Intrinsic Permeation and Anti-Inflammatory Evaluation of Curcumin, Bisdemethoxycurcumin and Bisdemethylcurcumin by a Validated HPLC-UV Method.

Curcumin shows anti-inflammatory activity, and it has been widely investigated for neurodegenerative diseases, adjuvant treatment in AIDS and antitumor activity against different tumors, among other activities. The goal of this work was to evaluate the capacity of curcumin and its derivatives (bisdemethoxycurcumin and bisdemethylcurcumin) in preventing the irritant effects of topically applied xylol and to assess the intrinsic capacity of curcuminoids in permeating human skin by ex vivo permeation tests. Its secondary goal was to validate an HPLC method to simultaneously determine the curcuminoids in the samples from the ex vivo permeation studies and drug extraction from the skin. Curcuminoid quantification was performed using an RP-C18 column, at isocratic conditions of elution and a detection wavelength of 265 nm. The method was specific with a suitable peak resolution, as well as linear, precise, and accurate in the range of 0.195-3.125 µg/mL for the three curcuminoids. Bisdemethylcurcumin showed the greatest permeation through the human skin, and it was the curcuminoid that was most retained within the human skin. The anti-inflammatory activity of the curcuminoids was evaluated in vivo using a xylol-induced inflammation model in rats. Histological studies were performed to observe any changes in morphology at the microscopic level, and these three curcuminoids were found to be respectful within the skin structure. These results show that these three curcuminoids are suitable for anti-inflammatory formulations for dermal applications, and they can be properly quantified using HPLC-UV.

Luminescence of Macrocyclic Mononuclear DyIII Complexes and Their Immobilization on Functionalized Silicon-Based Surfaces.

Two mononuclear DyIII complexes, [Dy(L1)(NCS)3] (Dy-EDA) and [Dy(L2)(NCS)3] (Dy-DAP), where Ln (n = 1-2) corresponds to a macrocyclic ligand derived from 2,6-pyridinedicarboxaldehyde and ethylenediamine (L1) and 1,3-diaminepropane (L2) were immobilized on functionalized silicon-based surfaces. This was achieved by the microcontact printing (µCP) technique, generating patterns on a functionalized surface via covalent bond formation through the auxiliary -NCS ligands present in the macrocyclic complex species. With this strategy, it was possible to control the position of the immobilized molecules on the surface. Water contact angle measurements, X-ray photoelectron spectroscopy (XPS), infrared reflection absorption spectra (IRRAS), and atomic force microscopy (AFM) confirmed that the surfaces were successfully functionalized. Furthermore, the optical properties in a broad temperature range were investigated for the as-prepared compounds. At room temperature, Dy-EDA was shown to emit in the deep blue region (Commission Internationald'Eclairage (CIE): (0.175, 0.128)), while Dy-DAP in the white region (CIE: (0.252, 0.312)). The different CIE values were due to the contribution of the strong emission of the ligand in the case of Dy-EDA. Besides, surface photoluminescence measurements showed that the immobilized complexes retained their bulk emissive properties.

Room-Temperature Spin-Dependent Transport in Metalloporphyrin-Based Supramolecular Wires.

Here we present room-temperature spin-dependent charge transport measurements in single-molecule junctions made of metalloporphyrin-based supramolecular assemblies. They display large conductance switching for magnetoresistance in a single-molecule junction. The magnetoresistance depends acutely on the probed electron pathway through the supramolecular wire: those involving the metal center showed marked magnetoresistance effects as opposed to those exclusively involving the porphyrin ring which present nearly complete absence of spin-dependent charge transport. The molecular junction magnetoresistance is highly anisotropic, being observable when the magnetization of the ferromagnetic junction electrode is oriented along the main molecular junction axis, and almost suppressed when it is perpendicular. The key ingredients for the above effect to manifest are the electronic structure of the paramagnetic metalloporphyrin, and the spinterface created at the molecule-electrode contact.

Tuning Single-Molecule Conductance in Metalloporphyrin-Based Wires via Supramolecular Interactions.

Nature has developed supramolecular constructs to deliver outstanding charge-transport capabilities using metalloporphyrin-based supramolecular arrays. Herein we incorporate simple, naturally inspired supramolecular interactions via the axial complexation of metalloporphyrins into the formation of a single-molecule wire in a nanoscale gap. Small structural changes in the axial coordinating linkers result in dramatic changes in the transport properties of the metalloporphyrin-based wire. The increased flexibility of a pyridine-4-yl-methanethiol ligand due to an extra methyl group, as compared to a more rigid 4-pyridinethiol linker, allows the pyridine-4-yl-methanethiol ligand to adopt an unexpected highly conductive stacked structure between the two junction electrodes and the metalloporphyrin ring. DFT calculations reveal a molecular junction structure composed of a shifted stack of the two pyridinic linkers and the metalloporphyrin ring. In contrast, the more rigid 4-mercaptopyridine ligand presents a more classical lifted octahedral coordination of the metalloporphyrin metal center, leading to a longer electron pathway of lower conductance. This works opens to supramolecular electronics, a concept already exploited in natural organisms.

Boosting Self-Assembly Diversity in the Solid-State by Chiral/Non-Chiral ZnII -Porphyrin Crystallization.

A chiral ZnII porphyrin derivative 1 and its achiral analogue 2 were studied in the solid state. Considering the rich molecular recognition of designed metalloporphyrins 1 and 2 and their tendency to crystallize, they were recrystallized from two solvent mixtures (CH2 Cl2 /CH3 OH and CH2 Cl2 /hexane). As a result, four different crystalline arrangements (1 a,b and 2 a,b, from 0D to 2D) were obtained. Solid-state studies were performed on all the species to analyze the role played by chirality, solvent mixtures, and surfaces (mica and HOPG) in the supramolecular arrangements. By means of combinations of solvents and substrates a variety of microsized species was obtained, from vesicles to flower-shaped arrays, including geometrical microcrystals. Overall, the results emphasize the environmental susceptibility of metalloporphyrins and how this feature must be taken into account in their design.

Monolayer Contact Doping from a Silicon Oxide Source Substrate.

Monolayer contact doping (MLCD) is a modification of the monolayer doping (MLD) technique that involves monolayer formation of a dopant-containing adsorbate on a source substrate. This source substrate is subsequently brought into contact with the target substrate, upon which the dopant is driven into the target substrate by thermal annealing. Here, we report a modified MLCD process, in which we replace the commonly used Si source substrate by a thermally oxidized substrate with a 100 nm thick silicon oxide layer, functionalized with a monolayer of a dopant-containing silane. The thermal oxide potentially provides a better capping effect and effectively prevents the dopants from diffusing back into the source substrate. The use of easily accessible and processable silane monolayers provides access to a general and modifiable process for the introduction of dopants on the source substrate. As a proof of concept, a boron-rich carboranyl-alkoxysilane was used here to construct the monolayer that delivers the dopant, to boost the doping level in the target substrate. X-ray photoelectron spectroscopy (XPS) showed a successful grafting of the dopant adsorbate onto the SiO2 surface. The achieved doping levels after thermal annealing were similar to the doping levels acessible by MLD as demonstrated by secondary ion mass spectrometry measurements. The method shows good prospects, e.g. for use in the doping of Si nanostructures.

Distinguishing between Mechanical and Electrostatic Interaction in Single Pass Multi Frequency Electrostatic Force Microscopy Measurements on a Molecular Material.

Single-pass electrostatic force microscopy is postulated as one of the most advanced techniques in terms of spatial resolution and fastness in data acquisition for the study of electrostatic phenomena at the nanoscale. However, crosstalk anomalies, in which mechanical interactions combine with tip-sample electrostatic forces, are still a major issue to overcome, specifically in soft and biological samples. In this paper we propose a novel method based on bimodal-atomic force microscopy to distinguish mechanical crosstalk from electrostatic images. The method is based in the comparison of bimodal AFM images with electrostatic ones, where pure mechanical interaction can be discerned from a mixture of mechanical and electrostatic interactions. The proposed method is optimized and demonstrated using a supramolecular charge transfer material. Finally, the method is used as a tool to depict different crosstalk levels in tetrathiafulvalene-based (TTF) assemblies, discerning between electrical and mechanical interactions. This kind of observation is important for obtaining accurate descriptions of charge distribution in samples made from organic and molecular layers and materials.

Lung cancer in patients with chronic obstructive pulmonary disease. Development and validation of the COPD Lung Cancer Screening Score.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs. OBJECTIVES: To develop a predictive score for LC risk for patients with COPD. METHODS: The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP. MEASUREMENTS AND MAIN RESULTS: By regression analysis, age greater than 60, body mass index less than 25 kg/m(2), pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category. CONCLUSIONS: The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.

Improving selection criteria for lung cancer screening. The potential role of emphysema.

RATIONALE: Lung cancer (LC) screening using low-dose chest computed tomography is now recommended in several guidelines using the National Lung Screening Trial (NLST) entry criteria (age, 55-74; ≥30 pack-years; tobacco cessation within the previous 15 yr for former smokers). Concerns exist about their lack of sensitivity. OBJECTIVES: To evaluate the performance of NLST criteria in two different LC screening studies from Europe and the United States, and to explore the effect of using emphysema as a complementary criterion. METHODS: Participants from the Pamplona International Early Lung Action Detection Program (P-IELCAP; n = 3,061) and the Pittsburgh Lung Screening Study (PLuSS; n = 3,638) were considered. LC cumulative frequencies, incidence densities, and annual detection rates were calculated in three hypothetical cohorts, including subjects who met NLST criteria alone, those with computed tomography-detected emphysema, and those who met NLST criteria and/or had emphysema. MEASUREMENTS AND MAIN RESULTS: Thirty-six percent and 59% of P-IELCAP and PLuSS participants, respectively, met NLST criteria. Among these, higher LC incidence densities and detection rates were observed. However, applying NLST criteria to our original cohorts would miss as many as 39% of all LC. Annual screening of subjects meeting either NLST criteria or having emphysema detected most cancers (88% and 95% of incident LC of P-IELCAP and PLuSS, respectively) despite reducing the number of screened participants by as much as 52%. CONCLUSIONS: LC screening based solely on NLST criteria could miss a significant number of LC cases. Combining NLST criteria and emphysema to select screening candidates results in higher LC detection rates and a lower number of cancers missed.

Bottom-Up Hierarchical Self-Assembly of Chiral Porphyrins through Coordination and Hydrogen Bonds.

A series of chiral synthetic compounds is reported that shows intricate but specific hierarchical assembly because of varying positions of coordination and hydrogen bonds. The evolution of the aggregates (followed by absorption spectroscopy and temperature-dependent circular dichroism studies in solution) reveal the influence of the proportion of stereogenic centers in the side groups connected to the chromophore ring in their optical activity and the important role of pyridyl groups in the self-assembly of these chiral macrocycles. The optical activity spans 2 orders of magnitude depending on composition and constitution. Two of the aggregates show very high optical activity even though the isolated chromophores barely give a circular dichroism signal. Molecular modeling of the aggregates, starting from the pyridine-zinc(II) porphyrin interaction and working up, and calculation of the circular dichroism signal confirm the origin of this optical activity as the chiral supramolecular organization of the molecules. The aggregates show a broad absorption range, between approximately 390 and 475 nm for the transitions associated with the Soret region alone, that spans wavelengths far more than the isolated chromophore. The supramolecular assemblies of the metalloporphyrins in solution were deposited onto highly oriented pyrolitic graphite in order to study their hierarchy in assembly by atomic force microscopy. Zero and one-dimensional aggregates were observed, and a clear dependence on deposition temperature was shown, indicating that the hierarchical assembly took place largely in solution. Moreover, scanning electron microscopy images of porphyrins and metalloporphyrins precipitated under out-of-equilibrium conditions showed the dependence of the number and position of chiral amide groups in the formation of a fibrillar nanomaterial. The combination of coordination and hydrogen bonding in the complicated assembly of these molecules-where there is a clear hierarchy for zinc(II)-pyridyl interaction followed by hydrogen-bonding between amide groups, and then van der Waals interactions-paves the way for the preparation of molecular materials with multiple chromophore environments.

Efficient Chemical Modification of Carbon Nanotubes with Metallacarboranes.

As-produced single-walled carbon nanotubes (SWCNTs) tend to aggregate in bundles due to π-π interactions. Several approaches are nowadays available to debundle, at least partially, the nanotubes through surface modification by both covalent and noncovalent approaches. Herein, we explore different strategies to afford an efficient covalent functionalization of SWCNTs with cobaltabisdicarbollide anions. Aberration-corrected HRTEM analysis reveals the presence of metallacarboranes along the walls of the SWCNTs. This new family of materials presents an outstanding water dispersibility that facilitates its processability for potential applications.

Fluorescence of new o-carborane compounds with different fluorophores: can it be tuned?

Two sets of o-carborane derivatives incorporating fluorene and anthracene fragments as fluorophore groups have been successfully synthesized and characterized, and their photophysical properties studied. The first set, comprising fluorene-containing carboranes 6-9, was prepared by catalyzed hydrosilylation reactions of ethynylfluorene with appropriate carboranylsilanes. The compound 1-[(9,9-dioctyl-fluorene-2-yl)ethynyl]carborane (11) was synthesized by the reaction of 9,9-dioctyl-2-ethynylfluorene and decaborane (B10H14). Furthermore, reactions of the lithium salt of 11 with 1 equivalent of 4-(chloromethyl)styrene or 9-(chloromethyl)anthracene yielded compounds 12 and 13. Members of the second set of derivatives, comprising anthracene-containing carboranes, were synthesized by reactions of monolithium or dilithium salts of 1-Me-1,2-C2B10H11, 1-Ph-1,2-C2B10H11, and 1,2-C2B10H12 with 1 or 2 equivalents of 9-(chloromethyl)anthracene, respectively, to produce compounds 14-16. In addition, 2 equivalents of the monolithium salts of 1-Me-1,2-C2B10H11 (Me-o-carborane) and 1-Ph-1,2-C2B10H11 (Ph-o-carborane) were reacted with 9,10-bis(chloromethyl)anthracene to produce compounds 17 and 18, respectively. Fluorene derivatives 6-9 exhibit moderate fluorescence quantum yields (32-44 %), whereas 11-13, in which the fluorophore is bonded to the Ccluster (Cc), show very low emission intensity (6 %) or complete fluorescence quenching. The anthracenyl derivatives containing the Me-o-carborane moiety exhibit notably high fluorescence emissions, with ϕF = 82 and 94 %, whereas their Ph-o-carborane analogues are not fluorescent at all. For these compounds, we have observed a correlation between the Cc-Cc bond length and the fluorescence intensity in CH2Cl2 solution, comparable to that observed for previously reported styrene-containing carboranes. Thus, our hypothesis is that for systems of this type the fluorescence may be tuned and even predicted by changing the substituent on the adjacent Cc.

Biomolecules at interfaces: chiral, naturally.

Interfaces are a most important environment in natural and synthetic chemistries for a wide variety of processes, such as catalysis, recognition, separation, and so on. Naturally occurring systems have evolved to one handedness and the study of interfaces where biomolecules are located is a potentially revealing pursuit with regard to understanding the reasons and importance of stereochemistry in these environments. Equally, the spontaneous resolution of achiral and chiral compounds at interfaces could lead to explanations regarding the emergence of single handedness in proteins and sugars. Also, the attachment of biomolecules to surfaces leads to systems capable of stereoselective processes which may be useful for the applications mentioned above. The review covers systems ranging from small biomolecules studied under ultrapure conditions in vacuum to protein adsorption to surfaces in solution, and the techniques that can be used to study them.

A versatile methodology for the controlled synthesis of photoluminescent high-boron-content dendrimers.

Fluorescent star-shaped molecules and dendrimers with a 1,3,5-triphenylbenzene moiety as the core and 3 or 9 carborane derivatives at the periphery, have been prepared in very good yields by following different approaches. One procedure relies on the nucleophilic substitution of Br groups in 1,3,5-tris(4-(3-bromopropoxy)phenyl)benzene with the monolithium salts of methyl and phenyl-o-carborane. The second method is the hydrosilylation reactions on the peripheral allyl ether functions of 1,3,5-tris(4-allyloxy-phenyl)benzene and 1,3,5-tris(4-(3,4,5-trisallyloxybenzyloxy)phenyl)benzene with suitable carboranyl-silanes to produce different generations of dendrimers decorated with carboranyl fragments. This approach is very versatile and allows one to introduce long spacers between the fluorescent cores and the boron clusters, as well as to obtain a high loading of boron clusters. The removal of one boron atom from each cluster leads to high-boron-content water-soluble macromolecules. Thermogravimetric analyses show a higher thermal stability for the three-functionalized compounds than for those containing 9 clusters. All compounds exhibit photoluminescent properties at room temperature under ultraviolet irradiation with high quantum yields; these depend on the nature of the cluster and the substituent on the C(cluster). Cyclic voltammetry indicates that there is no electronic communication between the core and the peripheral carboranyl fragments. Due to the high boron content of these molecules, we currently focus our research on their biocompatibility, biodistribution in cells cultures, and potential applications for boron neutron capture therapy (BNCT).

A supramolecular approach to enzyme immobilization in micro-channels.

A supramolecular assembly scheme is developed to enable the facile in-situ immobilization of enzymes in a microfluidic channel system. A combination of orthogonal supramolecular interactions of host (ß-cyclodextrin)-guest (adamantane) and biotin-Streptavidin (SAv) interactions are employed to generate reusable homogeneous enzyme layers in microchannels. The structural integrity and catalytic activity of the immobilized enzyme calf-intestine alkaline phosphatase (AlkPh) is demonstrated. From the kinetic analysis of a dephosphorylation reaction, the specificity constant k(cat)/K(M) for immobilized alkaline phosphatase in the channels is on the order of 10(5) M(-1) s(-1) and comparable to known literature values in other environments. These observations are ascribed to the good access of the substrate to favorably oriented enzymes across the microchannel. Therefore, this study demonstrates the great potential for adopting a supramolecular assembly scheme to immobilize enzymes in microfluidic devices.

Supramolecularly oriented immobilization of proteins using cucurbit[8]uril.

A supramolecular strategy is used for oriented positioning of proteins on surfaces. A viologen-based guest molecule is attached to the surface, while a naphthol guest moiety is chemoselectively ligated to a yellow fluorescent protein. Cucurbit[8]uril (CB[8]) is used to link the proteins onto surfaces through specific charge-transfer interactions between naphthol and viologen inside the CB cavity. The assembly process is characterized using fluorescence and atomic force microscopy, surface plasmon resonance, IR-reflective absorption, and X-ray photoelectron spectroscopy measurements. Two different immobilization routes are followed to form patterns of the protein ternary complexes on the surfaces. Each immobilization route consists of three steps: (i) attaching the viologen to the glass using microcontact chemistry, (ii) blocking, and (iii) either incubation or microcontact printing of CB[8] and naphthol guests. In both cases uniform and stable fluorescent patterns are fabricated with a high signal-to-noise ratio. Control experiments confirm that CB[8] serves as a selective linking unit to form stable and homogeneous ternary surface-bound complexes as envisioned. The attachment of the yellow fluorescent protein complexes is shown to be reversible and reusable for assembly as studied using fluorescence microscopy.

Dielectric behavior of curcuminoid polymorphs on different substrates by direct soft vacuum deposition.

Our work examines the structural-electronic correlation of a new curcuminoid, AlkCCMoid, as a dielectric material on different substrates. For this purpose, we show a homemade sublimation method that allows the direct deposition of molecules on any type of matrix. The electronic properties of AlkCCMoid have been evaluated by measurements on single crystals, microcrystalline powder, and sublimated samples, respectively. GIWAXS studies on surfaces and XRD studies on powder have revealed the existence of polymorphs and the effect that substrates have on curcuminoid organization. We describe the dielectric nature of our system and identify how different polymorphs can affect electronic parameters such as permittivity, all corroborated by DFT calculations.

Broadening the scope of high structural dimensionality nanomaterials using pyridine-based curcuminoids.

We present a new heteroditopic ligand (3pyCCMoid) that contains the typical skeleton of a curcuminoid (CCMoid) decorated with two 3-pyridyl groups. The coordination of 3pyCCMoid with ZnII centres results in a set of novel coordination polymers (CPs) that display different architectures and dimensionalities (from 1D to 3D). Our work analyses how synthetic methods and slight changes in the reaction conditions affect the formation of the final materials. Great efforts have been devoted toward understanding the coordination entities that provide high dimensional systems, with emphasis on the characterization of 2D materials, including analyses of different types of substrates, stability and exfoliation in water. Here, we foresee the great use of CCMoids in the field of CPs and emphasize 3pyCCMoid as a new-born linker.

Orthogonal covalent and noncovalent functionalization of cyclodextrin-alkyne patterned surfaces.

The creation of cyclodextrin patterns on a fluorescent reporter surface by microcontact printing provides a versatile orthogonal surface modification method. The alkyne-beta-cyclodextrin surface is prepared through a "click" reaction on alkyne-terminated coumarin monolayers. The resulting alkyne-beta-cyclodextrin surface can be functionalized through supramolecular microcontact printing on cyclodextrin host patterns and by reactive microcontact printing-induced click chemistry on the alkyne-terminated patterns. The orthogonal covalent and supramolecular "host-guest" functionalization of the surface, and its specificity as well as selectivity, is demonstrated by sequential and one-step printing procedures.

π-Donor/π-Acceptor Interactions for the Encapsulation of Neurotransmitters on Functionalized Polysilicon-Based Microparticles.

Bipyridinium salts, commonly known as viologens, are π-acceptor molecules that strongly interact with π-donor compounds, such as porphyrins or amino acids, leading their self-assembling. These properties have promoted us to functionalize polysilicon microparticles with bipyridinium salts for the encapsulation and release of π-donor compounds such as catecholamines and indolamines. In this work, the synthesis and characterization of four gemini-type amphiphilic bipyridinium salts (1·4PF6-4·4PF6), and their immobilization either non-covalently or covalently on polysilicon surfaces and microparticles have been achieved. More importantly, they act as hosts for the subsequent incorporation of π-donor neurotransmitters such as dopamine, serotonin, adrenaline or noradrenaline. Ultraviolet-visible absorption and fluorescence spectroscopies and high-performance liquid chromatography were used to detect the formation of the complex in solution. The immobilization of bipyridinium salts and neurotransmitter incorporation on polysilicon surfaces was corroborated by contact angle measurements. The reduction in the bipyridinium moiety and the subsequent release of the neurotransmitter was achieved using ascorbic acid, or Vitamin C, as a triggering agent. Quantification of neurotransmitter encapsulated and released from the microparticles was performed using high-performance liquid chromatography. The cytotoxicity and genotoxicity studies of the bipyridinium salt 1·4PF6, which was selected for the non-covalent functionalization of the microparticles, demonstrated its low toxicity in the mouse fibroblast cell line (3T3/NIH), the human liver carcinoma cell line (HepG2) and the human epithelial colorectal adenocarcinoma cell line (Caco-2).