Visualizing electronic interactions between iron and carbon by X-ray chemical imaging and spectroscopy

The electronic interaction of a catalyst and its support is of vital importance to its catalytic performance. However, it is still a great challenge to directly probe the interaction due to the lack of well-defined models and efficient technical means. In this study, we report that pod-like carbon nanotubes with encapsulated iron particles (Pod-Fe) and scanning transmission X-ray microscopy (STXM) can be used as an ideal model and technique to study the electronic interaction between carbon shells and iron particles. The chemical imaging and spectroscopy of Pod-Fe by STXM show that the local electronic structures at C K-edge near edge (π*) of carbon shells can be significantly modified by the encapsulated iron particles, which promotes the adsorption of oxygen-containing species, and thereby further modifies the electronic structure (π* and σ*) of the carbon shells. Moreover, computed X-ray absorption near edge structure spectra (XANES) confirmed the electronic modifications of carbon shells by the encapsulated iron particles. The present study provides a direct evidence of electronic interactions with simultaneously collected images and spectra, which can promote the understanding towards the nature of active sites and supports.     

In vivo visible light-triggered drug release from an implanted depot

Controlling chemistry in space and time has offered scientists and engineers powerful tools for research and technology. For example, on-demand photo-triggered activation of neurotransmitters has revolutionized neuroscience. Non-invasive control of the availability of bioactive molecules in living organisms will undoubtedly lead to major advances; however, this requires the development of photosystems that efficiently respond to regions of the electromagnetic spectrum that innocuously penetrate tissue. To this end, we have developed a polymer that photochemically degrades upon absorption of one photon of visible light and demonstrated its potential for medical applications. Particles formulated from this polymer release molecular cargo in vitro and in vivo upon irradiation with blue visible light through a photoexpansile swelling mechanism.     

Bioorthogonal oxime ligation mediated in vivo cancer targeting

Current cancer targeting relying on specific biological interaction between the cell surface antigen and respective antibody or its analogue has proven to be effective in the treatment of different cancers; however, this strategy has its own limitations, such as the heterogeneity of cancer cells and immunogenicity of the biomacromolecule binding ligands. Bioorthogonal chemical conjugation has emerged as an attractive alternative to biological interaction for in vivo cancer targeting. Here, we report an in vivo cancer targeting strategy mediated by bioorthogonal oxime ligation. An oxyamine group, the artificial target, is introduced onto 4T1 murine breast cancer cells through liposome delivery and fusion. Poly(ethylene glycol)-polylactide (PEG-PLA) nanoparticles (NPs) are surface-functionalized with aldehyde groups as targeting ligands. The improved in vivo cancer targeting of PEG-PLA NPs is achieved through specific and efficient chemical reaction between the oxyamine and aldehyde groups.     

Conducting polyfurans by electropolymerization of oligofurans

Polyfurans have never been established as useful conjugated polymers, as previously they were considered to be inherently unstable and poorly conductive. Here, we show the preparation of stable and conducting polyfuran films by electropolymerization of a series of oligofurans of different chain lengths substituted with alkyl groups. The polyfuran films show good conductivity in the order of 1 S cm^–1, good environmental and electrochemical stabilities, very smooth morphologies (roughness 1–5 nm), long effective conjugation lengths, well-defined spectroelectrochemistry and electro-optical switching (in the Vis-NIR region), and have optical band-gaps in the range of 2.2–2.3 eV. A low oxidation potential needed for polymerization of oligofurans (compared to furan) is a key factor in achievement of improved properties of polyfurans reported in this work. DFT calculations and experiments show that polyfurans are much more rigid than polythiophenes, and alkyl substitution does not disturb backbone planarity and conjugation. The obtained properties of polyfuran films are similar or superior to the properties of electrochemically prepared poly(oligothiophene)s under similar conditions.     

Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles

A novel reaction for chelate-free, heat-induced metal ion binding and radiolabeling of ultra-small paramagnetic iron oxide nanoparticles (USPIOs) has been established. Radiochemical and non-radioactive labeling studies demonstrated that the reaction has a wide chemical scope and is applicable to p-, d- and f-block metal ions with varying ionic sizes and formal oxidation states from 2+ to 4+. Radiolabeling studies found that ⁸⁹Zr–Feraheme (⁸⁹Zr–FH or ⁸⁹Zr–ferumoxytol) can be isolated in 93 ± 3% radiochemical yield (RCY) and >98% radiochemical purity using size-exclusion chromatography. ⁸⁹Zr–FH was found to be thermodynamically and kinetically stable in vitro using a series of ligand challenge and plasma stability tests, and in vivo using PET/CT imaging and biodistribution studies in mice. Remarkably, ICP-MS and radiochemistry experiments showed that the same reaction conditions used to produce ⁸⁹Zr–FH can be employed with different radionuclides to yield ⁶⁴Cu–FH (66 ± 6% RCY) and ¹¹¹In–FH (91 ± 2% RCY). Electron magnetic resonance studies support a mechanism of binding involving metal ion association with the surface of the magnetite crystal core. Collectively, these data suggest that chelate-free labeling methods can be employed to facilitate clinical translation of a new class of multimodality PET/MRI radiotracers derived from metal-based nanoparticles. Further, this discovery is likely to have broader implications in drug delivery, metal separation science, ecotoxicology of nanoparticles and beyond.     

Mechanism and selectivity of the dinuclear iron benzoyl-coenzyme A epoxidase BoxB

Benzoyl-CoA epoxidase is a dinuclear iron enzyme that catalyzes the epoxidation reaction of the aromatic ring of benzoyl-CoA with chemo-, regio- and stereo-selectivity. It has been suggested that this enzyme may also catalyze the deoxygenation reaction of epoxide, suggesting a unique bifunctionality among the diiron enzymes. We report a density functional theory study of this enzyme aimed at elucidating its mechanism and the various selectivities. The epoxidation is suggested to start with the binding of the O₂ molecule to the diferrous center to generate a diferric peroxide complex, followed by concerted O–O bond cleavage and epoxide formation. Two different pathways have been located, leading to (2S,3R)-epoxy and (2R,3S)-epoxy products, with barriers of 17.6 and 20.4 kcal mol^–1, respectively. The barrier difference is 2.8 kcal mol^–1, corresponding to a diastereomeric excess of about 99 : 1. Further isomerization from epoxide to phenol is found to have quite a high barrier, which cannot compete with the product release step. After product release into solution, fast epoxide–oxepin isomerization and racemization can take place easily, leading to a racemic mixture of (2S,3R) and (2R,3S) products. The deoxygenation of epoxide to regenerate benzoyl-CoA by a diferrous form of the enzyme proceeds via a stepwise mechanism. The C2–O bond cleavage happens first, coupled with one electron transfer from one iron center to the substrate, to form a radical intermediate, which is followed by the second C3–O bond cleavage. The first step is rate-limiting with a barrier of only 10.8 kcal mol^–1. Further experimental studies are encouraged to verify our results.     

Novel artificial metalloenzymes by in vivo incorporation of metal-binding unnatural amino acids

Artificial metalloenzymes have emerged as an attractive new approach to enantioselective catalysis. Herein, we introduce a novel strategy for preparation of artificial metalloenzymes utilizing amber stop codon suppression methodology for the in vivo incorporation of metal-binding unnatural amino acids. The resulting artificial metalloenzymes were applied in catalytic asymmetric Friedel–Crafts alkylation reactions and up to 83% ee for the product was achieved.     

Synthesis and structural analysis of nonstoichiometric ternary fulleride K 1.5 Ba 0.25 CsC 60

The existence of cation-vacancy sites in fullerides might lead to long-range ordering and generate a new vacancy-ordered superstructure. The purpose of this work is to search whether or not long-range ordering of vacant tetrahedral sites, namely superstructure emerges in nonstoichiometric K _1.5 Ba _0.25 CsC ₆₀ fulleride. Therefore, K _1.5 Ba _0.25 CsC ₆₀ with cation-vacancy sites is synthesized using a precursor method to avoid inadequate stoichiometry control and formation of impurity phases within the target composition. For this purpose, first, phase-pure K ₆ C ₆₀ , Ba ₆ C ₆₀ and Cs ₆ C ₆₀ precursors are synthesized. Stoichiometric quantities of these precursors are used for further reaction with C ₆₀ to afford K _1.5 Ba _0.25 CsC ₆₀ . Rietveld analysis of the high-resolution synchrotron X-ray powder diffraction data of the precursors and K _1.5 Ba _0.25 CsC ₆₀ confirms that K ₆ C ₆₀ , Ba ₆ C ₆₀ and Cs ₆ C ₆₀ are single-phase and they crystallize in a body-centered-cubic structure ( Im 3) as reported in the literature. The analysis also shows that K _1.5 Ba _0.25 CsC ₆₀ phase can be perfectly modeled using a face-centered cubic structure. No new peaks appear which could have implied the appearance of a superstructure. This suggests that there is no long-range ordered arrangement of vacant tetrahedral sites in K _1.5 Ba _0.25 CsC ₆₀ .     

Tricyclic analogues of epidithiodioxopiperazine alkaloids with promising in vitro and in vivo antitumor activity

Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure–activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral administration. The short synthesis of molecules in this series will enable future mechanistic and translational studies of these structurally novel and highly promising clinical antitumor candidates.     

High-throughput imaging assay of multiple proteins via target-induced DNA assembly and cleavage

This work integrates target-induced DNA assembly and cleavage on a DNA chip to design a versatile imaging strategy as an assay for multiple proteins. The DNA assembly is achieved via immunological recognition to trigger the proximity hybridization for releasing a DNA sequence, which then hybridizes with FITC-DNA1 immobilized on the chip to induce the enzymatic cleavage of DNA1 and thus decrease the signals. The signal readout is performed with both fluorescent imaging of the left FITC and chemiluminescent (CL) imaging, by adding peroxidase labelled anti-FITC in assembly solution and CL substrates to produce CL emission. This one-step incubation can be completed in 30 min. The imaging method shows wide detection ranges and detection limits down to pg mL^–1 for the simultaneous detection of 4 protein biomarkers. This high-throughput strategy with good practicability can be easily extended to other protein analytes, providing a powerful protocol for protein analysis and clinical diagnosis.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

In vivo oral insulin delivery via covalent organic frameworks

With diabetes being the 7th leading cause of death worldwide, overcoming issues limiting the oral administration of insulin is of global significance. The development of imine-linked-covalent organic framework (nCOF) nanoparticles for oral insulin delivery to overcome these delivery barriers is herein reported. A gastro-resistant nCOF was prepared from layered nanosheets with insulin loaded between the nanosheet layers. The insulin-loaded nCOF exhibited insulin protection in digestive fluids in vitro as well as glucose-responsive release, and this hyperglycemia-induced release was confirmed in vivo in diabetic rats without noticeable toxic effects. This is strong evidence that nCOF-based oral insulin delivery systems could replace traditional subcutaneous injections easing insulin therapy.

We report the successful use of a gastro-resistant covalent organic framework for in vivo oral delivery of insulin.     

N-Heterocyclic carbene catalysed redox isomerisation of esters to functionalised benzaldehydes

N-Heterocyclic carbene catalysed redox isomerisation with reduction about the carbonyl has been developed in the transformation of trienyl esters to tetrasubstituted benzaldehydes. The reaction proceeds in good to excellent yield, and in cases that provide 2,2′-biaryls, enantioselectivity is observed. Mechanistic studies demonstrate the intermediacy of a cyclohexenyl β-lactone, while implicating formation of the homoenolate as turnover limiting.     

Magnetic circular dichroism and computational study of mononuclear and dinuclear iron(iv) complexes

High-valent iron(iv)-oxo species are key intermediates in the catalytic cycles of a range of O₂-activating iron enzymes. This work presents a detailed study of the electronic structures of mononuclear ([Fe^IV(O)(L)(NCMe)]²⁺, 1, L = tris(3,5-dimethyl-4-methoxylpyridyl-2-methyl)amine) and dinuclear ([(L)Fe^IV(O)(μ-O)Fe^IV(OH)(L)]³⁺, 2) iron(iv) complexes using absorption (ABS), magnetic circular dichroism (MCD) spectroscopy and wave-function-based quantum chemical calculations. For complex 1, the experimental MCD spectra at 2–10 K are dominated by a broad positive band between 12 000 and 18 000 cm^–1. As the temperature increases up to ∼20 K, this feature is gradually replaced by a derivative-shaped signal. The computed MCD spectra are in excellent agreement with experiment, which reproduce not only the excitation energies and the MCD signs of key transitions but also their temperature-dependent intensity variations. To further corroborate the assignments suggested by the calculations, the individual MCD sign for each transition is independently determined from the corresponding electron donating and accepting orbitals. Thus, unambiguous assignments can be made for the observed transitions in 1. The ABS/MCD data of complex 2 exhibit ten features that are assigned as ligand-field transitions or oxo- or hydroxo-to-metal charge transfer bands, based on MCD/ABS intensity ratios, calculated excitation energies, polarizations, and MCD signs. In comparison with complex 1, the electronic structure of the Fe^IV O site is not significantly perturbed by the binding to another iron(iv) center. This may explain the experimental finding that complexes 1 and 2 have similar reactivities toward C–H bond activation and O-atom transfer.     

A novel 18F-labelled high affinity agent for PET imaging of the translocator protein

The translocator protein (TSPO) is an important target for imaging focal neuroinflammation in diseases such as brain cancer, stroke and neurodegeneration, but current tracers for non-invasive imaging of TSPO have important limitations. We present the synthesis and evaluation of a novel 3-fluoromethylquinoline-2-carboxamide, AB5186, which was prepared in eight steps using a one-pot two component indium(iii)-catalysed reaction for the rapid and efficient assembly of the 4-phenylquinoline core. Biological assessment and the implementation of a physicochemical study showed AB5186 to have low nanomolar affinity for TSPO, as well as optimal plasma protein binding and membrane permeability properties. Generation of [¹⁸F]-AB5186 through ¹⁸F incorporation was achieved in good radiochemical yield and subsequent in vitro and ex vivo autoradiography revealed the ability of this compound to bind with specificity to TSPO in mouse glioblastoma xenografts. Initial positron emission tomography imaging of a glioma bearing mouse and a healthy baboon support the potential for [¹⁸F]-AB5186 use as a radiotracer for non-invasive TSPO imaging in vivo.     

Accurate molecular weight determination of small molecules via DOSY-NMR by using external calibration curves with normalized diffusion coefficients

Determination of the aggregation and solvation numbers of organometallic complexes in solution is an important task to increase insight in reaction mechanisms. Thus knowing which aggregates are formed during a reaction is of high interest to develop better selectivity and higher yields. Diffusion-ordered spectroscopy (DOSY), which separates NMR signals according to the diffusion coefficient, finds increasing use to identify species in solution. However, there still is no simple relationship between diffusion coefficient and molecular weight (MW). Some methods have been developed to estimate the MW but still with a significant error of ±30%. Here we describe a novel development of MW-determination by using an external calibration curve (ECC) approach with normalized diffusion coefficients. Taking the shape of the molecules into account enables accurate MW-predictions with a maximum error of smaller than ±9%. Moreover we show that the addition of multiple internal references is dispensable. One internal reference (that also can be the solvent) is sufficient. If the solvent signal is not accessible, 16 other internal standards (aliphatics and aromatics) are available to avoid signal overlapping problems and provide flexible choice of analytes. This method is independent of NMR-device properties and diversities in temperature or viscosity and offers an easy and robust method to determine accurate MWs in solution.     

In vivo evaluation of small-molecule thermoresponsive anticancer drugs potentiated by hyperthermia

Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers. Currently, the small molecule drugs used in combination with hyperthermia were not designed for this application. Herein, we report the evaluation of a chlorambucil and a ruthenium compound modified with a long fluorous chain, which exhibit thermoresponsive activity in colorectal adenocarcinoma xenografts in athymic mice in combination with mild hyperthermia (42 °C). Intraperitoneal injection of the derivatives followed by local hyperthermia showed a synergistic tumor growth reduction by 79% and 90% for the chlorambucil and ruthenium-based derivatives, respectively, with the latter exhibiting a higher synergy in combination with hyperthermia compared to the monotherapies. Histological analysis shows that both derivatives in combination with hyperthermia significantly decrease the number of proliferating tumor cells.     

Extending N-heterocyclic carbene ligands into the third dimension: a new type of hybrid phosphazane/NHC system

A simple, “click” synthetic approach to a new type of hybrid phosph(III)azane/NHC system is described. The presence of the phosphazane P₂N₂ ring unit, with P atoms flanking the NCN fragment and with this ring perpendicular to the binding site of the NHC, provides unique opportunities for modifying the electronic and steric character of these carbenes.     

One-pot synthesis of VO x /Al 2 O 3 as efficient catalysts for propane dehydrogenation

Vanadium oxides, as highly efficiently catalysts, are widely applied in various catalytic reactions, such as the dehydrogenation of light alkanes and epoxidation of alkenes. In this paper, a series of VO _x /Al ₂ O ₃ catalysts were fabricated by the 1-pot method for catalytic propane dehydrogenation. The results indicated that the VO _x /Al ₂ O ₃ catalysts with loading of 10 wt.% vanadium exhibited optimized catalytic performance. The as-prepared catalysts were characterized by N ₂ adsorption-desorption, XRD, TEM, H ₂ -TPR, and XPS to explore the texture properties, morphology, and electronic environment of vanadium. In addition, several vanadium catalysts were also prepared by the incipient wetness impregnation (IWI) method to compare their catalytic performance with the 1-pot synthesized catalysts. The catalysts synthesized by the 1-pot method exhibited higher selectivity of propylene and longer catalyst lifetime at high propane conversion when compared to the counterpart synthesized by the IWI method.