A highly sensitive and specific luminescent MOF determines nitric oxide production and quantifies hydrogen sulfide-mediated inhibition of nitric oxide in living cells.

The synthesis of a novel carboxylate-type organic linker-based luminescent MOF (Zn(H2L) (L1)) (named PUC2) (H2L = 2-aminoterephtalic acid, L1 = 1-(3-aminopropyl) imidazole) is reported by the solvothermal method and comprehensively characterized using single-crystal XRD, PXRD, FTIR, TGA, XPS, FESEM, HRTEM, and BET. PUC2 selectively reacts with nitric oxide (▪NO) with a detection limit of 0.08 µM, and a quenching constant (0.5 × 104 M-1) indicating a strong interaction with ▪NO. PUC2 sensitivity remains unaffected by cellular proteins or biologically relevant metals (Cu2+/ Fe3+/Mg2+/ Na+/K+/Zn2+), RNS/ROS, or H2S to score ▪NO in living cells. Lastly, we used PUC2 to demonstrate that H2S inhibition increases ▪NO production by ~ 14-30% in various living cells while exogenous H2S suppresses ▪NO production, indicating that the modulation of cellular ▪NO production by H2S is rather generic and not restricted to a particular cell type. In conclusion, PUC2 can successfully detect ▪NO production in living cells and environmental samples with considerable potential for its application in improving the understanding of the role of ▪NO in biological samples and study the inter-relationship between ▪NO and H2S.

Highly Efficient Mesoporous Carbonaceous CeO2 Catalyst for Dephosphorylation.

Phosphorus is fast becoming a critical element, as the global supply and demand are reaching unsustainable levels. Herein, the synthesis, characterization, and applicability of a novel biomass-derived mesoporous carbonaceous material decorated with CeO2 (CeO2-S400) as an efficient catalyst for the dephosphorylation of 4-nitrophenyl phosphate disodium salt hexahydrate are reported. The presence and distribution of CeO2 are evidenced by inductively coupled plasma mass spectrometry (ICP-MS) (118.7 mg/g), high-resolution transmission electron microscopy (HRTEM), and energy dispersive X-ray (EDX) mapping. The apparent rate constant for the efficient catalysis of 4-nitrophenyl phosphate disodium salt hexahydrate was 0.097 ± 0.01 for CeO2-ES and 0.15 ± 0.03 min-1 for CeO2-S400, which followed first-order kinetics. Rate constants normalized by the catalytic loading (k m) were 80.84 and 15.00 g-1 min-1 for CeO2-ES and CeO2-S400, respectively, and the normalized rate constants with respect to surface area were 3.38 and 0.04 m-2 min-1 for CeO2-ES and CeO2-S400, respectively. This indicates that the presence of CeO2 nanoparticles has a catalytic effect on the dephosphorylation reaction.

Stereoisomeric Pam2CS based TLR2 agonists: synthesis, structural modelling and activity as vaccine adjuvants.

Lipopeptides including diacylated Pam2CSK4 as well as triacylated Pam3CSK4 act as ligands of toll-like receptor (TLR)-2, a promising target for the development of vaccine adjuvants. The highly investigated Pam2CSK4 and Pam3CSK4, despite their aqueous solubility have not performed well as vaccine adjuvants which may be attributable to potential denaturation of protein antigens by these cationic surfactant-like lipopeptides. In the present investigation, we synthesized (R), (S) and racemic Pam2CS(OMe) analogs and their N-acetyl derivatives without the tetralysine component to systematically investigate the effect of stereochemistry at the thio-glycerol lipopeptide core of these lipopeptide based TLR2 agonists. The resulting compounds were compared using TLR2 reporter cell-based assays and the ability of the synthesized lipopeptides to stimulate cytokine production (IL-6, IL-10 and TNF-α) by freshly collected human PBMCs and CD40 and CD86 expressions by mouse spleen cells was also investigated. Notably, few synthesized lipopeptides were found to be potent TLR2/6 agonists, inducing cytokine production and upregulating CD40 and CD86 expressions. The TLR2/6 agonistic lipopeptides were further assessed for vaccine adjuvant effects in mice. The results confirmed that the R-stereochemistry at the thio-glycerol lipopeptide core was preferred for maximal TLR2/6 activity, as reflected in Th1 immune deviation, higher antibody levels and enhanced vaccine protection against a lethal influenza challenge.

Chitosan Hydrogels with Embedded Thermo- and pH-Responsive Microgels as a Potential Carrier for Controlled Release of Drugs.

We report a promising strategy based on chitosan (CS) hydrogels and dual temperature- and pH-responsive poly(N-isopropylacrylamide-co-methacrylic acid) (PNIPAM-co-MAA) microgels to facilitate release of a model drug, moxifloxacin (MFX). In this protocol, first, the microgels were prepared using a free radical copolymerization method, and subsequently, these carboxyl-group-rich soft particles were incorporated inside the hydrogel matrix using an EDC-NHS amidation method. Interestingly, the resulting microgel-embedded hydrogel composites (MG-HG) acting as a double barrier system largely reduced the drug release rate and prolonged the delivery time for up to 68 h, which was significantly longer than that obtained using microgels or hydrogels alone (20 h). On account of the dual-responsive features of the embedded microgels and the variation of water-solubility of drug molecules as a function of pH, MFX could be released in a controllable manner by regulating the temperature and pH of the delivery medium. The release kinetics followed a Korsmeyer-Peppas model, and the drug delivery mechanism was described by Fickian diffusion. Both the gel precursors and the hydrogel composites exhibited low cytotoxicity against mammalian cell lines (HeLa and HEK-293) and no deleterious hemolytic activity up to a certain higher concentration, indicating excellent biocompatibility of the materials. Thus, the unprecedented combination of modularity of physical properties caused by soft particle entrapment, unique macromolecular architecture, biocompatibility, and the general utility of the stimuli-responsive polymers offers a great promise to use these composite materials in drug delivery applications.

Development of Phosphatidylcholine/Tween 80 based biocompatible clove oil-in-water nanoemulsion as a green nanocarrier for controlled herbicide delivery.

Recently, the development of ecofriendly and biocompatible agrochemical delivery systems has garnered widespread attention because of their great potential in sustainable agri-food applications. Atrazine (ATZ) is a globally used herbicide used to control weeds, but it suffers from poor aqueous solubility, poor efficacy, and environmental loss. Herein, we report a novel, eco-friendly and biocompatible clove oil-based nanoemulsion as a green nanocarrier to enhance the solubility, bioavailability, and control release of ATZ. Food grade surfactants, Tween 80 and Phosphatidylcholine (PC) were used to formulate clove oil nanoemulsion with size <200 nm using ultrasonic emulsification technique, without any use of organic solvent. The ATZ encapsulation efficiency in NEm was greater than 95%. DLS confirms the nanosize (106 nm) and monodispersity of NEm. HRTEM reveals the spherical morphology of the nanodroplets. FTIR and DSC confirm the successful incorporation of ATZ inside the NEm oil droplet core. ATZ loaded NEm showed excellent thermal and storage stability, low Ostwald ripening rate, slow and sustained herbicide release behavior, which is of vital importance for an herbicide formulation. The release rate was better than commercial ATZ and free ATZ formulations. Results from herbicidal activity assays demonstrate that ATZ NEm exhibited excellent herbicidal activity even at low concentrations as compared to commercial ATZ analogs. In consideration of biocompatible excipients, free of organic solvent, and a simple fabrication process, ATZ loaded clove oil NEm can hold great potential in weed control and sustainable agri-food applications.

Combined delivery of TLR2 and TLR7 agonists by Nanostructured lipid carriers induces potent vaccine adjuvant activity in mice.

Toll-like receptor (TLR) agonists are promising adjuvants and the combination of TLR agonists enhance immune responses by providing synergistic immune activity via triggering different signalling pathways. However, systematic cytotoxicity due to the immediate release of such immune potentiators from the site of injection hampers its clinical performance. Nanostructured lipid carriers (NLCs) offer a possibility to incorporate multiple TLR agonists with high encapsulation efficiency and slow drug release. Herein, we synthesized NLCs from didodecyldimethylammonium bromide (D12DAB) and oleic acid and used these to co-encapsulate a Pam2CS derivative (T-2, TLR2 agonist) with an imidazoquinoline derivative (T-7, TLR7 agonist) as a combination vaccine adjuvant. Hydrodynamic diameter and zeta potential of the prepared NLCs were found to be in the range of 200-500 nm and 23-27 mV, respectively. Spherical shape and size of prepared NLCs were also assessed through Field Emission Scanning Electron Microscopy (FE-SEM) and Transmission Electron Microscopy (TEM) analysis. In-vitro release studies of T-7 demonstrated sustained release and the addition of lipopeptide T-2 augmented encapsulation efficiency (from 84 to 92.9%) with a slight trigger in the release percentage. All NLC formulations were screened in TLR2/1, TLR2/6, TLR7 and TLR8 reporter cell lines and loaded NLC formulation showed high TLR2 and TLR7 agonistic activity. Adjuvant potency was evaluated through intramuscular immunization of female C57BL/6 mice with recombinant hepatitis B surface antigen and influenza hemagglutinin protein. T-2 and T-7 loaded NLCs induced good protective efficacy in mice challenged with a lethal dose of influenza virus.

TLR2 Agonistic Small Molecules: Detailed Structure-Activity Relationship, Applications, and Future Prospects.

Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the various TLRs, TLR2 has a special place due to its ability to sense the widest repertoire of PAMPs owing to its heterodimerization with either TLR1 or TLR6, broadening its ligand diversity against pathogens. Various scaffolds are reported to activate TLR2, which include naturally occurring lipoproteins, synthetic lipopeptides, and small heterocyclic molecules. We described a detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR2 agonists to antigens, carbohydrates, polymers, and fluorophores. The approaches involved in delivery of TLR2 agonists such as lipidation of antigen, conjugation to polymers, phosphonic acids, and other linkers to achieve surface adsorption, liposomal formulation, and encapsulating nanoparticles are elaborated. The crystal structure analysis and computational modeling are also included with the structural features that facilitate TLR2 activation.

Yb(OTf)3-Catalyzed and Di-tert-butyl Dicarbonate-Mediated Decarboxylative Etherification and Esterification Reactions.

Protecting group chemistry has invariably captured the fascination of chemists because of its extensive viability in chemical synthesis. The present report describes our pioneer work of applying ytterbium triflate as a catalyst, for the reaction of alcohols with di-tert-butyl dicarbonate (Boc2O) leading to the formation of tert-butyl ethers. There exists no recorded evidence for the use of Yb(OTf)3 as a catalyst for the protection of alcohols to tert-butyl ethers, despite its excellent utility in various reactions. Yb(OTf)3 has been used predominantly in the catalytic deprotection studies such as selective deprotection of tert-butyl esters to carboxylic acids as well as prenyl ethers to alcohols. This study involved the critical evaluation of solvent, time, and temperature that finally led to an efficient protocol for the formation of tert-butyl ethers. Yb(OTf)3 catalyzed the formation of tert-butyl ethers, notably reducing the reaction time, which is exemplified by the achievement of up to 92% conversion of alcohols to tert-butyl ethers within an hour. Additionally, the report demonstrates the utility of this synthetic protocol for the protection of carboxylic acids.

Green Nanotechnology-Driven Drug Delivery Assemblies.

Green nanotechnology incorporates the principles of green chemistry and green engineering to fabricate innocuous and eco-friendly nanoassemblies to combat the problems affecting the human health or environment. Subsequently, amalgamation of green nanotechnology with drug delivery area has actually commenced a new realm of "green nanomedicine". The burgeoning demand for green nanotechnology-driven drug delivery systems has led to the development of different types of delivery devices, like inorganic (metallic) nanoparticles, quantum dots, organic polymeric nanoparticles, mesoporous silica nanoparticles, dendrimers, nanostructured lipid carriers, solid lipid nanoparticles, etc. The present article deals with a brief account of delivery devices produced from green methods and describes site-specific drug delivery systems (including their pros and cons) and their relevance in the field of green nanomedicine.

Correction: Understanding the role of co-surfactants in microemulsions on the growth of copper oxalate using SAXS.

Correction for 'Understanding the role of co-surfactants in microemulsions on the growth of copper oxalate using SAXS' by Sunaina et al., Phys. Chem. Chem. Phys., 2019, 21, 336-348.

Flexible plasmonic graphene oxide/heterostructures for dual-channel detection.

Graphene oxide (GO) films are deposited on flexible Kapton substrates and selectively modified to conductive reduced graphene oxide (rGO) electrodes using laser patterning. Based on this, we design, fabricate, and test a flexible sensor integrating laser-reduced GO with silver plasmonic nanostructures. The fabricated device results in dual transduction channels: for electrochemical and plasmonic nanostructure-based surface-enhanced Raman spectroscopy (SERS) detection. The spectroscopic analysis verifying the formation of rGO and the modification by silver nanostructures is performed by Raman, energy dispersive X-ray (EDX), and X-ray photoelectron spectroscopy (XPS). The morphological investigation is followed by optical and scanning electron microscopy imaging. In addition to pristine silver nanostructures, the Raman spectroscopy results show the formation of species such as Ag2O, Ag2CO3, and Ag2SOx. A dual-channel sensor device based on electrochemical and plasmonic detection is fabricated as a demonstration of our Ag-rGO flexible concept architecture. The dual-channel device performance is successfully demonstrated in the electrochemical and SERS detection of 4-nitrobenzenethiol (4-NBT) using the same device. Our results show that without Ag nanostructures the sensitivity in the electrochemical and optical channels is not sufficient to detect 4-NBT. The performance and stability of the silver modified device are also verified. This work demonstrates an inexpensive, highly efficient, and greener way that is compatible with solution-processing technology for the production of flexible GO-based electrochemical and SERS detection devices integrated with plasmonic nanostructures.

Understanding the role of co-surfactants in microemulsions on the growth of copper oxalate using SAXS.

This study is an effort to understand the mechanism of the effect of the chain length of co-surfactants on the growth of copper oxalate inside the core of reverse micelles using small angle X-ray scattering (SAXS). In this study, we have used two different kinds of co-surfactants viz. 1-butanol (C4) and 1-octanol (C8) for the formation of the microemulsions. Time-dependent SAXS studies were carried out for these two systems. The data were analyzed using both the model-independent approach and model-dependent approach. For microemulsions containing only water inside the core of reverse micelles (no ions), the shape of the reverse micelles was observed to be ellipsoid and spherical in nature for 1-butanol and 1-octanol respectively. For a system containing copper oxalate nanostructures, the fitting was carried out using the ellipsoidal core-shell model for reverse micelles and spheres, ellipsoids and cylinders for copper oxalate nanostructures with 1-butanol as the co-surfactant. With 1-octanol as the co-surfactant, the two contributions that were used were the spherical core-shell model for reverse micelles and spheres for copper oxalate nanostructures. Based on the analysis of SAXS data, a growth mechanism has been proposed. The study discussed here could open the field of understanding the growth mechanism of complex nanostructures formed using the microemulsion route.

Synthetic Toll-like receptor agonists for the development of powerful malaria vaccines: a patent review.

INTRODUCTION: Currently, there is no efficient vaccine available against clinical malaria. However, continuous efforts have been committed to develop powerful antimalarial vaccine by discovery of novel antigens with in-depth understanding of its nature, immunogenicity, and presentation (delivery adjuvants). Moreover, another important part of vaccine development includes discovery of better immunostimulatory formulation components (immunostimulants). A protective vaccine against malaria requires antigen-specific B and T helper cell responses as well as cytotoxic T lymphocyte (CTL) responses. A long-lasting B and T memory cell production is also required for effective malaria vaccine. Since activation of Toll-like receptors (TLRs) promotes both innate inflammatory responses as well as the induction of adaptive immunity, several initiatives have been mounted during the last few years for the use of TLR agonists as malaria vaccine adjuvants. AREAS COVERED: The review summarizes reports related to the use and development of TLR agonists as malaria vaccine adjuvants and describes various strategies involved for the selection of specific antigens and TLR agonists. EXPERT OPINION: TLR agonists are promising adjuvants for the development of effective malaria vaccine, allowing for both innate inflammatory responses as well as the induction of adaptive immunity.

An efficient and scalable synthesis of potent TLR2 agonistic PAM2CSK4.

Diacylated PAM2CSK4, a highly expensive lipopeptide with desirable aqueous solubility and a broad spectrum of cytokine/chemokine induction is a most potent dual (human and murine) Toll-Like Receptor-2 (TLR2) agonist. Besides such thrilling characteristics, its synthetic process is not reported in the literature. The present report describes an efficient and scalable 20 step synthesis of PAM2CSK4 in good yield (all steps > 60%) along with a clear description of the hindrances and easy solutions adopted in each step. Overall, a convergent synthetic approach was adopted involving synthesis of appropriately protected starting materials, synthesis of a key backbone skeleton PAM2CS, synthesis of a tetralysine fragment and the final coupling to yield PAM2CSK4. Tedious column chromatography was avoided on a large scale in many steps.

A fluorescent probe based on nitrogen doped graphene quantum dots for turn off sensing of explosive and detrimental water pollutant, TNP in aqueous medium.

This paper reports the carbonization assisted green approach for the fabrication of nitrogen doped graphene quantum dots (N-GQDs). The obtained N-GQDs displayed good water dispersibility and stability in the wide pH range. The as synthesized N-GQDs were used as a fluorescent probe for the sensing of explosive 2,4,6-trinitrophenol (TNP) in aqueous medium based on fluorescence resonance energy transfer (FRET), molecular interactions and charge transfer mechanism. The quenching efficiency was found to be linear in proportion to the TNP concentration within the range of 0-16µM with detection limit (LOD) of 0.92µM. The presented method was successfully applied to the sensing of TNP in tap and lake water samples with satisfactory results. Thus, N-GQDs were used as a selective, sensitive and turn off fluorescent sensor for the detection of perilous water contaminant i.e. TNP.

Probing location of anti-TB drugs loaded in Brij 96 microemulsions using thermoanalytical and photophysical approach.

The aim of this work is to monitor the changes in microstructure in nonionic Brij 96 microemulsions and to locate the solubilization loci of antituberculosis drugs (of variable solubility using photophysical and thermoanalytical properties. Using properties such as spectral shift, Stroke's shift, and anisotropy for two dyes, that is, Nile red (NR) and tris(2,2'-bipyridine)ruthenium(II) dichloride (RC), the structure of microemulsions has been investigated. With the help of spectral and deconvoluted analysis, it has been seen that rifampicin (RIF) shows a strong interaction with NR and isoniazid (INH) and pyrazinamide (PZA) with RC. It has been concluded that RIF molecules are mainly present at the interface toward oil side and INH toward hydrophilic side, whereas PZA remains in free water. The findings have been correlated with aqueous solubility drugs and partition coefficients. Differential scanning calorimetry elucidates the state of water in microheterogeneous environment and variation of different states, that is, free, bound, interphasal, and nonfreezable water with dilution. In addition, it confirmed the stability and location of the drugs in the prepared Brij 96 microemulsion formulations. A good agreement between both the studies has been achieved. These findings will help in elucidating the drug delivery properties of anti-TB drugs-loaded microemulsion formulations in future.

Synthesis of highly stable, water-dispersible copper nanoparticles as catalysts for nitrobenzene reduction.

We report an aqueous-phase synthetic route to copper nanoparticles (CuNPs) using a copper-surfactant complex and tests of their catalytic efficiency for a simple nitrophenol reduction reaction under atmospheric conditions. Highly stable, water-dispersed CuNPs were obtained with the aid of polyacrylic acid (PAA), but not with other dispersants like surfactants or polymethacrylic acid (PMAA). The diameter of the CuNPs could be controlled in the range of approximately 30-85 nm by modifying the ratio of the metal precursor to PAA. The catalytic reduction of p-nitrophenol to p-aminophenol takes place at the surface of CuNPs at room temperature and was accurately monitored by UV/Vis spectroscopy. The catalytic efficiency was found to be remarkably high for these PAA-capped CuNPs, given the fact that at the same time PAA is efficiently preventing their oxidation as well. The activity was found to increase as the size of the CuNPs decreased. It can therefore be concluded that the synthesized CuNPs are catalytically highly efficient in spite of the presence of a protective PAA coating, which provides them with a long shelf life and thereby enhances the application potential of these CuNPs.

Synthesis of silica nanoparticles covered with silver beads.

Procedures for producing silica nanoparticles suitable for further amino functionalization and subsequent decoration with silica beads were investigated in a comparative way. Several methods, one based on tetrapropylammonium hydroxide, the classical Stöber synthesis, and two with amino acids (either lysine or arginine) as catalysts were employed and followed by means of DLS, SAXS, and TEM. The amino acid methods proved to be by far the most satisfactory ones, yielding highly spherical and monodisperse nanoparticles with a tunable size range of 15-100 nm. The surface of the particles could be functionalized with propylamine, which enabled to obtain positive surface charge at low pH and to tune the zeta potential by the pH in the range of +/- 40 mV. Finally, the modified particles were used to reduce silver (I) ions at high pH, leading to the formation of very small silver beads covering the silica surface and yielding a nanocomposite with a "raspberry" structure. Interestingly, this could be achieved without using any complementary reducing agent besides the particles themselves, thereby opening a very simple path to the formation of composite metal containing colloidal systems.

Microwave-assisted synthesis of small Ru nanoparticles and their role in degradation of congo red.

Polyethyleneglycol (PEG) stabilized Ru nanoparticles (NPs) were synthesized by single pot rapid microwave (µW) method in presence of glucose as reducing agent. The µW reaction for different amounts of added glucose and PEG was monitored by UV-vis spectroscopy. Small sized NPs (2-5 nm) were obtained with appropriate amounts of glucose and PEG. The size of particles decreased with increasing µW power and decreasing irradiation time (keeping input energy constant), as observed by dynamic light scattering and transmission electron microscopy, which means one has size control via preparation process. X-ray diffraction pattern confirmed hcp lattice of synthesized Ru(0) NPs. To demonstrate their usefulness, a model reaction was selected in which degradation of azo bonds of congo red dye was catalyzed by Ru NPs. This is first report where Ru NPs were employed in catalytic decolorization of an azo dye, which is an important application in waste water treatment. It was found that the NPs acted as an electron mediator in transfer of electron from reducing agent to azo bond. Rate of the reaction increased drastically by introducing Ru NPs in the system and decolorization of dye was accelerated by factor of 200, which is substantial improvement in facilitating this important reaction.

Highly sensitive luminescent sensor for cyanide ion detection in aqueous solution based on PEG-coated ZnS nanoparticles.

Using polyethylene glycol (PEG) coated ZnS nanoparticles (NPs), a novel and highly sensitive luminescent sensor for cyanide ion detection in aqueous solution has been presented. ZnS NPs have been used to develop efficient luminescence sensor which exhibits high reproducibility and stability with the lowest limit of detection of 1.29×10(-6) mol L(-1). The observed limit of detection of the fabricated sensor is ~6 times lower than maximum value of cyanide permitted by United States Environmental Protection Agency for drinking water (7.69×10(-6) mol L(-1)). The interfering studies show that the developed sensor possesses good selectivity for cyanide ion even in presence of other coexisting ions. Importantly, to the best of our knowledge, this is the first report which demonstrates the utilization of PEG- coated ZnS NPs for efficient luminescence sensor for cyanide ion detection in aqueous solution. This work demonstrates that rapidly synthesized ZnS NPs can be used to fabricate efficient luminescence sensor for cyanide ion detection.