Elaborated study of Cu(II) carbosilane metallodendrimers bearing substituted iminopyridine moieties as antitumor agents.

Iminopyridine-decorated carbosilane metallodendrimers have recently emerged as a promising strategy in the treatment of cancer diseases. Their unique features such as the nanometric size, the multivalent nature and the structural perfection offer an extraordinary platform to explore structure-to-property relationships. Herein, we showcase the outstanding impact on the antitumor activity of a parameter not explored before: the iminopyridine substituents in meta position. New Cu(II) carbosilane metallodendrimers, bearing methyl or methoxy substituents in the pyridine ring, were synthesized and thoroughly characterized. Electron Paramagnetic Resonance (EPR) was exploited to unveil the properties of the metallodendrimers. This study confirmed the presence of different coordination modes of the Cu(II) ion (Cu-N2O2, Cu-N4 and Cu-O4), whose ratios were determined by the structural features of the dendritic molecules. These metallodendrimers exhibited IC50 values in the low micromolar range (<6 µM) in tumor cell lines such as HeLa and MCF-7. The subsequent in vitro assays on both healthy (PBMC) and tumor (U937) myeloid cells revealed two key facts which improved the cytotoxicity and selectivity of the metallodrug: First, maximizing the Cu-N2O2 coordination mode; second, adequately selecting the pair ring-substituent/metal-counterion. The most promising candidates, G1(-CH3)Cl (8) and G1(-OCH3)NO3(17), exhibited a substantial increase in the antitumor activity in U937 tumor cells, compared to the non-substituted counterparts, probably through two different ROS-production pathways.

Smart Synthesis of Trimethyl Ethoxysilane (TMS) Functionalized Core-Shell Magnetic Nanosorbents Fe3O4@SiO2: Process Optimization and Application for Extraction of Pesticides.

In the current study, a smart approach for synthesizing trimethyl ethoxysilane-decorated magnetic-core silica-nanoparticles (TMS-mcSNPs) and its effectiveness as nanosorbents have been exploited. While the magnetite core was synthesized using the modified Mössbauer method, Stöber method was employed to coat the magnetic particles. The objective of this work is to maximize the magnetic properties and to minimize both particle size (PS) and particle size distribution (PSD). Using a full factorial design (2k-FFD), the influences of four factors on the coating process was assessed by optimizing the three responses (magnetic properties, PS, and PSD). These four factors were: (1) concentration of tetraethyl-orthosilicate (TEOS); (2) concentration of ammonia; (3) dose of magnetite (Fe3O4); and (4) addition mode. Magnetic properties were calculated as the attraction weight. Scanning electron microscopy (SEM) was used to determine PS, and standard deviation (±SD) was calculated to determine the PSD. Composite desirability function (D) was used to consolidate the multiple responses into a single performance characteristic. Pareto chart of standardized effects together with analysis of variance (ANOVA) at 95.0 confidence interval (CI) were used to determine statistically significant variable(s). Trimethyl ethoxysilane-functionalized mcSNPs were further applied as nanosorbents for magnetic solid phase extraction (TMS-MSPE) of organophosphorus and carbamate pesticides.

Cu(II)-Catalysed ß-silylation of dehydroalanine residues in peptides and proteins.

We report the efficient and selective Cu(ii)-catalysed ß-silylation of naturally occurring dehydroalanine (Dha) residues in various ribosomally synthesized and post-translationally modified peptides (RiPPs). The method is also applicable to proteins, as was shown by the modification of a Dha residue that was chemically introduced into Small Ubiquitin-like Modifier (SUMO).

Synthesis, Characterization, Biomedical Application, Molecular Dynamic Simulation and Molecular Docking of Schiff Base Complex of Cu(II) Supported on Fe3O4/SiO2/APTS.

INTRODUCTION: Over the past several years, nano-based therapeutics were an effective cancer drug candidate in order to overcome the persistence of deadliest diseases and prevalence of multiple drug resistance (MDR). METHODS: The main objective of our program was to design organosilane-modified Fe3O4/SiO2/APTS(~NH2) core magnetic nanocomposites with functionalized copper-Schiff base complex through the use of (3-aminopropyl)triethoxysilane linker as chemotherapeutics to cancer cells. The nanoparticles were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), field emission scanning electron microscopy (FE-SEM), TEM, and vibrating sample magnetometer (VSM) techniques. All analyses corroborated the successful synthesis of the nanoparticles. In the second step, all compounds of magnetic nanoparticles were validated as antitumor drugs through the conventional MTT assay against K562 (myelogenous leukemia cancer) and apoptosis study by Annexin V/PI and AO/EB. The molecular dynamic simulations of nanoparticles were further carried out; afterwards, the optimization was performed using MM+, semi-empirical (AM1) and Ab Initio (STO-3G), ForciteGemo Opt, Forcite Dynamics, Forcite Energy and CASTEP in Materials studio 2017. RESULTS: The results showed that the anti-cancer activity was barely reduced after modifying the surface of the Fe3O4/SiO2/APTS nanoparticles with 2-hydroxy-3-methoxybenzaldehyde as Schiff base and then Cu(II) complex. The apoptosis study by Annexin V/PI and AO/EB stained cell nuclei was performed that apoptosis percentage of the nanoparticles increased upon increasing the thickness of Fe3O4 shell on the magnetite core. The docking studies of the synthesized compounds were conducted towards the DNA and Topoisomerase II via AutoDock 1.5.6 (The Scripps Research Institute, La Jolla, CA, USA). CONCLUSION: Results of biology activities and computational modeling demonstrate that nanoparticles were targeted drug delivery system in cancer treatment.

A Silyl Ether Based Fluorescent Probe for Rapid Monitoring of Endogenous Peroxynitrite Concentration and Imaging in Living Cells through Multicolor Emission.

The peroxynitrite ion (ONOO- ) has important roles in many biological processes. We have developed a multicolor ONOO- -sensing probe (SiONNOH) that undergoes deprotonation and desilylation processes, which result in several changes in the emission wavelengths. In response to different concentrations of ONOO- , the probe exhibits fluorescence changes from pink (595 nm at 2 eq. ONOO- ) to green (540 nm at 6 eq. ONOO- ) via orange (3 eq. ONOO- ) and yellow (4 eq. ONOO- ) under physiological conditions until no fluorescence signal is observed after ONOO- is completely eliminated by lipoic acid. The probe shows the high selectivity for ONOO- and the limit of detection is calculated to be 1.27 µM. Moreover, the probe shows the capacity to monitor the concentration ranges of ONOO- through multicolor fluorescence in living cells, which will greatly facilitate the rapid detection of ONOO- concentration ranges by the naked eye under a UV light without any precision instrumentation.

Nanoscaled Materials for Drug Delivery into Cells/Stem Cells.

The successful and efficient transport and delivery of drugs and biomolecules to cells/stem cells have revealed the main challenge in clinical therapy development. Special materials and systems are used in smart drug delivery to improve the effectiveness by controlling drug release and decreasing the side effects. Synthesized water-dispersible polymer-covalent organic framework nanocomposites are integrated via the assembly of PEG-modified monofunctional curcumin derivatives and amine-functionalized covalent organic frameworks for in vitro and in vivo drug delivery. The smart delivery system exhibits an efficient targeting strategy for cancer therapy and also demonstrates an important promise on the improvement of a smart system for cancer cell-/stem cell-targeted drug delivery.

Citric acid functionalized silane coupling versus post-grafting strategy for dual pH and saline responsive delivery of cisplatin by Fe3O4/carboxyl functionalized mesoporous SiO2 hybrid nanoparticles: A-synthesis, physicochemical and biological characterization.

Synthesis of monodisperse carboxylic acid-functionalized magnetic mesoporous silica nanoparticles is performed by either two-step sol-gel process or post-grafting using citric acid modified isocyanate silane coupling agent (MMSN-NCO-CA) or succinic anhydride modified magnetic mesoporous silica (MMSN-NH-SA). Morphology, structure and magnetic properties of bare and mesoporous silica coated Fe3O4 core were studied using various techniques such as FTIR, VSM, TEM, FESEM, XRD and N2 adsorption-desorption isotherms (BET). Cisplatin (cis-Pt) adsorption isotherms and its release profile in various media were investigated by ICP-OES. MMSN-NCO-CA with mean particle size 107 nm had lower surface area (87.5 m2/g) and larger pore size (6.9 nm) in comparison with MMSN-NH-SA (respective values of 151.2 m2/g and 3.5 nm). cis-Pt loading into particles followed a saturable adsorption with respect to the drug to particle mass ratios. More sustained release of cis-Pt was observed for MMSN-NCO-CA, though both nanoparticles exhibited a pH- and saline concentration-dependent drug release. In addition, general and cis-Pt specific cytotoxicity were examined by MTT assay in MDA-MB-231 breast cancer cell line, and to further detect apoptosis, acridine orange/ethidium bromide dual cell staining was investigated by fluorescence microscopy. In-vitro anti-tumor efficiency of cis-Pt loaded MMSN-NCO-CA and MMSN-NH-SA were similarly enhanced in comparison to free cis-Pt; however, more specific apoptotic death occurred for cis-Pt loaded MMSN-NCO-CA. Therefore, the as-synthesized citric acid functionalized core-shell magnetic mesoporous hybrid nanoparticles could be used as a promising drug carriers for cancer therapy in-vivo.

Complement proteins regulating macrophage polarisation on biomaterials.

One of the events occurring when a biomaterial is implanted in an host is the protein deposition onto its surface, which might regulate cell responses. When a biomaterial displays a compromised biocompatibility, distinct complement pathways can be activated to produce a foreign body reaction. In this article, we have designed different types of biomaterial surfaces to study the inflammation process. Here, we used different concentrations of (3-glycidoxypropyl)-trimethoxysilane (GPTMS), an organically-modified alkoxysilane as a precursor for the synthesis of various types of sol-gel materials functionalizing coatings for titanium implants to regulate biological responses. Our results showed that greater GPTMS surface concentrations induced greater secretion of TNF-α and IL-10 on RAW 264.7 macrophages. When implanted into rabbit tibia, osseointegration decreased with higher GPTMS concentrations. Interestingly, higher deposition of complement-related proteins C-reactive protein (CRP) and ficolin-2 (FCN2), two main activators of distinct complement pathways, was observed. Taking all together, inflammatory potential increase seems to be GPTMS concentration-dependent. Our results show that a greater adsorption of complement proteins can condition macrophage polarization.

H2 O2 -Responsive Organosilica-Doxorubicin Nanoparticles for Targeted Imaging and Killing of Cancer Cells Based on a Synthesized Silane-Borate Precursor.

Doxorubicin (Dox) is a widely used fluorescent chemotherapy drug. Its primary delivery systems, based on physical adsorption to silica nanoparticles, can lead to low drug loading. Direct loading of Dox via covalent bonds during the formation of silica nanoparticles has never been reported. In this work, we designed and synthesized a silane-borate precursor, which contains not only an alkoxysilane moiety to form organosilica nanoparticles but also a phenylboronic acid moiety to react with diol-containing compounds. Using this compound, the covalent loading of Dox during the preparation of organosilica nanoparticles was effectively realized with a high drug loading content up to 22.4 %. Further modification by hyaluronic acid (HA) bestowed the Si-Dox@HA nanoparticles with the ability to target CD44-overexpressing cancer cells. The Si-Dox@HA nanoparticles exhibited H2 O2 -responsive release of about 80 % Dox and displayed seven-fold selectivity for killing cancer cells over normal cells, relative to Dox and Si-Dox nanoparticles. Moreover, these Si-Dox@HA nanoparticles are also suitable for targeted fluorescence imaging of CD44-overexpressing cancer cells.

Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling.

An asymmetric Ni-catalyzed reductive cross-coupling has been developed to prepare enantioenriched allylic silanes. This enantioselective reductive alkenylation proceeds under mild conditions and exhibits good functional group tolerance. The chiral allylic silanes prepared here undergo a variety of stereospecific transformations, including intramolecular Hosomi-Sakurai reactions, to set vicinal stereogenic centers with excellent transfer of chirality.

Carbosilane metallodendrimers based on copper (II) complexes: Synthesis, EPR characterization and anticancer activity.

A series of new organometallic carbosilane dendrimers functionalized with Copper(II) complex on the surface were synthesized and characterized as potential anticancer agents. These metallodendrimers were synthesized through the reaction of dendritic ligands containing N,N- and N,O- donor atoms able to act as chelating agents with CuCl2 as metallic ion precursor. The structural characterization of these complexes was addressed through the use of different analytical and spectroscopical techniques. Particularly, an electron paramagnetic resonance study was performed to corroborate the coordination properties of these dendritic ligands. A preliminary study was carried out to establish the cytotoxicity of the new synthesized compounds in human prostate (PC3) and human cervical (HeLa) cancer cell lines in order to evaluate their potential as anticancer agents and compare their activity with other copper or analogous ruthenium metallodendrimers.

Doxorubicin-modified magnetic nanoparticles as a drug delivery system for magnetic resonance imaging-monitoring magnet-enhancing tumor chemotherapy.

In this study, we developed functionalized superparamagnetic iron oxide (SPIO) nanoparticles consisting of a magnetic Fe3O4 core and a shell of aqueous stable polyethylene glycol (PEG) conjugated with doxorubicin (Dox) (SPIO-PEG-D) for tumor magnetic resonance imaging (MRI) enhancement and chemotherapy. The size of SPIO nanoparticles was ~10 nm, which was visualized by transmission electron microscope. The hysteresis curve, generated with vibrating-sample magnetometer, showed that SPIO-PEG-D was superparamagnetic with an insignificant hysteresis. The transverse relaxivity (r 2) for SPIO-PEG-D was significantly higher than the longitudinal relaxivity (r 1) (r 2/r 1 >10). The half-life of Dox in blood circulation was prolonged by conjugating Dox on the surface of SPIO with PEG to reduce its degradation. The in vitro experiment showed that SPIO-PEG-D could cause DNA crosslink more serious, resulting in a lower DNA expression and a higher cell apoptosis for HT-29 cancer cells. The Prussian blue staining study showed that the tumors treated with SPIO-PEG-D under a magnetic field had a much higher intratumoral iron density than the tumors treated with SPIO-PEG-D alone. The in vivo MRI study showed that the T2-weighted signal enhancement was stronger for the group under a magnetic field, indicating that it had a better accumulation of SPIO-PEG-D in tumor tissues. In the anticancer efficiency study for SPIO-PEG-D, the results showed that there was a significantly smaller tumor size for the group with a magnetic field than the group without. The in vivo experiments also showed that this drug delivery system combined with a local magnetic field could reduce the side effects of cardiotoxicity and hepatotoxicity. The results showed that the developed SPIO-PEG-D nanoparticles own a great potential for MRI-monitoring magnet-enhancing tumor chemotherapy.

Silole-Based Red Fluorescent Organic Dots for Bright Two-Photon Fluorescence In vitro Cell and In vivo Blood Vessel Imaging.

Robust luminescent dyes with efficient two-photon fluorescence are highly desirable for biological imaging applications, but those suitable for organic dots fabrication are still rare because of aggregation-caused quenching. In this work, a red fluorescent silole, 2,5-bis[5-(dimesitylboranyl)thiophen-2-yl]-1-methyl-1,3,4-triphenylsilole ((MesB)2 DTTPS), is synthesized and characterized. (MesB)2 DTTPS exhibits enhanced fluorescence efficiency in nanoaggregates, indicative of aggregation-enhanced emission (AEE). The organic dots fabricated by encapsulating (MesB)2 DTTPS within lipid-PEG show red fluorescence peaking at 598 nm and a high fluorescence quantum yield of 32%. Upon excitation at 820 nm, the dots show a large two-photon absorption cross section of 3.43 × 10(5) GM, which yields a two-photon action cross section of 1.09 × 10(5) GM. These (MesB)2 DTTPS dots show good biocompatibility and are successfully applied to one-photon and two-photon fluorescence imaging of MCF-7 cells and two-photon in vivo visualization of the blood vascular of mouse muscle in a high-contrast and noninvasive manner. Moreover, the 3D blood vasculature located at the mouse ear skin with a depth of over 100 µm can also be visualized clearly, providing the spatiotemporal information about the whole blood vascular network.

Access to α,α-Disubstituted Disilylated Amino Acids and Their Use in Solid-Phase Peptide Synthesis.

A concise synthetic pathway yielding to hydrophobic α,α-disubstituted disilylated amino acids based on a hydrosilylation reaction is described. As a first example of utilization in solid-phase peptide synthesis, TESDpg was introduced in replacement of Aib in an alamethicin sequence, leading to analogues with modified physicochemical properties and conserved helical structures. This study highlights the potential of these new amino acids as tools for peptide modulation.

Adlayer-mediated antibody immobilization to stainless steel for potential application to endothelial progenitor cell capture.

This work describes the straightforward surface modification of 316L stainless steel with BTS, S-(11-trichlorosilylundecanyl)-benzenethiosulfonate, a thiol-reactive trichlorosilane cross-linker molecule designed to form intermediary coatings with subsequent biofunctionalization capability. The strategy is more specifically exemplified with the immobilization of intact antibodies and their Fab' fragments. Both surface derivatization steps are thoroughly characterized by means of X-ray photoelectron spectroscopy. The antigen binding capability of both types of biofunctionalized surfaces is subsequently assessed by fluorescence microscopy. It was determined that BTS adlayers achieve robust immobilization of both intact and fragmented antibodies, while preserving antigen binding activity. Another key finding was the observation that the Fab' fragment immobilization strategy would constitute a preferential option over that involving intact antibodies in the context of in vivo capture of endothelial progenitor cells in stent applications.

Low-valent iron(i) amido olefin complexes as promotors for dehydrogenation reactions.

Fe(I) compounds including hydrogenases show remarkable properties and reactivities. Several iron(I) complexes have been established in stoichiometric reactions as model compounds for N2 or CO2 activation. The development of well-defined iron(I) complexes for catalytic transformations remains a challenge. The few examples include cross-coupling reactions, hydrogenations of terminal olefins, and azide functionalizations. Here the syntheses and properties of bimetallic complexes [MFe(I) (trop2 dae)(solv)] (M=Na, solv=3 thf; M=Li, solv=2 Et2 O; trop=5H-dibenzo[a,d]cyclo-hepten-5-yl, dae=(N-CH2 -CH2 -N) with a d(7) Fe low-spin valence-electron configuration are reported. Both compounds promote the dehydrogenation of N,N-dimethylaminoborane, and the former is a precatalyst for the dehydrogenative alcoholysis of silanes. No indications for heterogeneous catalyses were found. High activities and complete conversions were observed particularly with [NaFe(I) (trop2 dae)(thf)3 ].

A new way to silicone-based peptide polymers.

We describe a new class of silicone-containing peptide polymers obtained by a straightforward polymerization in water using tailored chlorodimethylsilyl peptide blocks as monomeric units. This general strategy is applicable to any type of peptide sequences, yielding linear or branched polymer chains composed of well-defined peptide sequences.

Synthesis of new anionic carbosilane dendrimers via thiol-ene chemistry and their antiviral behaviour.

A synthetic strategy has been developed for the preparation of anionic carbosilane dendrimers bearing sulfonate or carboxylate groups at their periphery by means of thiol-ene chemistry. It offers significant advantages, such as milder reaction conditions, shorter reaction times and more facile purification methods, when compared with other synthetic protocols used previously, e.g. hydrosilylation followed by a Michael-type addition or azide-alkyne coupling reactions. Molecular dynamics simulations of the second generation anionic dendrimers addressing shape and size effects of the terminal groups and conformational variability indicated that the core eccentricity and flexibility might need to be taken into account for toxicity and interaction with viral and/or cellular receptors, respectively. The biocompatibility of anionic carbosilane dendrimers has been explored showing differences between silicon-cored and polyphenoxo-cored dendrimers. In addition, silicon-cored dendrimers achieved 85-90% of HIV inhibition without inducing inflammation or vaginal irritation in mice, which makes them likely candidates for readily available, good and safe topical vaginal microbicides against HIV.

Design and synthesis of lipidic organoalkoxysilanes for the self-assembly of liposomal nanohybrid cerasomes with controlled drug release properties.

This paper reports the facile design and synthesis of a series of lipidic organoalkoxysilanes with different numbers of triethoxysilane headgroups and hydrophobic alkyl chains linked by glycerol and pentaerythritol for the construction of cerasomes with regulated surface siloxane density and controlled release behavior. It was found that the number of triethoxysilane headgroups affected the properties of the cerasomes for encapsulation efficiency, drug loading capacity, and release behavior. For both water-soluble doxorubicin (DOX) and water-insoluble paclitaxel (PTX), the release rate from the cerasomes decreased as the number of triethoxysilane headgroups increased. The slower release rate from the cerasomes was attributed to the higher density of the siloxane network on the surface of the cerasomes, which blocks the drug release channels. In contrast to the release results with DOX, the introduction of one more hydrophobic alkyl chain into the cerasome-forming lipid resulted in a slower release rate of PTX from the cerasomes due to the formation of a more compact cerasome bilayer. An MTT viability assay showed that all of these drug-loaded cerasomes inhibited proliferation of the HepG2 cancer cell line. The fine tuning of the chemical structure of the cerasome-forming lipids would foster a new strategy to precisely regulate the release rate of drugs from cerasomes.

Regioselective allene hydrosilylation catalyzed by N-heterocyclic carbene complexes of nickel and palladium.

Regioselective methods for allene hydrosilylation have been developed, with regioselectivity being governed primarily by the choice of metal. Alkenylsilanes are produced via nickel catalysis with larger N-heterocyclic carbene (NHC) ligands, and allylsilanes are produced via palladium catalysis with smaller NHC ligands. These complementary methods allow either regioisomeric product to be obtained with exceptional regiocontrol.