Gene/Protein Disease Symptom Drug Enzyme Compound
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Recently, chemically synthesized short interfering RNA (siRNA) duplexes have been used with success for gene silencing. Chemical modification is desired for therapeutic applications to improve biostability and pharmacokinetic properties; chemical modification may also provide insight into the mechanism of silencing. siRNA duplexes containing the 2,4-difluorotoluyl ribonucleoside (rF) were synthesized to evaluate the effect of noncanonical nucleoside mimetics on RNA interference. 5'-Modification of the guide strand with rF did not alter silencing relative to unmodified control. Internal uridine to rF substitutions were well-tolerated. Thermal melting analysis showed that the base pair between rF and adenosine (A) was destabilizing relative to a uridine-adenosine pair, although it was slightly less destabilizing than other mismatches. The crystal structure of a duplex containing rFoA pairs showed local structural variations relative to a canonical RNA helix. As the fluorine atoms cannot act as hydrogen bond acceptors and are more hydrophobic than uridine, there was an absence of a well-ordered water structure around the rF residues in both grooves. siRNAs with the rF modification effectively silenced gene expression and offered improved nuclease resistance in serum; therefore, evaluation of this modification in therapeutic siRNAs is warranted.
ACS Chem Biol 2006 Apr 25
PMID:Gene silencing activity of siRNAs with a ribo-difluorotoluyl nucleotide. 1716 65

Short interfering RNA (siRNA) duplexes are currently being evaluated as antisense agents for gene silencing. Chemical modification of siRNAs is widely expected to be required for therapeutic applications in order to improve delivery, biostability and pharmacokinetic properties. Beyond potential improvements in the efficacy of oligoribonucleotides, chemical modification may also provide insight into the mechanism of mRNA downregulation mediated by the RNA-protein effector complexes (RNA-induced silencing complex or RISC). We have studied the in vitro activity in HeLa cells of siRNA duplexes against firefly luciferase with substitutions in the guide strand of U for the apolar ribo-2,4-difluorotoluyl nucleotide (rF) [Xia, J. et al. (2006) ACS Chem. Biol., 1, 176-183] as well as of C for rF. Whereas an internal rF:A pair adjacent to the Ago2 ('slicer' enzyme) cleavage site did not affect silencing relative to the native siRNA duplex, the rF:G pair and other mismatches such as A:G or A:A were not tolerated. The crystal structure at atomic resolution determined for an RNA dodecamer duplex with rF opposite G manifests only minor deviations between the geometries of rF:G and the native U:G wobble pair. This is in contrast to the previously found, significant deviations between the geometries of rF:A and U:A pairs. Comparison between the structures of the RNA duplex containing rF:G and a new structure of an RNA with A:G mismatches with the structures of standard Watson-Crick pairs in canonical duplex RNA leads to the conclusion that local widening of the duplex formed by the siRNA guide strand and the targeted region of mRNA is the most likely reason for the intolerance of human Ago2 (hAgo2), the RISC endonuclease, toward internal mismatch pairs involving native or chemically modified RNA. Contrary to the influence of shape, the thermodynamic stabilities of siRNA duplexes with single rF:A, A:A, G:A or C:A (instead of U:A) or rF:G pairs (instead of C:G) show no obvious correlation with their activities. However, incorporation of three rF:A pairs into an siRNA duplex leads to loss of activity. Our structural and stability data also shed light on the role of organic fluorine as a hydrogen bond acceptor. Accordingly, UV melting (T(M)) data, osmotic stress measurements, X-ray crystallography at atomic resolution and the results of semi-empirical calculations are all consistent with the existence of weak hydrogen bonds between fluorine and the H-N1(G) amino group in rF:G pairs of the investigated RNA dodecamers.
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PMID:Crystal structure, stability and in vitro RNAi activity of oligoribonucleotides containing the ribo-difluorotoluyl nucleotide: insights into substrate requirements by the human RISC Ago2 enzyme. 1788 74

Ultrathin films are important nanoscale structures that are used extensively in a variety of technological contexts. However, it has traditionally been difficult and costly to fabricate detachable and purely inorganic high aspect ratio films with controlled thickness and good uniformity. Here we report a versatile method to make separable purely inorganic membranes of various metal oxides such as Nb(2)O(5), TiO(2), WO(3), and Ta(2)O(5) with thicknesses ranging from 30 to 150 nm. Fluoride ions are migrated through the oxide film and upon arrival at the oxide-metal interface form a sacrificial soluble oxyfluoride layer. Fluorine also plays a role in controlling the porosity of the films. The study exposes the mechanism behind the detachment process that is largely due to the fast migration of fluoride anions relative to oxygen anions. The resulting films have a wide range of potential applications as catalysts or catalyst supports, filtration membranes, sensors, and more.
ACS Nano 2008 Nov 25
PMID:Universal method for the fabrication of detachable ultrathin films of several transition metal oxides. 1920 4

The fluorescent dye Alexa Fluor 488 or the anticancer drug doxorubicin is attached to the surface and inner pore walls of mesoporous Si particles by covalent attachment, and the oxidation-induced release of each molecule is studied. The molecules are bound to the Si matrix using a 10-undecenoic acid linker, which is attached by thermal hydrosilylation. Loading capacity of the microparticles using this method is approximately 0.5 and 45 mg/g of porous Si microparticle for Alexa Fluor 488 and doxorubicin, respectively. The Si-C-bound assembly is initially stable in aqueous solution, although oxidation of the underlying Si matrix results in conversion to silicon oxide and slow release of the linker-molecule complex by hydrolysis of the Si-O attachment points. When the attached molecule is a fluorophore (Alexa Fluor 488 or doxorubicin), its fluorescence is effectively quenched by the semiconducting silicon matrix. As the particle oxidizes in water, the fluorescence intensity of the attached dye increases due to growth of the insulating silicon oxide layer and, ultimately, dye release from the surface. The recovery of fluorescence in the microparticle and the release of the molecule into solution are monitored in real-time by fluorescence microscopy. Both processes are accelerated by introduction of the oxidizing species peroxynitrite to the aqueous solution. The oxidation-triggered release of the anticancer drug doxorubicin to HeLa cells is demonstrated.
ACS Nano 2008 Nov 25
PMID:Oxidation-triggered release of fluorescent molecules or drugs from mesoporous Si microparticles. 1920 8

We present the synthesis of a modular delivery system that is composed of two main macromolecular building blocks, dendritic molecular transporter molecules and a polymeric scaffold in a size dimension of 5-10 nm. The conjugated dendritic molecular transporter units proved to be critical for the delivery of the polymer nanoparticle into 3T3 cells and illustrates the dendritic molecular transporter promoted intracellular uptake of polymer particles derived from intramolecular chain collapse processes. In a sequence of modification steps, pyridinyldithio linker was introduced to undergo thiol-disulfide exchange reactions with peptide sequences containing cysteine amino acid units to furnish peptide-nanoparticle conjugates with cleavable disulfide linkers. The intracellular uptake of the nanoparticle conjugates and the delivery of the peptidic cargo were studied via dual labeling of the nanoparticle with Alexa Fluor 568 dye and fluorescein (FITC) markers on the peptide in mammalian cell lines such as NIH 3T3 cells via confocal microscopy. In this work, we have demonstrated the assembly of a novel nanoscopic delivery system in which the conjugated dendritic molecular transporter molecules facilitated the rapid cellular uptake of a nanoparticle-peptide conjugate with up to 25 copies of peptidic cargo to establish new venues for the implementation of protein and oligonucleotide drugs.
ACS Nano 2009 Feb 24
PMID:Molecular dendritic transporter nanoparticle vectors provide efficient intracellular delivery of peptides. 1923 78

Recently, a flow-based selectin-dependent method for the capture and enrichment of specific types of cells (CD34+ hematopoetic stem and progenitor cells and human leukemia HL60) from peripheral blood was demonstrated. However, these devices depend on a monolayer of selectin protein, which has been shown to have a maximum binding efficiency as a function of surface area. A novel surface coating of colloidal silica nanoparticles was designed that alters the surface roughness resulting in increased surface area. The nanoparticles were adhered using either an inorganic titanate resinous coating or an organic polymer of poly-L-lysine. Using Alexa Fluor 647 conjugated P-selectin, an increase in protein adsorption of up to 35% when compared to control was observed. During perfusion experiments using P-selectin-coated microtubes, we observed increased cell capture and greatly decreased rolling velocity at equivalent protein concentration compared to nonparticle control. Atomic force microscopy showed increased surface roughness consistent with the nanoparticle mean diameter, suggesting a monolayer of particles. These results support the coating's potential to improve existing cell capture implantable devices for a variety of therapeutic and scientific uses.
ACS Nano 2010 Jan 26
PMID:Nanoparticle coatings for enhanced capture of flowing cells in microtubes. 2001 20

Boron nitride (BN) is a promising semiconductor with a wide band gap ( approximately 6 eV). Here, we report the synthesis of vertically aligned BN nanosheets (BNNSs) on silicon substrates by microwave plasma chemical vapor deposition from a gas mixture of BF(3)-N(2)-H(2). The size, shape, thickness, density, and alignment of the BNNSs were well-controlled by appropriately changing the growth conditions. With changing the gas flow rates of BF(3) and H(2) as well as their ratio, the BNNSs evolve from three-dimensional with branches to two-dimensional with smooth surface and their thickness changes from 20 to below 5 nm. The growth of the BNNSs rather than uniform granular films is attributed to the particular chemical properties of the gas system, mainly the strong etching effect of fluorine. The alignment of the BNNSs is possibly induced by the electrical field generated in plasma sheath. Strong UV light emission with a broad band ranging from 200 to 400 nm and superhydrophobicity with contact angles over 150 degrees were obtained for the vertically aligned BNNSs. The present BNNSs possess the properties complementary to carbon nanosheets such as intrinsically semiconducting, high temperature stability, and high chemical inertness and may find applications in ultraviolet nanoelectronics, catalyst supports, electron field emission, and self-cleaning coatings, etc., especially those working at high temperature and in harsh environments.
ACS Nano 2010 Jan 26
PMID:Vertically aligned boron nitride nanosheets: chemical vapor synthesis, ultraviolet light emission, and superhydrophobicity. 2004 71

A series of poly(arylene ethynylene) conjugated polyelectrolytes (CPEs) substituted with carboxylic acid side groups have been synthesized and characterized. The polymers feature a backbone consisting of a carboxylated dialkoxyphenylene-1,4-ethynylene unit alternating with a second arylene ethynylene moiety of variable electron demand. The HOMO-LUMO gap is varied across the series, giving rise to a set of four polymers that have absorption maxima ranging from 404 to 495 nm. The CPEs adsorb effectively from solution onto nanostructured TiO(2) films, giving rise to TiO(2)/CPE films that absorb approximately 90% of the incident light at the absorption band maximum. The photocurrent generation efficiency of the TiO(2)/CPE films was examined in a solar cell configuration using an I(3)(-)/I(-) propylene carbonate electrolyte and a Pt/fluorine-doped tin oxide counter electrode. Most of the films exhibit good photocurrent generation efficiency with a peak quantum efficiency of approximately 50% at wavelengths corresponding to the polymers' absorption band maximum. Interestingly, the photocurrent generation efficiency for the lowest-band-gap polymer is substantially lower compared to the other three systems. This effect is attributed to efficient nonradiative decay of excitons at trap sites arising from interchain contacts distal from the TiO(2)/CPE interface.
ACS Appl Mater Interfaces 2009 Feb
PMID:Variable-band-gap poly(arylene ethynylene) conjugated polyelectrolytes adsorbed on nanocrystalline TiO(2): photocurrent efficiency as a function of the band gap. 2035 27

The present paper reports a very simple and low-cost fluorine-free superhydrophobic coating prepared by spray-coating metal alkylcarboxylates, for example, Cu[CH(3)(CH(2))(10)COO](2), onto virtually any substrates. Superhydrophobicity with a static water contact angle of about 160 degrees and a sliding angle of 5 degrees was achieved from the proper precursor concentration. The advantages of the present approach include the cheap and fluorine-free raw materials, environmentally benign solvents, an industrial implementation method, and easy repairability and applicability so as to make a great application potential in practice. The hydrophobicity of coatings and the adhesion to water were found to be dependent on the surface morphology that was governed by the precursor concentrations from which coatings were prepared. The static wetting behavior of water droplets with different sizes gentlly deposited on the coatings was studied in more detail and correlated to theories, i.e., Wenzel's and Cassie's models. The results indicated that nanoribbon-textured coatings prepared from low precursor concentration (0.02 M) exhibited a transition from the metastable Cassie-Baxter state to the Wenzel state with increments in the droplet volume, and eventually droplets firmly stick to the surface even when the droplet was gently deposited on the surface. Surface coatings with dual roughness at both microscale and nanometer scale were formed as the concentration (0.04 M) was increased and conferred a stable Cassie state, even for increased droplet size and increased droplet deposit speed.
ACS Appl Mater Interfaces 2009 Aug
PMID:Spray-coated fluorine-free superhydrophobic coatings with easy repairability and applicability. 2035 80

An inverted-type organic bulk-heterojunction solar cell inserting zinc oxide (ZnO) as an electron collection electrode, fluorine-doped tin oxide (FTO)/ZnO/[6,6]-phenyl-C(61)-butyric acid methyl ester:regioregular poly(3-hexylthiophene) (PCBM:P3HT)/poly(3,4-ethylenedioxylenethiophene):poly(4-styrenesulfonic acid) (PEDOT:PSS)/Au, was fabricated in air and characterized by an alternating current impedance spectroscopy (IS). In the IS measurement, we observed reproducibly the electric resistance and capacitance components originating from ZnO and organic active layers, and we found that the depletion layer functioning to take out the photocurrent to the external circuit was formed in both the ZnO and PCBM:P3HT layers at the ZnO/PCBM:P3HT interface. In this letter, we propose that this IS measurement is effective for evaluating the electric properties of several layers with capacitance components in organic thin-film solar cells.
ACS Appl Mater Interfaces 2009 Oct
PMID:Characterization of inverted-type organic solar cells with a ZnO layer as the electron collection electrode by ac impedance spectroscopy. 2035 41


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