Impact of Additive Hydrophilicity on Mixed Dye-Nonionic Surfactant Micelles: Micelle Morphology and Dye Localization.

The nonionic surfactant pentaethylene glycol-monododecylether C12E5 forms micelles in aqueous solutions with a lower critical solution temperature. This characteristic solution behavior of C12E5 is independent of the pH. Such micelles are used to solubilize a large variety of active guest molecules like for instance dyestuffs. An example is an acidic azo dye termed Blue used as a hair colorant. Depending on the pH, Blue gradually changes its hydrophilicity from the protonated BlueH at pH = 2 to the bivalent anion Blue2- at pH = 13 while keeping the shape and size of Blue essentially unchanged. These features of C12E5 and Blue offer the unique chance to investigate the sole impact of a tunable hydrophilicity of a guest molecule on the solution behavior of mixed micelles of the guest and C12E5. Accordingly, the present work establishes a phase diagram of Blue-C12E5 micelles and analyzes their morphology including the spatial distribution of Blue in the micelles as a function of the hydrophilicity of Blue. Small angle neutron scattering reveals the size and shape of the micelles, and detailed contrast matching of the C12E5 supported by 1H NMR with NOESY provided insight into the localization of Blue within the micelles as its hydrophilicity changes.

Tuning conductivity while maintaining mechanical properties in perylene bisimide hydrogels at physiological pH.

By using different salts as a method to achieve gelation of two different amino-acid-functionalised perylene bisimides, we were able to tune reduction potentials while maintaining the mechanical and optical properties of the system all at pH 7.4.

Combination of a pH-responsive peptide amphiphile and a conventional antibiotic in treating Gram-negative bacteria.

BACKGROUND: Clinical treatments ofgastric infections using antibiotics suffer from the undesired killing of commensal bacteria and emergence of antibiotic resistance. It is desirable to develop pH-responsive antimicrobial peptides (AMPs) that kill pathogenic bacteria such as H. pyloriand resistant E. coli under acidic environment with minimal impact to commensal bacteria whilst not causing antibiotic resistance. EXPERIMENTS: Using a combined approach of cell assays, molecular dynamics (MD) simulations and membrane models facilitating biophysical and biochemical measurements including small angle neutron scattering (SANS), we have characterized the pH-responsive physiochemical properties and antimicrobial performance of two amphiphilic AMPs, GIIKDIIKDIIKDI-NH2 and GIIKKIIDDIIKKI-NH2 (denoted as 3D and 2D, respectively), that were designed by selective substitutions of cationic residues of Lys (K) in the extensively studied AMP G(IIKK)3I-NH2 with anionic residue Asp (D). FINDINGS: Whilst 2D kept non-ordered coils across the entire pH range studied, 3D displayed a range of secondary structures when pH was shifted from basic to acidic, with distinct self-assembly into nanofibers in aqueous environment. Further experimental and modeling studies revealed that the AMPs interacted differently with the inner and outer membranes of Gram-negative bacteria in a pH-responsive manner and that the structural features characterized by membrane leakage and intramembrane nanoaggregates revealed from fluorescence spectroscopy and SANS were well linked to antimicrobial actions. Different antimicrobial efficacies of 2D and 3D were underlined by the interplay between their ability to bind to the outer membrane lipid LPS (lipopolysaccharide), outer membrane permeability change and inner membrane depolarization and leakage. Furthermore, AMP's binding with the inner membrane under acidic condition caused both the dissipation of membrane potential (Δψ) and the continuous dissipation of transmembrane ΔpH, with Δψ and ΔpH being the key components of the proton motive force. Combinations of antibiotic (Minocycline) with the pH-responsive AMP generated the synergistic effects against Gram-negative bacteria only under acidic condition. These features are crucial to target applications to gastric infections, anti-acne and wound healing.

Photoacid-macroion assemblies: how photo-excitation switches the size of nano-objects.

Electrostatic self-assembly of photoacids with oppositely charged macroions yields supramolecular nano-objects in aqueous solutions, whose size is controlled through light irradiation. Nano-assemblies are formed due to electrostatic attractions and mutual hydrogen bonding of the photoacids. Irradiation with UV light leads to the deprotonation of the photoacid and, consequently, a change in particle size. Overall, the hydrodynamic radii of the well-defined photoacid-macroion nano-objects lie between 130 and 370 nm. For a set of photoacids, we determine the acidity constants in the ground and excited state, discuss the sizes of photoacid-macroion nano-objects (by dynamic and static light scattering), their composition and the particle shapes (by small-angle neutron scattering), and relate their charge characteristics to size, structure and shape. We investigate the association thermodynamics and relate nanoscale structures to thermodynamics and, in turn, thermodynamics to molecular features, particularly the ionization energy of the photoacid hydroxyl group proton. Structure-directing effects completely differ from those for previously investigated systems, with hydrogen bonding and entropic effects playing a major role herein. This combined approach allows developing a comprehensive understanding of assembly formation and photo-response, anchored in molecular parameters (pKa, ionization energy, substituent group location), charge characteristics, and the association enthalpy and entropy. This fundamental understanding again paves the way for tailoring application solutions with novel photoresponsive materials.

Nanostructure in Amphiphile-Based Deep Eutectic Solvents.

Deep eutectic solvents (DESs) are an emerging class of modern, often "green" solvents with unique properties. Recently, a deep eutectic system based on amphiphilic surfactant N-alkyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (C12 & C14 sulfobetaine) and (1S)-(+)-10-camphor-sulfonic acid in the molar ratio 1:1.5 has been reported. Nanostructuring can be expected in this DES due to the nature of the components. In this work, we have investigated the native nanostructure in the DES comprising C12-C18 alkyl chain sulfobetaines with camphor sulfonic acid and how it interacts with polar and nonpolar species, water and dodecane, respectively, using small angle neutron scattering. By using contrast variation to highlight the relative position of the solvent components and additives, we can resolve the structure of the solvent and how it changes upon interaction with water and dodecane. Scattering from the neat DES shows structures corresponding to the self-assembly of sulfobetaines; the size of the structure increases as the alkyl chain length of the sulfobetaines increases. Water and dodecane interact, respectively, with the hydrophilic and hydrophobic moieties in the DES structure, primarily the sulfobetaine, thereby swelling and solvating the entire structure. The extent of the shift of the peak position, and the swelling, depend on concentration of the additive. The solution phase organization and the interaction of polar and nonpolar species as observed here, have the potential to affect the ordering of inorganic or polymeric materials grown in such solvents, paving new avenues for templating applications.

The H-D-isotope effect of heavy water affecting ligand-mediated nanoparticle formation in SANS and NMR experiments.

An isotopic effect of normal (H2O) vs. heavy water (D2O) is well known to fundamentally affect the structure and chemical properties of proteins, for instance. Here, we correlate the results from small angle X-ray and neutron scattering (SAXS, SANS) with high-resolution scanning transmission electron microscopy to track the evolution of CdS nanoparticle size and crystallinity from aqueous solution in the presence of the organic ligand ethylenediaminetetraacetate (EDTA) at room temperature in both H2O and D2O. We provide evidence via SANS experiments that exchanging H2O with D2O impacts nanoparticle formation by changing the equilibria and dynamics of EDTA clusters in solution as investigated by nuclear magnetic resonance analysis. The colloidal stability of the CdS nanoparticles, covered by a layer of [Cd(EDTA)]2- complexes, is significantly reduced in D2O despite the strong stabilizing effect of EDTA in suspensions of normal water. Hence, conclusions about nanoparticle formation mechanisms from D2O solutions reveal limited transferability to reactions in normal water due to isotopic effects, which thus need to be discussed for contrast match experiments.

Double-Wavelength-Switchable Molecular Self-Assembly of a Photoacid and Spirooxazine in an Aqueous Solution.

Quadruple-switchable nanoscale assemblies are built by combining two types of water-soluble molecular photoswitches through dipole-dipole interaction. Uniting the wavelength-specific proton dissociation of a photoacid and ring-opening of an anionic spirooxazine results in an assembly that can be addressed by irradiation with two different wavelengths: pH and darkness.

SANS contrast matching for the unambiguous localization of anionic dye in cationic surfactant micelles.

Contrast variation in small-angle neutron scattering (SANS) was successfully applied to localize the anionic azo dye Blue in co-assemblies with the cationic surfactant dodecyltrimethylammoniumbromide (DTAB). For this purpose, the scattering contrast between DTAB and the aqueous solvent was eliminated by SANS contrast matching, leaving only the scattering signal from Blue to be detected. Results obtained by contrast matching were confirmed by NOESY NMR-spectroscopy, showing that Blue interacts with the positively charged DTAB head groups and with up to the 4th neighbouring methylene group of the DTAB C12-alkyl chain. Its localization in the outer layer of the Blue-DTAB co-assembly explains the uniaxial growth of spheroidal DTAB micelles to wormlike micelles with increasing [Blue] : [DTAB] ratio from 0 : 1 to 1 : 3. This is in line with the concept of the packing parameter for amphiphilic substances.

Arabinoxylan in Water through SANS: Single-Chain Conformation, Chain Overlap, and Clustering.

Using small-angle neutron scattering (SANS), we examine the structure and conformational behavior of wheat arabinoxylan (AX) prepared at various concentrations in a sodium phosphate aqueous buffer. As for another major hemicellulose, xyloglucan, we observe a small number of large clusters surrounded by AX chains that behave exactly as a polymer in good solvent with a Flory exponent ν = 0.588. The fit of the data at high q-values to a standard worm-like chain model gives the persistence length lp = 45 Å and cross section of the chains 2Rc = 11-12 Å. In addition, using a dedicated modeling approach, we extract from the SANS data at the intermediate q-range the correlation length ξ of the solutions in the semidilute regime. The decay of ξ with concentration follows a scaling law that further confirms the self-avoiding statistical behavior of the AX chains. This first comprehensive study about the properties of water-soluble AX at different length scales may help in the development of products and processes involving AX as a substitute for fossil carbon molecules.

Comparative study of the self-assembly behaviour of 3-chloro-4-hydroxy-phenylazo dyes.

The complexity of intermolecular interactions and the difficulty to predict assembly behaviour solely based on chemical constitution was demonstrated by studying the self-assembly of three one-fold negatively charged 3-chloro-4-hydroxy-phenylazo dyes (Yellow, Blue and Red). Dye self-assembly was investigated using UV/vis- and NMR-spectroscopy, light- and small-angle neutron scattering. Significant differences between the three dyes were observed. While Yellow does not self-assemble, Red assembles into higher-order aggregates and Blue forms well-defined H-aggregate dimers with a dimerization constant of KD = (728 ± 8) L mol-1. Differences between dyes were suggested to emerge from variations in the propensity to form π-π-interactions due to electrostatic repulsion, sterical constraints and hydrogen-bonding interactions.

Comparative study of the co-assembly behaviour of 3-chloro-4-hydroxy-phenylazo dyes with DTAB.

The co-assembly of three one-fold negatively charged 3-chloro-4-hydroxy-phenylazo dyes (Yellow, Blue and Red) with the cationic surfactant dodecyltrimethylammoniumbromide (DTAB) was studied to probe dye-DTAB binding stoichiometry and assembly morphology. For each dye, phase separation was observed above a given dye : DTAB ratio with the ratio depending on the dye. While Yellow and DTAB showed liquid/liquid phase separation above Yellow : DTAB = 1 : 1.67, crystalline dye-DTAB complexes were observed for Blue-DTAB and Red-DTAB above Blue : DTAB = 1 : 2.56 and Red : DTAB = 1 : 2.94 respecively. In homogeneous solution, UV/vis spectroscopic investigations suggest stochiometries of Yellow : DTAB = 1 : 2, Blue : DTAB = 1 : 3 and Red : DTAB = 1 : 4. It was concluded, that Yellow exhibits the highest dye : DTAB binding stoichiometry in both, dye-surfactant complexes in the 2-phase region and in solution, whereas the lowest dye : DTAB binding stoichiometry was observed for Red-DTAB in both cases. The observed stoichiometries are inversely correlated to the impact dye addition has on the morphology of DTAB micelles. Generally, addition of dye to DTAB micelles leads to a reduction in spontaneous curvature of these micelles and to the formation of triaxial ellipsoidal or cylindrical micelles from oblate ellipsoidal DTAB micelles. At a DTAB concentration of 30 mM and a dye concentration of 5 mM, this effect was most pronounced for Red and least pronounced for Yellow, whilst Blue showed an intermediate effect.

The Colloidal Stability of Apolar Nanoparticles in Solvent Mixtures.

Solvent engineering is a powerful and versatile method to tune colloidal stability. Here, we link the molecular structure of apolar ligand shells on gold nanoparticles with their colloidal stability in solvent mixtures. The agglomeration temperature of the particles was measured with small-angle X-ray scattering. It depended on solvent composition and changed linearly for hexane-hexadecane mixtures, but nonlinearly for cyclohexane-hexadecane and hexanol-hexadecane mixtures. Molecular dynamics (MD) simulations indicate that agglomeration is dominated by temperature-dependent ligand order in the alkane mixtures and that the temperature at which the ligand shell orders depends on the solvent composition near the ligands, which can differ substantially from the bulk composition. Small-angle neutron scattering confirmed that, at intermediate solvent compositions above the agglomeration temperature, the fraction of cyclohexane near the ligands was larger than in the bulk. The enrichment of cyclohexane near the ligands stabilized their disordered state, which, consequently, led to the experimentally observed nonlinear trend of the agglomeration temperature. In contrast, hexanol was depleted from the ligand shell at all temperatures. This again stabilized the disordered state. Furthermore, we found that agglomeration at high hexanol fractions was driven by a solvophobic effect that exceeded the influence of ligand order. The results show that strong nonlinearities in the colloidal stability of nanoparticle dispersions in solvent mixtures are directly linked to the molecular details of ligand-solvent and solvent-solvent interactions, which can be used to precisely tune stability.

Self-Sorting in Diastereomeric Mixtures of Functionalized Dipeptides.

Self-sorting in functionalized dipeptide systems can be driven by the chirality of a single amino acid, both at a high pH in the micellar state and at a low pH in the gel state. The structures formed are affected to some degree by the relative concentrations of each component showing the complexity of such an approach. The structures underpinning the gel network are predefined by the micellar structures at a high pH. Here, we describe the systems prepared from two dipeptide-based gelators that differ only by the chirality of one of the amino acids. We provide firm evidence for self-sorting in the micellar and gel phases using small-angle neutron scattering and cryo-transmission electron microscopy (cryo-TEM), showing that complete self-sorting occurs across a range of relative concentrations.

Self-Healing of Charged Microgels in Neutral and Charged Environments.

The softness of microgels depends on many aspects, such as particle characteristic lengths, sample concentration, chemical composition of the sample, and elastic moduli of the particle. Here, the response to crowding of ionic microgels is studied. Charged and uncharged ionic microgels are studied in concentrated suspensions of both neutral and ionic microgels with the same swollen size. The combination of small-angle X-ray and neutron scattering with contrast variation allows us to probe both the particle-to-particle arrangement and the response of individual ionic microgels to crowding. When the ionic microgels are uncharged, initial isotropic deswelling followed by faceting is observed. Therefore, the ionizable groups in the polymeric network do not affect the response of the ionic microgel to crowding, which is similar to what has been reported for neutral microgels. In contrast, the kind of microgels composing the matrix plays a key role once the ionic microgels are charged. If the matrix is composed of neutral microgels, a pronounced faceting and negligible deswelling is observed. When only charged ionic microgels are present in the suspension, isotropic deswelling without faceting is dominant.

Enzyme-Triggered l-α/d-Peptide Hydrogels as a Long-Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs.

Eradicating HIV/AIDS by 2030 is a central goal of the World Health Organization. Patient adherence to complicated dosage regimens remains a key barrier. There is a need for convenient long-acting formulations that deliver drugs over sustained periods. This paper presents an alternative platform, an injectable in situ forming hydrogel implant to deliver a model antiretroviral drug (zidovudine [AZT]) over 28 days. The formulation is a self-assembling ultrashort d or l-α peptide hydrogelator, namely phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY[p]-OH), covalently conjugated to zidovudine via an ester linkage. Rheological analysis demonstrates phosphatase enzyme instructed self-assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggest hydrogels form narrow radius (≈2 nm), large length fibers closely fitting the flexible cylinder elliptical model. d-Peptides are particularly promising for long-acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progress under physiological conditions (37 °C, pH 7.4, H2 O). Subcutaneous administration of Napffk(AZT)Y[p]G-OH in Sprague Dawley rats demonstrate zidovudine blood plasma concentrations within the half maximal inhibitory concentration (IC50 ) range (30-130 ng mL-1 ) for 35 days. This work is a proof-of-concept for the development of a long-acting combined injectable in situ forming peptide hydrogel implant. These products are imperative given their potential impact on society.

Effect of Nanodiamond Sizes on the Efficiency of the Quasi-Specular Reflection of Cold Neutrons.

Nanomaterials can intensively scatter and/or reflect radiation. Such processes and materials are of theoretical and practical interest. Here, we study the quasi-specular reflections (QSRs) of cold neutrons (CNs) and the reflections of very cold neutrons (VCNs) from nanodiamond (ND) powders. The fluorination of ND increased its efficiency by removing/replacing hydrogen, which is otherwise the dominant cause of neutron loss due to incoherent scattering. The probability of the diffuse reflection of VCNs increased for certain neutron wavelengths by using appropriate ND sizes. Based on model concepts of the interaction of CNs with ND, and in reference to our previous work, we assume that the angular distribution of quasi-specularly reflected CNs is narrower, and that the probability of QSRs of longer wavelength neutrons increases if we increase the characteristic sizes of NDs compared to standard detonation nanodiamonds (DNDs). However, the probability of QSRs of CNs with wavelengths below the cutoff of ~4.12 Å decreases due to diffraction scattering on the ND crystal lattice. We experimentally compared the QSRs of CNs from ~4.3 nm and ~15.0 nm ND. Our qualitative conclusions and numerical estimates can help optimize the parameters of ND for specific practical applications based on the QSRs of CNs.

Joining Two Switches in One Nano-Object: Photoacidity and Photoisomerization in Electrostatic Self-Assembly.

Multi-switchable supramolecular nano-objects that respond to irradiation of different wavelengths with changes in size and shape have been built from two different water-soluble molecular switches, joined by attachment to the same polyelectrolyte. Accordingly, two wavelength-specific reactions, namely the excited-state proton dissociation of a photoacid and the cis-trans isomerization of an azo dye, are combined in one supramolecular nano-object that is stable in aqueous solution. The concept has potential in the fields of sensors, molecular motors, and transport.

Process Dependent Complexity in Multicomponent Gels.

Mixing low molecular weight gelators (LMWGs) can be used to combine favorable properties of the individual components within a multifunctional gel. Such multicomponent systems are complex enough in themselves but the method of combining components is not commonly considered something to influence self-assembly. Herein, two multicomponent systems comprising of a naphthalene-based dipeptide hydrogelator and one of two modified naphthalene diimides (NDIs), one of which forms gels, and the other does not, are investigated. These systems are probed, examining the structures formed and their gel properties (when preparing a solution from either a mixed powder of both components or by mixing pre-formed solutions of each component) using rheology, small angle neutron scattering (SANS), and absorbance spectroscopy. It is found that by altering the method of preparation, it is can either induce self-sorting or co-assembly within the fibers formed that underpin the gel network.

Controlling the Morphology in Electrostatic Self-Assembly via Light.

Electrostatic self-assembly of macroions is an emerging area with great potential in the development of nanoscale functional objects, where photo-irradiation responsiveness can either elevate or suppress the self-assembly. The ability to control the size and shape of macroion assemblies would greatly facilitate the fabrication of desired nano-objects that can be harnessed in various applications such as catalysis, drug delivery, bio-sensors, and actuators. Here, we demonstrate that a polyelectrolyte with a size of 5 nm and multivalent counterions with a size of 1 nm can produce well-defined nanostructures ranging in size from 10-1000 nm in an aqueous environment by utilizing the concept of electrostatic self-assembly and other intermolecular non-covalent interactions including dipole-dipole interactions. The pH- and photoresponsiveness of polyelectrolytes and azo dyes provide diverse parameters to tune the nanostructures. Our findings demonstrate a facile approach to fabricating and manipulating self-assembled nanoparticles using light and neutron scattering techniques.

Beyond simple self-healing: How anisotropic nanogels adapt their shape to their environment.

The response of soft colloids to crowding depends sensitively on the particles' compressibility. Nanogel suspensions provide model systems that are often studied to better understand the properties of soft materials and complex fluids from the formation of colloidal crystals to the flow of viruses, blood, or platelet cells in the body. Large spherical nanogels, when embedded in a matrix of smaller nanogels, have the unique ability to spontaneously deswell to match their size to that of the nanogel composing the matrix. In contrast to hard colloids, this self-healing mechanism allows for crystal formation without giving rise to point defects or dislocations. Here, we show that anisotropic ellipsoidal nanogels adapt both their size and their shape depending on the nature of the particles composing the matrix in which they are embedded. Using small-angle neutron scattering with contrast variation, we show that ellipsoidal nanogels become spherical when embedded in a matrix of spherical nanogels. In contrast, the anisotropy of the ellipsoid is enhanced when they are embedded in a matrix of anisotropic nanogels. Our experimental data are supported by Monte Carlo simulations that reproduce the trend of decreasing aspect ratio of ellipsoidal nanogels with increasing crowding by a matrix of spherical nanogels.