivative. The incubation of cells with this conjugate did not reveal any significant reduction in cell viability with respect to the parent albumin. The perfluorotoluene-labeled albumin has been demonstrated to act as a promising agent for in vivo 19F MRI.

Chitosan-coated poly(lactic-co-glycolic acid) perfluorooctyl bromide nanoparticles for cell labeling in 19F magnetic resonance imaging

Noninvasive therapeutic cell tracking methods in living animals are important for understanding cell function and fate in connection with cell therapy. Here we report a new particle system based on chitosan-coated poly(lactic-co-glycolic acid) perfluorooctyl bromide (PLGA PFOB) nanoparticles designed for 19F magnetic resonance imaging (MRI) cell tracking. Chitosan was adsorbed onto the PLGA PFOB nanoparticles through electric interactions, which led to an increase in the hydrodynamic size and a surface charge proportional to the coating weight ratio. Confocal laser scanning microscopy, flow cytometry analysis and 19F-MRI showed that to achieve the highest labeling efficiency in vitro, the optimal weight ratio of chitosan to the PLGA PFOB nanoparticles was 1:10 for human mesenchymal stem cells (hMSCs) and 1:100 for Raw 264.7 macrophages. In vivo19F-MRI showed that 19F labeled hMSCs remained at the injected site 24h after injection. Thus, this study validates that chitosan-coated PLGA PFOB nanoparticles have the potential to track cell migration in vivo.

Abstract 215: Tracking transplanted cells with paramagnetic fluorinated nanoemulsions

Abstract Visualization of distinct cell populations in vivo is one of the most formidable challenges in biomedical sciences. Clinical translation of cutting-edge therapies that involve administration of live immunotherapeutic or stem cells can benefit from understanding the fate of injected cells in vivo. Magnetic resonance imaging (MRI) is emerging as a prime method for non-invasive, longitudinal cell tracking. Fluorine-19 MRI (19F MRI) involves the use of non-radioactive 19F label in the form of biologically inert, cytocompatible perfluorocarbons (PFC). Immediately prior to injection, cells of interest are labeled ex vivo with water-based PFC nanoemulsions. 19F MRI yields background-free images of labeled cells in an anatomical context provided by conventional 1H MRI. Both datasets are acquired on the same scanner in one imaging session. This technology has recently been used to detect immunotherapeutic dendritic cells delivered to colorectal adenocarcinoma patients. We sought to enhance sensitivity and versatility of 19F MRI by using paramagnetic relaxation agents. Covalent modification of clinically relevant PFCs with metal-binding ligands enabled stable and uniform incorporation of gadolinium and iron in the fluorous phase of nanoemulsions. Paramagnetic relaxation enhancement resulted in up to 50-fold reduction in 19F longitudinal relaxation time (T1) compared to state-of-the-art commercial tracers. The ultralow 19F T1 of our paramagnetic tracers enabled in vivo cell tracking with rapid, three-dimensional, zero time-to-echo (ZTE) 19F MRI pulse sequences in mice bearing subcutaneous allografts of 19F-labeled GL261 cells. Moreover, the high local concentration of paramagnetic metals imparted negative contrast in T2*-weighted 1H images. Combination of the new agents with conventional 19F tracers comprises a previously unavailable toolbox of 19F contrast agents, selectively detectable by appropriate acquisition methods. This enables “multicolor” 19F MRI tracking of multiple cell populations, e.g., for monitoring the interaction of host immune cells with injected therapeutic cells or cancer xenografts. Overall, the design of biocompatible, fast-relaxing 19F tracers addresses the issue of modest sensitivity of 19F MRI and reduces the barriers to widespread adoption of this powerful imaging technique. Citation Format: Alexander A. Kislukhin, Hongyan Xu, Stephen R. Adams, Kazim Narsinh, Roger Y. Tsien, Eric T. Ahrens. Tracking transplanted cells with paramagnetic fluorinated nanoemulsions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 215. doi:10.1158/1538-7445.AM2015-215

Monitoring the Stability of Perfluorocarbon Nanoemulsions by Cryo-TEM Image Analysis and Dynamic Light Scattering.

Perfluorocarbon nanoemulsions (PFC-NE) are disperse systems consisting of nanoscale liquid perfluorocarbon droplets stabilized by an emulsifier, usually phospholipids. Perfluorocarbons are chemically inert and non-toxic substances that are exhaled after in vivo administration. The manufacture of PFC-NE can be done in large scales by means of high pressure homogenization or microfluidization. Originally investigated as oxygen carriers for cases of severe blood loss, their application nowadays is more focused on using them as marker agents in 19F Magnetic Resonance Imaging (19F MRI). 19F is scarce in organisms and thus PFC-NE are a promising tool for highly specific and non-invasive imaging of inflammation via 19F MRI. Neutrophils, monocytes and macrophages phagocytize PFC-NE and subsequently migrate to inflamed tissues. This technique has proven feasibility in numerous disease models in mice, rabbits and mini pigs. The translation to clinical trials in human needs the development of a stable nanoemulsion whose droplet size is well characterized over a long storage time. Usually dynamic light scattering (DLS) is applied as the standard method for determining particle sizes in the nanometer range. Our study uses a second method, analysis of transmission electron microscopy images of cryo-fixed samples (Cryo-TEM), to evaluate stability of PFC-NE in comparison to DLS. Four nanoemulsions of different composition are observed for one year. The results indicate that DLS alone cannot reveal the changes in particle size, but can even mislead to a positive estimation of stability. The combination with Cryo-TEM images gives more insight in the particulate evolution, both techniques supporting one another. The study is one further step in the development of analytical tools for the evaluation of a clinically applicable perfluorooctylbromide nanoemulsion.

Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions.

Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.

Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury.

In the extension phase of acute kidney injury, microvascular thrombosis, inflammation, vasoconstriction, and vascular endothelial cell dysfunction promote progressive damage to renal parenchyma after reperfusion. In this study, we hypothesized that direct targeting and pharmaceutical knockdown of activated thrombin at the sites of injury with a selective nanoparticle (NP)-based thrombin inhibitor, PPACK (phenylalanine-proline-arginine-chloromethylketone), would improve kidney reperfusion and protect renal function after transient warm ischemia in rodent models. Saline- or plain NP-treated animals were employed as controls. In vivo 19F magnetic resonance imaging revealed that kidney nonreperfusion was evident within 3 h after global kidney reperfusion at 34 ± 13% area in the saline group and 43 ± 12% area in the plain NP group and substantially reduced to 17 ± 4% (∼50% decrease, P < 0.05) in the PPACK NP pretreatment group. PPACK NP pretreatment prevented an increase in serum creatinine concentration within 24 h after ischemia-reperfusion, reflecting preserved renal function. Histologic analysis illustrated substantially reduced intrarenal thrombin accumulation within 24 h after reperfusion for PPACK NP-treated kidneys (0.11% ± 0.06%) compared with saline-treated kidneys (0.58 ± 0.37%). These results suggest a direct role for thrombin in the pathophysiology of AKI and a nanomedicine-based preventative strategy for improving kidney reperfusion after transient warm ischemia.

Cell tracking using (19)F magnetic resonance imaging: technical aspects and challenges towards clinical applications.

(19)F MRI is emerging as a new imaging technique for cell tracking. It is particularly attractive because of its potential for direct and precise cell quantification. The most important challenge towards in vivo applications is the sensitivity of the technique, i.e. the detection limit in a reasonable imaging time. Optimal sensitivity can be achieved with dedicated (19)F compounds together with specifically adapted hardware and acquisition methods. In this paper we introduce the (19)F MRI technique focusing on these key sensitivity issues and review the state-of-the-art of (19)F MRI and developments towards its clinical use. We calculate (19)F detection limits reported in preclinical cell and clinical (19)F drug studies in terms of tissue concentration in a 1 cm(3) voxel, as an alternate way to compare detection limits. We estimate that a tissue concentration of a few millimoles per litre (mM) of (19)F is required for a human study at a resolution of 1 cm(3).

Novel 19F Activatable Probe for the Detection of Matrix Metalloprotease-2 Activity by MRI/MRS

Matrix metalloproteases (MMPs) have been found to be highly expressed in a variety of malignant tumor tissues. Noninvasive visualization of MMP activity may play an important role in the diagnosis of MMP associated diseases. Here we report the design and synthesis of a set of fluorine-19 dendron-based magnetic resonance imaging (MRI) probes for real-time imaging of MMP-2 activity. The probes have the following features: (a) symmetrical fluorine atoms; (b) the number of fluorine atoms can be increased through facile chemical modification; (c) readily accessible peptide sequence as the MMP-2 substrate; (d) activatable 19F signal (off/on mode) via paramagnetic metal ion incorporation. Following optimization for water solubility, one of the probes was selected to evaluate MMP-2 activity by 19F magnetic resonance spectroscopy (MRS). Our results showed that the fluorine signal increased by 8.5-fold in the presence of MMP-2. The specific cleavage site was verified by mass spectrometry. The selected probe was further applied to detect secreted MMP-2 activity of living SCC7 squamous cell carcinoma cells. The fluorine signal was increased by 4.8-fold by MRS analysis after 24 h incubation with SCC7 cells. This type of fluorine probe can be applied to evaluate other enzyme activities by simply tuning the substrate structures. This symmetrical fluorine dendron-based probe design extends the scope of the existing 19F MRI agents and provides a simple but robust method for real-time 19F MRI application.

Thrombin-inhibiting nanoparticles rapidly constitute versatile and detectable anticlotting surfaces

Restoring an antithrombotic surface to suppress ongoing thrombosis is an appealing strategy for treatment of acute cardiovascular disorders such as erosion of atherosclerotic plaque. An antithrombotic surface would present an alternative to systemic anticoagulation with attendant risks of bleeding. We have designed thrombin-targeted nanoparticles (NPs) that bind to sites of active clotting to extinguish local thrombin activity and inhibit platelet deposition while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA) ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro. Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to laser injury of the carotid artery. NPs significantly delayed thrombotic occlusion of the artery, whereas an equivalent bolus of free inhibitor was ineffective. For thrombin-inhibiting NPs, only a short-lived (∼10 min) systemic effect on bleeding time was observed, despite prolonged clot inhibition. Imaging and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of the PFC NP. 19F MRI confirmed colocalization of particles with arterial thrombi, and quantitative 19F spectroscopy demonstrated specific binding and retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly form and image a new antithrombotic surface in acute vascular syndromes while minimizing risks of bleeding would permit a safer method of passivating active lesions than current systemic anticoagulant regimes.

Su2017 In Vivo Performance of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transport

A novel trifluorinated cholic acid derivative, CA-lys-TFA, was designed and synthesized for use as a tool to measure bile acid transport noninvasively using magnetic resonance imaging (MRI). In the present study, the in vivo performance of CA-lys-TFA for measuring bile acid transport by MRI was investigated in mice. Gallbladder CA-lys-TFA content was quantified using MRI and liquid chromatography/tandem mass spectrometry. Results in wild-type (WT) C57BL/6J mice were compared to those in mice lacking expression of Asbt, the ileal bile acid transporter. 19F signals emanating from the gallbladders of WT mice 7 h after oral gavage with 150 mg/kg CA-lys-TFA were reproducibly detected by MRI. Asbt-deficient mice administered the same dose had undetectable 19F signals by MRI, and gallbladder bile CA-lys-TFA levels were 30-fold lower compared to WT animals. To our knowledge, this represents the first report of in vivo imaging of an orally absorbed drug using 19F MRI. Fluorinated bile acid analogues have potential...