The spectroelectrochemical response of small silver particles was studied in aqueous solution using an optically transparent, thin layer electrode. The position of the surface plasmon band of the colloidal silver was found to depend on the applied electrode potential. It varied from 400 nm in air, corresponding to a redox potential of +0.15 V vs Ag/AgCl, to about 392 nm at −0.6 V vs Ag/AgCl. A value of 80 ± 10 μF cm-2 for the double-layer capacitance of the silver−water interface was obtained on the basis of the spectroelectrochemical shift. The equilibration kinetics of the particles with the electrode obeyed the Cottrell equation. However, the number of electrons transferred at each particle−electrode encounter was found to be potential dependent and reached 1600 ± 300 at potentials more negative than −0.4 V vs Ag/AgCl. The evidence suggests that this particle charging current occurs via electron tunneling across the particle and electrode double layers and not by contact electrification. Changes in the redox potential of the particles due to added chemical reductants could also be directly monitored by laser doppler electrophoresis.
A novel reduced iron metal-organic framework nanoparticle with cytotoxicity specific to cancer cells is presented. This nanoparticle was prepared via a hydrothermal method, reduced using hydroquinone, and finally conjugated with folic acid (namely, rMOF-FA). The synthesized nanoparticle shows the controlled release of iron in an acidic ex-vivo environment. Iron present on the rMOF-FA and released into solution can react with high levels of hydrogen peroxide found specifically in cancer cells to increase the hydroxyl radical concentration. The hydroxyl radicals oxidize proteins, lipids, and/or DNA within the biological system to decrease cell viability. In vitro experiments demonstrate that this novel nanoparticle is cytotoxic to cancer cells (HeLa) through generation of OH inside the cells. At low concentrations of rMOF-FA, the cancer cell viability decreases dramatically, with no obvious reduction of normal cell (NIH-3T3) viability. The calculated half-maximum inhibitory concentration value (IC) was 43 μg/mL for HeLa cells, which was significantly higher than 105 μg/mL for NIH-3T3. This work thus demonstrates a new type of agent for controlled hydroxyl radical generation using the Fenton reaction to kill the tumor cells.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
Electrokinetic transport behavior in nanochannels is different to that in larger sized channels. Specifically, molecular dynamics (MD) simulations in nanochannels have demonstrated two little understood phenomena which are not observed in microchannels, being : (i) the decrease of average electroosmotic mobility at high surface charge density, and (ii) the decrease of channel conductance at high salt concentrations, as the surface charge is increased. However, current electric double layer models do not capture these results. In this study we provide evidence that this inconsistency primarily arises from the neglect of the viscoelectric effect (being the increase of local viscosity near charged surfaces due to water molecule orientation) in conventional continuum models. It is shown that predictions of electroosmotic mobility in a slit nanochannel, derived from a viscoelectricmodified continuum model, are in quantitative agreement with previous MD simulation results. Furthermore, viscoelectric effects are found to dominate over ion steric and dielectric saturation effects in both electroosmotic and ion transport processes. Finally, we indicate that mechanisms of the previous MD-observed phenomena can be well-explained by the viscoelectric theory.
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