Multispectral MRI with Dual Fluorinated Probes to Track Mononuclear Cell Activity in Mice.

Background MRI with fluorine 19 (19F) probes has shown an ability to track immune cell activity with a specific, stable, and quantitative signal. In addition, the chemical shift differences of selected 19F probes make dual-probe imaging possible. To improve 19F MRI sensitivity for dual-probe imaging, optimal fluorine probes are needed. Purpose To develop multispectral 19F MRI to image immune cell activity in vivo using 19F nanoparticles of two distinct fluorocarbons. Materials and Methods Both 19F nanoparticles formulated with two fluorocarbons with distinct resonance frequencies and a high fluorine payload were characterized in terms of size, stability, MR profile, and relaxation times at 7 T. 19F MRI sensitivity was tested on labeling cells both in vitro and in vivo in C57BL/6 mice after conditional ablation of myeloid cells through the inhibition of colony-stimulating factor-1 receptor (CSF1Ri) to monitor the change of immune cells phagocytosis. Fluorine MRI data were acquired at the resonance frequency of each fluorocarbon by using a three-dimensional fast spin-echo sequence. Fluorescent dyes were also inserted into 19F nanoparticles to allow flow-cytometric and confocal microscopy analysis of labeled cells. Fluorine signal-to-noise ratio (SNR) was compared by using two-way repeated measures analysis of variance with Bonferroni post hoc correction. Results Fluorine MRI demonstrated high sensitivity and high specificity in the imaging of mononuclear cells both in vitro and in vivo. In combination with proton MRI, a map of 19F nuclei from each fluorocarbon was obtained without overlaps or artifacts. In vitro cell viability was unchanged, and 8000 cells with a high SNR (>8) were detected. In vivo high fluorine signal was observed in the bone marrow (SNR > 15) immediately after CSF1Ri treatment interruption, which correlated with high uptake by neutrophils and monocytes at flow cytometry. Conclusion By assessing in vivo MRI of mononuclear cell phagocytic ability with 19F nanoparticles, MRI with dual 19F probes can effectively track immune cell activity in combination with current MRI protocols. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Bulte in this issue.

Efficient Encapsulation of Fluorinated Drugs in the Confined Space of Water-Dispersible Fluorous Supraparticles.

Fluorophobic-driven assemblies of gold nanomaterials were stabilized into water-dispersible fluorous supraparticles by the film-forming protein hydrophobin II. The strategy makes use of fluorous nanomaterials of different dimensions to engineer size and inner functionalization of the resulting confined space. The inner fluorous compartments allow efficient encapsulation and transport of high loadings of partially fluorinated drug molecules in water.

Double Stereodifferentiation in the Asymmetric Dihydroxylation of Optically Active Olefins.

A study of the stereochemical control on the asymmetric dihydroxylation of the double bond of optically active vinyl epoxides and their derivatives (bromo derivatives, azido derivatives, and vinyl aziridines) was carried out and the obtained results are herein reported. The most interesting results were obtained on trans α,ß-unsaturated epoxy esters, which were successfully converted with a diastereomeric ratio >80% into the corresponding diols using either the matched or the mismatched conditions, depending on the ligand used. Unprotected bromo derivatives and unprotected aziridines did not afford significant results, while for the protected bromo derivatives, azido derivatives, and N-Boc protected aziridines the matched conditions led to a diastereomeric ratio >95%. Chirality 28:387-393, 2016. © 2016 Wiley Periodicals, Inc.

A superfluorinated molecular probe for highly sensitive in vivo(19)F-MRI.

(19)F-MRI offers unique opportunities to image diseases and track cells and therapeutic agents in vivo. Herein we report a superfluorinated molecular probe, herein called PERFECTA, possessing excellent cellular compatibility, and whose spectral properties, relaxation times, and sensitivity are promising for in vivo (19)F-MRI applications. The molecule, which bears 36 equivalent (19)F atoms and shows a single intense resonance peak, is easily synthesized via a simple one-step reaction and is formulated in water with high stability using trivial reagents and methods.

The ortho and meta magnesiation of functionalized anilines and amino-substituted pyridines and pyrazines at room temperature.

A practical ortho,meta, (or even ortho,ortho') magnesiation of trifluoroacetamides of anilines, aminopyridines, and aminopyrazines at room temperature was performed with TMPMgCl⋅LiCl or TMP(2) Mg⋅2 LiCl. These magnesiations are compatible with several carbonyl functionalities and allow access to polysubstituted anilides in satisfactory yields.

Nanoparticles for "two color" 19F magnetic resonance imaging: Towards combined imaging of biodistribution and degradation.

The use of polymeric nanoparticles (NPs) as therapeutics has been steadily increasing over past decades. In vivo imaging of NPs is necessary to advance the therapeutic performance. 19F Magnetic Resonance Imaging (19F MRI) offers multiple advantages for in vivo imaging. However, design of a probe for both biodistribution and degradation has not been realized yet. We developed polymeric NPs loaded with two fluorocarbons as promising imaging tools to monitor NP biodistribution and degradation by 19F MRI. These 200 nm NPs consist of poly(lactic-co-glycolic acid) (PLGA) loaded with perfluoro-15-crown-5 ether (PFCE) and PERFECTA. PERFECTA/PFCE-PLGA NPs have a fractal sphere structure, in which both fluorocarbons are distributed in the polymeric matrix of the fractal building blocks, which differs from PFCE-PLGA NPs and is unique for fluorocarbon-loaded colloids. This structure leads to changes of magnetic resonance properties of both fluorocarbons after hydrolysis of NPs. PERFECTA/PFCE-PLGA NPs are colloidally stable in serum and biocompatible. Both fluorocarbons show a single resonance in 19F MRI that can be imaged separately using different excitation pulses. In the future, these findings may be used for biodistribution and degradation studies of NPs by 19F MRI in vivo using "two color" labeling leading to improvement of drug delivery agents.

Synthesis of potential HIV integrase inhibitors inspired by natural polyphenol structures.

Drawing inspiration from the structural features of some natural polyphenols, the synthesis of two different model compounds as potential inhibitors of HIV integrase (IN) has been described. The former was characterised by a diketo acid (DKA) bioisostere, such as a ß-hydroxycarbonyl moiety, between two fragments containing aromatic groups, while in the latter an epoxide linked two polyoxygenated aromatic residues. The moieties present in the structures are thought to function by chelating divalent metal ions on the enzyme catalytic site. Overall, 10 compounds were prepared and some of that submitted to molecular modelling studies (to investigate their interactions with the active site of IN), to metal titration studies (to detect their chelating capability) and to biological assays.

Crystallographic insights into the structural aspects of thioctic acid based halogen-bond donor for the functionalization of gold nanoparticles.

The synthesis and self-assembly capabilities of a new halogen-bond donor ligand, 2,3,5,6-tetrafluoro-4-iodophenyl 5-(1,2-dithiolan-3-yl)pentanoate (1), are reported. The crystal structure of ligand (1) and the formation of a cocrystal with 1,2-di(4-pyridyl)ethylene, (1)·(2), both show halogen bonds involving the 4-iodotetrafluorobenzene moiety. Ligand (1), being a self-complementary unit, forms an infinite halogen-bonded chain driven by the S...I synthon, while the cocrystal (1)·(2) self-assembles into a discrete trimeric entity driven by the N...I synthon. Ligand (1) was also successfully used to functionalize the surface of gold nanoparticles, AuNP-(1). Experiments on the dispersibility profile of AuNP-(1) demonstrated the potential of halogen bonding in facilitating the dispersion of modified NPs with halogen-bond donors in pyridine.

Synthesis, molecular modeling and biological evaluation of two new chicoric acid analogs.

Two conformationally constrained compounds similar to chicoric acid but lacking the catechol and carboxyl groups were prepared. In these analogues, the single bond between the two caffeoyl fragments has been replaced with a chiral oxirane ring and both aromatic residues modified protecting completely or partially the catechol moiety as methyl ether. Preliminary molecular modelling studies carried out on the two analogues showed interactions near the active site of HIV integrase; however, in comparison with raltegravir, the biological evaluation confirmed that CAA-1 and CAA-2 were unable to inhibit infection at lower concentration.

Bioreducible Hydrophobin-Stabilized Supraparticles for Selective Intracellular Release.

One of the main hurdles in nanomedicine is the low stability of drug-nanocarrier complexes as well as the drug delivery efficiency in the region-of-interest. Here, we describe the use of the film-forming protein hydrophobin HFBII to organize dodecanethiol-protected gold nanoparticles (NPs) into well-defined supraparticles (SPs). The obtained SPs are exceptionally stable in vivo and efficiently encapsulate hydrophobic drug molecules. The HFBII film prevents massive release of the encapsulated drug, which, instead, is activated by selective SP disassembly triggered intracellularly by glutathione reduction of the protein film. As a consequence, the therapeutic efficiency of an encapsulated anticancer drug is highly enhanced (2 orders of magnitude decrease in IC50). Biodistribution and pharmacokinetics studies demonstrate the high stability of the loaded SPs in the bloodstream and the selective release of the payloads once taken up in the tissues. Overall, our results provide a rationale for the development of bioreducible and multifunctional nanomedicines.

Stereoselective synthesis of (+)-1-deoxyaltronojirimycin.

A stereocontrolled, facile and high-yield approach for producing (+)-altroDNJ, has been developed starting from the inexpensive commercial cis 2-butene-1,4-diol. Sharpless epoxidation and a subsequent dihydroxylation were used for the introduction of all stereocentres; finally, the ring closure under basic conditions afforded the piperidine heterocycle.