19F MRI Contrast Agents Research Articles

Hyperbranched Polymeric 19F MRI Contrast Agents with Long T2 Relaxation Time Based on β-Cyclodextrin and Phosphorycholine.

19F magnetic resonance imaging (19F MRI) is gaining attention as an emerging diagnostic technology. Effective 19F MRI contrast agents (CAs) for in vivo applications require a long transverse (or spin-spin) relaxation time (T2), short longitudinal (or spin-lattice) relaxation time (T1), high fluorine content, and excellent biocompatibility. Here, we present a novel hyperbranched polymeric 19F MRI CA based on β-cyclodextrin and phosphorylcholine. The influence of the branching degree and fluorine content on T2 was thoroughly investigated. Results demonstrated a maximum fluorine content of 11.85% and a T2 of 612 ms. This hyperbranched polymeric 19F MRI CA exhibited both great biocompatibility against cells and organs of mice and high-performance imaging capabilities both in vitro and in vivo. The research provides positive insights into the synthesis strategies, topological design, and selection of fluorine tags for 19F MRI CAs.

Preparation of PFPE-Based Polymeric Nanoparticles via Polymerization-Induced Self-Assembly as Contrast Agents for 19F MRI.

Fluorine-19 magnetic resonance imaging (19F MRI) probes have received considerable research interest as imaging contrast agents (CAs), but they remain neglected and underutilized due to the limited fluorine content or poor performance of fluorinated tracers. Here, we present polymeric nanoparticles (NPs) as 19F MRI CAs with a simple synthesis method and promising imaging performance. First, hydrophilic random copolymers were synthesized from oligo(ethylene glycol) methyl ether acrylate and perfluoropolyether methacrylate by reversible addition-fragmentation chain transfer (RAFT) polymerization. The optimal fluorine content, polymer concentration, and cytotoxicity as 19F MRI CAs were investigated in detail. Then, the optimal copolymer was selected as the macromolecular chain transfer agent, and the chain extension was performed with 2-(perfluorooctyl ethyl methacrylate). Subsequently, the NPs with different morphologies, such as ellipsoidal, spherical nanoparticles and vesicles, were prepared in situ by the RAFT-mediated polymerization-induced self-assembly method. In addition, the 19F MRI signal and cytotoxicity studies further confirmed that these polymeric NPs are nontoxic and have great potential as promising 19F MRI CAs for biological applications.

Fluorinated hydrogel nanoparticles with regulable fluorine contents and T2 relaxation times as 19F MRI contrast agents.

Medical imaging contrast agents that are able to provide detailed biological information have attracted increasing attention. Among the new emerging imaging contrast agents, 19F magnetic resonance imaging contrast agents (19F MRI CAs) are extremely promising for their weak background disturbing signal from the body. However, to prepare 19F MRI CAs with a long T2 relaxation time and excellent biocompatibility in a simple and highly effective strategy is still a challenge. Herein, we report a new type of 19F MRI hydrogel nanocontrast agents (19F MRI HNCAs) synthesized by a surfactant-free emulsion polymerization with commercial fluorinated monomers. The T2 relaxation time of 19F MRI HNCA-1 was found to be 25-40 ms, guaranteeing its good imaging ability in vitro. In addition, according to an investigation into the relationship between the fluorine content and 19F MRI signal intensity, the 19F MRI signal intensity was not only determined by the fluorine content in 19F MRI HNCAs but also by the hydration microenvironment around the fluorine atoms. Moreover, 19F MRI HNCAs demonstrated excellent biocompatibility and imaging capability inside cells. The primary exploration demonstrated that 19F MRI HNCAs as a new type of 19F MRI contrast agent hold potential for imaging lesion sites and tracking cells in vivo by 19F MRI technology.

PH‐Sensitive Polymethacrylates as Potential Contrast Agents in 19F MRI

Abstract19F MRI is a promising method of diagnosis that can complement the commonly used 1H MRI with gadolinium contrast agents. Copolymers containing fluoroorganic groups demonstrate many advantages as potential 19F MRI contrast agents. In this work, a series of copolymers based on 2,2,2‐trifluoroethyl methacrylate (TFEMA), 1,1,1,3,3,3‐hexafluoroisopropyl methacrylate (HFiPMA), 2‐(dimethylamino)ethyl methacrylate (DMAEMA), or 2‐hydroxyethyl methacrylate (HEMA) units are prepared using atom transfer radical polymerization. The highest S/N values in a 19F NMR spectra is achieved with a copolymer containing 15–25 wt% TFEMA or 18–22 wt% HFiPMA. Copolymers of HFiPMA show a strong effect of pH on T1 and T2 relaxation times while only T2 is significantly affected for the TFEMA copolymers. DFT calculations reveal that the phenomenon is most likely caused by the pH‐induced changes in the distance of fluoroorganic groups within a polymer chain.

Tumor micro-environment sensitive 19F-magnetic resonance imaging in vivo

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 (F4PTA) as a pH-sensitive 19F MRI contrast agent, which remained stable in a neutral condition, but could release free F4PTA 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.

Superhydrophilic fluorinated polymer and nanogel for high-performance 19F magnetic resonance imaging

19F magnetic resonance imaging (19F MRI), a kind of non-invasive and non-radioactive diagnostic technique with no endogenous background signals, opens up new research avenues for accurate molecular imaging studies. However, 19F MRI is manily limited by the performance of contrast agents. Here, for the first time, we presented the zwitterionic fluorinated polymer and nanogel as new types of superhydrophilic, sensitive and ultra-stable 19F MRI contrast agents. The superhydrophilicity of carboxybetaine zwitterionic structure completely overcame the hydrophobic aggregation-induced signal attenuation associated with amphiphilic fluorinated polymer-based nanoprobes. In addition, the superhydrophilic contrast agent exhibited distinct advantages, including high 19F-content (19.1 wt%), superior resistance to protein adsorption, constant MR properties and 19F MRS-based quantitative determination in complex biological fluids, and intense 19F MRI signals in the whole-body images after intravenous injection. In combination with angiogenesis targeting ligand, the superhydrophilic contrast agent was applied for the unambiguous detection of tumor. Importantly, computational algorithm was established for the directly quantitative determination of bioavailability and tumor-to-whole body ratio (TBR) from the in vivo19F MRI dataset, providing real-time information with non-invasive manner. Finally, crosslinked nanogels were developed with significantly prolonged systemic circulation, of which intense 19F MRI signals nonspecifically distributed in the aortaventralis and blood-rich organs, instead of being trapped steadily in liver as with the state-of-the-art superhydrophobic perfluocarbon nanoemulsions. Overall, this kind of superhydrophilic, zwitterionic fluorinated polymer and nanogel could be defined as a new generation of high-performance 19F MRI contrast agents, which hold great potential for image-based unambiguous disease detection and computational quantification.

Design of fluorinated hyperbranched polyether copolymers for 19F MRI nanotheranostics

19F MRI contrast agents and drug nanocarriers based on fluorinated hyperbranched polyether copolymers.

Fluorinated Glycopolymers as Reduction-responsive 19F MRI Agents for Targeted Imaging of Cancer.

Imaging agents that can be targeted to specific diseases and respond to the microenvironment of the diseased tissue are of considerable interest due to their potential in diagnosing and managing diseases. Here we report a new class of branched fluorinated glycopolymers as 19F MRI contrast agents that respond to a reductive environment, for targeted imaging of cancer. The fluorinated glycopolymers can be readily prepared by a one-pot RAFT polymerization of glucose- and fluorine-containing monomers in the presence of a disulfide-containing cross-linking monomer. The incorporation of glucose units along the polymer chain enables these fluorinated glycopolymers to effectively target cancer cells due to interactions with the overexpressed sugar transporters present on the cell surface. In addition, the polymers exhibit an enhanced 19F MRI signal in response to a reductive environment, one of the unique hallmarks of many cancer cells, demonstrating their potential as promising candidates for targeted imaging of cancer.

Cyclotriphosphazene, a scaffold for 19F MRI contrast agents

A cyclotriphosphazene substituted with six 3,5-bis(trifluoromethyl) benzyloxy units was designed as a novel 19F MRI contrast agent. The resulting molecule has 36 magnetically equivalent fluorine atoms and exhibited suitable MRI properties with high imaging sensitivity, confirming the proof-of-concept as a convenient scaffold for the production of new 19F MRI contrasts agents.

Paramagnetic lanthanide chelates for multicontrast MRI.

The preparation of a paramagnetic chelator that serves as a platform for multicontrast MRI, and can be utilized either as a T1-weighted, paraCEST or (19)F MRI contrast agent is reported. Its europium(iii) complex exhibits an extremely slow water exchange rate which is optimal for the use in CEST MRI. The potential of this platform was demonstrated through a series of MRI studies on tube phantoms and animals.

Water soluble poly(styrene sulfonate)-b-poly(vinylidene fluoride)-b-poly(styrene sulfonate) triblock copolymer nanoparticles

Water-soluble PNaSS-b-PVDF-b-PNaSS triblock copolymer.

19F MRI Probes with Tunable Switches and Highly Sensitive 19F MRI Nanoprobes

Abstract Magnetic resonance imaging (MRI) is an imaging modality adequate for in vivo studies. Therefore, many scientists are interested in the development of MRI probes capable of detecting enzyme activities in vivo. 19F MRI is useful for monitoring particular biosignals, cells, and target tissues, due to the absence of background signals in living organisms. Therefore, highly sensitive 19F MRI contrast agents are in great demand for their practical applications. However, we have faced the following challenges: (1) increasing the number of fluorine atoms decreases the solubility of the molecular probes, and (2) the restriction of the molecular mobility attenuates the 19F MRI signals. Herein, we developed novel multifunctional core–shell nanoparticles to solve these problems. They are composed of a core micelle filled with liquid perfluorocarbon and a robust silica shell. These core–shell nanoparticles have superior properties such as high sensitivity, surface-modifiability, biocompatibility, and sufficient in vivo stability. By the adequate surface modifications, gene expression in living cells and tumor tissue in living mice were successfully detected by 19F MRI.

Polyfluorinated bis-styrylbenzenes as amyloid-β plaque binding ligands

Detection of cerebral β-amyloid (Aβ) by targeted contrast agents remains of great interest to aid the in vivo diagnosis of Alzheimer’s disease (AD). Bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. To further explore their potency as 19F MRI contrast agents we synthetized several novel fluorinated bis-styrylbenzenes and studied their fluorescent properties and amyloid-β binding characteristics. The compounds showed a high affinity for Aβ plaques on murine and human brain sections. Interestingly, competitive binding experiments demonstrated that they bound to a different binding site than chrysamine G. Despite their high logP values, many bis-styrylbenzenes were able to enter the brain and label murine amyloid in vivo. Unfortunately initial post-mortem 19F NMR studies showed that these compounds as yet do not warrant further MRI studies due to the reduction of the 19F signal in the environment of the brain.

Multifunctional Core–Shell Silica Nanoparticles for Highly Sensitive 19F Magnetic Resonance Imaging

19F magnetic resonance imaging (19F MRI) is useful for monitoring particular signals from biological samples, cells, and target tissues, because background signals are missing in animal bodies. Therefore, highly sensitive 19F MRI contrast agents are in great demand for their practical applications. However, we have faced the following challenges: 1) increasing the number of fluorine atoms decreases the solubility of the molecular probes, and 2) the restriction of the molecular mobility attenuates the 19F MRI signals. Herein, we developed novel multifunctional core–shell nanoparticles to solve these issues. They are composed of a core micelle filled with liquid perfluorocarbon and a robust silica shell. These core–shell nanoparticles have superior properties such as high sensitivity, modifiability of the surface, biocompatibility, and sufficient in vivo stability. By the adequate surface modifications, gene expression in living cells and tumor tissue in living mice were successfully detected by 19F MRI.

Multifunctional Core–Shell Silica Nanoparticles for Highly Sensitive 19F Magnetic Resonance Imaging

Abstract19F magnetic resonance imaging (19F MRI) is useful for monitoring particular signals from biological samples, cells, and target tissues, because background signals are missing in animal bodies. Therefore, highly sensitive 19F MRI contrast agents are in great demand for their practical applications. However, we have faced the following challenges: 1) increasing the number of fluorine atoms decreases the solubility of the molecular probes, and 2) the restriction of the molecular mobility attenuates the 19F MRI signals. Herein, we developed novel multifunctional core–shell nanoparticles to solve these issues. They are composed of a core micelle filled with liquid perfluorocarbon and a robust silica shell. These core–shell nanoparticles have superior properties such as high sensitivity, modifiability of the surface, biocompatibility, and sufficient in vivo stability. By the adequate surface modifications, gene expression in living cells and tumor tissue in living mice were successfully detected by 19F MRI.

Biodegradable core crosslinked star polymer nanoparticles as19F MRI contrast agents for selective imaging

With the aim of developing stimuli-responsive imaging agents, we report here the synthesis of core crosslinked star (CCS) polymers and their evaluation as pH-sensitive 19F magnetic resonance imaging (19F MRI) contrast agents. Block copolymers consisting of poly(ethylene glycol)methyl ether methacrylate (PPEGMA) as the first block and a copolymer of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,2-trifluoroethyl methacrylate (TFEMA) as the second block were synthesised using RAFT polymerisation. The polymerisation kinetics were studied in detail. The block copolymers were then used as arm precursors for the arm-first synthesis of CCS polymers through RAFT dispersion polymerisation. The synthetic conditions were investigated and optimised. CCS polymers with a degradable core were also synthesised and evaluated as 19F MRI contrast agents. The degradation of the core was confirmed by treatment with various reducing agents. The particle size, 19F NMR signal and relaxation times as well as 19F MRI imaging performance of the CCS polymers were studied at a range of value of solution pH. Significant enhancement of the image intensity was observed when the pH was decreased from 8 to 5, indicating that the CCS nanoparticles could be used as 19F MRI contrast agents for the detection of the acidic environment within tumour tissue.

495. Validation of Cellular Function and Imaging Capability of CD34+ Stem Cells Labeled with a 19F MRI Contrast Agent

495. Validation of Cellular Function and Imaging Capability of CD34+ Stem Cells Labeled with a 19F MRI Contrast Agent

Non-invasive imaging of transplanted human neural stem cells and ECM scaffold remodeling in the stroke-damaged rat brain by 19F- and diffusion-MRI

Transplantation of human neural stem cells (hNSCs) is emerging as a viable treatment for stroke related brain injury. However, intraparenchymal grafts do not regenerate lost tissue, but rather integrate into the host parenchyma without significantly affecting the lesion cavity. Providing a structural support for the delivered cells appears important for cell based therapeutic approaches. The non-invasive monitoring of therapeutic methods would provide valuable information regarding therapeutic strategies but remains a challenge. Labeling transplanted cells with metal-based 1H-magnetic resonance imaging (MRI) contrast agents affects the visualization of the lesion cavity. Herein, we demonstrate that a 19F-MRI contrast agent can adequately monitor the distribution of transplanted cells, whilst allowing an evaluation of the lesion cavity and the formation of new tissue on 1H-MRI scans. Twenty percent of cells labeled with the 19F agent were of host origin, potentially reflecting the re-uptake of label from dead transplanted cells. Both T2- and diffusion-weighted MRI scans indicated that transplantation of hNSCs suspended in a gel form of a xenogeneic extracellular matrix (ECM) bioscaffold resulted in uniformly distributed cells throughout the lesion cavity. However, diffusion MRI indicated that the injected materials did not yet establish diffusion barriers (i.e. cellular network, fiber tracts) normally found within striatal tissue. The ECM bioscaffold therefore provides an important support to hNSCs for the creation of de novo tissue and multi-nuclei MRI represents an adept method for the visualization of some aspects of this process. However, significant developments of both the transplantation paradigm, as well as regenerative imaging, are required to successfully create new tissue in the lesion cavity and to monitor this process non-invasively.

Water-Soluble Fluorinated Polymer Nanoparticle as 19F MRI Contrast Agent Prepared by Living Random Copolymerization from Dendrimer Initiator

Abstract Water-soluble fluorinated polymer nanoparticles (PNPs) with well-defined structure were successfully prepared as a 19F MRI contrast agent by living radical copolymerization of 2,2,3,3-tetrafluoropropyl methacrylate (TFPMA) and tert-butyl methacrylate (tBMA) initiated from a dendritic macroinitiator. The obtained polymers were hydrolyzed and then converted into a sodium salt, yielding water-soluble fluorinated dendritic-star copolymers (PAMAM-g-PTFPMA-co-PMANa). The copolymer showed a sphere-like structure and the diameter increased in the range of 12–25 nm with the increase of the molecular weight. In 19F NMR properties, the T1 and T2 relaxation times were evaluated to be 400 and 70–80 ms, respectively, and were not significantly affected by the molecular weight of the copolymers. 19F MRI in vitro signals can be visualized at the lowest concentration of 0.5 mM (F atom) and detectable even at concentrations lower than 0.2 µM (particle concentration) under this experimental condition, indicating the high sensitivity due to the accumulated fluorine atoms into nanoparticle. Furthermore, in vivo MRI demonstrated the feasibility of the water-soluble fluorinated PNP as a new type of 19F MRI contrast agent.