Aura Tintaru

Metabolomics approach to thyroid nodules: A high-resolution magic-angle spinning nuclear magnetic resonance–based study

BACKGROUND Proton magnetic resonance spectroscopy of operative specimens has been reported to successfully differentiate normal tissue from malignant thyroid tissue. We used a new high-resolution magnetic resonance spectroscopy technique for the differentiation of benign and malignant thyroid neoplasms. METHODS Histological specimens from 72 patients undergoing a total thyroidectomy were processed into a 4-mm ZrO(2) high-resolution magic angle spinning (HRMAS) rotor with 5 μL of D(2)O. A Bruker Avance spectrometer operating at 400 MHz for the (1)H frequency and equipped with a (1)H/(13)C/(31)P HRMAS probe was used. RESULTS Normal and neoplastic thyroid tissues could be discriminated from each other by different relative concentrations of several amino acids and lipids, as well as benign and malignant neoplasms, that differed in terms of a greater lactate and taurine and a lesser lipid choline, phosphocholine, myo-inositol, and scyllo-inositol levels in malignant samples. A statistical analysis with a receiver operating characteristic curve revealed that 77% of the samples were accurately predicted. Similar results were obtained with specimens obtained from ex vivo aspirates. CONCLUSION A further development of this project will be to use the metabolomics approach on specimens obtained from aspirates in vivo after the resolution of technical problems attributable to possible contamination.

Conformational sensitivity of conjugated poly(ethylene oxide)-poly(amidoamine) molecules to cations adducted upon electrospray ionization – A mass spectrometry, ion mobility and molecular modeling study

Tandem mass spectrometry and ion mobility spectrometry experiments were performed on multiply charged molecules formed upon conjugation of a poly(amidoamine) (PAMAM) dendrimer with a poly(ethylene oxide) (PEO) linear polymer to evidence any conformational modification as a function of their charge state (2+ to 4+) and of the adducted cation (H(+)vs Li(+)). Experimental findings were rationalized by molecular dynamics simulations. The G0 PAMAM head-group could accommodate up to three protons, with protonated terminal amine group enclosed in a pseudo 18-crown-6 ring formed by the PEO segment. This particular conformation enabled a hydrogen bond network which allowed long-range proton transfer to occur during collisionally activated dissociation. In contrast, lithium adduction was found to mainly occur onto oxygen atoms of the polyether, each Li(+) cation being coordinated by a 12-crown-4 pseudo structure. As a result, for the studied polymeric segment (Mn=1500gmol(-1)), PEO-PAMAM hybrid molecules exhibited a more expanded shape when adducted to lithium as compared to proton.

A post-polymerization functionalization strategy for the synthesis of sulfonyl (trifluoromethanesulfonyl)imide functionalized (co)polymers

In this Communication, we report the synthesis of a series of potassium sulfonyl (trifluoromethanesulfonyl)imide (STFSI) derivatives, bearing at one extremity the STFSI group and at the other extremity either bromo, azido or amine groups. The resultant STFSI derivatives were subsequently used in the post-polymerization functionalization of (co)polymers to yield functionalized (co)polymers by exploiting the highly efficient coupling reactions, namely alkylation, amidation and alkyne–azide cycloaddition.

Structural characterization of new defective molecules in poly(amidoamide) dendrimers by combining mass spectrometry and nuclear magnetic resonance.

A new side-reaction occurring during divergent synthesis of PAMAM dendrimers (generations G0-G2) was revealed by mass spectrometric detection of defective molecules with a net gain of a single carbon atom as compared to expected compounds. Combining MS/MS experiments performed on different electrosprayed precursor ions (protonated molecules and lithiated adducts) with NMR analyses allowed the origin of these by-products to be elucidated. Modification of one ethylenediamine end-group of perfect dendrimers into a cyclic imidazolidine moiety was induced by formaldehyde present at trace level in the methanol solvent used as the synthesis medium. Dendrimers studied here were purposely constructed from a triethanolamine core to make them more flexible, as compared to NH3- or ethylenediamine-core PAMAM, and hence improve their interaction with DNA. Occurrence of this side-reaction would be favored by the particular flexibility of the dendrimer branches.

Poly(Aminoester) Dendrimers: Design, Synthesis and Characterization

Poly(aminoester) dendrimers are particularly appealing for drug delivery due to their advantageous properties including biodegradability, potentially lower toxicity and possibility of diverse chemical conjugations. In the course of the COST Action TD0802, we have developed a novel strategy for the synthesis of poly(aminoester) dendrimers based on active cyanomethyl ester intermediates and the iteration of 4 consecutive steps involving deprotection, activation, transesterification and scavenging. The overall synthesis can be performed under very mild conditions, allowing the corresponding products to be obtained in pure form and with good yields after easy purification.

Chiral Fidelity in the Diastereoselective and Enantiospecific Synthesis of Indenes from Axially Chiral Benzylidene Cyclanes

Enantioenriched indenes were reached through a chirality conversion strategy using original axially chiral benzylidene cyclanes. Good to high remote diastereocontrol and excellent enantiocontrol were observed in this cascade involving copper-catalyzed homologation of terminal alkynes, in situ allenoate formation and Alder-ene cyclization.

Suppressing background signals in solid state NMR via the Electronic Mixing-Mediated Annihilation (EMMA) method

A simple procedure to effectively suppress background signals arising from various probe head components (e.g. stator, rotors, inserts) in solid state NMR is presented. Similarly to the ERETIC™ method, which uses an electronic signal as an internal standard for quantification, the proposed scheme is based on an electronically generated time-dependent signal that is injected into the receiver coil of the NMR probe head during signal acquisition. More specifically, the line shape, width and frequency of this electronic signal are determined by deconvoluting the background signal in the frequency domain. This deconvoluted signal is then converted into a time-dependent function through inverse Fourier Transform, which is used to generate the shaped pulse that is fed into the receiver coil during the acquisition of the Free Induction Decay. The power of the shaped pulse is adjusted to match the intensity of the background signal, and its phase is shifted by 180° with respect to the receiver reference phase. This so-called Electronic Mixing-Mediated Annihilation (EMMA) methodology is demonstrated here with a (13)C Single Pulse Magic Angle Spinning spectrum of an isotopically enriched (13)C histidine solid sample recorded under quantitative conditions.

Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors

Significance Nanotechnology-based imaging is expected to bring breakthroughs in cancer diagnosis by improving imaging sensitivity and specificity while reducing toxicity. Here, we developed an innovative nanosystem for positron emission tomography (PET) imaging based on a self-assembling amphiphilic dendrimer. This dendrimer assembled spontaneously into uniform supramolecular nanomicelles with abundant PET reporting units on the surface. By harnessing both dendrimeric multivalence and the “enhanced permeation and retention” (EPR) effect, this dendrimer nanosystem effectively accumulated in tumors, leading to exceedingly sensitive and specific imaging of various tumors, especially those that are otherwise undetectable using the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). This study illustrates the power of nanotechnology based on self-assembling dendrimers to provide an effective platform for bioimaging and related biomedical applications. Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the “enhanced permeation and retention” (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low–glucose-uptake tumors that are otherwise undetectable using [18F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.

Anomerization of Acrylated Glucose During Traveling Wave Ion Mobility Spectrometry

AbstractAnomerization of simple sugars in the liquid phase is known as an acid- and base-catalyzed process, which highly depends on solvent polarity. This reaction is reported here to occur in the gas phase, during traveling wave ion mobility spectrometry (TWIMS) experiments aimed at separating α- and β-anomers of penta-acrylated glucose generated as ammonium adducts in electrospray ionization. This compound was available in two samples prepared from glucose dissolved in solvents of different polarity, namely tetrahydrofuran (THF) and N,N-dimethylacetamide (DMAC), and analyzed by electrospray tandem mass spectrometry (ESI-MS/MS) as well as traveling wave ion mobility (ESI-TWIMS-MS). In MS/MS, an anchimerically-assisted process was found to be unique to the electrosprayed α-anomer, and was only observed for the THF sample. In ESI-TWIMS-MS, a signal was measured at the drift time expected for the α-anomer for both the THF and DMAC samples, in apparent contradiction to the MS/MS results, which indicated that the α-anomer was not present in the DMAC sample. However, MS/MS experiments performed after TWIMS separation revealed that ammonium adducts of the α-anomer produced from each sample, although exhibiting the same collision cross section, were clearly different. Indeed, while the α-anomer actually present in the THF sample was electrosprayed with the ammonium adducted at the C2 acrylate, its homologue only observed when the DMAC sample was subjected to TWIMS hold the adducted ammonium at the C1 acrylate. These findings were explained by a β/α inter-conversion upon injection in the TWIMS cell, as supported by theoretical calculation and dynamic molecular modeling. Graphical Abstractᅟ