Synthesis and Properties of Rhomboidal Macrocyclic Subunits of Graphdiyne-Like Nanoribbons

Rhomboidal macrocyclic subunits of graphdiyne-like nanoribbon (GDNR) bearing both alkyne and diyne units, allowing for multichannel π-conjugation, were synthesized using an oxidative Glaser-type ring closing reaction. These subunits, called the “meshes” of the nanoribbon, possess phenyl groups with decyloxy solubilizing chains on each corner. The yields of the ring closing reaction highly depend on the metal (Cu or Pd) catalyst used for the macrocyclization step. Increasing the width of the meshes from one macrocycle to two fused macrocycles resulted in a decrease of the bandgap by 0.23 eV as shown by optical spectroscopy. The optimized geometries of the meshes alongside their HOMO and LUMO orbitals were calculated using DFT calculations at the B3LYP/6-31+G** level of theory. The results showed a nearly planar conformation for both meshes with HOMO and LUMO orbitals entirely delocalized over the molecules

Enhancing the Coverage of the Urinary Metabolome by Sheathless Capillary Electrophoresis-Mass Spectrometry

Sheathless capillary electrophoresis-mass spectrometry (CE-MS), using a porous tip sprayer, is proposed for the first time for highly sensitive metabolic profiling of human urine. A representative metabolite mixture and human urine were used for evaluation of the sheathless CE-MS platform. For test compounds, relative standard deviations (RSDs) for migration times and peak areas were below 2% and 12%, respectively, and an injection volume of only ∼8 nL resulted in detection limits between 11 and 120 nM. Approximately 900 molecular features were detected in human urine by sheathless CE-MS whereas about 300 molecular features were found with classical sheath-liquid CE-MS. This difference can probably be attributed to an improved ionization efficiency and increased sensitivity at low flow-rate conditions. The integration of transient-isotachophoresis (t-ITP) as an in-capillary preconcentration procedure in sheathless CE-MS further resulted in subnanomolar limits of detection for compounds of the metabolite mixture, and more than 1300 molecular features were observed in urine. Compared to the classical CE-MS approaches, the integration of t-ITP combined with the use of a sheathless interface provides up to 2 orders of magnitude sensitivity improvement. Hence, sheathless CE-MS can be used for in-depth metabolic profiling of biological samples, and we anticipate that this approach will yield unique information in the field of metabolomics

Design, Synthesis, and Applications of Potential Substitutes of <i>t</i>-Bu-Phosphinooxazoline in Pd-Catalyzed Asymmetric Transformations and Their Use for the Improvement of the Enantioselectivity in the Pd-Catalyzed Allylation Reaction of Fluorinated Allyl Enol Carbonates

The design, synthesis, and applications of potential substitutes of <i>t</i>-Bu-PHOX in asymmetric catalysis is reported. The design relies on the incorporation of geminal substituents at C5 in combination with a substituent at C4 other than <i>t</i>-butyl (<i>i</i>-Pr, <i>i</i>-Bu, or <i>s</i>-Bu). Most of these new members of the PHOX ligand family behave similarly in terms of stereoinduction to <i>t</i>-Bu-PHOX in three palladium-catalyzed asymmetric transformations. Electronically modified ligands were also prepared and used to improve the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates

Rapid Synthesis of PEGylated Ultrasmall Gadolinium Oxide Nanoparticles for Cell Labeling and Tracking with MRI

Ultrasmall paramagnetic Gd₂O₃ nanoparticles have been developed as contrast agents for molecular and cellular preclinical MRI procedures. These small particles (mean diameter <5 nm) have the highest Gd density of all paramagnetic contrast agents. They generate strong positive contrast enhancement in <i>T</i>₁-weighted MRI. Signal enhancement is modulated by the interactions of water molecules with Gd, and very small particles provide the optimal surface-to-volume ratios necessary to reach high relaxivities. Conventional Gd₂O₃ nanocrystal synthesis techniques, and subsequent polyethylene glycol (PEG) grafting procedures are usually time-consuming and recovery losses are also limitative. The present study reports on a new, fast, and efficient one-pot Gd₂O₃ synthesis technique that provides PEGylated nanoparticles of very small size (mean diameter = 1.3 nm). Readily coated with PEG, the particles are colloidally stable in aqueous media and provide high longitudial relaxivities and small <i>r</i>₂/<i>r</i>₁ ratios (<i>r</i>₁ = 14.2 mM^–1 s^–1 at 60 MHz; <i>r</i>₂/<i>r</i>₁ = 1.20), ideal for <i>T</i>₁-weighted MRI. In this study, F98 brain cancer cells (glioblastoma multiforme) were labeled with the contrast agent and implanted in vivo (mice brains). The labeled cells appeared positively contrasted at least 48 h after implantation. Each one of the implanted animals developed a brain tumor. The performance of PEG-Gd₂O₃ was also compared with that of commercially available iron oxide nanoparticles. This study demonstrated that ultrasmall PEG-Gd₂O₃ nanoparticles provide strong positive contrast enhancement in <i>T</i>₁-weighted imaging, and allow the visualization of labeled cells implanted in vivo

Synthesis of Carboxylate Cp*Zr(IV) Species: Toward the Formation of Novel Metallocavitands

With the intent of generating metallocavitands isostructural to species [(CpZr)₃(μ³-O)­(μ²-OH)₃­(κ_O,O,μ²-O₂C­(R))₃]⁺, the reaction of Cp*₂ZrCl₂ and Cp*ZrCl₃ with phenylcarboxylic acids was carried out. Depending on the reaction conditions, five new complexes were obtained, which consisted of Cp*₂ZrCl­(κ²-OOCPh) (<b>1</b>), (Cp*ZrCl­(κ²-OOCPh))₂­(μ-κ²-OOCPh)₂ (<b>2</b>), [(Cp*Zr­(κ²-OOCPh))₂­(μ-κ²-OOCPh)₂­(μ²-OH)₂]·Et₂O (<b>3</b>·<b>Et</b>_<b>2</b><b>O</b>), [[Cp*ZrCl₂]­(μ-Cl)­(μ-OH)­(μ-O₂CC₆H₅)­[Cp*Zr]]₂­(μ-O₂CC₆H₅)₂ (<b>4</b>), and [Cp*ZrCl₄]­[(Cp*Zr)₃­(κ₂-OOC­(C₆H₄Br)₃­(μ₃-O)­(μ₂-Cl)₂­(μ₂-O<i>H</i>)] [<b>5</b>]⁺[<b>Cp*ZrCl</b>_<b>4</b>]⁻. The structural characterization of the five complexes was carried out. Species <b>3</b>·<b>Et</b>_<b>2</b><b>O</b> exhibits host–guest properties where the diethyl ether molecule is included in a cavity formed by two carboxylate moieties. The secondary interactions between the cavity and the diethyl ether molecule affect the structural parameters of the complex, as demonstrated be the comparison of the density functional theory models for <b>3</b> and <b>3</b>·<b>Et</b>_<b>2</b><b>O</b>. Species <b>5</b> was shown to be isostructural to the [(CpZr)₃­(μ³-O)­(μ²-OH)₃­(κ_O,O,μ²-O₂C­(R))₃]⁺ metallocavitands

Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast in <i>T</i>₁‑Weighted Magnetic Resonance Imaging

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) have been used as vascular contrast agents in magnetic resonance imaging (MRI), mainly for their capacity to generate negative contrast. To use USPIOs as positive contrast agents, it is necessary to achieve increased colloidal stability and signal-enhancement performance. Their molecular coatings must be carefully chosen, so that the vascular blood-pool contrast agents lead to long blood turnover times. However, to avoid long-term toxicological effects, they must also be cleared rapidly through the urinary or gastrointestinal pathways. In this context, highly stable USPIOs showing “positive” contrast in MRI and optimal clearance rates call for the development of robust biocompatible molecular coatings. In the present study, USPIOs were stabilized with a multidentate block copolymer (MDBC), using a one-pot polyol synthesis method in the presence of a MDBC. Two types of MDBCs having pendant COOH groups in the anchoring block were developed: a polymer with linear-poly­(ethylene glycol) (PEG) blocks and a polymer containing brushed-PEG blocks. The synthesized superparamagnetic Fe₃O₄ crystals were uniform (5–8 nm in diameter), showed ultrasmall hydrodynamic diameters in dynamic light scattering, and were stable in physiological liquids. MDBC-coated USPIOs were analyzed in relaxometry, and the formulations showing the strongest potential for <i>T</i>₁-weighted vascular imaging (<i>r</i>₂/<i>r</i>₁: ∼4) were selected for in vivo MRI. Intravascular injections performed in the mouse model indicated long blood retention times and high signal enhancement in MRI for nanoparticles coated with linear-PEG block coatings. These results also indicate that MDBC/USPIOs could be used in vascular MRI applications, where the nanoparticles must transit the blood for several hours, followed by an efficient clearance in the next days following injection. The use of MDBCs as nanoparticle coatings could open new possibilities in the design of USPIOs for targeted molecular MRI

Intratumoral Injection of Low-Energy Photon-Emitting Gold Nanoparticles: A Microdosimetric Monte Carlo-Based Model

Gold nanoparticles (Au NPs) distributed in the vicinity of low-dose rate (LDR) brachytherapy seeds could multiply their efficacy thanks to the secondary emissions induced by the photoelectric effect. Injections of radioactive LDR gold nanoparticles (LDR Au NPs), instead of conventional millimeter-size radioactive seeds surrounded by Au NPs, could further enhance the dose by distributing the radioactivity more precisely and homogeneously in tumors. However, the potential of LDR Au NPs as an emerging strategy to treat cancer is strongly dependent on the macroscopic diffusion of the NPs in tumors, as well as on their microscopic internalization within the cells. Understanding the relationship between interstitial and intracellular distribution of NPs, and the outcomes of dose deposition in the cancer tissue is essential for considering future applications of radioactive Au NPs in oncology. Here, LDR Au NPs (¹⁰³Pd:Pd@Au-PEG NPs) were injected in prostate cancer tumors. The particles were visualized at time-points by computed tomography imaging (<i>in vivo</i>), transmission electron microscopy (<i>ex vivo</i>), and optical microscopy (<i>ex vivo</i>). These data were used in a Monte Carlo-based dosimetric model to reveal the dose deposition produced by LDR Au NPs both at tumoral and cellular scales. ¹⁰³Pd:Pd@Au-PEG NPs injected in tumors produce a strong dose enhancement at the intracellular level. However, energy deposition is mainly confined around vesicles filled with NPs, and not necessarily close to the nuclei. This suggests that indirect damage caused by the production of reactive oxygen species might be the leading therapeutic mechanism of tumor growth control, over direct damage to the DNA

Versatile Reactivity of Phosphagermaallene Tip(<i>t</i>‑Bu)GeCPMes* with α‑Ethylenic Esters

The phosphagermaallene Tip­(<i>t</i>-Bu)­GeCPMes* (<b>1</b>) (Tip = 2,4,6-triisopropylphenyl, Mes* = 2,4,6-tri-<i>tert</i>-butylphenyl) reacts with methyl crotonate, methyl cinnamate, and methyl fumarate according to a [2+2] cycloaddition between the GeC and CO double bonds to afford oxagermacyclobutanes <b>2</b>–<b>4</b>. With methyl maleate, a [2+4] cycloaddition is observed between the GeC double bond and the OC–CC moiety, leading to oxagermacyclohexene <b>5</b>. With methyl acrylate, phosphagermaallene <b>1</b> behaves as a 1,3-dipole, giving a transient five-membered-ring germa­(phosphino)­carbene, which rearranges by insertion of the carbenic carbon atom into a CH bond of a <i>tert</i>-butyl group of the Mes* group to afford the tricyclic derivative <b>8</b>. These results have been supported by a theoretical approach in order to describe the reaction pathways and explain the different experimental results

MnO-Labeled Cells: Positive Contrast Enhancement in MRI

Manganese oxide (MnO) nanoparticles have been suggested as a promising “positive” MRI contrast agent for cellular and molecular studies. Mn-based contrast agents could enable <i>T</i>₁-weighted quantitative cell tracking procedures in vivo based on signal enhancement. In this study, ultrasmall MnO particles were synthesized and coated with thiolated molecules (DMSA) and polyethylene glycol (PEG) to allow enhanced cell labeling properties and colloidal stability. This coating allowed the fabrication of individual ultrasmall nanoparticles of MnO (USPMnO) as well as of nanoaggregates of the same material (SPMnO). Particle size was measured by TEM and DLS. Physico-chemical properties were characterized by XPS and FTIR. The relaxometric properties of these aqueous suspensions were measured at various magnetic fields. The suspensions provided strong positive contrast enhancement in <i>T</i>₁-weighted imaging due to high longitudinal relaxivities (<i>r</i>₁) and low <i>r</i>₂/<i>r</i>₁ ratios (USPMnO: <i>r</i>₁ = 3.4 ± 0.1 mM^–1s^–1, <i>r</i>₂/<i>r</i>₁ = 3.2; SPMnO: <i>r</i>₁ = 17.0 ± 0.5 mM^–1s^–1, <i>r</i>₂/<i>r</i>₁ = 4.0, at 1.41T). HT-1080 cancer cells incubated with the contrast agents were clearly visualized in MRI for Mn contents >1.1 pg Mn/cell. The viability of cells was not affected, contrarily to cells labeled with an equivalent concentration of Mn²⁺ ions. A higher signal per cell was found for SPMnO-labeled compared with USPMnO-labeled cells, due to the higher relaxometric properties of the agglomerates. As a result, the “positive” signal enhancement effect is not significantly affected upon agglomeration of MnO particles in endosomes. This is a major requirement in the development of reliable cell tracking procedures using <i>T</i>₁-weighted imaging sequences. This study confirms the potential of SPMnO and USPMnO to establish more quantitative cell tracking procedures with MRI